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Aims: No data are available on early initiation of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in patients with acute coronary syndrome (ACS) in the real world. This study investigates the effects of PCSK9i started at time of ACS hospitalization on lipid control and major cardiovascular (CV) events in the real world., Methods and Results: The lipid control outcome was the percentage of patients reaching the LDL-C target of <55 mg/dL at first lipid control. The clinical outcome was the incidence of composite major CV events (all-cause death, non-fatal MI, non-fatal stroke, and ischaemia-driven revascularization) during a follow-up in relation to quartiles of LDL-C at first lipid control. We included 771 patients with ACS from the AT-TARGET-IT registry, receiving PCSK9i prescription during hospitalization or at discharge. Median LDL-C was 137 mg/dL and decreased to 43 mg/dL at first lipid control. 527 (68.3%) patients achieved LDL-C target at the first lipid control at a median time of 37 days from hospitalization; of them, 404 (76.8%) were discharged on statin plus ezetimibe background therapy. Event curves through a median follow-up of 11 months across quartiles of LDL-C showed a stepwise lower risk of 4P-MACE, 3P-MACE, all-cause mortality, and ischaemia-driven revascularization in lower quartile of LDL-C values at first lipid control (<23 mg/dL) and in patients reaching LDL-C < 55 mg/dL., Conclusion: Intensive and early lipid-lowering therapy using PCSK9i in patients with ACS (strike early-strike strong strategy) is safe and effective in clinical practice and associated with a reduction of residual CV risk., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objectives: The aim of this analysis was to investigate the impact of hepatitis B virus (HBV) coinfection on the risk of HIV viral rebound (VR) after achieving suppression for the first time following initiation of antiretroviral therapy (ART) in the real-world setting., Design: Patients living with HIV (PLWH) who were enrolled in the ICONA Foundation Study cohort and achieved viral suppression ≤50 copies/mL for the first time after starting ART were prospectively evaluated and divided in three exposure groups according to serology test results: (a) HIV-monoinfected; (b) HIV-positive/HBcAb-positive/HBsAg-negative; (c) HIV-positive/HBsAg-positive. The occurrence of VR, defined as two consecutive HIV-RNA values >50 copies/mL after achieving viral suppression for the first time (baseline), was investigated., Methods: Standard survival analysis by means of Kaplan-Meier curves and Cox regression analysis with the serology exposure fitted as a time-fixed covariate measured at baseline was employed after controlling for key confounding factors., Results: Of a total of 5657 patients included, 4090 (72%) were HIV-monoinfected, 1342 (23.7%)were HBcAb-positive, and 225 (3.9%) were HbsAg-positive coinfected. Overall, 654 (11.5%) PLWH experienced VR > 50 copies/mL during follow-up. After controlling for all sources of measured confounding, coinfected PLWH showed an increased risk of experiencing VR compared with those who were HIV-monoinfected. In particular, the strongest associations were seen for the HIV/HBsAg-positive participants [adjusted hazard ratio (aHR) = 1.56, 95% confidence interval (CI): 1.03-2.38, p = 0.037] but an excess of risk was also seen in those who were HIV-positive/HBcAb-positive/HBsAg-negative (aHR = 1.25, 95% CI: 1.00-1.55, p = 0.047)., Conclusions: Coinfection with HBV seems to have an impact on the probability of maintaining HIV viral suppression achieved for the first time after ART initiation. Of note, even PLWH positive for HBcAb, a marker of inactive HBV infection, appeared to be at higher risk of VR compared with those who were HIV-monoinfected and their HIV-RNA should be carefully monitored., (© 2024 British HIV Association.)

Background: In systemic sclerosis (SSc), cardiac involvement is frequent, heterogeneous, and related to a poor prognosis. Due to a longer life expectancy, the development of degenerative aortic stenosis (AS) is not uncommon. The aim of this article is to report the characteristics of AS in SSc, analyzing the rate of progression, the management, and the outcome., Methods: This is a case series conducted at the Department of Cardiology of Monaldi Hospital, Naples, Italy., Results: From January 2007 to December 2022, we analyzed 234 patients with SSc. Ten/234 patients (4.3%) showed severe AS and were included in the analysis (age 75.5 years [IQR 58-84], nine females). Nine had limited and one diffuse SSc. Two patients were in NHYA/WHO II and eight in NYHA/WHO III. All had degenerative three-leaflet AS. Two patients showed severe AS at the first evaluation, and eight developed severe AS during the follow-up, with a time progression from moderate to severe AS of 3.2 ± 1.1 years (progression rate -0.190 ± 0.012 cm 2 /year for aortic valve area, 8.6 ± 6.1 mmHg/year for mean aortic gradient, 16 ± 7 mmHg/year for peak aortic gradient, and 0.5 ± 0.3 m/s/year for aortic peak velocity). Seven out of 10 patients underwent transcatheter aortic valve implantation (TAVI), one underwent surgical aortic valve replacement (SAVR), one was left untreated, and one was on a waiting list for TAVI. No major complications after TAVI or SAVR occurred. At a mean follow-up of 5.9 ± 3.9 years, eight patients are alive and two died., Conclusion: Severe AS is a relevant cardiac complication of SSc and must be considered in the screening and during the follow-up. Its rapid progression rate may tentatively be due to autoimmunity, degenerative burden, and chronic inflammation.

The introduction of artemisinin combination therapies (ACTs) has significantly reduced the burden of Plasmodium falciparum malaria, yet the emergence of artemisinin partial resistance (ART-R) as well as partner drug resistance threatens these gains. Recent confirmations of prevalent de novo ART-R mutations in Africa, in particular in Rwanda, Uganda and Ethiopia, underscore the urgency of addressing this issue in Africa. Our objective is to characterise this evolving resistance landscape in Africa and understand the speed with which ART-R will continue to spread. We produce estimates of both ART-R and partner drug resistance by bringing together WHO, WWARN and MalariaGen Pf7k data on antimalarial resistance in combination with a literature review. We integrate these estimates within a mathematical modelling approach, aincorporating to estimate parameters known to impact the selection of ART-R for each malaria-endemic country and explore scenarios of ART-R spread and establishment. We identify 16 malaria-endemic countries in Africa to prioritise for surveillance and future deployment of alternative antimalarial strategies, based on ART-R reaching greater than 10% prevalence by 2040 under current malaria burden and effective-treatment coverage. If resistance continues to spread at current rates with no change in drug policy, we predict that partner drug resistance will emerge and the mean percentage of treatment failure across Africa will reach 30.74% by 2060 (parameter uncertainty range: 24.98% - 34.54%). This translates to an alarming number of treatment failures, with 52,980,600 absolute cases of treatment failure predicted in 2060 in Africa (parameter uncertainty range: 26,374,200 - 93,672,400) based on current effective treatment coverage. Our results provide a refined and updated prediction model for the emergence of ART-R to help guide antimalarial policy and prioritise future surveillance efforts and innovation in Africa. These results put into stark context the speed with which antimalarial resistance may spread in Africa if left unchecked, confirming the need for swift and decisive action in formulating antimalarial treatment policies focused on furthering malaria control and containing antimalarial resistance in Africa. The rise of artemisinin partial resistance (ART-R) and increasing partner drug tolerance by Plasmodium falciparum malaria in Africa threatens to undo malaria control efforts. Recent confirmations of de novo ART-R markers in Rwanda, Uganda, and Ethiopia highlight the urgent need to address this threat in Africa, where the vast majority of cases and deaths occur. This study characterises the resistance landscape and predicts the spread of antimalarial resistance across Africa. We estimate and map the current levels of resistance markers related to artemisinin and its partner drugs using WHO, WWARN, and MalariaGen Pf7k data. We combine these estimates with current malaria transmission and treatment data and use an established individual-based model of malaria resistance to simulate future resistance spread. We identify 16 African countries at highest risk of ART-R for prioritisation of enhanced surveillance and alternative antimalarial strategies. We project that, without policy changes, ART-R will exceed 10% in these regions by 2040. By 2060, if resistance spreads unchecked, we predict mean treatment failure rates will reach 30.74% (parameter uncertainty range: 24.98% - 34.54%) across Africa. This alarming spread of resistance is predicted to cause 52.98 million treatment failures (uncertainty range: 26.37 million - 93.67 million) in 2060. The impact of antimalarial resistance in Africa, if left unchecked, would hugely damage efforts to reduce malaria burden. Our results underscore the critical need for swift policy action to contain resistance and guide future surveillance and intervention efforts., Competing Interests: Declaration of Interests OJW received personal consultancy fees from Clinton Health Access Initiative related to artemisinin resistance modelling.

Objectives: The current knowledge about the role of comorbidities in systemic sclerosis (SSc) is limited. Therefore, the aim of this study was to evaluate the prevalence of comorbidities and their impact on disease activity and prognosis in the Systemic sclerosis PRogression INvestiGation (SPRING) registry., Methods: SSc patients from the SPRING registry, fulfilling the ACR/EULAR 2013 classification criteria, with complete data on baseline comorbidities were enrolled. The Charlson comorbidity index (CCI) was used to quantify the overall comorbidity burden. The disease activity was calculated using the revised EUSTAR activity index (AI). The impact of SSc features on CCI, the effect of CCI on SSc disease activity and mortality were tested with multivariable regression models., Results: Among 1910 SSc patients enrolled, 67.3 % had at least one comorbidity at baseline. The most frequent comorbidities were systemic arterial hypertension (23.7 %), osteoporosis (12.9 %) and dyslipidemia (11 %). The mean value of CCI score was 2.0 ± 1.8. When patients were grouped according to increasing levels of CCI, a clear separation in the distribution of SSc-related clinical features could be observed. Among over 900 patients with available follow-up, no association between baseline CCI and changes in disease activity was observed. Conversely, the risk of death over time was independently predicted by both CCI and AI., Conclusions: Comorbidities and disease activity independently impact on the prognosis of SSc patients. This suggests that the management of comorbidities, together with the reduction of disease activity, is fundamental to improve patient survival., Competing Interests: Declaration of competing interest Orlandi M, Bellando-Randone S, Ferri C, Foti R, Codullo V, De Angelis R, Cuomo G, Campochiaro C, Luca Magnani, Cacciapaglia F, Ariani A, Giuggioli D, and Guiducci S have no conflict of interest to declare. Matucci-Cerinic M received fees from Actelion, Janssen, Inventiva, Bayer, Biogen, Boehringer, CSL Behring, Corbus, Galapagos, Mitsubishi, Samsung, Regeneron, Acceleron, MSD, Chemomab, Lilly, Pfizer, Roche. Bruni C received consulting fees and/or honoraria from Eli-Lilly, Boehringer Ingelheim, Research grants from Gruppo Italiano Lotta alla Sclerodermia (GILS), European Scleroderma Trials and Research Group (EUSTAR), Scleroderma Clinical Trials Consortium (SCTC), Scleroderma Research Foundation (SRF), Novartis foundation for biomedical research. Congress supports from Boehringer-Ingelheim. Educational grants from AbbVie and Wellcome Trust., (Copyright © 2024. Published by Elsevier B.V.)

Ebola virus disease poses a recurring risk to human health. We conducted a systematic review (PROSPERO CRD42023393345) of Ebola virus disease transmission models and parameters published from database inception to July 7, 2023, from PubMed and Web of Science. Two people screened each abstract and full text. Papers were extracted with a bespoke Access database, 10% were double extracted. We extracted 1280 parameters and 295 models from 522 papers. Basic reproduction number estimates were highly variable, as were effective reproduction numbers, likely reflecting spatiotemporal variability in interventions. Random-effect estimates were 15·4 days (95% CI 13·2-17·5) for the serial interval, 8·5 days (7·7-9·2) for the incubation period, 9·3 days (8·5-10·1) for the symptom-onset-to-death delay, and 13·0 days (10·4-15·7) for symptom-onset-to-recovery. Common effect estimates were similar, albeit with narrower CIs. Case-fatality ratio estimates were generally high but highly variable, which could reflect heterogeneity in underlying risk factors. Although a substantial body of literature exists on Ebola virus disease models and epidemiological parameter estimates, many of these studies focus on the west African Ebola epidemic and are primarily associated with Zaire Ebola virus, which leaves a key gap in our knowledge regarding other Ebola virus species and outbreak contexts., Competing Interests: Declaration of interests AC reports payment from Pfizer for teaching mathematical modelling of infectious diseases. PD reports payment from WHO for consulting on integrated modelling. AC was supported by the Academy of Medical Sciences Springboard scheme (reference SBF005\1044). CM acknowledges the Schmidt Foundation for research funding (grant code 6–22–63345). PD and TN received funding from Community Jameel. DJ has received funding from the Wellcome Trust and Royal Society (216427/Z/19/Z) and PhD funding from Engineering and Physical Sciences Research Council. GC-D has received funding from the Royal Society. RM has received funding from the National Institute for Health and Care Research Health Protection Research Unit in Emerging and Zoonotic Infections, a partnership between the UK Health Security Agency, University of Oxford, University of Liverpool, and Liverpool School of Tropical Medicine (grant code NIHR200907). JW has received research funding from the Wellcome Trust (grant 102169/Z/13/Z). RKN and DN have received research funding from the Medical Research Council Doctoral Training Partnership (grant MR/N014103/1). KM acknowledges research funding from the Imperial College President's PhD Scholarship. AF acknowledges funding from the commonwealth scholarship commission. KF acknowledges funding from the Bill & Melinda Gates Foundation, Gavi, and the Wellcome Trust. HJTU has received funding from the Moderna Charitable Foundation. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Recently revised WHO guidelines on malaria chemoprevention have opened the door to more tailored implementation. Countries face choices on whether to replace old drugs, target additional age groups, and adapt delivery schedules according to local drug resistance levels and malaria transmission patterns. Regular routine assessment of protective efficacy of chemoprevention is key. Here, we apply a novel modelling approach to aid the design and analysis of chemoprevention trials and generate measures of protection that can be applied across a range of transmission settings., Methods and Findings: We developed a model of genotype-specific drug protection, which accounts for underlying risk of infection and circulating genotypes. Using a Bayesian framework, we fitted the model to multiple simulated scenarios to explore variations in study design, setting, and participant characteristics. We find that a placebo or control group with no drug protection is valuable but not always feasible. An alternative approach is a single-arm trial with an extended follow-up (>42 days), which allows measurement of the underlying infection risk after drug protection wanes, as long as transmission is relatively constant. We show that the currently recommended 28-day follow-up in a single-arm trial results in low precision of estimated 30-day chemoprevention efficacy and low power in determining genotype differences of 12 days in the duration of protection (power = 1.4%). Extending follow-up to 42 days increased precision and power (71.5%) in settings with constant transmission over this time period. However, in settings of unstable transmission, protective efficacy in a single-arm trial was overestimated by 24.3% if recruitment occurred during increasing transmission and underestimated by 15.8% when recruitment occurred during declining transmission. Protective efficacy was estimated with greater precision in high transmission settings, and power to detect differences by resistance genotype was lower in scenarios where the resistant genotype was either rare or too common., Conclusions: These findings have important implications for the current guidelines on chemoprevention efficacy studies and will be valuable for informing where these studies should be optimally placed. The results underscore the need for a comparator group in seasonal settings and provide evidence that the extension of follow-up in single-arm trials improves the accuracy of measures of protective efficacy in settings with more stable transmission. Extension of follow-up may pose logistical challenges to trial feasibility and associated costs. However, these studies may not need to be repeated multiple times, as the estimates of drug protection against different genotypes can be applied to different settings by adjusting for transmission intensity and frequency of resistance., Competing Interests: LCO has received a research grant from Merck pharmaceutical. RG is funded through a Unitaid grant that funds the Plus Project for his work at the London School of Hygiene and Tropical Medicine and works as an independent consultant paid by USAID, Population Services International and Bill and Melinda Gates Foundation., (Copyright: © 2024 Mousa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The 2023 Marburg virus disease outbreaks in Equatorial Guinea and Tanzania highlighted the importance of better understanding this lethal pathogen. We did a systematic review (PROSPERO CRD42023393345) of peer-reviewed articles reporting historical outbreaks, modelling studies, and epidemiological parameters focused on Marburg virus disease. We searched PubMed and Web of Science from database inception to March 31, 2023. Two reviewers evaluated all titles and abstracts with consensus-based decision making. To ensure agreement, 13 (31%) of 42 studies were double-extracted and a custom-designed quality assessment questionnaire was used for risk of bias assessment. We present detailed information on 478 reported cases and 385 deaths from Marburg virus disease. Analysis of historical outbreaks and seroprevalence estimates suggests the possibility of undetected Marburg virus disease outbreaks, asymptomatic transmission, or cross-reactivity with other pathogens, or a combination of these. Only one study presented a mathematical model of Marburg virus transmission. We estimate an unadjusted, pooled total random effect case fatality ratio of 61·9% (95% CI 38·8-80·6; I 2 =93%). We identify epidemiological parameters relating to transmission and natural history, for which there are few estimates. This systematic review and the accompanying database provide a comprehensive overview of Marburg virus disease epidemiology and identify key knowledge gaps, contributing crucial information for mathematical models to support future Marburg virus disease epidemic responses., Competing Interests: Declaration of interests AC reports payment from Pfizer for teaching mathematical modelling of infectious diseases. PD reports payment from WHO for consulting on integrated modelling. All other authors declare no competing interests. The views expressed are those of the authors and not necessarily those of the National Institute for Health and Care Research (NIHR), UK Health Security Agency, or the Department of Health and Social Care. NI is currently employed by the Wellcome Trust. However, the Wellcome Trust had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: To investigate pregnancy outcomes in women with autoimmune rheumatic diseases (ARD) in the Italian prospective cohort study P-RHEUM.it., Methods: Pregnant women with different ARD were enrolled for up to 20 gestational weeks in 29 Rheumatology Centres for 5 years (2018-2023). Maternal and infant information were collected in a web-based database., Results: We analysed 866 pregnancies in 851 patients (systemic lupus erythematosus was the most represented disease, 19.6%). Maternal disease flares were observed in 135 (15.6%) pregnancies. 53 (6.1%) pregnancies were induced by assisted reproduction techniques, 61 (7%) ended in miscarriage and 11 (1.3%) underwent elective termination. Obstetrical complications occurred in 261 (30.1%) pregnancies, including 2.3% pre-eclampsia. Two cases of congenital heart block were observed out of 157 pregnancies (1.3%) with anti-Ro/SSA. Regarding treatments, 244 (28.2%) pregnancies were treated with glucocorticoids, 388 (44.8%) with hydroxychloroquine, 85 (9.8%) with conventional synthetic disease-modifying anti-rheumatic drugs and 122 (14.1%) with biological disease-modifying anti-rheumatic drugs. Live births were 794 (91.7%), mostly at term (84.9%); four perinatal deaths (0.5%) occurred. Among 790 newborns, 31 (3.9%) were small-for-gestational-age and 169 (21.4%) had perinatal complications. Exclusive maternal breast feeding was received by 404 (46.7%) neonates. The Edinburgh Postnatal Depression Scale was compiled by 414 women (52.4%); 89 (21.5%) scored positive for emotional distress., Conclusions: Multiple factors including preconception counselling and treat-to-target with pregnancy-compatible medications may have contributed to mitigate disease-related risk factors, yielding limited disease flares, good pregnancy outcomes and frequency of complications which were similar to the Italian general obstetric population. Disease-specific issues need to be further addressed to plan preventative measures., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Intravenous iloprost has been widely used for the treatment of systemic sclerosis peripheral vasculopathy. No agreement has been found on the regimen and the dosage of intravenous iloprost in different scleroderma subset conditions. This study aimed to evaluate the modalities of intravenous iloprost administration within a large cohort of systemic sclerosis patients from the SPRING Registry and to identify any associated clinical-demographic, instrumental or therapeutic data., Patients and Methods: Data of systemic sclerosis patients treated with intravenous iloprost for at least 1 year (case group) were retrospectively analyzed, including different timing and duration of intravenous iloprost session, and compared with those of untreated patients (control group)., Results: Out of 1895 analyzed patients, 937 (49%) received intravenous iloprost treatment, while 958 (51%) were assigned to the control group. Among cases, about 70% were treated every 4 weeks, 24% with an interval of more than 4 weeks, and only 6% of less than 4 weeks. Most patients receiving the treatment every 4 weeks, or less, underwent infusion cycle for 1 day only, while if it was scheduled with an interval of more than 4 weeks, a total number of 5 consecutive days of infusions was the preferred regimen. The comparison between the two groups revealed that patients treated with intravenous iloprost had a higher frequency of DUs (p < 0.001), pitting scars (p < 0.001), diffuse cutaneous involvement (p < 0.001), interstitial lung disease (p < 0.002), as well as higher rates of anti-topoisomerase I, " late " scleroderma pattern at nailfold videocapillaroscopy. These findings were confirmed by multivariate analysis., Conclusion: Our data provide a picture on the Italian use of intravenous iloprost among systemic sclerosis patients and showed that it was usually employed in patients with a more aggressive spectrum of the disease. The disparity of intravenous iloprost treatment strategies in the different centers suggests the need of a rational therapeutical approach based on the clinical characteristics of different patients' subsets., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Idiopathic immune myopathies (IIMs) are autoimmune diseases caused by immune-mediated muscle damage. The etiology remains unclear. Epidemiological and experimental studies, both in animals and humans, hint at viruses as major environmental factors able to trigger aberrant immune responses through many different mechanisms. However, only a few cases of either dermatomyositis or polymyositis following a specific viral infection have been reported in the literature. The objective of this study is to describe the clinical features and the treatment strategy of 2 cases of polymyositis developing shortly after chickenpox and mumps, respectively, and to review the existing literature on the topic. The clinical records of the 2 patients suspected to have developed inflammatory myositis following a viral infection were reviewed. Their clinical history, main laboratory findings, and treatment outcome are presented here. Moreover, a literature search was performed in the PubMed and MEDLINE databases to identify reports describing the association between viral infections and IIMs in patients aged ≥18. The 2 patients reported here developed polymyositis shortly after chickenpox and mumps, respectively, suggesting a causal role for viruses in triggering autoimmunity. Only a few reports published between 1990 and 2020 were found in the literature, possibly linking infections to myositis development. Intravenous immunoglobulin and rituximab were effective for the treatment of viral-triggered polymyositis.

Introduction: The objective of the study was to develop machine learning (ML) models that predict the percentage weight change in each interval of time in antiretroviral therapy-experienced people living with HIV., Methods: This was an observational study that comprised consecutive people living with HIV attending Modena HIV Metabolic Clinic with at least 2 visits. Data were partitioned in an 80/20 training/test set to generate 10 progressively parsimonious predictive ML models. Weight gain was defined as any weight change >5%, at the next visit. SHapley Additive exPlanations values were used to quantify the positive or negative impact of any single variable included in each model on the predicted weight changes., Results: A total of 3,321 patients generated 18,322 observations. At the last observation, the median age was 50 years and 69% patients were male. Model 1 (the only 1 including body composition assessed with dual-energy x-ray absorptiometry) had an accuracy greater than 90%. This model could predict weight at the next visit with an error of <5%., Conclusions: ML models with the inclusion of body composition and metabolic and endocrinological variables had an excellent performance. The parsimonious models available in standard clinical evaluation are insufficient to obtain reliable prediction, but are good enough to predict who will not experience weight gain., Competing Interests: G.G. and C.M. received research grant and speaker honorarium from Gilead, ViiV, MERCK, and Jansen. G.G. and C.M. attended advisory boards of Gilead, ViiV, and MERCK. Other authors reported no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The objectives of this study were to describe the trajectories of bone mineral density (BMD) and trabecular bone score (TBS) changes throughout pre-menopause (reproductive phase and menopausal transition) and post-menopause (early and late menopause) in women with HIV (WWH) undergoing different antiretroviral therapies (ARTs) and explore the risk factors associated with those changes., Methods: This was an observational longitudinal retrospective study in WWH with a minimum of two DEXA evaluations comprising BMD and TBS measurements, both in the pre-menopausal and post-menopausal periods. Menopause was determined according to the STRAW+10 criteria, comprising four periods: the reproductive period, menopausal transition, and early- and late-menopausal periods. Mixed-effects models were fitted to estimate the trajectories of the two outcomes (BMD and TBS) over time. Annualized lumbar BMD and TBS absolute and percentage changes were calculated in each STRAW+10 time window. A backward elimination procedure was applied to obtain the final model, including the predictors that affected the trajectories of BMD or TBS over time., Results: A total of 202 WWH, all Caucasian, were included. In detail, 1954 BMD and 195 TBS data were analyzed. The median number of DEXA evaluations per woman was 10 (IQR: 7, 12). The median observation periods per patient were 12.0 years (IQR = 8.9-14.4) for BMD and 6.0 years (IQR: 4.3, 7.9) for TBS. The prevalence of osteopenia (63% vs. 76%; p < 0.001) and osteoporosis (16% vs. 36%; p < 0.001) increased significantly between the pre-menopausal and post-menopausal periods. Both BMD (1.03 (±0.14) vs. 0.92 (±0.12) g/cm 2 ; p < 0.001) and TBS (1.41 (IQR: 1.35, 1.45) vs. 1.32 (IQR: 1.28, 1.39); p < 0.001) decreased significantly between the two periods. The trend in BMD decreased across the four STRAW+10 periods, with a slight attenuation only in the late-menopausal period when compared with the other intervals. The TBS slope did not significantly change throughout menopause. The delta mean values of TBS in WWH were lower between the menopausal transition and reproductive period compared with the difference between menopause and menopausal transition., Conclusions: Both BMD and TBS significantly decreased over time. The slope of the change in BMD and TBS significantly decreased in the menopausal transition, suggesting that this period should be considered by clinicians as a key time during which to assess bone health and modifiable risk factors in WWH.

Since 8th March 2020 up to the time of writing, we have been producing near real-time weekly estimates of SARS-CoV-2 transmissibility and forecasts of deaths due to COVID-19 for all countries with evidence of sustained transmission, shared online. We also developed a novel heuristic to combine weekly estimates of transmissibility to produce forecasts over a 4-week horizon. Here we present a retrospective evaluation of the forecasts produced between 8th March to 29th November 2020 for 81 countries. We evaluated the robustness of the forecasts produced in real-time using relative error, coverage probability, and comparisons with null models. During the 39-week period covered by this study, both the short- and medium-term forecasts captured well the epidemic trajectory across different waves of COVID-19 infections with small relative errors over the forecast horizon. The model was well calibrated with 56.3% and 45.6% of the observations lying in the 50% Credible Interval in 1-week and 4-week ahead forecasts respectively. The retrospective evaluation of our models shows that simple transmission models calibrated using routine disease surveillance data can reliably capture the epidemic trajectory in multiple countries. The medium-term forecasts can be used in conjunction with the short-term forecasts of COVID-19 mortality as a useful planning tool as countries continue to relax public health measures., Competing Interests: AC has received payment from Pfizer for teaching of mathematical modelling of infectious diseases. All other authors have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Bhatia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The aim of this randomized clinical trial (RCT) was to compare immunological changes in virally suppressed people living with HIV (PLWH) switching from a three-drug regimen (3DR) to a two-drug regimen (2DR)., Methods: An open-label, prospective RCT enrolling PLWH receiving a 3DR who switched to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) or dolutegravir/lamivudine (DTG/3TC) was performed. Blood was taken at baseline and months 6 and 12. The primary outcome was the change in CD4+ or CD8+ T-cell counts and CD4/CD8 ratio over time points. The secondary outcomes were the changes in immunological and inflammatory parameters. Parametric mixed-linear models with random intercepts and slopes were fitted separately for each marker after controlling for potential confounders., Results: Between the two arms (33 PLWH each), there was no difference in CD4+ or CD8+ T cells, CD4/CD8 ratio, and IL-6 trajectories. PLWH switching to DTG/3TC had increased levels of both transitional memory and terminally differentiated CD4+ T cells (arm-time interaction p-value = 0.02) and to a lesser extent for the corresponding CD8+ T-cell subsets (p = 0.09). Significantly lower levels of non-classical monocytes were detected in the B/F/TAF arm at T6 (diff = -6.7 cells/mm 3 ; 95% CI; -16, +2.6; p-value for interaction between arm and time = 0.03). All differences were attenuated at T12., Conclusion: No evidence for a difference in absolute CD4+ and CD8+ T-cell counts, CD4/CD8 ratio, and IL-6 trajectories by study arm over 12 months was found. PLWH on DTG/3TC showed higher levels of terminally differentiated and exhausted CD4+ and CD8+ T lymphocytes and non-classical monocytes at T6. Further studies are warranted to better understand the clinical impact of our results., Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT04054089., Competing Interests: GG and CM received a research grant and a speaker honorarium from Gilead, ViiV, MERCK, and Jansen. GG and CM are on the advisory boards of Gilead, ViiV, and MERCK. JM received a speaker honorarium from Gilead and ViiV. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cossarizza, Cozzi-Lepri, Mattioli, Paolini, Neroni, De Biasi, Tartaro, Borella, Fidanza, Gibellini, Beghetto, Roncaglia, Nardini, Milic, Menozzi, Cuomo, Digaetano, Orlando, Borghi, Guaraldi and Mussini.)

Introduction: The impact of COVID-19 pandemic represents a serious challenge for 'frail' patients' populations with inflammatory autoimmune systemic diseases such as systemic sclerosis (SSc). We investigated the prevalence and severity of COVID-19, as well the effects of COVID-19 vaccination campaign in a large series of SSc patients followed for the entire period (first 38 months) of pandemic., Patients and Method: This prospective survey study included 1755 unselected SSc patients (186 M, 1,569F; mean age 58.7 ± 13.4SD years, mean disease duration 8.8 ± 7.3SD years) recruited in part by telephone survey at 37 referral centers from February 2020 to April 2023. The following parameters were carefully evaluated: i. demographic, clinical, serological, and therapeutical features; ii. prevalence and severity of COVID-19; and iii. safety, immunogenicity, and efficacy of COVID-19 vaccines., Results: The prevalence of COVID-19 recorded during the whole pandemic was significantly higher compared to Italian general population (47.3 % vs 43.3 %, p < 0.000), as well the COVID-19-related mortality (1.91 % vs 0.72 %, p < 0.001). As regards the putative prognostic factors of worse outcome, COVID-19 positive patients with SSc-related interstitial lung involvement showed significantly higher percentage of COVID-19-related hospitalization compared to those without (5.85 % vs 1.73 %; p < 0.0001), as well as of mortality rate (2.01 % vs 0.4 %; p = 0.002). Over half of patients (56.3 %) received the first two plus one booster dose of vaccine; while a fourth dose was administered to 35.6 %, and only few of them (1.99 %) had five or more doses of vaccine. Of note, an impaired seroconversion was recorded in 25.6 % of individuals after the first 2 doses of vaccine, and in 8.4 % of patients also after the booster dose. Furthermore, the absence of T-cell immunoreactivity was observed in 3/7 patients tested by QuantiFERON® SARSCoV-2 Starter Set (Qiagen). The efficacy of vaccines, evaluated by comparing the COVID-19-related death rate recorded during pre- and post-vaccination pandemic periods, revealed a quite stable outcome in SSc patients ( death rate from 2.54 % to 1.76 %; p = ns), despite the significant drop of mortality observed in the Italian general population (from 2.95 % to 0.29 %; p < 0.0001)., Conclusions: An increased COVID-19 prevalence and mortality rate was recorded in SSc patients; moreover, the efficacy of vaccines in term of improved outcomes was less evident in SSc compared to Italian general population. This discrepancy might be explained by concomitant adverse prognostic factors: increased rate of non-responders to vaccine in SSc series, low percentage of individuals with four or more doses of vaccine, ongoing immunomodulating treatments, disease-related interstitial lung disease, and/or reduced preventive measures in the second half of pandemic. A careful monitoring of response to COVID-19 vaccines together with adequate preventive/therapeutical strategies are highly recommendable in the near course of pandemic in this frail patients' population., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Alessandro Antonelli reports financial support was provided by Italian 10.13039/100009647Ministry of Health, Ricerca Finalizzata (RF-2021-12374986) Destinatario istituzionale: Regione Toscana. Unità Operative:U.O.1: Azienda Ospedaliero-Universitaria Pisana; U.O.2: Azienda Ospedaliero-Universitaria Aldo Moro Bari; U.O.3: Azienda Ospedaliero-Universitaria Modena, CUP Master: D55E22000670001., (© 2023 Published by Elsevier B.V.)

Background: Several studies described the cross-sectional characteristics of systemic sclerosis patients and coexisting primary biliary cholangitis, but longitudinal prognostic data are lacking., Aims: To describe the systemic sclerosis-primary biliary cholangitis phenotype, including baseline characteristics and outcomes., Methods: We performed a multicentre the European Scleroderma Trials and Research Group study of systemic sclerosis patients with primary biliary cholangitis or with primary biliary cholangitis-specific antibodies, matched with systemic sclerosis controls free from hepatobiliary involvement matched for disease duration and cutaneous subset. Data were recorded at baseline and at the last available visit., Results: A total of 261 patients were enrolled (115 primary biliary cholangitis-systemic sclerosis, 161 systemic sclerosis). At baseline, systemic sclerosis-primary biliary cholangitis patients had a higher prevalence of anti-centromere antibodies ( p  = 0.0023) and a lower prevalence of complete absence of digital ulcers. The milder vascular involvement was confirmed at follow-up when crucial differences emerged in the percentage of patients experiencing digital ulcers; a significantly higher number of patients who never experienced digital ulcers were observed among primary biliary cholangitis-systemic sclerosis patients ( p  = 0.0015). Moreover, a greater incidence of pulmonary arterial hypertension ( p  < 0.001) and of conduction blocks ( p  = 0.0256) was observed in systemic sclerosis patients without primary biliary cholangitis. Patients with primary biliary cholangitis had higher levels of liver enzymes at baseline than systemic sclerosis patients; a significant decrease in liver enzymes was observed at follow-up. Out of 18 patients with cholangitis, one received a liver transplant at follow-up., Conclusion: Our data show that systemic sclerosis-primary biliary cholangitis exhibit a mild systemic sclerosis and primary biliary cholangitis phenotype with outcomes being in general favourable., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: G.L., P.A., O.D., K.A., Y.B.-M., E.H., A.B.-G., E.D.L., S.R., F.I., E.R., L.G., R.I., S.B.-R., L.G., L.B., C.B., S.M., P.N., I.S., D.K., V.C., U.A.W., C.M., S.G., M.-E.T., L.T., G.C., M.K., M.M.-C. and Y.A. have no conflict of interests (COIs) to declare. F.I. received honoraria or speaking fees from AbbVie, BMS, Galapagos, MSD, Lilly and Pfizer outside this work. C.B. received consulting fees and/or honoraria from Actelion and Boehringer Ingelheim; research grants from the Gruppo Italiano Lotta alla Sclerodermia (GILS), the European Scleroderma Trials and Research Group (EUSTAR) and the Scleroderma Clinical Trials Consortium (SCTC); educational grants from AbbVie; all outside the submitted work. V.S. is the Senior Clinical Investigator of the Research Foundation – Flanders (Belgium) (FWO) [1.8.029.20N]. The FWO was not involved in study design, collection, analysis and interpretation of data and writing of the report, nor in the decision to submit the manuscript for publication., (© The Author(s) 2023.)

Coronavirus disease of 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may be complicated by life-threatening interstitial pneumonia. SARS-CoV-2 infection may also damage several tissues and/or organs beyond the lungs, including the liver. However, controversy still exists as to whether SARS-CoV-2-induced liver alterations can have an impact on the outcome of COVID-19. The aim of this study was therefore to assess whether SARS-CoV-2-infected patients with liver abnormalities at the time of hospital referral had a worse outcome with respect to patients with no liver biochemistry alterations. To this end, the medical records of 123 patients admitted to our COVID center between the end of 2020 and spring 2021 were retrospectively reviewed. Patients were divided into two groups: those with normal liver biochemistries (group 1, 77 patients) and those with altered liver function tests (group 2, 46 patients). Serum levels of aminotransferases (AST and ALT) and bile duct cell injury markers (γ-GT and ALP) were used to dichotomize patients. A higher percentage of patients with liver enzyme alterations were found to develop COVID-19 pneumonia with respect to group 1 patients (74% vs. 65%); moreover, they needed more days of respiratory support and, more importantly, more intensive administration of supplemental oxygen. A statistically significant correlation was also found between aminotransferase levels and duration of respiratory support. The mortality rate was not superior in group 2 vs. group 1 patients. In conclusion, liver abnormalities on admission predisposed COVID-19 patients to development of more severe interstitial pneumonia, because of a longer requirement for supplemental oxygen and a more intensive respiratory support, indicative of a worse disease evolution in these patients.

Objective: The aim of the study was to evaluate the association between the tricuspid annular plane systolic excursion (TAPSE)/systolic pulmonary artery pressure (sPAP) ratio and estimated glomerular filtration rate (eGFR) and their association with mortality in the European Scleroderma Trials and Research (EUSTAR) cohort., Methods: Patients with systemic sclerosis (SSc) from the EUSTAR database with TAPSE, sPAP, and parameters required to calculate eGFR were included. Logistic regression and Cox regression analysis were performed to evaluate TAPSE/sPAP as a risk factor for chronic kidney disease (CKD) and overall survival., Results: A total of 2,370 patients with SSc were included; 284 (12%) patients had CKD stage 3a-5. TAPSE/sPAP (odds ratio [OR] 0.479; 95% CI 0.310-0.743; P < 0.001), arterial hypertension (OR 3.118; 95% CI 2.173-4.475; P < 0.001), diastolic dysfunction (OR 1.670; 95% CI 1.148-2.428; P < 0.01), and N-terminal pro-B-type natriuretic peptide (OR 1.165; 95% CI 1.041-1.304; P < 0.01) were associated with CKD stage 3a-5. TAPSE/sPAP ≤0.32 mm/mm Hg (hazard ratio [HR] 3.589; 95% CI 2.236-5.761; P < 0.001), eGFR <60 mL/min per 1.73 m 2 (HR 2.818; 95% CI 1.777-4.468; P < 0.001), and age (HR 1.782; 95% CI 1.348-2.356; P < 0.001) were the most significant predictive factors for all-cause mortality. A total of 276 patients with SSc had pulmonary hypertension (PH) confirmed by right heart catheterization, with 69 (25%) having CKD stage 3a-5. No difference was found in eGFR between patients with PH with reduced or normal cardiac index., Conclusion: Reduced TAPSE/sPAP ratio is independently associated with CKD. TAPSE/sPAP ratio ≤0.32 mm/mm Hg and eGFR <60 mL/min per 1.73 m 2 are prognostic factors for all-cause mortality. In patients with SSc with PH, eGFR is independent by reduced cardiac output., (© 2023 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: To better define the spectrum of new-onset post-COVID-19 and post-COVID-19 vaccine inflammatory rheumatic diseases (IRD) from a large multicentric observational study., Methods: Consecutive cases of IRD encountered during a 12-month period and satisfying one of the following inclusion criteria: (a) onset of the rheumatic manifestations within 4 weeks from SARS-CoV-2 infection or (b) onset of the rheumatic manifestations within 4 weeks from the administration of one of the COVID-19 vaccines ws recruited., Results: The final analysis cohort comprised 267 patients, of which 122 (45.2%) in the post-COVID-19 and 145 (54.8%) in the postvaccine cohort. Distribution of IRD categories differed between the two cohorts: the post-COVID-19 cohort had a higher percentage of patients classified as having inflammatory joint diseases (IJD, 52.5% vs 37.2%, p=0.013) while the post-vaccine cohort had a higher prevalence of patients classified as polymyalgia rheumatica (PMR, 33.1% vs 21.3%, p=0.032). No differences were detected in the percentage of patients diagnosed with connective tissue diseases (CTD 19.7% vs 20.7%, p=0.837) or vasculitis (6.6% vs 9.0%, p=0.467). Despite the short follow-up period, IJD and PMR patients' response to first-line therapy was favourable, with both groups achieving a drop in baseline disease activity scores of ~30% and ~70% respectively., Conclusion: Our article reports the largest cohort published to date of new-onset IRD following SARS-CoV-2 infection or COVID-19 vaccines. Although causality cannot be ascertained, the spectrum of possible clinical manifestations is broad and includes IJD, PMR, CTD and vasculitis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Systemic sclerosis (SSc) is a rare, multisystemic disorder of connective tissue characterized by widespread inflammation, vascular abnormalities, and both skin and visceral organ fibrosis. Tissue fibrosis is the final phase of a complex biological process of immune activation and vascular damage. Objectives The aim of the study was to assess hepatic fibrosis and steatosis in SSc patients by transient elastography (TE). Methods Fifty-nine SSc patients fulfilling the 2013 ACR/EULAR classification criteria were recruited. Clinical and laboratory findings, modified Rodnan skin score (mRSS), activity index, videocapillaroscopy, echocardiography, and lung function data were analyzed. Liver stiffness (LS) was measured by transient elastography (TE), with 7 kPa used as the cut-off value for significant liver fibrosis. In addition, hepatic steatosis was evaluated by means of controlled attenuation parameter (CAP) findings. Specifically, CAP values ≥ 238 ≤ 259 dB/m were considered consistent with mild steatosis (S1), values ≥ 260 ≤ 290 dB/m were compatible with moderate steatosis (S2), and values ≥ 291 dB/m were indicative of severe steatosis (S3). Results The median age of patients was 51 years, with a median disease duration of 6 years. The median LS was 4.5 (2.9-8.3) kPa; 69.5% of patients had no evidence of fibrosis (F0); 27.1% displayed LS values between 5.2 and 7 kPa; and only 3.4% of patients had LS values > 7 kPa (F3). The median CAP value for liver steatosis was 223 dB/m (IQR: 164-343). Overall, 66.1% of patients did not show evidence of steatosis (CAP values < 238 dB/m); 15.2% showed values consistent with mild (S1) steatosis (CAP value ≥ 238 ≤ 259 dB/m); 13.5% had moderate (S2) steatosis (CAP value ≥ 260 ≤ 290 dB/m); and 5.1% were deemed to have severe steatosis (S3) due to CAP values ≥ 291 dB/m. Conclusions Although systemic sclerosis is associated with fibrosis of the skin and several organs, only 3.4% of our patient population showed evidence of marked liver fibrosis, which is the same prevalence as that expected in the general population. Therefore, fibrosis of the liver did not appear to be a significant concern in SSc patients, albeit moderate fibrosis could still be detected in a significant proportion of subjects. A prolonged follow-up may clarify whether liver fibrosis in SSc patients may still progress. Likewise, the prevalence of significant steatosis was low (5.1%) and depended on the same variables associated with fatty liver disease in the general population. TE was shown to be an easy and valuable method for detection and screening of hepatic fibrosis in SSc patients with no additional risk factors for liver disease and may be useful to assess the potential progression of liver fibrosis over time.

Objective: The aim of this prospective cross sectional study was to evaluate the cranial structure and condylar asymmetry of adult patients with rheumatoid arthritis (RA) diagnosed after 25 years of age compared to a healthy adult control group., Methods: Eighteen adult patients (57.4 ± 11.4 years) with RA were compared with a control group. Cephalometric analysis and the Habets method for the calculation of the condylar asymmetry were used. The main cephalometric data investigated were focused on the diagnosis of hyperdivergent cranial structure (NSL/ML, NL/ML), backwards rotation of the mandible (Fh/ML), short vertical ramus (Ar:Go), steep mandibular plane (ML/Oc)., Results: The cephalometric data considered were not significantly different in the RA vs controls except for the steepness of the occlusal plane (NL/Oc), which was steeper in the patients group (P < 0.02) and the ramus of the mandible which was greater in patients. The asymmetry of the condyles was significant (P < 0.003) and different from the control group, but that of the ramus was not., Conclusions: In this study, RA patients diagnosed after 25 years of age did not show a different pattern of growth with respect to the control group. As expected, the condyles showed a difference being asymmetrical in RA patients due to the high turnover of this joint reacting to severe systemic inflammation in conditions of continuous functional work, load and forces. This study follows a previous study with the same research plan conducted on young JIA patients who showed a different pattern of growth of the skull leading to a severe hyperdivergent cranial structure with backward rotation of the mandible; this is mainly due to the insufficient growth of the condylar site exposed to the inflammatory process during development. Unlike JIA patients, this study showed that RA patients follow an individual growth pattern not affected by inflammation, even if they show joint asymmetry., (© 2023. The Author(s).)

We study the low-energy limit of Wilson lines (charged impurities) in conformal gauge theories in 2+1 and 3+1 dimensions. As a function of the representation of the Wilson line, certain defect operators can become marginal, leading to interesting renormalization group flows and for sufficiently large representations to complete or partial screening by charged fields. This result is universal: in large enough representations, Wilson lines are screened by the charged matter fields. We observe that the onset of the screening instability is associated with fixed-point mergers. We study this phenomenon in a variety of applications. In some cases, the screening of the Wilson lines takes place by dimensional transmutation and the generation of an exponentially large scale. We identify the space of infrared conformal Wilson lines in weakly coupled gauge theories in 3+1 dimensions and determine the screening cloud due to bosons or fermions. We also study QED in 2+1 dimensions in the large N&#95;{f} limit and identify the nontrivial conformal Wilson lines. We briefly discuss 't Hooft lines in 3+1-dimensional gauge theories and find that they are screened in weakly coupled gauge theories with simply connected gauge groups. In non-Abelian gauge theories with S duality, this together with our analysis of the Wilson lines gives a compelling picture for the screening of the line operators as a function of the coupling.

Rheumatic musculoskeletal diseases or RMD [rheumatoid arthritis (RA) and spondyloarthritis (SpA)] are systemic inflammatory diseases for which there are no biomarkers capable of predicting treatments with a higher likelihood of response in naive patients. In addition, the expiration of the anti-TNF blocking drugs' patents has resulted in the availability of anti-TNF biosimilar drugs with the same efficacy and safety than originators but at significantly reduced prices. To guarantee a personalized therapeutic approach to RMD treatment, a board of rheumatologists and stakeholders from the Campania region, Italy, developed a clinically applicable arthritis therapeutic algorithm to guide rheumatologists (DATA project). The general methodology relied on a Delphi technique forecast to produce a set of statements that summarized the experts' consensus. Selected clinical scenarios were discussed in light of the available evidence, and there were two rounds of voting on the therapeutic approaches. Separate discussions were held regarding rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. The decision-making factors for each disease were clinical presentation, demographics, and comorbidities. In this paper, we describe a virtuous process between rheumatologists and healthcare system stakeholders that resulted in the development of a shared therapeutic algorithm for RMD patients naive to bDMARDs.

Due to the aging of the population, in 70% of cases, a new cancer diagnosis equals a cancer diagnosis in a geriatric patient. In this population, beyond the concept of mortality and morbidity, functional capacity, disability, and quality of life remain crucial. In fact, when the functional status is preserved, the pathogenetic curve towards disability will stop or even regress. The present systematic review investigated the effectiveness of physical exercise, as part of a holistic assessment of the patient, for preventing disability and improving the patient's quality of life, and partially reducing all-cause mortality. This evidence must point towards decentralization of care by implementing the development of rehabilitation programs for elderly cancer patients either before or after anti-cancer therapy.

Although shown to be effective in improving survival and quality of life in patients with cancer, some treatments are well-known causes of cardiotoxicity, such as anthracyclines, monoclonal antibodies against human epidermal growth factor receptor 2 (HER2) and radiotherapy. To prevent cardiovascular disease (CVD) in patients living with cancer, cardiologists and oncologists promoted the development of cardio-oncology, an interdisciplinary field which aims to further improving life expectancy in these patients. Cardio-oncology rehabilitation (CORE), through correction of risk factors, prescription of drug therapies and structured exercise programs, tries to improve symptoms, quality of life, cardiorespiratory fitness (CRF) and survival in patients with cancer. Different imaging modalities can be used to evaluate the real effectiveness of exercise training on cardiac function. Among these, the global longitudinal strain (GLS) has recently aroused interest, thanks to its high sensitivity and specificity for cardiac dysfunction detection due to advanced ultrasound programs. This review summarizes the evidence on the usefulness of GLS in patients with cancer undergoing cardiac rehabilitation programs.

Objectives: To compare real-world persistence, effectiveness and tolerability of ustekinumab versus TNF inhibitors (TNFi) in psoriatic arthritis (PsA)., Methods: One-year data from Italian subjects enrolled in the PsABio study (PsA patients receiving 1st- to 3rd-line treatment with ustekinumab or TNFi) were evaluated. Treatment persistence was analysed using Kaplan-Meier curves; hazard ratios (HR) of stopping treatment, and the corresponding 95% confidence intervals (CI), were computed through Cox regression models. Proportions of patients reaching clinical effectiveness endpoints were analysed using logistic regression, including propensity score (PS) adjustment for imbalanced baseline covariates, and non-response imputation if treatment was stopped/switched., Results: Among 222 participants with follow-up data (effectiveness set), 101 received ustekinumab and 121 TNFi. In the ustekinumab group, 74.3% continued treatment up to 12±3 months compared to 63.6% in the TNFi group. Ustekinumab showed better persistence than TNFi, overall and in specific subgroups (females, monotherapy without methotrexate, BMI <25 or >30 kg/m2, patients receiving ustekinumab as 2nd-line treatment instead of a second TNFi). Overall, the PS-adjusted HR of treatment discontinuation was 0.46 (95% CI: 0.26-0.82) for ustekinumab vs. TNFi. cDAPSA LDA/remission was achieved in 43.5% of ustekinumab and 43.6% of TNFi-treated patients, while MDA was achieved in 24.2% and 28.0% of patients, respectively. After PS adjustment, odds ratios of clinical effectiveness did not differ significantly. Both treatments showed an acceptable safety profile., Conclusions: This prospective, real-life study found a better persistence of ustekinumab than TNFi in PsA patients. At 1 year, both treatments showed similar effectiveness.

Objective: To describe demographic, clinical and laboratory features of systemic sclerosis sine scleroderma (ssSSc) in a large multicentre systemic sclerosis (SSc) cohort., Methods: Data involving 1808 SSc patients from Italian Systemic sclerosis PRogression INvestiGation registry were collected. The ssSSc was defined by the absence of any cutaneous sclerosis and/or puffy fingers. Clinical and serological features of ssSSc were compared with limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) subsets., Results: Among patients with SSc, only 61 (3.4%) were classified as having ssSSc (F/M=19/1). Time from Raynaud's phenomenon (RP) onset to diagnosis was longer in ssSSc (3 years, IQR 1-16.5) than lcSSc (2 years, IQR 0-7), and dcSSc (1 year, IQR 0-3) (p<0.001). Clinical ssSSc phenotype was comparable to lcSSc, except for digital pitting scars (DPS) (19.7% vs 42%, p=0.01), but significantly milder than dcSSc, particularly for digital ulcers (DU) (6.6% vs 35.7%, p<0.001), oesophagus (46.2% vs 63.5%, p=0.009), lung (mean diffusion capacity for carbon monoxide 72.2±19.6 vs 62.4±22.8, p=0.009; mean forced vital capacity 105.6±21.7 vs 89.2±20.9, p<0.001) and major videocapillaroscopic alterations (late pattern 8.6% vs 47.6%, p<0.001). Moreover, in ssSSc the percentages of anticentromere and antitopoisomerase were comparable to lcSSc (40% and 18.3% vs 36.7% and 26.6%), but divergent respect to dcSSc (8.6% and 67.4%, p<0.001)., Conclusion: The ssSSc is a quite rare disease variant characterised by clinico-serological features comparable to lcSSc, but significantly different from dcSSc. Overall, longer RP duration, low percentages of DPS and peripheral microvascular abnormalities, and increased anti-centromere seropositivity distinguish ssSSc. Further investigations based on national registries might provide useful insights on the actual relevance of the ssSSc within the scleroderma spectrum., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Invasion of the malaria vector Anopheles stephensi across the Horn of Africa threatens control efforts across the continent, particularly in urban settings where the vector is able to proliferate. Malaria transmission is primarily determined by the abundance of dominant vectors, which often varies seasonally with rainfall. However, it remains unclear how An. stephensi abundance changes throughout the year, despite this being a crucial input to surveillance and control activities. We collate longitudinal catch data from across its endemic range to better understand the vector's seasonal dynamics and explore the implications of this seasonality for malaria surveillance and control across the Horn of Africa. Our analyses reveal pronounced variation in seasonal dynamics, the timing and nature of which are poorly predicted by rainfall patterns. Instead, they are associated with temperature and patterns of land use; frequently differing between rural and urban settings. Our results show that timing entomological surveys to coincide with rainy periods is unlikely to improve the likelihood of detecting An. stephensi. Integrating these results into a malaria transmission model, we show that timing indoor residual spraying campaigns to coincide with peak rainfall offers little improvement in reducing disease burden compared to starting in a random month. Our results suggest that unlike other malaria vectors in Africa, rainfall may be a poor guide to predicting the timing of peaks in An. stephensi -driven malaria transmission. This highlights the urgent need for longitudinal entomological monitoring of the vector in its new environments given recent invasion and potential spread across the continent.

Background: Vascular dysfunction and its concomitant multi-organ involvement, including cardiac involvement, affects prognosis in systemic sclerosis (SSc) patients. Regular exercise has demonstrated to be able to improve vascular function in SSc. However, the effects of an exercise program on the heart and specifically in right ventricular (RV) morphology and function in SSc have yet to be explored. The study aimed to examine whether a 3-month combined exercise program can affect RV morphology and function in SSc patients., Methods: Twenty-eight SSc patients were randomly allocated to either the exercise training (ET) or the control (CON) group. Baseline and follow-up assessments consisted of a cardiopulmonary exercise test along with both a conventional and a two-dimensional speckle tracking echocardiography (2DSTE) focused on RV morphology and function. Following the baseline assessments, Group ET participated in a supervised combined exercise program for 12 weeks, while group CON received their usual care., Results: The ET group demonstrated increases in peak oxygen consumption by 25.1% ( p < 0.001), global RV free wall longitudinal systolic strain by 6.69% ( p < 0.03), RV free wall longitudinal systolic strain of the basal segment by 13.5% ( p < 0.001), and global RV four-chamber longitudinal systolic strain by 6.76% ( p < 0.03) following the exercise program. No differences were observed in group CON., Conclusions: Combined exercise improved cardiorespiratory efficiency and indices of RV systolic function, as assessed by the 2DSTE, in SSc patients.

Introduction: Nintedanib (NTD) has been shown to be effective in systemic sclerosis (SSc)-interstitial lung disease (ILD). Here we describe the efficacy and safety of NTD in a real-life setting., Methods: Patients with SSc-ILD treated with NTD were retrospectively evaluated at 12 months prior to NTD introduction; at baseline and at 12 months after NTD introduction. The following parameters were recorded: SSc clinical features, NTD tolerability, pulmonary function tests and modified Rodnan skin score (mRSS)., Results: 90 patients with SSc-ILD (65% female, mean age 57.6±13.4 years, mean disease duration 8.8±7.6 years) were identified. The majority were positive for anti-topoisomerase I (75%) and 77 (85%) patients were on immunosuppressants. A significant decline in %predicted forced vital capacity (%pFVC) in the 12 months prior to NTD introduction was observed in 60%. At 12 months after NTD introduction, follow-up data were available for 40 (44%) patients and they showed a stabilisation in %pFVC (64±14 to 62±19, p=0.416). The percentage of patients with significant lung progression at 12 months was significantly lower compared with the previous 12 months (60% vs 17.5%, p=0.007). No significant mRSS change was observed. Gastrointestinal (GI) side effects were recorded in 35 (39%) patients. After a mean time of 3.6±3.1 months, NTD was maintained after dose adjustment in 23 (25%) patients. In nine (10%) patients, NTD was stopped after a median time of 4.5 (1-6) months. During the follow-up, four patients died., Conclusions: In a real-life clinical scenario, NTD, in combination with immunosuppressants, may stabilise lung function. GI side effects are frequent and NTD dose adjustment may be necessary to retain the drug in patients with SSc-ILD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: It has recently become possible to assess lung vascular and parenchymal changes quantitatively in thoracic CT images using automated software tools. We investigated the vessel parameters of patients with SSc, quantified by CT imaging, and correlated them with interstitial lung disease (ILD) features., Methods: SSc patients undergoing standard of care pulmonary function testing and CT evaluation were retrospectively evaluated. CT images were analysed for ILD patterns and total pulmonary vascular volume (PVV) extents with Imbio lung texture analysis. Vascular analysis (volumes, numbers and densities of vessels, separating arteries and veins) was performed with an in-house developed software. A threshold of 5% ILD extent was chosen to define the presence of ILD, and commonly used cut-offs of lung function were adopted., Results: A total of 79 patients [52 women, 40 ILD, mean age 56.2 (s.d. 14.2) years, total ILD extent 9.5 (10.7)%, PVV/lung volume % 2.8%] were enrolled. Vascular parameters for total and separated PVV significantly correlated with functional parameters and ILD pattern extents. SSc-associated ILD (SSc-ILD) patients presented with an increased number and volume of arterial vessels, in particular those between 2 and 4 mm of diameter, and with a higher density of arteries and veins of <6 mm in diameter. Considering radiological and functional criteria concomitantly, as well as the descriptive trends from the longitudinal evaluations, the normalized PVVs, vessel numbers and densities increased progressively with the increase/worsening of ILD extent and functional impairment., Conclusion: In SSc patients CT vessel parameters increase in parallel with ILD extent and functional impairment, and may represent a biomarker of SSc-ILD severity., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background : The birth of a preterm infant and his/her immediate admittance to the Neonatal Intensive Care Unit (NICU) are sudden, unexpected, stressful and painful events for parents. In the last decade, in response to the increased awareness of the stressful experiences of parents, much attention has been paid to Family-Centered Care (FCC) and the implementation of the Newborn Individualized Developmental Care and Assessment Program (NIDCAP). According to the NIDCAP model, the infant-parents' dyad is the core of the care provided by the NICU professionals to reduce the stress experienced by parents. So far, the literature does not show a clear correlation between parental experiences and the NICU practices according NIDCAP principles. Aims : To explore how parents of preterm infants experienced the NIDCAP-based care from admission to discharge, in particular, their relationships with NICU professionals and with other parents, and the organization of the couple's daily activities during this process. Design : Qualitative exploratory study. Methods : Twelve parents of preterm infants born between January 2018 and December 2020 at the NICU of Modena, with a gestational age at birth of less than 30 weeks and/or a birth weight of less than 1250 g, were recruited. Three couples had twins, and the total number of infants was 15. All infants were followed for up to 24 months post-term age (PTA) for neurological outcomes. Each couple was given a semi-structured online interview about their experience during their infant's hospitalization in the NICU up to discharge. The interview was developed around three time points: birth, hospitalization and discharge. The data analysis was conducted according to the template analysis method. Results : The admission to the NICU was unexpected and extraordinary, and its impact was contained by the skilled staff who were capable of welcoming the parents and making them feel they were involved and active collaborators in the care of their infant. The emotional experience was compared to being in a blender; they were overwhelmed by changing emotions, ranging from terrible fear to extreme joy. The couple's activities of daily life were reorganized after the infant's birth and admission to the NICU. Fathers felt unbalanced and alone in taking care of their partners and their children. Conclusions : This is the first study in Italy to explore parental experience in an NICU implementing NIDCAP-based care. The NIDCAP approach in the NICU of Modena helps parents to be involved early, to develop parental skills, and to be prepared for the transition home; and it also facilitates and enhances the relationship between parents and NICU staff.

Background: Acute respiratory distress syndrome (ARDS) is one of the most severe complications of SARS-CoV-2 infection. Non-Invasive Respiratory Support (NRS) as Continuous Positive Airway Pressure (CPAP) and/or Non-Invasive Ventilation (NIV) has been proven as effective in the management of SARS-CoV-2-related ARDS. However, the most appropriate timing for start NRS is unknown., Methods: We conducted a prospective pilot study including all consecutive patients who developed moderate SARS-CoV-2-related ARDS during hospitalization. Patients were randomly divided into two intervention groups according to ARDS severity (assessed by PaO 2 /FiO 2 -P/F) at NRS beginning: group A started CPAP/NIV when P/F was ≤ 200 and group B started CPAP/NIV when P/F was ≤ 150. Eligible patients who did not give their consent to CPAP/NIV until the severe stage of ARDS and started non-invasive treatment when P/F ≤ 100 (group C) was added. The considered outcomes were in-hospital mortality, oro-tracheal intubation (OTI) and days of hospitalization., Results: Among 146 eligible patients, 29 underwent CPAP/NIV when P/F was ≤ 200 (Group A), 68 when P/F was ≤ 150 (Group B) and 31 patients agreed to non-invasive treatment only when P/F was ≤ 100 (Group C). Starting NRS at P/F level between 151 and 200 did not results in significant differences in the outcomes as compared to treatment starting with P/F ranging 101-150. Conversely, patients undergone CPAP/NIV in a moderate stage (P/F 101-200) had a significantly lower in-hospital mortality rate (13.4 vs. 29.0%, p = 0.044) and hospitalization length (14 vs. 15 days, p = 0.038) than those in the severe stage (P/F ≤ 100). Age and need for continuous ventilation were independent predictors of CPAP/NIV failure., Conclusions: Starting CPAP/NIV in patients with SARS-CoV-2-related ARDS in moderate stage (100 > P/F ≤ 200) is associated to a reduction of both in-hospital mortality and hospitalization length compared to the severe stage (P/F ≤ 100). Starting CPAP/NIV with a P/F > 150 does not appear to be of clinical utility., (© 2022. The Author(s).)

Background: Pain, related to Raynaud's phenomenon or digital ulceration, has been identified as very prevalent and debilitating symptoms of systemic sclerosis (SSc), both significantly affecting patients' quality of life (QoL). Pharmacological therapeutic strategies were found not to be sufficiently effective in the management of SSc-induced pain and fatigue, and evidence for exercise is scarce. As yet, the effects of a long-term, tailored exercise programme on pain and fatigue in patients with SSc have not been explored. In addition to pain and fatigue, this study aims to evaluate the effects of exercise on QoL, physical fitness, functional capacity, and vascular structure in people with SSc (PwSSc)., Methods: This will be a multicentre (n = 6) randomised controlled clinical trial to assess the effect of a previously established, supervised 12-week combined exercise programme on pain and fatigue as compared to no exercise in PwSSc. The study will recruit 180 patients with SSc that will be allocated randomly to two groups. Group A will perform the exercise programme parallel to standard usual care and group B will receive usual care alone. Patients in the exercise group will undertake two, 45-min sessions each week consisting of 30-min high-intensity interval training (HIIT) (30-s 100% peak power output/30-s passive recovery) on an arm crank ergometer and 15 min of upper body circuit resistance training. Patients will be assessed before as well as at 3 and 6 months following randomisation. Primary outcomes of the study will be pain and fatigue assessed via questionnaires. Secondary outcomes include quality of life, structure of digital microvasculature, body composition, physical fitness, and functional capacity., Discussion: Data from this multi-centre research clinical trial will primarily be used to establish the effectiveness of a combined exercise protocol to improve pain and fatigue in SSc. In parallel, this study will be the first to explore the effects of long-term exercise on potential microvascular alterations assessed via NVC. Overall, this study will provide sufficient data to inform current clinical practice guidelines and may lead to an improvement of QoL for patients with SSc., Trial Registration: ClinicalTrials.gov NCT05234671. Registered on 14 January 2022., (© 2022. The Author(s).)

Objectives: To investigate differences in coronavirus disease 2019 (COVID-19) mortality between patients with rheumatic musculoskeletal diseases (RMD) and the general population in Italy., Methods: We analysed the data from the national surveillance study promoted by the Italian Society for Rheumatology (CONTROL-19 database) including patients with RMD and COVID-19 between 26 March 2020 and 29 November 2020, compared with official data from the Italian population (within the same period) adjusted for age, sex and geographic location. The main outcome of the analyses was mortality. The relationship between RMD and mortality was analysed using adjusted logistic models and sensitivity analyses were conducted to support the robustness of our results., Results: We included 668 RMD patients (62.7% with inflammatory arthritis, 28.6% with systemic autoimmune diseases), who had a mean age of 58.4 years and of which 66% were female. Compared to the general population, the RMD population showed an increased risk of death (OR 3.10 (95% CI 2.29-4.12)), independently from the differences in age and sex distribution. Even after considering the potential influence of surveillance bias, the OR was 2.08 (95% CI: 1.55-2.73). Such excess of risk was more evident in the subgroup of younger patients, and more consistent in women. Subjects with systemic autoimmune diseases showed a higher risk of death than patients with any other RMDs., Conclusions: Patients with RMD and COVID-19 infection evidenced a significant increase in mortality during the first pandemic phases in Italy. These findings support the need for strong SARS-CoV-2 prevention in patients with rheumatic diseases.

Introduction: Systemic sclerosis (SSc) is characterized by a complex etiopathogenesis encompassing both host genetic and environmental -infectious/toxic- factors responsible for altered fibrogenesis and diffuse microangiopathy. A wide spectrum of clinical phenotypes may be observed in patients' populations from different geographical areas. We investigated the prevalence of specific clinical and serological phenotypes in patients with definite SSc enrolled at tertiary referral centres in different Italian geographical macro-areas. The observed findings were compared with those reported in the world literature., Materials and Methods: The clinical features of 1538 patients (161 M, 10.5%; mean age 59.8 ± 26.9 yrs.; mean disease duration 8.9 ± 7.7 yrs) with definite SSc recruited in 38 tertiary referral centres of the SPRING (Systemic sclerosis Progression INvestiGation Group) registry promoted by Italian Society of Rheumatology (SIR) were obtained and clustered according to Italian geographical macroareas., Results: Patients living in Southern Italy were characterized by more severe clinical and/or serological SSc phenotypes compared to those in Northern and Central Italy; namely, they show increased percentages of diffuse cutaneous SSc, digital ulcers, sicca syndrome, muscle involvement, arthritis, cardiopulmonary symptoms, interstitial lung involvement at HRCT, as well increased prevalence of serum anti-Scl70 autoantibodies. In the same SSc population immunusppressive drugs were frequently employed. The review of the literature underlined the geographical heterogeneity of SSc phenotypes, even if the observed findings are scarcely comparable due to the variability of methodological approaches., Conclusion: The phenotypical differences among SSc patients' subgroups from Italian macro-areas might be correlated to genetic/environmental co-factors, and possibly to a not equally distributed national network of information and healthcare facilities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Background: The heart is commonly involved in COVID-19, and rhythm disorders have been largely reported., Objective: To evaluate the association of some non-cardiac and cardiac comorbidities and QT dispersion with arrhythmias and their impact on outcomes in hospitalized patients with COVID-19., Methods: Each patient underwent cardiac telemetry monitoring through the entire hospitalization period, laboratory analyses, 12-lead ECG, and lung imaging examination. Patients with arrhythmia were divided into three groups (bradyarrhythmias, tachyarrhythmias, and tachy- and bradyarrhythmias)., Results: Two-hundred patients completed the study (males, 123; mean age, 70.1 years); of these, 80 patients (40%) exhibited rhythm disorders on telemetry. Patients with arrhythmia were older ( p < 0.0001), had a greater number of comorbidities ( p < 0.0001), higher values of creatinine ( p = 0.007), B-type natriuretic peptide ( p < 0.0001), troponin ( p < 0.0001), C-reactive protein ( p = 0.01), ferritin ( p = 0.001), D-dimer ( p < 0.0001), procalcitonin ( p = 0.0008), QT interval ( p = 0.002), QTc interval ( p = 0.04), and QTc dispersion ( p = 0.01), and lower values of sodium ( p = 0.03), magnesium ( p = 0.04), glomerular filtration rate ( p < 0.0001), and hemoglobin ( p = 0.008) as compared to patients without arrhythmia. By comparing the three subgroups of patients, no significant differences were found. At multivariate analysis, age [odds ratio (OR) = 1.14 (95% CI: 1.07-1.22); p = 0.0004], coronary artery disease [OR = 12.7 (95% CI: 2.38-68.01); p = 0.005], and circulating troponin [OR = 1.05 (95% CI: 1.003-1.10); p = 0.04] represented risk factors independently associated with arrhythmia. All-cause in-hospital mortality was ∼40-fold higher among patients with arrhythmia [OR = 39.66 (95% CI: 5.20-302.51); p = 0.0004]., Conclusion: Arrhythmias are associated with aging, coronary artery disease, subtle myocardial injury, hyperinflammatory status, coagulative unbalance, and prolonged QTc dispersion in patients with COVID-19, and confer a worse in-hospital prognosis. Given its usefulness, routinary use of cardiac telemetry should be encouraged in COVID wards., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cozzolino, Romano, Nevola, Marrone, Umano, Cuomo, Rinaldi, Adinolfi and Vanvitelli COVID Collaborators.)

Background: Remdesivir is an antiviral used to treat coronavirus disease 2019 (COVID-19), which improves some clinical outcomes. Dexamethasone has been shown to be effective in reducing mortality. It has been hypothesized that combination of these two drugs can improve mortality. We evaluated the effect of combination on mortality of COVID-19 patients requiring O2 therapy., Methods: A prospective quasi-experimental study, including two independent, sequential controlled cohorts, one received remdesivir-dexamethasone and the other dexamethasone alone, was designed. All COVID-19 patients requiring supplemental O2 therapy were enrolled consecutively. The sample size to power mortality was a priori calculated. The primary endpoints were 30-day mortality and viral clearance differences. Secondary endpoints were differences in hospitalization times, improvement in respiratory failure (PO2/FiO2) and inflammatory indices (fibrinogen, CRP, neutrophil/lymphocyte ratio, D-Dimer). Kaplan-Meier curves and the log-rank test were used to evaluate significant differences in mortality between groups., Results: In total, 151 COVID-19 patients were enrolled (remdesivir/dexamethasone group, 76, and dexamethasone alone, 75). No differences in demographic, clinical, and laboratory characteristics were observed between the 2 groups at baseline. Faster viral clearance occurred in the remdesivir/dexamethasone group compared to dexamethasone alone (median 6 vs 16 days; P < .001). The 30-day mortality in the remdesivir/dexamethasone group was 1.3%, whereas in dexamethasone alone was 16% (P < .005). In the remdesivir/dexamethasone group compared to dexamethasone alone there was a reduction in hospitalization days (P < .0001) and a faster improvement in both respiratory function and inflammatory markers., Conclusions: Remdesivir/dexamethasone treatment is associated with significant reduction in mortality, length of hospitalization, and faster SARS-CoV-2 clearance, compared to dexamethasone alone., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Cardiovascular disease is the most important cause of death worldwide in recent years; an increasing trend is also shown in organ transplant patients subjected to immunosuppressive therapies, in which cardiovascular diseases represent one of the most frequent causes of long-term mortality. This is also linked to immunosuppressant-induced dyslipidemia, which occurs in 27 to 71% of organ transplant recipients. The aim of this review is to clarify the pathophysiological mechanisms underlying dyslipidemia in patients treated with immunosuppressants to identify immunosuppressive therapies which do not cause dyslipidemia or therapeutic pathways effective in reducing hypercholesterolemia, hypertriglyceridemia, or both, without further adverse events.

Autoimmune systemic diseases (ASD) show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed at evaluating the seroconversion elicited by COVID-19 vaccine over the entire vaccination cycle including the booster dose. Among 478 unselected ASD patients originally evaluated at the end of the first vaccination cycle (time 1), 344 individuals were re-evaluated after a 6-month period (time 2), and 244 after the booster vaccine dose (time 3). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was assessed by measuring serum IgG-neutralizing antibody (NAb) on samples obtained at the three time points in both patients and 502 age-matched controls. In the 244 ASD group that received booster vaccine and monitored over the entire follow-up, the mean serum NAb levels (time 1, 2, and 3: 696.8 ± 52.68, 370.8 ± 41.92, and 1527 ± 74.16SD BAU/mL, respectively; p < 0.0001) were constantly lower compared to controls (p < 0.0001), but they significantly increased after the booster dose compared to the first two measurements (p < 0.0001). The percentage of patients with absent/suboptimal response to vaccine significantly decreased after the booster dose compared to the first and second evaluations (time 1, 2, and 3: from 28.2% to 46.3%, and to 7.8%, respectively; p < 0.0001). Of note, the percentage of patients with absent/suboptimal response after the booster dose was significantly higher compared to controls (19/244, 7.8% vs 1/502, 0.2%; p < 0.0001). Similarly, treatment with immune-modifiers increased the percentage of patients exhibiting absent/suboptimal response (16/122, 13.1% vs 3/122, 2.46%; p = 0.0031). Overall, the above findings indicate the usefulness of booster vaccine administration in ASD patients. Moreover, the persistence of a significantly higher percentage of individuals without effective seroconversion (7.8%), even after the booster dose, warrants for careful monitoring of NAb levels in all ASD patients to identify those with increased risk of infection. In this particularly frail patients' setting, tailored vaccination and/or therapeutic strategy are highly advisable., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Dyslipidemia is a widespread risk factor in solid organ transplant patients, due to many reasons, such as the use of immunosuppressive drugs, with a consequent increase in cardiovascular diseases in this population. PCSK9 is an enzyme mainly known for its role in altering LDL levels, consequently increasing cardiovascular risk. Monoclonal antibody PCSK9 inhibitors demonstrated remarkable efficacy in the general population in reducing LDL cholesterol levels and preventing cardiovascular disease. In transplant patients, these drugs are still poorly used, despite having comparable efficacy to the general population and giving fewer drug interactions with immunosuppressants. Furthermore, there is enough evidence that PCSK9 also plays a role in other pathways, such as inflammation, which is particularly dangerous for graft survival. In this review, the current evidence on the function of PCSK9 and the use of its inhibitors will be discussed, particularly in transplant patients, in which they may provide additional benefits.

Background: Understanding the characteristics and natural history of novel pathogens is crucial to inform successful control measures. Japan was one of the first affected countries in the COVID-19 pandemic reporting their first case on 14 January 2020. Interventions including airport screening, contact tracing, and cluster investigations were quickly implemented. Here we present insights from the first 3 months of the epidemic in Japan based on detailed case data., Methods: We conducted descriptive analyses based on information systematically extracted from individual case reports from 13 January to 31 March 2020 including patient demographics, date of report and symptom onset, symptom progression, travel history, and contact type. We analysed symptom progression and estimated the time-varying reproduction number, R t , correcting for epidemic growth using an established Bayesian framework. Key delays and the age-specific probability of transmission were estimated using data on exposures and transmission pairs., Results: The corrected fitted mean onset-to-reporting delay after the peak was 4 days (standard deviation: ± 2 days). Early transmission was driven primarily by returning travellers with R t peaking at 2.4 (95% CrI: 1.6, 3.3) nationally. In the final week of the trusted period (16-23 March 2020), R t accounting for importations diverged from overall R t at 1.1 (95% CrI: 1.0, 1.2) compared to 1.5 (95% CrI: 1.3, 1.6), respectively. Household (39.0%) and workplace (11.6%) exposures were the most frequently reported potential source of infection. The estimated probability of transmission was assortative by age with individuals more likely to infect, and be infected by, contacts in a similar age group to them. Across all age groups, cases most frequently onset with cough, fever, and fatigue. There were no reported cases of patients < 20 years old developing pneumonia or severe respiratory symptoms., Conclusions: Information collected in the early phases of an outbreak are important in characterising any novel pathogen. The availability of timely and detailed data and appropriate analyses is critical to estimate and understand a pathogen's transmissibility, high-risk settings for transmission, and key symptoms. These insights can help to inform urgent response strategies., (© 2022. The Author(s).)

Iron deficiency anemia (IDA) is frequent after cardiac surgery and is associated with increased morbidity and mortality. In a retrospective study, we analyzed 106 patients with IDA (hemoglobin [Hb] ≤ 12 g/dl in women and ≤ 13 g/dl in men, transferrin saturation [TSAT] ≤ 20%) on admission to a Cardiac Rehabilitation Unit after cardiac surgery. The patients were divided into two groups, one was treated with oral sucrosomial iron (SI) and the other with intravenous ferric carboxymaltose (FCM). Patients received a single 1000 mg dose of FCM from the day after admission to rehabilitation (T1), or a 120 mg/day dose of SI from T1 until discharge (T2); after discharge, SI was reduced to 30 mg/day until the end of follow-up (T3). Hb was evaluated at T1, T2 and T3; the other hematological parameters at T1 and T3; natriuretic peptides at T1, T2 and T3; 6-minute walk test (6MWT) at T1 and T2. Folate, vitamin B12 and reticulocytes were sampled on admission. Folate deficiency was documented in 60.4% of patients. Hb increased in both groups with no significant differences between the two treatments (p = 0.397). The other iron metabolism parameters (sideremia, transferrin, TSAT) displayed similar behavior, showing a significant increase at T3 (p < 0.001) with both therapies, although the increase was faster with FCM. Ferritin - high on admission - decreased at T3 in the SI group and rose significantly in the FCM group (SI 219.5 vs. FCM 689 ng/ml p < 0.0001). The 6MWT increased significantly at T2, with an overlap between SI and FCM. In conclusion, the results of this study show that SI and FCM exhibit the same effectiveness on IDA; the response time to therapy of both treatments is also equally fast. SI and FCM induce a similar increase in functional capacity. The study shows that SI can be a viable alternative to FCM after cardiac surgery in terms of effectiveness and tolerability., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Background Coronavirus disease 2019 (COVID-19) can be complicated by interstitial pneumonia, possibly leading to severe acute respiratory failure and death. Because of variable evolution ranging from asymptomatic cases to the need for invasive ventilation, COVID-19 outcomes cannot be precisely predicted on admission. The aim of this study was to provide a simple tool able to predict the outcome of COVID-19 pneumonia on admission to a low-intensity ward in order to better plan management strategies for these patients. Methods The clinical records of 123 eligible patients were reviewed. The following variables were analyzed on admission: chest computed tomography severity score (CTSS), PaO2/FiO2 ratio, lactate dehydrogenase (LDH), neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio, C-reactive protein (CRP), fibrinogen, D-dimer, aspartate aminotransferase (AST), alanine aminotransferase, alkaline phosphatase, and albumin. The main outcome was the intensity of respiratory support (RS). To simplify the statistical analysis, patients were split into two main groups: those requiring no or low/moderate oxygen support (group 1); and those needing subintensive/intensive RS up to mechanical ventilation (group 2). Results The RS intensity was significantly associated with higher CTSS and NLR scores; lower PaO2/FiO2 ratios; and higher serum levels of LDH, CRP, D-dimer, and AST. After multivariate logistic regression and ROC curve analysis, CTSS and LDH were shown to be the best predictors of respiratory function worsening. Conclusions Two easy-to-obtain parameters (CTSS and LDH) were able to reliably predict a worse evolution of COVID-19 pneumonia with values of >7 and >328 U/L, respectively.

Heart failure (HF) is a chronic, progressive, and inexorable syndrome affecting worldwide billion of patients (equally distributed among men and women), with prevalence estimate of 1-3% in developed countries. HF leads to enormous direct and indirect costs, and because of ageing population, the total number of HF patients keep rising, approximately 10% in patients > 65 years old. Exercise training (ET) is widely recognized as an evidence-based adjunct treatment modality for patients with HF, and growing evidence is emerging among elderly patients with HF. We used relevant data from literature search (PubMed, Medline, EMBASE) highlighting the epidemiology of HF; focusing on central and peripheral mechanisms underlying the beneficial effect of ET in HF patients; and on frail HF elderly patients undergoing ET. Since many Countries ordered a lockdown in early stages pandemic trying to limit infections, COVID-19 pandemic, and its limitation to exercise-based cardiac rehabilitation operativity was also discussed. ET exerts both central and peripheral adaptations that clinically translate into anti-remodeling effects, increased functional capacity and reduced morbidity and mortality. Ideally, ET programs should be prescribed in a patient-tailored approach, particularly in frail elderly patients with HF. In conclusion, given the complexity of HF syndrome, combining, and tailoring different ET modalities is mandatory. A procedural algorithm according to patient's baseline clinical characteristics [i.e., functional capacity, comorbidity, frailty status (muscle strength, balance, usual daily activities, hearing and vision impairment, sarcopenia, and inability to actively exercise), logistics, individual preferences and goals] has been proposed. Increasing long-term adherence and reaching the frailest patients are challenging goals for future initiatives in the field., Competing Interests: The authors declare no conflict of interest. Francesco Giallauria is serving as one of the Editorial Board members of this journal. We declare that Francesco Giallauria had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Kazuhiro P. Izawa and Peter H. Brubaker., (Copyright: © 2022 The Author(s). Published by IMR Press.)

Background: Syphilis represents a major public health concern disproportionately affecting HIV positive patients and, in many cases, both infections are newly diagnosed at the same time. To date, limited studies are available on syphilis incidence in patients with a new HIV diagnosis., Methods: Patients newly diagnosed with HIV in 2010-2018 were included in the study and screening tests for syphilis were performed at baseline and at least once a year. Primary aims were to analyze the incidence rate of HIV-syphilis coinfection and syphilis reinfection. Secondary objective was to identify characteristics independently associated with coinfection and reinfection., Results: Of 500 newly diagnosed HIV patients, 20% presented a concomitant positive syphilis serology. Among them, 54 patients had a serology indicative for an active syphilis requiring therapy, while 46 had a history of prior treatments. The independent factors for syphilis acquisition were: MSM contact (OR=2.64; 95% CI: 1.48-4.72; P<0.001), male gender (OR=2.43; 95% CI: 1.08-5.48; P=0.032), and age (OR=1.03; 95% CI: 1.01-1.05; P=0.005 per year increasing). Presence of syphilis at the time of HIV diagnosis remained fairly stable during the study period (P for trend, P=0.689). We observed 52 syphilis reinfections related to 37 people. Patients with at least one reinfection were all males and 86.5% MSM., Conclusions: Males and MSM with HIV presented high rates of syphilis coinfection and reinfection suggesting persistent high-risk sexual behaviors and the need for appropriate intervention strategies in order to early detect and treat syphilis avoiding life-threatening complications and the spread of the infection in the community.

Fibromyalgia syndrome (sFM) is one of the most common causes of chronic pain. This study aimed to assess the presence of small and large fiber impairment in fibromyalgic patients by applying validated scores used in the screening for diabetic neuropathy. The endpoints for the study were the assessment of neuropathy prevalence in sFM patients using the NerveCheck Master (NCM), the Michigan Neuropathy Screening Instrument (MNSI), the Diabetic Neuropathy Symptom (DNS) and the Douleur Neuropathique 4 Questions (DN4). The sample was composed of 46 subjects: subjects with sFM (n = 23) and healthy controls (HC) (n = 23). The positivity rates in each group for DN4 were significantly different (p < 0.001), with a prevalence in symptomatic subjects of 56.3% (n = 9) among sFM individuals. A similar difference was also observed with the DNS total score (p < 0.001). NCM and MNSI did not disclose significant differences between the two groups. This finding seems to confirm the data regarding the prevalence of a neuropathic pain in sFM patients.

Objective: The first pandemic phase of COVID-19 in Italy was characterized by high in-hospital mortality ranging from 23% to 38%. During the third pandemic phase there has been an improvement in the management and treatment of COVID-19, so mortality and predictors may have changed. A prospective study was planned to identify predictors of mortality during the third pandemic phase., Patients and Methods: From 15 December 2020 to 15 May 2021, 208 patients were hospitalized (median age: 64 years; males: 58.6%); 83% had a median of 2 (IQR,1-4) comorbidities; pneumonia was present in 89.8%. Patients were monitored remotely for respiratory function and ECG trace for 24 hours/day. Management and treatment were done following the timing and dosage recommended by international guidelines., Results: 79.2% of patients necessitated O2-therapy. ARDS was present in 46.1% of patients and 45.4% received non-invasive ventilation and 11.1% required ICU treatment. 38% developed arrhythmias which were identified early by telemetry and promptly treated. The in-hospital mortality rate was 10%. At multivariate analysis independent predictors of mortality were: older age (R-R for≥70 years: 5.44), number of comorbidities ≥3 (R-R 2.72), eGFR ≤60 ml/min (RR 2.91), high d-Dimer (R-R for≥1,000 ng/ml:7.53), and low PaO2/FiO2 (R-R for <200: 3.21)., Conclusions: Management and treatment adherence to recommendations, use of telemetry, and no overcrowding appear to reduce mortality. Advanced age, number of comorbidities, severe renal failure, high d-Dimer and low P/F remain predictors of poor outcome. The data help to identify current high-risk COVID-19 patients in whom management has yet to be optimized, who require the greatest therapeutic effort, and subjects in whom vaccination is mandatory.