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Extensive research efforts are being carried out to evaluate and improve the reliability of computing devices, either through beam experiments or simulation-based fault injection. Unfortunately, it is still largely unclear to which extend fault injection can provide an accurate error rate estimation at early stages and if beam experiments can be used to identify the weakest resources in a device. The challenges associated with reliability evaluation grow with the increase of complexity of the hardware and the software. In this paper, we combine and analyze data gathered with extensive beam experiments (on the final physical CPU hardware) and microarchitectural fault injections (on early microarchitectural CPU models). We target a standalone Arm Cortex-A5 and an Arm Cortex-A9 integrated in an SoC and evaluate their reliability in bare-metal and Linux-based configurations. We find that both the SoC integration and the OS presence increase the system DUEs (Detected Unrecoverable Errors) rate (for different reasons) but do not significantly impact the SDCs (Silent Data Corruptions) rate which is solely attributed to the CPU core. Our reliability analysis demonstrates that, even considering SoC integration and OS inclusion, early, pre-silicon microarchitecture-level fault injection delivers accurate SDC rates estimations and lower bounds for the DUE rates.

Many safe and effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations dramatically reduce risks of coronavirus disease 2019 (COVID-19) complications and deaths. We aimed to describe cases of SARS-CoV-2 infection among patients with chronic liver disease (CLD) and liver transplant (LT) recipients with at least one prior COVID-19 vaccine dose. The SECURE-Liver and COVID-Hep international reporting registries were used to identify laboratory-confirmed COVID-19 in CLD and LT patients who received a COVID-19 vaccination. Of the 342 cases of lab-confirmed SARS-CoV-2 infections in the era after vaccine licensing, 40 patients (21 with CLD and 19 with LT) had at least one prior COVID-19 vaccination, including 12 who were fully vaccinated (���2 weeks after second dose). Of the 21 patients with CLD (90% with cirrhosis), 7 (33%) were hospitalized, 1 (5%) was admitted to the intensive care unit (ICU), and 0 died. In the LT cohort (n = 19), there were 6 hospitalizations (32%), including 3 (16%) resulting in mechanical ventilation and 2 (11%) resulting in death. All three cases of severe COVID-19 occurred in patients who had a single vaccine dose within the last 1-2 weeks. In contemporary patients with CLD, rates of symptomatic infection, hospitalization, ICU admission, invasive ventilation, and death were numerically higher in unvaccinated individuals. Conclusion: This case series demonstrates the potential for COVID-19 infections among patients with CLD and LT recipients who had received the COVID-19 vaccination. Vaccination against SARS-CoV-2 appears to result in favorable outcomes as attested by the absence of mechanical ventilation, ICU, or death among fully vaccinated patients.

Objectives : The aim of this study is to identify the prevalence of benign, premalignant and malignant gynecological pathologies in women with adenomyosis who underwent gynecological surgery. Material and methods : The medical records collected between 1985 and 2020 were retrospectively reviewed. The pathology reports were studied from 647 cases where adenomyosis was presented. The estimated prevalence of benign, premalignant and malignant gynecological disorders in the general population was further evaluated. Results : The mean age of women with adenomyosis was 54.1 ± 10.4 years old. Out of 647 patients, in 18.5% of the specimens we detected isolated adenomyosis and in 81.5% of cases a coexistence of one or more gynecological diseases, while in 84 out of 647 patients (13%) there was coexistence of adenomyosis with more than one gynecological condition (benign or malignancy). Among all cases, uterine leiomyomas were observed in 61.3% of patients, followed by endometrial polyps (11.9%), endometriosis (11.6%), endometrial hyperplasia (7.1%), endometrial cancer (3.6%), ovarian (1.4%) and cervical cancer (0.8%) (p < 0.001). Additionally, we found that women with a simultaneous co-existence of adenomyosis, leiomyomas and endometrial polyps or hyperplasia were younger (p < 0.01) in comparison to cases with malignancy. Conclusions : Adenomyosis presents a common benign but often progressing myometrial condition that it is underestimated in clinical practice. Even though some studies suggest a potential association with several gynecological pathologies, we did not confirm a significant difference of adenomyosis prevalence between benign, premalignant and malignant gynecological conditions compared with the general population. Further investigation is required to confirm our results.

Background & Aims: Predictors of successful nucleo(s)tide analogue (NA) therapy withdrawal remain elusive. We studied the relationship between end-of-treatment levels of hepatitis B core-related antigen (HBcrAg) and hepatitis B surface antigen (HBsAg) and outcome after therapy cessation. Methods: Patients who discontinued NA therapy in centers in Asia and Europe were enrolled. HBcrAg and HBsAg were measured at treatment cessation, and associations with off-treatment outcomes were explored. The SCALE-B (Surface antigen, Core-related antigen, Age, ALT, and tenofovir for HBV) score was calculated as previously reported. End points included sustained virologic response (VR; hepatitis B virus DNA level 3× upper limit of normal). Re-treated patients were considered nonresponders. Results: We analyzed 572 patients, 457 (80%) were Asian and 95 (17%) were hepatitis B e antigen positive at the start of NA therapy. The median treatment duration was 295 weeks. VR was observed in 267 (47%), HBsAg loss was observed in 24 (4.2%), and ALT flare was observed in 92 (16%). VR (67% vs 42%) and HBsAg loss (15% vs 1.5%) was observed more frequently in non-Asian patients when compared to Asian patients (P < .001). Lower HBcrAg levels were associated with higher rates of VR (odds ratio [OR], 0.701; P < .001) and HBsAg loss (OR, 0.476; P < .001), and lower rates of ALT flares (OR, 1.288; P = .005). Similar results were observed with HBsAg (VR: OR, 0.812; P = .011; HBsAg loss: OR, 0.380; P < .001; and ALT flare: OR, 1.833; P < .001). Lower SCALE-B scores were associated with higher rates of VR, HBsAg loss, and lower rates of ALT flares in both Asian and non-Asian patients (P < .001). Conclusions: In this multicenter study, off-treatment outcomes after NA cessation varied with ethnicity. Lower levels of HBcrAg and HBsAg were associated with favorable outcomes. A risk score comprising both factors can be used for risk stratification.

The effectiveness of T cell-mediated rejection (TCMR) therapy for achieving histological remission remains undefined in patients on modern immunosuppression. We systematically identified, critically appraised and summarized the incidence and histological outcomes after TCMR treatment in patients on tacrolimus (Tac) and mycophenolic acid (MPA). English-language publications were searched in MEDLINE (Ovid), Embase (Ovid), Cochrane Central (Ovid), CINAHL (EBSCO), Clinicaltrials.gov (NLM) up to January 2021. Study quality was assessed with National Institutes of Health Study Quality Tool. We pooled results using an inverse variance, random-effects model and report the binomial proportions with associated 95% confidence intervals (95% CI). Statistical heterogeneity was explored using the I2 statistic. From 2,875 screened citations, we included 12 studies (1,255 participants). Fifty-eight percent were good/high quality while the rest were moderate quality. Thirty-nine percent of patients (95%CI 0.26-0.53, I2 77%) had persistent ≥Banff Borderline TCMR 2-9 months after anti-rejection therapy. Pulse steroids and augmented maintenance immunosuppression were mainstays of therapy, but considerable practice heterogeneity was present. A high proportion of biopsy-proven rejection exists after treatment emphasizing the importance of histology to characterize remission. Anti-rejection therapy is foundational to transplant management but well-designed clinical trials in patients on Tac/MPA immunosuppression are lacking to define the optimal therapeutic approach.

Background Low lymphocyte-to-monocyte ratio and high platelet-to-lymphocyte ratio have been reported to be poor prognostic indicators in various solid tumors, but the prognostic significance in rectal cancer remains controversial. Objectives We sought to determine the prognostic value of lymphocyte-to-monocyte ratio and platelet-to-lymphocyte ratio following curative-intent surgery for rectal cancer. Data sources Following PRISMA guidelines (PROSPERO, ID: CRD42020190880), PubMed and Embase databases were searched through January 2021 including 3 other registered medical databases. Study selection Studies evaluating the impact of pretreatment lymphocyte-to-monocyte ratio and platelet-to-lymphocyte ratio on overall or disease-free survival in patients undergoing curative rectal cancer resection were selected. Main outcomes measures The main outcome measures were overall and disease-free survival. Results A total of 23 studies (6683 patients) were included; lymphocyte-to-monocyte ratio and platelet-to-lymphocyte ratio were evaluated in 14 and 16 studies, respectively. Low lymphocyte-to-monocyte ratio was associated with poorer overall survival (HR 1.57, 95% CI 1.29-1.90, P Limitations The retrospective nature of most included studies was a limitation. Conclusions Pretreatment lymphocyte-to-monocyte ratio, but not platelet-to-lymphocyte ratio, correlates with tumor response to neoadjuvant chemoradiotherapy and poorer prognosis after curative-intent surgery for rectal cancer, and it potentially represents a simple and reliable biomarker that could help optimize individualized clinical-decision making in high-risk patients.PROSPERO, ID: CRD42020190880.

Contains fulltext : 248305.pdf (Publisher’s version ) (Closed access) CONTEXT: Treatment of metastatic urothelial carcinoma is currently undergoing a rapid evolution. OBJECTIVE: This overview presents the updated European Association of Urology (EAU) guidelines for metastatic urothelial carcinoma. EVIDENCE ACQUISITION: A comprehensive scoping exercise covering the topic of metastatic urothelial carcinoma is performed annually by the Guidelines Panel. Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries, resulting in yearly guideline updates. EVIDENCE SYNTHESIS: Platinum-based chemotherapy is the recommended first-line standard therapy for all patients fit to receive either cisplatin or carboplatin. Patients positive for programmed death ligand 1 (PD-L1) and ineligible for cisplatin may receive immunotherapy (atezolizumab or pembrolizumab). In case of nonprogressive disease on platinum-based chemotherapy, subsequent maintenance immunotherapy (avelumab) is recommended. For patients without maintenance therapy, the recommended second-line regimen is immunotherapy (pembrolizumab). Later-line treatment has undergone recent advances: the antibody-drug conjugate enfortumab vedotin demonstrated improved overall survival and the fibroblast growth factor receptor (FGFR) inhibitor erdafitinib appears active in case of FGFR3 alterations. CONCLUSIONS: This 2021 update of the EAU guideline provides detailed and contemporary information on the treatment of metastatic urothelial carcinoma for incorporation into clinical practice. PATIENT SUMMARY: In recent years, several new treatment options have been introduced for patients with metastatic urothelial cancer (including bladder cancer and cancer of the upper urinary tract and urethra). These include immunotherapy and targeted treatments. This updated guideline informs clinicians and patients about optimal tailoring of treatment of affected patients.

Background: Macrophage activation-like syndrome (MALS) and complex immune dysregulation (CID) often underlie acute respiratory distress (ARDS) in COVID-19. We aimed to investigate the effect of personalized immunotherapy on clinical improvement of critical COVID-19. Methods: In this open-label prospective trial, 102 patients with ARDS by SARS-CoV-2 were screened for MALS (ferritin >4,420 ng/mL) and CID (ferritin ≤4,420 ng/mL and low human leukocyte antigen (HLA)-DR expression on CD14-monocytes). Patients with MALS or CID with increased aminotransferases received intravenous anakinra; those with CID and normal aminotransferases received tocilizumab. The primary outcome was ≥25% decrease in the Sequential Organ Failure Assessment (SOFA) score and/or 50% increase in the respiratory ratio by day 8; 28-day mortality, change of SOFA score by day 28, serum biomarkers, and cytokine production by mononuclear cells were secondary endpoints. Results: The primary study endpoint was met in 58.3% of anakinra-treated patients and in 33.3% of tocilizumab-treated patients (p: 0.01). Most patients in both groups received dexamethasone as standard of care. No differences were found in secondary outcomes, mortality, and SOFA score changes. Ferritin decreased among anakinra-treated patients; interleukin-6, soluble urokinase plasminogen activator receptor, and HLA-DR expression increased among tocilizumab-treated patients. Survivors by day 28 who received anakinra were distributed to lower severity levels of the WHO clinical progression scale. Greater incidence of secondary infections was found with tocilizumab treatment. Conclusion: Immune assessment resulted in favorable anakinra responses among critically ill patients with COVID-19 and features of MALS.

The rising prevalence of nonalcoholic fatty liver disease (NAFLD) and NAFLD‐related cirrhosis in the United States and globally highlights the need to better understand the mechanisms causing progression of hepatic steatosis to fibrosing steatohepatitis and cirrhosis in a small proportion of patients with NAFLD. Accumulating evidence suggests that lipotoxicity mediated by hepatic free cholesterol (FC) overload is a mechanistic driver for necroinflammation and fibrosis, characteristic of nonalcoholic steatohepatitis (NASH), in many animal models and also in some patients with NASH. Diet, lifestyle, obesity, key genetic polymorphisms, and hyperinsulinemia secondary to insulin resistance are pivotal drivers leading to aberrant cholesterol signaling, which leads to accumulation of FC within hepatocytes. FC overload in hepatocytes can lead to ER stress, mitochondrial dysfunction, development of toxic oxysterols, and cholesterol crystallization in lipid droplets, which in turn lead to hepatocyte apoptosis, necrosis, or pyroptosis. Activation of Kupffer cells and hepatic stellate cells by hepatocyte signaling and cholesterol loading contributes to this inflammation and leads to hepatic fibrosis. Cholesterol accumulation in hepatocytes can be readily prevented or reversed by statins. Observational studies suggest that use of statins in NASH not only decreases the substantially increased cardiovascular risk, but may ameliorate liver pathology. Conclusion: Hepatic FC loading may result in cholesterol‐associated steatohepatitis and play an important role in the development and progression of NASH. Statins appear to provide significant benefit in preventing progression to NASH and NASH‐cirrhosis. Randomized controlled trials are needed to demonstrate whether statins or statin/ezetimibe combination can effectively reverse steatohepatitis and liver fibrosis in patients with NASH., Free cholesterol accumulates in the liver in some patients with NAFLF and promotes the necroinflammation and fibrosis typical of NASH. Cholesterol‐associated steatohepatitis (CASH) plays an important role in the development and progression of NASH. Randomized controlled trials are needed to demonstrate whether statins or statin/ezetimibe combination can effectively reverse steatohepatitis and liver fibrosis in patients with NASH.

The results of a simulation-based evaluation of several policies for vaccine rollout are reported, particularly focusing on the effects of delaying the second dose of two-dose vaccines. In the presence of limited vaccine supply, the specific policy choice is a pressing issue for several countries worldwide, and the adopted course of action will affect the extension or easing of non-pharmaceutical interventions in the next months. We employ a suitably generalised, age-structure, stochastic SEIR (Susceptible → Exposed → Infectious → Removed) epidemic model that can accommodate quantitative descriptions of the major effects resulting from distinct vaccination strategies. The different rates of social contacts among distinct age-groups (as well as some other model parameters) are informed by a recent survey conducted in Greece, but the conclusions are much more widely applicable. The results are summarised and evaluated in terms of the total number of deaths and infections as well as life years lost. The optimal strategy is found to be one based on fully vaccinating the elderly/at risk as quickly as possible, while extending the time-interval between the two vaccine doses to 12 weeks for all individuals below 75 years old, in agreement with epidemic theory which suggests targeting a combination of susceptibility and infectivity. This policy, which is similar to the approaches adopted in the UK and in Canada, is found to be effective in reducing deaths and life years lost in the period while vaccination is still being carried out.

Background and aims The burden of hepatocellular carcinoma (HCC) is substantial. To address gaps in HCC care, the American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) aimed to develop a standard set of process-based measures and patient-reported outcomes along the HCC care continuum. Approach and results We identified candidate process and outcomes measures for HCC care based on structured literature review. A 13-member panel with content expertise across the HCC care continuum evaluated candidate measures on importance and performance gap using a modified Delphi approach (two rounds of rating) to define the final set of measures. Candidate patient-reported outcomes (PRO) based on a structured scoping review were ranked by 74 patients with HCC across 7 diverse institutions. Out of 135 measures, 29 measures made the final set. These covered surveillance (6 measures), diagnosis (6 measures), staging (2 measures), treatment (10 measures), and outcomes (5 measures). Examples included the use of ultrasound (± alpha-fetoprotein [AFP]) every 6 months, need for surveillance in high-risk populations, diagnostic testing for patients with a new AFP elevation, multidisciplinary liver tumor board (MLTB) review of Liver Imaging-Reporting and Data System 4 lesions, standard evaluation at diagnosis, treatment recommendations based on Barcelona Clinic Liver Cancer staging, MLTB discussion of treatment options, appropriate referral for evaluation of liver transplantation candidacy, and role of palliative therapy. PROs include those related to pain, anxiety, fear of treatment, and uncertainty about the best individual treatment and the future. Conclusions The AASLD PMC has developed a set of explicit quality measures in HCC care to help bridge the gap between guideline recommendations and measurable processes and outcomes. Measurement and subsequent implementation of these metrics could be a central step in the improvement of patient care and outcomes in this high-risk population.

BACKGROUND: Opportunity to redefine the care journeys for those living with primary biliary cholangitis (PBC) includes facilitating access to enhanced (PBC-dedicated) programmes by nonspecialist risk 'flagging' of patients. OBJECTIVE: To develop a nonexpert PBC stratification tool to help care pathway choices (standard vs. enhanced) choices in PBC. METHODS: We included ursodeoxycholic acid-treated patients with PBC from the Global PBC Study Group. The performance of baseline and 1-year clinical markers with transplant-free survival was assessed to develop the 'ABA' tool using Age (A), Bilirubin (B), and Alkaline phosphatase (A). Added value of fibrosis estimation was assessed. RESULTS: 'ABA' classification mapped three risk groups (n = 2226): low [Age > 50 years, bilirubin ≤ 1 × ULN, alkaline phosphatase (ALP) ≤ 3 × ULN], high (Age ≤ 50 years, bilirubin > 1 × ULN, ALP > 3 × ULN), and intermediate (other). Transplant-free survival at 10 years in the low-, intermediate-, and high-risk groups were 89, 77, and 59% at baseline and 86, 76, and 40% at 1 year, respectively. We propose that high-risk patients at baseline be directly triaged to enhanced (PBC-dedicated) care and the remaining be reassessed at 1 year. Modelling showed after 1 year 46% patients were proposed to enhanced care and 54% to standard care. The 'ABA' mapped pathways facilitated identification of patients at risk based on a young age, as compared to traditional liver biochemical stratification. In patients proposed to standard care, estimated fibrosis stage had ongoing prognostic value. CONCLUSION: Nonspecialist use of the 'ABA' risk tool could prioritize care journey choices for patients with PBC.

BACKGROUND Non-invasive tests (NITs), such as Fibrosis-4 index (FIB-4) and the aspartate aminotransferase-to-platelet ratio index (APRI), developed using classical statistical methods, are increasingly used for determining liver fibrosis stages and recommended in treatment guidelines replacing the liver biopsy. Application of conventional cutoffs of FIB-4 and APRI resulted in high rates of misclassification of fibrosis stages. AIM There is an unmet need for more accurate NITs that can overcome the limitations of FIB-4 and APRI. PATIENTS AND METHODS Machine learning with the random forest algorithm was used to develop a non-invasive index using retrospective data of 7238 patients with biopsy-proven chronic hepatitis C from two centers in Egypt; derivation dataset (n = 1821) and validation set in the second center (n = 5417). Receiver operator curve analysis was used to define cutoffs for different stages of fibrosis. Performance of the new score was externally validated in cohorts from two other sites in Egypt (n = 560) and seven different countries (n = 1317). Fibrosis stages were determined using the METAVIR score. Results were also compared with three established tools (FIB-4, APRI, and the aspartate aminotransferase-to-alanine aminotransferase ratio [AAR]). RESULTS Age in addition to readily available laboratory parameters such as aspartate, and alanine aminotransferases, alkaline phosphatase, albumin (g/dl), and platelet count (/cm3 ) correlated with the biopsy-derived stage of liver fibrosis in the derivation cohort and were used to construct the model for predicting the fibrosis stage by applying the random forest algorithm, resulting in an FIB-6 index, which can be calculated easily at http://fib6.elriah.info. Application of the cutoff values derived from the derivation group on the validation groups yielded very good performance in ruling out cirrhosis (negative predictive value [NPV] = 97.7%), compensated advance liver disease (NPV = 90.2%), and significant fibrosis (NPV = 65.7%). In the external validation groups from different countries, FIB-6 demonstrated higher sensitivity and NPV than FIB-4, APRI, and AAR. CONCLUSION FIB-6 score is a non-invasive, simple, and accurate test for ruling out liver cirrhosis and compensated advance liver disease in patients with chronic hepatitis C and performs better than APRI, FIB-4, and AAR.

Although cervical endometriosis represents a rare condition, there is evidence that implicates a complex interaction with other gynecological pathologies. This study aims to highlight this entity and further to explore the impact of oncological pathology of female genital tract on patients with cervical endometriosis. We retrospectively investigated the medical and pathological reports of 27 cases with cervical endometriosis, which were diagnosed by tissue biopsy. The results of the study show a relationship between CIN (cervical intraepithelial neoplasia) cases 19/27 (70percent) and cervical endometriosis. CIN I was more frequently found compared to patients with CIN II and CIN III. Furthermore, a high prevalence of HPV (human papilloma virus) was confirmed. Out of 27 patients, 2 cases with cervical (7.4percent), 2 with endometrial (7.4percent) and 3 with ovarian cancer (11.1percent) were detected. We confirmed the coexistence of more than one malignant gynecological pathology with cervical endometriosis in four cases (14.8percent). To conclude, cervical endometriosis is a rare disease co-existing considerably with premalignant and malignant gynecological conditions according to our data. Although the pathophysiology and genetics of cervical dysplasia is well delineated, further research is needed to establish the association between cervical endometriosis and gynecological premalignant and malignant pathology.

© 2021 Wiley. This is the peer reviewed version of the following article: Usman, O., Alola, A. A. & Ike, G. N. (2021). Modelling the effect of energy consumption on different environmental indicators in the United States: The role of financial development and renewable energy innovations. Natural Resources Forum 45(4), 441-463, which has been published in final form at https://doi.org/10.1111/1477-8947.12242. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.

Background The impact of prior fragility fractures and osteoporosis treatment before total hip arthroplasty (THA) on postoperative complications is unclear. The purpose of this study was to characterize the effect of prior fragility fractures and preoperative osteoporosis treatment on short-term complications and secondary fragility fractures after THA. Methods A propensity score–matched retrospective cohort study was conducted using a commercially available database to (1) characterize the impact of prior fragility fractures on rates of short-term complications after THA and (2) evaluate if osteoporosis treatment before arthroplasty reduces risk of postoperative complications. Rates of periprosthetic fracture, revision THA, and fragility fractures were compared via multivariable logistic regression. Results After 1:1 propensity score matching, 2188 patients were assigned to each cohort. Patients with a fragility fracture in the 3 years preceding THA were more likely to sustain a periprosthetic fracture (1 year: 1.7% vs 1.0%, odds ratio [OR] 1.89; 2 years: 2.1% vs 1.1%, OR 1.82), fragility fracture (1 year: 4.7% vs 1.1%, OR 3.59; 2 years: 6.7% vs 1.7%, OR 3.21), and revision THA (1 year: 2.7% vs 1.7%, OR 1.65; 2 years: 3.1% vs 1.9%, OR 1.58). Among patients with a prior fragility fracture, only 13.8% received osteoporosis pharmacotherapy before THA. Rates of all complications were statistically comparable postoperatively for patients with and without pre-THA osteoporosis treatment. Conclusions Fragility fractures within 3 years before THA are associated with significantly increased risk of periprosthetic fracture, all-cause revision, and secondary fragility fractures postoperatively. Preoperative osteoporosis treatment may not decrease risk of postoperative complications.

Alcohol use can cause hepatic necroinflammation and worsening portal hypertension in patients with cirrhosis. We aimed to evaluate the associations between degree of alcohol use and clinical liver-related outcomes according to etiology of cirrhosis. In this retrospective cohort analysis, 44,349 U.S. veterans with cirrhosis from alcohol-associated liver disease (ALD), chronic hepatitis C virus (HCV) infection, or nonalcoholic fatty liver disease were identified who completed the Alcohol Use Disorders Identification Test Consumption questionnaire in 2012. Based on this score, level of alcohol use was categorized as none, low level, or unhealthy. Multivariable Cox proportional hazards regression was used to assess for associations between alcohol use and mortality, cirrhosis decompensation (new ascites, encephalopathy, or variceal bleeding), and hepatocellular carcinoma (HCC). At baseline, 36.4% of patients endorsed alcohol use and 17.1% had unhealthy alcohol use. During a mean 4.9 years of follow-up, 25,806 (57.9%) patients died, 9,409 (21.4%) developed a new decompensation, and 4,733 (11.1%) developed HCC. In patients with ALD-cirrhosis and HCV-cirrhosis, unhealthy alcohol use, compared with no alcohol use, was associated with higher risks of mortality (adjusted hazard ratio [aHR] = 1.13, 95% confidence interval [CI] = 1.07-1.19 and aHR = 1.14, 95% CI = 1.08-1.20, respectively) and decompensation (aHR = 1.18, 95% CI = 1.07-1.30 and aHR = 1.08, 95% CI = 1.00-1.16, respectively). Alcohol use was not associated with HCC, regardless of cirrhosis etiology. Conclusion: Unhealthy alcohol use was common in patients with cirrhosis and was associated with higher risks of mortality and cirrhosis decompensation in patients with HCV-cirrhosis and ALD-cirrhosis. Therefore, health care providers should make every effort to help patients achieve abstinence. The lack of association between alcohol use and HCC merits further investigation.

OBJECTIVES: To evaluate the usefulness of radiological re-staging after two and four cycles of neoadjuvant chemotherapy (NAC), the impact of re-staging on further patient management, and the correlation between clinical and final pathological tumour stage at radical cystectomy (RC). PATIENTS AND METHODS: We conducted a longitudinal, single-centre, cohort study of prospectively collected consecutive patients who underwent NAC and RC for urothelial muscle-invasive bladder cancer between July 2001 and December 2017. Patients underwent repeated computed tomography scans for re-staging after two cycles of NAC and after completion of NAC before RC. RESULTS: Of 180 patients, 110 had ≥four cycles of NAC and had complete imaging available. In the entire cohort, further patient management was only changed in 2/180 patients (1.1%) after two cycles of NAC based on radiological findings. Patients who were stable after two cycles but then downstaged after at least four cycles of NAC had a similarly lowered risk of death (hazard ratio [HR] 0.53). Only one patient downstaged after two cycles was subsequently upstaged after four cycles. Clinical downstaging was observed in 51 patients (46%), 55 patients (50%) had no change in clinical stage and four patients (3.6%) were clinically upstaged. Patients clinically downstaged after four cycles of NAC had a lower risk of death (HR 0.49, 95% confidence interval 0.25-0.94; P = 0.033) compared to those with no change or upstaged after completion of NAC. CONCLUSIONS: Re-staging of muscle-invasive bladder cancer after two cycles of NAC offers little additional information, rarely changes patient management, and may therefore be omitted, whereas re-staging after completion of NAC by CT is a strong predictor of overall survival.

Online groups have pervasively become platforms for association and interaction. Hence, it is important to study how interactions on these virtual groups affect the selves of individual group members, and whether communication activities in these groups lead to formation of virtual identities of active members which is distinguishable from their non-mediated identity. To analyze the development of virtual identity, four focus group discussions of ten youthful participants each, who were members of various online groups, were conducted and eight social media experts were interviewed. Concepts of Communication Theory of Identity (CTI) and Uses and Gratification Theory were employed to analyze collected data in assessing how online group interactions that involve fashioning identity, impression management, anonymity and pro-social behavior lead to formation of online group members virtual identity. We first interrogate how these online groups shape behavior online by interrogating the individual group member’s conversations and actions online and paralleling them with their conversations and actions offline. Second, using the three-dimensional identity formation model (Crocetti, Rubini, & Meeus, 2008), we crystalize how these online interactions and behavior cause individual group member’s to feel, think and understand themselves in ways that promote a unique online-self, which we refer to as the virtual identity.

Background According to current guidelines, bone scintigraphy is not routinely indicated in patients with invasive bladder cancer prior to radical cystectomy unless specific symptoms are present. These guidelines, however, are based on sparse data of low quality. Objective To assess the clinical impact of routine staging bone scintigraphy on further patient management. Design, setting, and participants A retrospective, single-center study of 1287 consecutive patients, who were scheduled to undergo radical cystectomy due to invasive bladder cancer between January 2000 and December 2017, was conducted. All patients were prospectively followed up according to our institutional protocol. Intervention Bone scintigraphy as staging imaging prior to radical cystectomy. Outcome measurements and statistical analysis The primary endpoint was the change in intended patient management. Secondary endpoints were the need for additional imaging, the diagnostic performance of baseline bone scintigraphy, and the association between clinical and radiological findings on bone metastases and survival. Logistic and Cox regression models were used for univariate and multivariate analyses. Results and limitations Of 1287 patients scheduled for radical cystectomy, 1148 (89%) underwent bone scintigraphy as staging imaging. Overall, baseline bone scintigraphy led to a change in the intended management in 19/1148 (1.7%) patients. Additional imaging was performed in 44/1148 (4%) patients. Although positive bone scintigraphy findings were associated with the occurrence/development of bone metastases, the diagnostic performance of baseline bone scintigraphy was generally poor (positive predictive value, negative predictive value, sensitivity, and specificity were 56%, 89%, 27%, and 96%, respectively). Higher clinical tumor stage and the nonperformance of cystectomy had negative impacts on cancer-specific survival and overall survival, while positive bone scintigraphy was associated with worse cancer-specific survival. This study was limited by its retrospective nature and the lack of follow-up bone scintigraphy in all patients. Conclusions These results demonstrate the limited value of bone scintigraphy in the staging of invasive bladder cancer and do not support its routine use. Patient summary In this study, we looked at the clinical impact of bone scintigraphy on the diagnostics of patients with invasive bladder cancer. We found that routine staging bone scintigraphy had limited impact on further patient management. We conclude that bone scintigraphy should not be part of routine staging in patients with invasive bladder cancer.

Background Salvage radiotherapy (SRT) is utilized for biochemical progression of prostate cancer after radical prostatectomy (RP). Objective To report the outcomes of the SAKK 09/10 trial comparing conventional and dose-intensified SRT. Design, setting, and participants SAKK 09/10 was a randomized, multicenter, phase 3 trial that recruited men with biochemical progression after RP. Intervention Patients were randomly assigned to conventional-dose (64 Gy) or dose-intensified SRT (70 Gy) to the prostate bed without hormonal therapy. Outcome measurements and statistical analysis The primary endpoint was freedom from biochemical progression (FFBP). Secondary endpoints included clinical progression-free survival (PFS), time to hormonal treatment, overall survival (OS), acute and late toxicity (Common Terminology Criteria for Adverse Events v4.0), and quality of life (QoL). Results and limitations Between February 2011 and April 2014, 350 patients were randomly assigned to 64 Gy (n = 175) or 70 Gy (n = 175). Median prostate-specific antigen at randomization was 0.3 ng/ml. After median follow-up of 6.2 yr, the median FFBP was 8.2 yr in the 64 Gy arm and 7.6 in the 70 Gy arm (log-rank p = 0.4), with a hazard ratio of 1.14 (95% confidence interval 0.82–1.60). The 6-year FFBP rates were 62% and 61%, respectively. No significant differences in clinical PFS, time to hormonal treatment, or OS were observed. Late grade 2 and 3 genitourinary toxicity was observed in 35 (21%) and 13 (7.9%) patients in the 64 Gy arm, and 46 (26%) and seven (4%) in the 70 Gy arm, respectively (p = 0.8). Late grade 2 and 3 gastrointestinal toxicity was observed in 12 (7.3%) and seven patients (4.2%) in the 64 Gy arm, and 35 (20%) and four (2.3%) in the 70 Gy arm, respectively (p = 0.009). There were no significant differences in QoL. Conclusions Conventional-dose SRT to the prostate bed is sufficient in patients with early biochemical progression of prostate cancer after RP. Patient summary The optimal radiation therapy dose for patients who have increased tumor markers after surgery for prostate cancer is unclear. We found that administering a higher dose only increased the gastrointestinal side effects without providing any benefits to the patient. This clinical trial is registered on ClinicalTrials.gov as NCT01272050.

Optimization methods in conjunction with computational fluid dynamics are a key tool in advancing current rotor design. High-fidelity optimization of unsteady rotor flows in forward flight, however...

Postoperative new-onset depression (NOD) has gained recent attention as a previously unrecognized complication which may put patients at risk for poor outcomes after elective total hip arthroplasty. We aimed to investigate risk factors for the development of NOD after total knee arthroplasty (TKA) and assess its association with postoperative complications.This is a retrospective, population-level investigation of elective TKA patients. Patients with a preoperative diagnosis of depression were excluded from this study. Two groups were compared: patients who were diagnosed with depression within one year after TKA (NOD) and those who did not (control). The association of both preoperative patient factors and postoperative surgical and medical complications with NOD was then determined using multivariate and univariate analyses.Of 196,728 unique TKA patients in our cohort, 5351 (2.72%) were diagnosed with NOD within one year of TKA. Age54 year old, female gender, preoperative anxiety disorder, drug, alcohol, and/or tobacco use, multiple comorbidities, and opioid use before TKA were all associated with a diagnosis of NOD postoperatively (all P.001). Postoperative NOD was associated with periprosthetic fracture (OR 2.11; 95% CI 1.29-3.52; P = .033), aseptic failure (OR 1.61; 95% CI 1.24-2.07; P = .020), prosthetic joint infection (OR 1.55, 95% CI 1.30-1.85; P.001), stroke (OR 1.24; 95% CI 1.09-1.42; P = .006), and venous thromboembolism (OR 1.24; 95% CI 1.12-1.37; P.001).Post-TKA NOD is common and is associated with poor outcomes. This may aid surgeons in developing both anticipatory measures and institute preventative measures for patients at risk for developing NOD.

Treating neovascular age-related macular degeneration with intravitreal aflibercept treat-and-extend (TE) can reduce treatment burden. ARIES assessed whether intravitreal aflibercept early-start TE was noninferior to late-start TE.A randomized, open-label, Phase 3b/4 study that included treatment-naïve patients aged ≥50 years with the best-corrected visual acuity 73-25 Early Treatment Diabetic Retinopathy Study letters and active choroidal neovascularization secondary to AMD. Patients received 2 mg intravitreal aflibercept at Week (W) 0, W4, W8, and W16. At W16, patients were randomized 1:1 to early-start (2W interval adjustments) or late-start TE (8W intervals until W48 then 2W interval adjustments). Primary endpoint: the best-corrected visual acuity change from randomization to W104.Two-hundred seventy-one patients were randomized. The mean (SD) best-corrected visual acuity at baseline was 60.2 (12.1; early-TE) and 61.3 (10.8; late-TE) letters. The mean (SD) best-corrected visual acuity change (W16-104) was -2.1 (11.4) versus -0.4 (8.4) letters (early-TE vs. late-TE; least-squares mean difference: -2.0; 95% confidence interval: -4.75 to 0.71; P = 0.0162 for noninferior); +4.3 (13.4) versus +7.9 (11.9) letters (W0-104). The mean (SD) number of injections was 12.0 (2.3) versus 13.0 (1.8). From baseline to W104, 93.4% and 96.2% maintained best-corrected visual acuity; the mean (SD) central retinal thickness change was -161.6 (135.6) µm and -158.6 (125.1) µm. The last injection interval (W104) was ≥12W for 47.2% and 51.9% of patients.Outcomes were similar between patients with neovascular age-related macular degeneration treated with an intravitreal aflibercept early-TE or late-TE regimen after initial dosing, with one injection difference over 2 years.ClinicalTrials.gov Identifier: NCT02581891 https://clinicaltrials.gov/ct2/show/NCT02581891. Supplemental Digital Contents (files 1 http://links.lww.com/IAE/B419).

The informed consent to blood transfusion is a patient centered care where the health care provider is ethically obliged and legally compelled to disclose the details, alternatives and consequences of a procedure such as blood donation or transfusion and obtain from the patient a prior consent before it is carried out. However, this newly evolving practice is largely constrained in many developing countries of Africa and this study sought to identify constraints and advance remedies. Literature search on PubMed, PubMed Central, Google Scholar, and African Journal on Line (AJOL) as well as print material literatures where applicable was used to retrieve 66 publications whose contents met the criteria for inclusion into the study. Constraints range from nondisclosure or defective disclosure, knowledge gaps of health care providers and non-comprehension of consent-based information by patients, illiteracy, religious and cultural practices, poor funding and administrative bottlenecks like non provision of consent forms or consent-based information materials as well as weak structures of effective oversight for compliance of health institutions by governmental regulating agencies. Physic like deployment of contentious professional development (CPD) activities for different professionals, focused training on consent-related guidelines, public awareness and education on prevailing social, religious and cultural impediments, research and localization of institution specific challenges. Additionally, proactive economic policies like the deployment of insurance indemnity covers for healthcare workers with negligent liabilities in order to dissuade health care providers from practicing defensive medicine which is inimical to quality health care delivery. There is a need for more researches on constraints prevalent in each developing country in Africa for a more appreciable advancement of the practice.

Introduction The tobacco industry has for decades been associated with environmental damage, health-related diseases, human rights violations and corruption issues. The World Health Organisation formulated the Framework Convention on Tobacco Control with the aim of controlling tobacco production and consumption. Most of the countries on the continent of Africa were also the target of the framework given the high importation and use of tobacco products. The main aim of this study was to find out the current status of tobacco control policies and their effectiveness in Africa. Material and methods This study was a systematic literature review that was conducted between the months of August and November 2020 by extracting data from the databases of PubMed, Elsevier Scopus and Web of Science. Only English articles were culled from the retrieved papers. Out of the 910 papers retrieved, only 17 papers from African countries were selected on the quality synthesis after meeting the inclusion criteria. Results The results of the study showed that three governance resources were identified of regulatory (64.70%, N=11) which had smoke-free environment, advertisement bans, and cessation programs, economics (29.41%, N=5) which were taxation measures and informative (5.886%, N=1) which were mass media campaigns. Furthermore, Western African countries especially South Africa reported many pronouncements on smoke-free environment and taxation measures. Mass media campaigns proved to be more effective policies as compared to others. Conclusion This study recommends that the future research should be done on the effectiveness of mixed policy instruments as compared to single application. Furthermore, the researcher recommends the use of more informative policies in dealing with inelastic behaviours like those related to tobacco due to the addictive nature.

Background Unilateral coronal craniosynostosis (UCS) is the third most prevalent form of craniosynostosis. Traditional treatment of UCS has been achieved with fronto-orbital advancement and cranial vault remodeling (FOAR), but utilization of cranial distraction osteogenesis (DO) techniques has increased. This study aims to compare perioperative complications and reoperation trends in FOAR versus DO techniques at a single institution. Methods An Institutional Review Board-approved retrospective review was performed from January 1999 to November 2018 at a single institution. Patients were those that have undergone FOAR or DO with an anterior rotational flap technique as previously described. Indications for secondary procedures included: contour deformities, relapse, surgical site infection, and persistent cranial defects. Results Eighty-one patients with UCS were identified, 64 patients underwent FOAR and 17 patients underwent DO. When perioperative characteristics were compared, patients who underwent DO were younger in age, however, there was no significant difference in transfusion requirement or length of stay between patient cohorts. Surgery time was increased in DO patients. When perioperative complications were compared, more intraoperative dural tears were observed in the FOAR cohort. When unplanned reoperation rates were compared, patients who had undergone FOAR had a statistically significant higher reoperation rates at 5 years of follow up. When including routine distractor removal as a reoperation, reoperative rate was increased in the DO cohort. No difference in reoperation rates was noted at 5 years following index operation. Conclusions The safety profile of DO is similar to that of traditional FOAR techniques for treatment of UCS. Longer-term follow-up studies are needed to elucidate whether outcomes are durable, but the unplanned reoperation rate in DO is less than that of FOAR at 5 years and presents several advantages that warrants its use in patients with UCS.

BACKGROUND AND AIMS: Whether patients with cirrhosis have increased risk of SARS-CoV-2 infection and the extent to which infection and cirrhosis increase the risk of adverse patient outcomes remain unclear. APPROACH AND RESULTS: We identified 88,747 patients tested for SARS-CoV-2 between 3/1/20-5/14/20 in the Veterans Affairs (VA) national healthcare system, including 75,315 with no cirrhosis-SARS-CoV-2 negative (C0-S0), 9826 with no cirrhosis-SARS-CoV-2 positive (C0-S1); 3301 with cirrhosis-SARS-CoV-2 negative (C1-S0); and 305 with cirrhosis-SARS-CoV-2 positive (C1-S1). Patients were followed through 6/22/20. Hospitalization, mechanical ventilation and death were modeled in time-to-event analyses using Cox proportional hazards regression. Patients with cirrhosis were less likely to test positive than patients without cirrhosis (8.5% vs. 11.5%, adjusted odds ratio 0.83, 95% CI 0.69-0.99). Thirty-day mortality and ventilation rates increased progressively from C0-S0 (2.3% and 1.6%), to C1-S0 (5.2% and 3.6%), to C0-S1 (10.6% and 6.5%), to C1-S1(17.1% and 13.0%). Among patients with cirrhosis, those who tested positive for SARS-CoV-2 were 4.1 times more likely to undergo mechanical ventilation (adjusted hazard ratio [aHR] 4.12, 95% CI 2.79-6.10) and 3.5 times more likely to die (aHR 3.54, 95% CI 2.55-4.90) than those who tested negative. Among patients with SARS-CoV-2 infection, those with cirrhosis were more likely to be hospitalized (aHR 1.37, 95% CI 1.12-1.66), undergo ventilation (aHR 1.61, 95% CI 1.05-2.46) or die (aHR 1.65, 95% CI 1.18-2.30) than patients without cirrhosis. Among patients with cirrhosis and SARS-CoV-2 infection, the most important predictors of mortality were advanced age, cirrhosis decompensation and high MELD score. CONCLUSIONS: SARS-CoV-2 infection was associated with a 3.5-fold increase in mortality in patients with cirrhosis. Cirrhosis was associated with a 1.7-fold increase in mortality in patients with SARS-CoV-2 infection.

This short overview and updates expresses our brain-and-heart homage to George Emil Palade, “the most influential cell biologist ever”. In his 1971 paper Palade wrote for Albert Claude, the founder of biological electron microscopic method: “Seldom has a field owed so much to a single man”. Herein, we articulate the same words for George Palade, the Teacher of many generations in cell biology research and education. Accordingly, we focus on two paradigm shifts in the cell biology, namely (i) the transition from light to transmission electron microscopy in studying cell protein secretion made by George Palade, and (ii) the transition from contractile to secretory phenotype of vascular smooth muscle cells made by Maria Daria Haust followed and developed by our research group. Altogether, we argue that one of the present challenges in vascular biology is to cultivate secreto-centric thinking and thus further focusing on how we could make the vascular muscle’s secretory pathways work for the benefit of human’s cardiovascular health.

Aims Infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may lead to the development of severe respiratory failure. In hospitalized-patients, prompt interruption of the virus-driven inflammatory process by using combination treatments seems theoretically of outmost importance. Our aim was to investigate the hypothesis of multifaceted management of these patients. Methods A treatment algorithm based on ferritin was applied in 311 patients (67.2% males; median age 63-years; moderate disease, n=101; severe, n=210). Patients with ferritin

Climate-Smart Agriculture (CSA) strategies have been introduced in Nyando basin (comprising Kisumu and Kericho Counties) in Kenya, and farmers have comparatively taken up the practices. This has resulted in diversification of farming crops/livestock and incomes to bridge seasonal shortfalls under erratic harsh weather conditions due to climate change. The main objective of the study was to determine how smallholder farmers bridge seasonal incomes variations. This study demonstrates income diversification probabilities on four outcomes of climate-smart agriculture; agricultural practices, sales of goods and services, gifts/remittances, and savings (deposits/retrievals). Additionally, gender aspects were aggregated on the same in climate-smart villages (CSVs) and non-CSVs communities. The study used household-level financial diaries panel data, collected in 2019/2020 from 124 samples of farmers selected by a multistage sampling technique. Descriptive statistics and multinomial logistic model were used to determine risk/probability of income sources and mobility (livelihood diversification) from a set of strategies. Results indicated that agriculture diversification activities (sale of goods and services and agricultural practices) as income sources were seasonal-sensitive and during droughts households diversified to gifts/ remittances and savings. Education, age and household size were noteworthy aspects that influenced the choice of livelihood diversification strategies there were gender differences in sources of contributions to household transactions whereby women mainly relied on Gifts/Loans/Credit/Advances while sales of goods and services were exhibited in men. CSVs predictors on all the income sources over the year were negative and not significant indicating greater probability of CSVs shifting incomes sources to sales of goods than the non- CSVs. Key words: Climate smart agriculture (CSA), financial diaries, gender, diversification, season, income bridging, rural Kenya.

BACKGROUND: In patients with non-invasive urothelial carcinoma of the prostatic urethra (PUC), treatment with Bacillus Calmette-Guérin (BCG) could be beneficial. OBJECTIVE: To assess the response rates to BCG in the different tumor stages, to describe the clinical impact of transurethral resection of the prostate (TURP) before BCG treatment, and to review the side effects of BCG treatment for PUC. METHODS: A systematic search was conducted using the PubMed database to identify original studies between 1977 and 2019 reporting on PUC and BCG. RESULTS: Of a total of 865 studies, ten were considered for evidence synthesis. An indication for BCG treatment was found in non-stromal invasive stages (Tis pu, Tis pd) and in stromal infiltrating cases (T1) of primary and secondary PUC when transitional cell carcinoma was the histology of origin. Studies including patients treated with TURP before BCG showed a better local response in the prostatic urethra with a higher disease free survival (DFS) (80–100% vs. 63–89%) and progression free survival (PFS) (90–100% vs. 75–94%) than patients in studies in which no TURP was performed. However, this difference in recurrence and progression in the prostate neither affected the total PFS (57–75% vs. 58–93%), nor the disease specific survival (70–100% vs. 66–100%). CONCLUSIONS: The use of resection loop biopsies of the prostatic urethra in appropriate cases during the primary work-up for suspected PUC, as well as the use of the current TNM classification for PUC, need to be improved. BCG therapy for non-stromal invasive stages of PUC show a good local response. Local response is further improved by a TURP before BCG therapy, although the overall prognosis does not seem to be affected. Further evidence for BCG treatment in the rare cases of stromal invasive PUC is needed. Specific side effects of BCG treatment for PUC are not reported.

Elastic optical networks employing multi-core fibers (MCF-EON) have the potential to expand significantly the transmission capacity of optical transport. However, wide deployment of such networks depends on addressing effectively two critical challenges: inter-core crosstalk, which may cause serious signal performance degradation in an MCF link, and survivability against network failures that may cause enormous data loss. In this article, we consider the design of MCF-EONs with shared-backup path protection (SBPP), one of the most efficient techniques for protecting network traffic. Specifically, we tackle the crosstalk-aware routing, core, and spectrum assignment (CA-RCSA) problem with the objective of jointly minimizing the network spectrum resources used and the total inter-core crosstalk. We formulate the problem as an integer linear programming (ILP) model subject to strict inter-core crosstalk limits for each provisioned lightpath, and we also propose an auxiliary graph (AG) based heuristic algorithm for lightpath provisioning. Simulation studies show that our algorithm is effective in terms of the objectives, and it is efficient to perform close to the ILP model in small networks, for which solving the ILP is feasible.

BACKGROUND & AIMS Autoimmune hepatitis (AIH) affects both sexes and all age groups. However, very few studies have focused specifically on the characteristics and outcome of AIH in patients aged 70 y or older. METHODS 25/234 patients with well-established AIH and disease onset at ≥70-y (median: 73-y) were analysed and compared to the rest patients (median: 47 y). Treatment response was assessed in all patients from both groups who were eligible for treatment (n = 202). RESULTS Disease presentation was mainly insidious in both groups (19/25, 76% vs. 134/209, 64.1%; P = .313). At diagnosis, older patients had lower alaninoaminotrasferase (101[433] vs. 199[441] IU/L, P

Background We aimed to describe trends in adverse outcomes among patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between February and September 2020 within a national healthcare system. Methods We identified enrollees in the national United States Veterans Affairs healthcare system who tested positive for SARS-CoV-2 between 28 February 2020 and 30 September 2020 (n = 55 952), with follow-up extending to 19 November 2020. We determined trends over time in incidence of the following outcomes that occurred within 30 days of testing positive: hospitalization, intensive care unit (ICU) admission, mechanical ventilation, and death. Results Between February and July 2020, there were marked downward trends in the 30-day incidence of hospitalization (44.2% to 15.8%), ICU admission (20.3% to 5.3%), mechanical ventilation (12.7% to 2.2%), and death (12.5% to 4.4%), which subsequently plateaued between July and September 2020. These trends persisted after adjustment for sociodemographic characteristics, comorbid conditions, documented symptoms, and laboratory tests, including among subgroups of patients hospitalized, admitted to the ICU, or treated with mechanical ventilation. From February to September, there were decreases in the use of hydroxychloroquine (56.5% to 0%), azithromycin (48.3% to 16.6%), vasopressors (20.6% to 8.7%), and dialysis (11.6% to 3.8%) and increases in the use of dexamethasone (3.4% to 53.1%), other corticosteroids (4.9% to 29.0%), and remdesivir (1.7% to 45.4%) among hospitalized patients. Conclusions The risk of adverse outcomes in SARS-CoV-2–positive patients decreased markedly between February and July, with subsequent stabilization from July to September. These trends were not explained by changes in measured baseline patient characteristics and may reflect changing treatment practices or viral pathogenicity.

Microgrids have gained significant interest over the last 20 years and are perceived as key components of future power systems. Microgrids are defined as distribution networks with distributed energy resources (DERs) (e.g., distributed generators, storage devices, and controllable loads) operating in a controlled and coordinated way. Moreover, microgrids should have clear electrical boundaries and the ability to operate connected to the main power network or islanded. The coordinated control of microgrid resources increases energy efficiency, minimizes the overall energy consumption, and reduces the environmental impacts of energy production. At the same time, the ability of microgrids to seamlessly transition to islanded operation when upstream network faults occur increases the reliability and resilience of the customer supply. Furthermore, microgrids have been adopted as prominent and viable solutions for rural electrification in developing countries, isolated areas, or areas with weak power transmission infrastructures.

Optical single-event transients (OSETs) were measured for the first time in integrated silicon-photonic waveguides. A custom test fixture and novel experimental setup were used at the U.S. Naval Research Laboratory to induce a dense cloud of electron–hole pairs (EHPs) in a waveguide by the two-photon absorption process. Experimental data showed that the fractional (or percent) extinction of the optical power in the waveguide due to an OSET is dependent on the number of injected EHPs. This fractional extinction was also shown to be constant regardless of the optical power level in the waveguide. These OSETs are a direct result of a reduction in the optical transmission ratio due to transient free-carrier absorption. The peak of the largest measured OSET degraded the transmission ratio by 15%, which, according to simulations, corresponds to roughly $9\times 10^{19}$ cm−3 peak EHP generation. Simulation results suggest that the EHP density levels generated by heavy ions in space could potentially cause up to 100% fractional extinction of light in the waveguide, that is, total loss of the optical signal. A simulation technique to predict the OSET effects in any arbitrary photonic circuit is shown. Here, an electrooptic modulator was used as an example. The results of this study pose concerns for use of integrated silicon photonics for radiation-intensive applications.

Stress is a constant threat for homeostasis and is represented by different extrinsic and intrinsic stimuli (stressors, Hans Selye’s "noxious agents"), such as aggressive behavior, fear, diseases, physical activity, drugs, surgical injury, and environmental and physiological changes. Our organisms respond to stress by activating the adaptive stress system to activate compensatory responses for restoring homeostasis. Nerve Growth Factor (NGF) was discovered as a signaling molecule involved in survival, protection, differentiation, and proliferation of sympathetic and peripheral sensory neurons. NGF mediates stress with an important role in translating environmental stimuli into physiological and pathological feedbacks since NGF levels undergo important variations after exposure to stressful events. Psychological stress, lifestyle stress, and oxidative stress are well known to increase the risk of mental disorders such as schizophrenia, major depressive disorders, bipolar disorder, alcohol use disorders and metabolic disorders such as metabolic syndrome. This review reports recent works describing the activity of NGF in mental and metabolic disorders related to stress.

BACKGROUND Unicoronal craniosynostosis is associated with orbital restriction and asymmetry. Surgical treatment aims to both correct the aesthetic deformity and prevent the development of ocular dysfunction. We used orbital quadrant and hemispheric volumetric analysis to assess orbital restriction and compare the effectiveness of distraction osteogenesis with anterior rotational cranial flap (DO) and bilateral fronto-orbital advancement and cranial vault remodeling (FOAR) with respect to the correction of orbital restriction in patients with unicoronal craniosynostosis. METHODS A retrospective review of all patients with a diagnosis of unicoronal craniosynostosis and treated with either DO or FOAR from 2000 to 2019 was performed. Preoperative and postoperative total orbital volumes, as well as quadrant and hemispheric volume ratios, were calculated from 3-dimensional head computed tomography scans. Selected preoperative and postoperative orbital measurements, including the maxillary length of the orbit (MLO; zygomaticofrontal suture to the top of zygomatic arch) and the sphenoid length of the orbit (SLO; the top of sphenoid suture to the top of zygomatic arch), were also obtained. RESULTS Data were available for 28 patients with unicoronal craniosynostosis. Mean preoperative total orbital volume was significantly smaller on the synostotic side compared with the nonsynostotic side (10.94 vs 12.20 cm3, P = 0.04). Preoperative MLO and SLO were significantly longer on the synostotic side compared with the nonsynostotic side (MLO: 20.26 vs 17.75 mm, P < 0.001; SLO: 26.91 vs 24.93 mm, P = 0.01). Distraction osteogenesis and FOAR produced significantly different changes in orbital quadrant and/or hemispheric volume ratios on the nonsynostotic side but not on the synostotic side. CONCLUSIONS Before correction, patients with unicoronal craniosynostosis have significantly smaller total orbital volumes on the synostotic side compared with the nonsynostotic side and significantly greater MLO and SLO on the synostotic side compared with the nonsynostotic side. There is no significant difference between DO and FOAR with regard to correcting the observed orbital restriction in these patients.

In revision total knee arthroplasty, joint kinematics must be maintained amid bone and ligamentous insufficiency. Current modular designs address defects while allowing for intraoperative prosthesis customization through a variety of stem extensions and constraints. Additional constraint improves knee stability while increasing stress at the implant-host interface and modular junction of the implant. This renders the prosthetic stem-condyle junction more prone to fatigue failure. We report 2 cases of prosthetic stem-condyle junction failure in in a varus-valgus constrained revision total knee arthroplasty.

CONTEXT Pelvic lymph node dissection (PLND) yields the most accurate staging in patients undergoing radical prostatectomy (RP) for prostate cancer (PCa), although it can be associated with morbidity. OBJECTIVE To systematically evaluate the impact of PLND extent on perioperative morbidity in patients undergoing RP. A new PLND-related complication assessment tool is proposed. EVIDENCE ACQUISITION A systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) was conducted. MEDLINE/PubMed, Scopus, Embase and Web of Science databases were searched to yield studies discussing perioperative complications following RP and PLND. The extent of PLND was classified according to the European Association of Urology PCa guidelines. Studies were categorized according to the extent of PLND. Intra- and postoperative complications were classified as "strongly," "likely," or "unlikely" related to PLND. Anatomical site of perioperative complications was recorded. A cumulative meta-analysis of comparative studies was conducted using Review Manager 5.3 (Cochrane Collaboration, Oxford, UK). EVIDENCE SYNTHESIS Our search generated 3645 papers, with 176 studies meeting the inclusion criteria. Details of 77 303 patients were analyzed. Of these studies, 84 (47.7%), combining data on 28 428 patients, described intraoperative complications as an outcome of interest. Overall, 534 (1.8%) patients reported one or more intraoperative complications. Postoperative complications were reported in 151 (85.7%) studies, combining data on 73 629 patients. Overall, 10 401 (14.1%) patients reported one or more postoperative complication. The most reported postoperative complication strongly related to PLND was lymphocele (90.6%). The pooled meta-analysis revealed that RP���+���limited PLND/standard PLND had a significantly decreased risk of experiencing any intraoperative complication (risk ratio [RR]: 0.55; p���=��� 0.01) and postoperative complication strongly related to PLND (RR: 0.46; p���=���

The flow of high-speed air in ducts may result in the occurrence of multiple shock-wave/boundary-layer interactions. Understanding the consequences of such interactions, which may include distortion of the velocity field, enhanced turbulence production, and flow separation, is of great importance in understanding the operating limits and performance of a number of systems, for example, the high-speed intake of an air-breathing missile. In this paper, the results of a computational study of multiple shock-wave/boundary-layer interactions occurring within a high-speed intake are presented. All of the results were obtained using the in-house computational fluid dynamics solver of Glasgow University, HMB3. First simulations of a Mach$$M=1.61$$M=1.61multiple shock-wave/boundary-layer interaction in a rectangular duct were performed. The$$M=1.61$$M=1.61case, for which experimental data is available, was used to establish a robust numerical approach, particularly with respect to initial and boundary conditions. A number of turbulence modelling strategies were also investigated. The results suggest that Reynolds-stress-based turbulence models are better suited than linear eddy-viscosity models. This is attributed to better handling of complex strain, in particular modelling of the corner separation. The corner separations affect the separation at the centre of the domain which in turn alters the structure of the initial shock and the subsequent interaction. Having established a robust numerical approach, the results of a parametric study investigating the effect of Mach number, Reynolds number, and confinement on the baseline solution are then presented. Performance metrics are defined to help characterize the effect of the interactions. The results suggest that reduced flow confinement is beneficial for higher-pressure recovery.

Lipoprotein disorders are a major risk factor for atherosclerotic neuro-cardiovascular disease (ACVD) and are heavily influenced by lifestyle, including alcohol drinking. Moderate drinkers have a lower ACVD risk than abstainers due to their higher levels of high-density lipoprotein (HDL) cholesterol, an important protective factor against ACVD. On the contrary, heavy drinking increases ACVD risk. According to an extensive literature body, ethanol intoxication modifies lipid serum profile and induces endothelial dysfunction. Single nucleotide polymorphisms may influence the relationship between alcohol drinking, HDL cholesterol level, and atherosclerotic risk. The risk of ACVD in heavy drinkers seems enhanced in patients with apolipoprotein E4 allele, interleukin- 6-174 polymorphism, and cholesteryl ester transfer protein TaqIB polymorphism. Apolipoprotein E4 is a known risk factor for ACVD, while apolipoprotein E2 has mixed effects. Therefore, even if a “protective role” may be attributed to moderate drinking, this effect cannot be extended to everyone.

Background We investigated associations between baseline use of immunosuppressive drugs and severity of Coronavirus Disease 2019 (COVID-19) in autoimmune hepatitis (AIH). Patients and methods Data of AIH patients with laboratory confirmed COVID-19 were retrospectively collected from 15 countries. The outcomes of AIH patients who were on immunosuppression at the time of COVID-19 were compared to patients who were not on AIH medication. The clinical courses of COVID-19 were classified as (i)-no hospitalization, (ii)-hospitalization without oxygen supplementation, (iii)-hospitalization with oxygen supplementation by nasal cannula or mask, (iv)-intensive care unit (ICU) admission with non-invasive mechanical ventilation, (v)-ICU admission with invasive mechanical ventilation or (vi)-death and analysed using ordinal logistic regression. Results We included 254 AIH patients (79.5%, female) with a median age of 50 (range, 17-85) years. At the onset of COVID-19, 234 patients (92.1%) were on treatment with glucocorticoids (n = 156), thiopurines (n = 151), mycophenolate mofetil (n = 22) or tacrolimus (n = 16), alone or in combinations. Overall, 94 (37%) patients were hospitalized and 18 (7.1%) patients died. Use of systemic glucocorticoids (adjusted odds ratio [aOR] 4.73, 95% CI 1.12-25.89) and thiopurines (aOR 4.78, 95% CI 1.33-23.50) for AIH was associated with worse COVID-19 severity, after adjusting for age-sex, comorbidities and presence of cirrhosis. Baseline treatment with mycophenolate mofetil (aOR 3.56, 95% CI 0.76-20.56) and tacrolimus (aOR 4.09, 95% CI 0.69-27.00) were also associated with more severe COVID-19 courses in a smaller subset of treated patients. Conclusion Baseline treatment with systemic glucocorticoids or thiopurines prior to the onset of COVID-19 was significantly associated with COVID-19 severity in patients with AIH., Italian Ministry of University and Research (MIUR)-Department of Excellence project PREMIA (PREcision MedIcine Approach: bringing biomarker research to clinic), A. Gerussi, L. Cristoferi, and P. Invernizzi acknowledge that this research was partially supported by the Italian Ministry of University and Research (MIUR)-Department of Excellence project PREMIA (PREcision MedIcine Approach: bringing biomarker research to clinic).

Background Non-operative management (NOM) of acute appendicitis has been assessed in several studies before COVID-19 pandemic. This systematic review aimed to assess the extent of adoption, efficacy, and safety of NOM of acute appendicitis in the setting of COVID-19. Methods This was a PRISMA-compliant systematic review of the literature. Electronic databases and Google Scholar were queried for studies that applied NOM of acute appendicitis during COVID-19. The main outcome measures were the rates of NOM application during the pandemic as compared to the pre-pandemic period, failure and complication rates of NOM. Failure was defined as the need for appendectomy during NOM and complications included development of appendicular mass or abscess. Results Fourteen studies (2140 patients) were included. The male to female ratio was 1.44:1 and median age was 34. Nine hundred fifty-nine (44.8%) patients had a trial of NOM. The weighted mean rate of NOM application was 50.1% (95%CI: 29.8–70.5%). The application of NOM during the pandemic was significantly more likely than its application before COVID-19 (OR = 6.7, p < 0.001). The weight mean failure rate of NOM was 16.4% (95%CI: 9.4–23.4). NOM failure was more likely in children and patients with complicated appendicitis. The weighted mean complication rate after NOM was 4.5% (95%CI: 1.4–7.7). NOM had significantly lower odds for complications than appendectomy (OR = 0.36, p = 0.03). There was no mortality after application of NOM. Conclusion NOM of acute appendicitis in the setting of COVID-19 may be a safe, short-term alternative to surgery with acceptably low failure and complication rates. Supplementary Information The online version contains supplementary material available at 10.1007/s11605-021-04988-1.

Primary aldosteronism (PA) is the most frequent type of endocrine hypertension. In our previous studies, we introduced two modified diagnostic tests for PA, the post-dexamethasone saline infusion test (DSIT) and the overnight dexamethasone, captopril, and valsartan test (DCVT). In this study, we aimed to validate both tests in respect to the biochemical and clinical response of a cohort of hypertensive patients in pre- and post-surgical setting. We retrospectively studied 41 hypertensive patients (16 males), with a median (IQR, range) age of 50 (16, 35–74) years and positive histology for adrenal adenoma. Preoperatively, all patients had a single adenoma on CT and a diagnosis of PA with either DSIT or DCVT. The defined daily dose (DDD) of hypertensive drugs was assessed pre- and postoperatively. DSIT or DCVT and basal ARR were reassessed postoperatively. Two of the 41 patients failed to suppress aldosterone post-surgery, leading to a post-adrenalectomy biochemical cure rate of 95%, while blood pressure was improved in 36 patients, leading to a clinical cure rate of 88% as assessed by the DDD methodology. The present study was a proof-of-concept process to validate two modified diagnostic tests for PA in clinical practice. These tests, used to diagnose a group of patients with PA, successfully assessed their biochemical cure post-adrenalectomy at rates similar to those reported in the literature.

Background and Objectives Distinguishing primary biliary cholangitis (PBC) from other cholestatic diseases at the histological level could be assisted by new methods, such as immunohistochemical staining of specific antigens. Methods We evaluated whether the detection of promyelocytic leukemia protein (PML) can serve as a specific and sensitive marker for PBC diagnosis. Liver biopsies from 26 PBC patients, 20 primary sclerosing cholangitis (PSC), 37 viral hepatitis, 11 non-alcoholic steatohepatitis (NASH) and 5 normal patients were investigated after immunostaining with the anti-PML monoclonal PG-M3, IgG1 antibody. Results Immunoreactivity in bile ducts was expressed by the PML-score (quotient of positive ducts to the total number of portal tracts multiplied by 2). PML-score was higher in PBC as compared to controls (P < 0.001). Using a cutoff of 0.18, PML-score proved highly sensitive (84.6%) and specific (89.7%) for confirming PBC as compared to only 5% of PSC, 9.1% of NASH and 13.5% of viral hepatitis patients (P < 0.001). Irrespective of the underlying disease, patients with PML-score > 0.18 were older (P = 0.007), more often females (P < 0.001) with higher ALP (P < 0.001), γ-GT (P = 0.001) and IgM (P < 0.001) compared to the patients with PML-score < 0.18. Conclusions We postulate that a simple PML immunohistochemical test could be sufficient for histopathological discrimination of PBC in problematic cases of undefined cholestatic disorders, including small-duct PSC and AMA-negative PBC cases.

Aims Differential diagnosis of autoimmune hepatitis (AIH) incorporates various liver diseases, including alcoholic liver disease (ALD). We report on clinical, laboratory and outcome characteristics of AIH patients who were initially referred as ALD based on increased alcohol consumption (AIH/ALD). Methods From 2000-2019, we retrospectively identified 12 AIH/ALD patients [9 males, age: 61 (30-73) years] in our prospective data base of 317 AIH patients. Results AIH diagnosis was based on aminotransferases elevation in 10 patients, high IgG in 8, compatible autoantibody profile in all and typical/compatible histology in all 9 with available biopsy. There were no significant differences of baseline demographics, presentation, cirrhosis at diagnosis, response to treatment and simplified score compared to 45 age- and sex-matched AIH patients without alcohol consumption and 44 age- and sex-matched ALD patients. However, the AIH/ALD cohort was characterized by more frequent progression to cirrhosis, higher liver-related deaths and overall mortality compared to AIH, though similar to the ALD group. AST/ALT ratio>1 seems to bear a good positive (0.84) and negative predictive value (0.88) for ALD and AIH diagnosis, respectively, but cannot help in discriminating the AIH/ALD variant. Conclusions AIH should not be forgotten in patients with alcohol use when clinical and laboratory features hint towards the diagnosis of AIH/ALD variant as this group seems to have worse outcome compared to those with AIH alone suggesting the need for closer follow-up and surveillance. Reliable autoantibody testing and cautious interpretation of liver histology appear mandatory for AIH diagnosis in these difficult to diagnose cases.