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• Infectious diarrhea was assessed in 140 allogeneic hematopoietic cell recipients. • The cumulative incidence of at least one episode after 1 year was 32%. • The incidence rate was the highest in the pre-engraftment phase. • Most frequently observed were Clostridioides difficile, adenovirus, Enteropathogenic Escherichia coli and Campylobacter jejuni. To determine the incidence of infectious diarrhea after allogeneic hematopoietic cell transplantation (HCT) using a multiplex polymerase chain reaction assay and assess risk factors for developing infectious diarrhea. This was a single-center retrospective study of 140 consecutive allogeneic HCT recipients. Infectious diarrhea was assessed using a laboratory-developed multiplex polymerase chain reaction the first year after transplantation. The incidence rate of infectious diarrhea episodes was 47 per 100 person-years, with the highest rate observed in the pre-engraftment phase. Most episodes were seen as nosocomial infections (38%) and most affected patients (82%) had only one episode of infectious diarrhea. The cumulative incidence of at least one episode of infectious diarrhea was 32% after 1 year. Nonrelapse mortality was higher in transplant recipients with at least one episode of infectious diarrhea (hazard ratio (HR) 2.02, 95% CI = 1.07-3.80). The most frequently observed pathogens were Clostridium difficile , adenovirus, Enteropathogenic Escherichia coli, and Campylobacter jejuni. Patients with acute lower gastrointestinal graft-vs-host disease stage 3 or 4 (HR 3.68, 95% CI = 1.57-8.63) conferred a higher risk for a first infectious diarrhea episode. Infectious diarrhea after allogeneic HCT was seen in about one-third of the patients, mostly as nosocomial infection in the pre-engraftment phase. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. [ABSTRACT FROM AUTHOR]

The human gut harbours a tremendously diverse and abundant microbial community that correlates with, and even modulates, many health-related processes. The mucosal interfaces are particularly active sites of microorganism-host interplay. Growing insight into the characteristic composition and functionality of the mucosal microbiota has revealed that the microbiota is involved in mucosal barrier integrity and immune function. This involvement affects proinflammatory and anti-inflammatory processes not only at the epithelial level, but also at remote sites such as the joints. Here, we review the role of the gut microbiota in shaping local and systemic immune responses and how disturbances in the host-microorganism interplay can potentially affect the development and progression of rheumatic diseases. Increasing our understanding of how to promote host-microorganism homeostasis could therefore reveal novel strategies for the prevention or alleviation of rheumatic disease. [ABSTRACT FROM AUTHOR]

Antinuclear antibodies are a hallmark feature of generalized autoimmune diseases, including systemic lupus erythematosus and systemic sclerosis. However, the processes underlying the loss of tolerance against nuclear self-constituents remain largely unresolved. Using mice deficient in lymphotoxin and Hox11, we report that approximately 25% of mice lacking secondary lymphoid organs spontaneously develop specific antinuclear antibodies. Interestingly, we find this phenotype is not caused by a defect in central tolerance. Rather, cell-specific deletion and in vivo lymphotoxin blockade link these systemic autoimmune responses to the formation of gut-associated lymphoid tissue in the neonatal period of life. We further demonstrate antinuclear antibody production is influenced by the presence of commensal gut flora, in particular increased colonization with segmented filamentous bacteria, and IL-17 receptor signaling. Together, these data indicate that neonatal colonization of gut microbiota influences generalized autoimmunity in adult life. [ABSTRACT FROM AUTHOR]

Objectives. To determine how sensitively SSc-associated ANAs are detected by a standard identification algorithm compared with an extensive panel of ANA identification assays, and to assess the distribution of SSc-associated ANAs and SSc organ system involvement in patients without skin involvement (limited SSc).Methods. Serum samples from 145 consecutive monocentric SSc patients fulfilling LeRoy and Medgser’s criteria for early SSc were studied. ANAs were detected by IIF on HEp-2000 cells and identified by western blotting, protein radio-immunoprecipitation, RNA immunoprecipitation and line immunoassay (LIA). SSc organ involvement was assessed according to a modification of Medsger’s disease severity scale.Results. At least one specific ANA reactivity was present in 88% of the patients. The standard algorithm (IIF and LIA) found at least one specific ANA in 74% of the patients. The main reactivities missed by this algorithm were anti-RNA polymerase III, anti-PM/Scl and anti-Th/To. Eighty-three percent of the patients with limited SSc had at least one ANA. ACAs and anti-Th/To antibodies were significantly associated with limited SSc, whereas anti-topoisomerase I and anti-RNA polymerase III were observed less frequently. SSc organ system involvement was present in 63% of the patients with limited SSc, most of whom had lung involvement.Conclusions. Standard algorithms for ANA identification lack sensitivity for the detection of SSc-associated ANA and should be supplemented with additional assays, especially in a clinical environment that has particular interest in SSc. The spectrum of SSc-associated ANA differs according to the presence or absence of skin involvement. [ABSTRACT FROM PUBLISHER]

Introduction: In Belgium, oral HIV pre‐exposure prophylaxis (PrEP) is primarily provided in specialized clinical settings. Optimal implementation of PrEP services can help to substantially reduce HIV transmission. However, insights into implementation processes, and their complex interactions with local context, are limited. This study examined factors that influence providers' adaptive responses in the implementation of PrEP services in Belgian HIV clinics. Methods: We conducted a qualitative multiple case study on PrEP care implementation in eight HIV clinics. Thirty‐six semi‐structured interviews were conducted between January 2021 and May 2022 with a purposive sample of PrEP care providers (e.g. physicians, nurses, psychologists), supplemented by 50 hours of observations of healthcare settings and clinical interactions. Field notes from observations and verbatim interview transcripts were thematically analysed guided by a refined iteration of extended Normalisation Process Theory. Results: Implementing PrEP care in a centralized service delivery system required considerable adaptive capacity of providers to balance the increasing workload with an adequate response to PrEP users' individual care needs. As a result, clinic structures were re‐organized to allow for more efficient PrEP care processes, compatible with other clinic‐level priorities. Providers adapted clinical and policy norms on PrEP care (e.g. related to PrEP prescribing practices and which providers can deliver PrEP services), to flexibly tailor care to individual clients' situations. Interprofessional relationships were reconfigured in line with organizational and clinical adaptations; these included task‐shifting from physicians to nurses, leading them to become increasingly trained and specialized in PrEP care. As nurse involvement grew, they adopted a crucial role in responding to PrEP users' non‐medical needs (e.g. providing psychosocial support). Moreover, clinicians' growing collaboration with sexologists and psychologists, and interactions with PrEP users' family physician, became crucial in addressing complex psychosocial needs of PrEP clients, while also alleviating the burden of care on busy HIV clinics. Conclusions: Our study in Belgian HIV clinics reveals that the implementation of PrEP care presents a complex—multifaceted—undertaking that requires substantial adaptive work to ensure seamless integration within existing health services. To optimize integration in different settings, policies and guidelines governing PrEP care implementation should allow for sufficient flexibility and tailoring according to respective local health systems. [ABSTRACT FROM AUTHOR]

Background: Vancomycin is a commonly prescribed antibiotic to treat gram-positive infections. The efficacy of vancomycin is known to be directly related to the pharmacokinetic/pharmacodynamic (PK/PD) index of the area under the concentration-time curve (AUC) divided by the minimal inhibitory concentration (MIC) of the pathogen. However, in most countries, steady-state plasma concentrations are used as a surrogate parameter of target AUC/MIC, but this practice has some drawbacks. Hence, direct AUC-guided monitoring of vancomycin using model-informed precision dosing (MIPD) tools has been proposed for earlier attainment of target concentrations and reducing vancomycin-related nephrotoxicity. However, solid scientific evidence for these benefits in clinical practice is still lacking. This randomized controlled trial (RCT) aims to investigate the clinical utility of MIPD dosing of vancomycin administered via continuous infusion in hospitalized adults. Methods: Participants from 11 wards at two Belgian hospitals are randomly allocated to the intervention group or the standard-of-care comparator group. In the intervention group, clinical pharmacists perform dose calculations using CE-labeled MIPD software and target an AUC24h of 400 to 600 mg × h/L, whereas patients in the comparator group receive standard-of-care dosing and monitoring according to the institutional guidelines. The primary endpoint is the proportion of patients reaching the target AUC24h/MIC of 400–600 between 48 and 72 h after start of vancomycin treatment. Secondary endpoints are the proportion of patients with (worsening) acute kidney injury (AKI) during and until 48 h after stop of vancomycin treatment, the proportion of patients reaching target AUC24h/MIC of 400–600 between 72 and 96 h after start of vancomycin treatment, and the proportion of time within the target AUC24h/MIC of 400–600. Discussion: This trial will clarify the propagated benefits and provide new insights into how to optimally monitor vancomycin treatment. Trial registration: EudraCT number: 2021-003670-31. Registered June 28, 2021. ClinicalTrials.gov identifier: NCT05535075. Registered September 10, 2022. Protocol version 3, protocol date: April 21, 2023. [ABSTRACT FROM AUTHOR]

Objectives: Our objective was to evaluate the efficacy, durability, and tolerability of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) in a real‐world setting in Belgium. Methods: This was a retrospective, multicentre cohort study involving adult treatment‐naïve (TN) and treatment‐experienced (TE) people living with HIV receiving BIC/FTC/TAF between 1 January 2019 and 30 September 2020. The primary outcome was rate of virological suppression (plasma HIV‐1 viral load <50 copies/mL; on‐treatment analysis) at weeks 24 and 48. The main secondary outcomes included loss of virological suppression (LVS; two consecutive viral loads of >200 copies/mL after being virologically suppressed) by week 48 and analysis of resistance‐associated mutations at time of LVS; tolerability of BIC/FTC/TAF over the 48‐week study period; and change in weight and proportion of participants reporting a >10% weight gain at week 48. Results: Overall, 2001 participants were included. Through 48 weeks, overall rate of virological suppression was 93.5%, with similar results observed in the following subgroups: age ≥50 years (92.7%), women (92.8%), Black sub‐Saharan African (91%), TN (94%), TE (93.2%), and non‐suppressed at baseline (86.6%). LVS was observed in 0.7% (n = 14) of participants, with one participant developing resistance‐associated mutations to nucleoside reverse transcriptase inhibitors (184 V) and integrase strand transfer inhibitors (263KR). Of the 131 (6.5%) treatment discontinuations, the most common reason was an adverse event (2.4%), with the most frequent being central nervous system/psychiatric (0.4%) and gastrointestinal (0.4%) toxicity. Median weight gain at week 48 was 2 kg (interquartile range −1 to 5), and a >10% weight increase was observed in 11.6% of participants. Conclusion: In this large real‐world cohort, BIC/FTC/TAF showed excellent virological efficacy in a diverse population of patients with HIV. Rare occurrence of emergent drug resistance was observed, and treatment was well tolerated. [ABSTRACT FROM AUTHOR]

Short-term humoral and cellular immune responses are diminished after BNT162b2 messenger ribonucleic acid coronavirus disease 2019 (COVID-19) vaccination in COVID-19-naive nursing home residents, a population particularly vulnerable to the disease. We found both responses to decline after 4 weeks and remain lower than those of healthcare workers after 24 weeks, with an estimated half-life of the antibody response of 47 days. At 4 weeks, older age was significantly associated with a decreased humoral response, and diabetes mellitus and active malignancy were associated with a decreased cellular response. Our results imply that COVID-19-naive nursing home residents are a target group for booster vaccination trials. [ABSTRACT FROM AUTHOR]

• Molnupiravir and nirmatrelvir/ritonavir are administered to patients with mild COVID-19 to prevent worsening of disease. • Hospitalisation and mortality rates with molnupiravir vs. nirmatrelvir/ritonavir were compared in patients with leukaemia or lymphoma. • No statistically significant differences between treatments for hospitalisation, mortality rates or survival probability. • Results support the use of molnupiravir in patients with haematological malignancies in Europe. • Patients with nirmatrelvir/ritonavir-related contraindications and drug-drug interactions may benefit from molnupiravir treatment. Molnupiravir and nirmatrelvir/ritonavir are antivirals used to prevent progression to severe SARS-CoV-2 infections and decrease hospitalisation and mortality rates. Nirmatrelvir/ritonavir was authorised in Europe in December 2021, whereas molnupiravir is not yet licensed in Europe as of February 2022. Molnupiravir may be an alternative to nirmatrelvir/ritonavir because it is associated with fewer drug-drug interactions and contraindications. A caveat for molnupiravir is the mode of action induces viral mutations. Mortality rate reduction with molnupiravir was less pronounced than that with nirmatrelvir/ritonavir in patients without haematological malignancy. Little is known about the comparative efficacy of the two drugs in patients with haematological malignancy at high-risk of severe COVID-19. Thus, molnupiravir and nirmatrelvir/ritonavir were compared in a cohort of patients with haematological malignancies. Clinical data from patients treated with molnupiravir or nirmatrelvir/ritonavir monotherapy for COVID-19 were retrieved from the EPICOVIDEHA registry. Patients treated with molnupiravir were matched by sex, age (±10 years), and severity of baseline haematological malignancy to controls treated with nirmatrelvir/ritonavir. A total of 116 patients receiving molnupiravir for the clinical management of COVID-19 were matched to an equal number of controls receiving nirmatrelvir/ritonavir. In each of the groups, 68 (59%) patients were male; with a median age of 64 years (interquartile range [IQR] 53-74) for molnupiravir recipients and 64 years (IQR 54-73) for nirmatrelvir/ritonavir recipients; 56.9% (n=66) of the patients had controlled baseline haematological malignancy, 12.9% (n=15) had stable disease, and 30.2% (n=35) had active disease at COVID-19 onset in each group. During COVID-19 infection, one third of patients from each group were admitted to hospital. Although a similar proportion of patients in the two groups were vaccinated (molnupiravir n=77, 66% vs. nirmatrelvir/ritonavir n=87, 75%), more of those treated with nirmatrelvir/ritonavir had received four vaccine doses (n=27, 23%) compared with those treated with molnupiravir (n=5, 4%) (P <0.001). No differences were detected in COVID-19 severity (P =0.39) or hospitalisation (P =1.0). No statistically significant differences were identified in overall mortality rate (P =0.78) or survival probability (d30 P =0.19, d60 P =0.67, d90 P =0.68, last day of follow up P =0.68). Deaths were either attributed to COVID-19, or the infection was judged by the treating physician to have contributed to death. Hospitalisation and mortality rates with molnupiravir were comparable to those with nirmatrelvir/ritonavir in high-risk patients with haematological malignancies and COVID-19. Molnupiravir is a plausible alternative to nirmatrelvir/ritonavir for COVID-19 treatment in patients with haematological malignancy. [ABSTRACT FROM AUTHOR]

Background: Detection of systemic sclerosis-associated autoantibodies (SSc-Ab) is mostly restricted to anti-centromere and anti-topoisomerase-I. However, anti-RNA-polymerase-III and anti-PM/Scl are also important diagnostic markers for the disease supporting their incorporation in the laboratory repertoire. The aim of this study was to compare different testing strategies integrating the identification of these extra SSc-Ab in a routine testing algorithm. Methods: Sera from 144 consecutive SSc-patients and 265 controls were screened for antinuclear antibodies (ANA) by indirect immunofluorescence (ANA IIF) and tested for anti-extractable nuclear antigen (ENA) using five different assays that differ in their ability to detect SSc-Ab [two screening enzyme immunossays (EIA) with antigen mixtures, one multi-parameter line-immunoassay and two EIA with individual antigens]. Results: The application of SSc-Ab testing in cascade with the routine ANA/anti-ENA tests improved diagnostic performance characteristics. Besides the type of algorithm, also the number of antigens included in the screening EIA as well as the expected patient/control ratio, influenced the average expected costs and the number of additional SSc-Ab tests to be performed. In laboratories with an expected patient/control ratio of 0.002, cascade testing was most exploited by the use of a screening EIA that included all SSc-Ab as a secondary test after ANA IIF. Conclusions: Restriction of the performance of additional SSc-Ab assays based on the results of prior ANA/anti-ENA tests is a cost-effective strategy allowing optimized use of laboratory resources with minimal loss in diagnostic capacity. [ABSTRACT FROM AUTHOR]

Summary: Dendritic cells (DCs) regulate both immunity and tolerance. Here we have shown that the ubiquitin editing enzyme A20 (Tnfaip3) determines the activation threshold of DCs, via control of canonical NF-κB activation. Tnfaip3 fl/fl Cd11c-cre + mice lacking A20 in DCs demonstrated spontaneous proliferation of conventional and double-negative T cells, their conversion to interferon-γ (IFN-γ)-producing effector cells, and expansion of plasma cells. They developed ds-DNA antibodies, nephritis, the antiphospholipid syndrome, and lymphosplenomegaly—features of systemic lupus erythematosus—and extramedullary hematopoiesis. A20-deficient DCs were resistant to apoptosis, caused by increased sensitivity to CD40L and RANKL prosurvival signals and upregulation of antiapoptotic proteins Bcl-2 and Bcl-x. They captured injected apoptotic cells more efficiently, resisted the inhibitory effects of apoptotic cells, and induced self-reactive effector lymphocytes. Because genetic polymorphisms in TNFAIP3 are associated with human autoimmune disorders, these findings identify A20-mediated control of DC activation as a crucial checkpoint in the development of systemic autoimmunity. [Copyright &y& Elsevier]