Abrocitinib effect on patient-reported outcomes in patients with moderate-to-severe atopic dermatitis: Results from phase 3 studies, including the long-term extension JADE EXTEND study.

BACKGROUND: Abrocitinib improved signs and symptoms of moderate-to-severe atopic dermatitis (AD) at Weeks 12 and 16 in phase 3 studies, with a manageable safety profile. Patient-reported outcomes with long-term abrocitinib treatment were not reported. OBJECTIVE: To evaluate patient-reported outcomes with long-term abrocitinib treatment in patients with moderate-to-severe AD. METHODS: JADE EXTEND (NCT03422822) is an ongoing, phase 3, long-term extension study that enrolled patients from previous abrocitinib AD trials. This analysis includes patients from the phase 3 trials JADE MONO-1 (NCT03349060), JADE MONO-2 (NCT03575871) and JADE COMPARE (NCT03720470) who completed the full treatment period of placebo or abrocitinib (200 or 100 mg once daily) and subsequently entered JADE EXTEND and were randomised to receive once-daily abrocitinib 200 or 100 mg. Patient-reported endpoints to Week 48 included the proportion of patients who achieved Dermatology Life Quality Index (DLQI) scores of 0/1 (no effect of AD on quality of life [QoL]) and a ≥4-point improvement in Patient-Oriented Eczema Measure (POEM) score (clinically meaningful improvement). Data cut-off: April 22, 2020. RESULTS: Baseline DLQI mean scores were 15.4 and 15.3 in the abrocitinib 200- and 100-mg groups, respectively, which corresponded to a 'very large effect' on QoL; at Week 48, mean DLQI scores were lower with abrocitinib 200 mg (4.6; 'small effect' on QoL) and abrocitinib 100 mg (5.9; 'moderate effect' on QoL). Baseline POEM mean scores were 20.4 and 20.5 in the abrocitinib 200- and 100-mg groups, respectively; at Week 48, mean POEM scores were 8.2 and 11.0. Week 48 patient-reported responses with abrocitinib 200 mg and abrocitinib 100 mg were 44% and 34% for DLQI 0/1, and 90% and 77% for a ≥4-point reduction in POEM score. CONCLUSION: In patients with moderate-to-severe AD, long-term abrocitinib treatment resulted in clinically meaningful improvement in patient-reported symptoms of AD, including QoL.

Vulnerable newborn types: analysis of subnational, population-based birth cohorts for 541 285 live births in 23 countries, 2000-2021.

OBJECTIVE: To examine prevalence of novel newborn types among 541 285 live births in 23 countries from 2000 to 2021. DESIGN: Descriptive multi-country secondary data analysis. SETTING: Subnational, population-based birth cohort studies (n = 45) in 23 low- and middle-income countries (LMICs) spanning 2000-2021. POPULATION: Liveborn infants. METHODS: Subnational, population-based studies with high-quality birth outcome data from LMICs were invited to join the Vulnerable Newborn Measurement Collaboration. We defined distinct newborn types using gestational age (preterm [PT], term [T]), birthweight for gestational age using INTERGROWTH-21st standards (small for gestational age [SGA], appropriate for gestational age [AGA] or large for gestational age [LGA]), and birthweight (low birthweight, LBW [<2500 g], nonLBW) as ten types (using all three outcomes), six types (by excluding the birthweight categorisation), and four types (by collapsing the AGA and LGA categories). We defined small types as those with at least one classification of LBW, PT or SGA. We presented study characteristics, participant characteristics, data missingness, and prevalence of newborn types by region and study. RESULTS: Among 541 285 live births, 476 939 (88.1%) had non-missing and plausible values for gestational age, birthweight and sex required to construct the newborn types. The median prevalences of ten types across studies were T+AGA+nonLBW (58.0%), T+LGA+nonLBW (3.3%), T+AGA+LBW (0.5%), T+SGA+nonLBW (14.2%), T+SGA+LBW (7.1%), PT+LGA+nonLBW (1.6%), PT+LGA+LBW (0.2%), PT+AGA+nonLBW (3.7%), PT+AGA+LBW (3.6%) and PT+SGA+LBW (1.0%). The median prevalence of small types (six types, 37.6%) varied across studies and within regions and was higher in Southern Asia (52.4%) than in Sub-Saharan Africa (34.9%). CONCLUSIONS: Further investigation is needed to describe the mortality risks associated with newborn types and understand the implications of this framework for local targeting of interventions to prevent adverse pregnancy outcomes in LMICs.

The genomic landscape of familial glioma.

Glioma is a rare brain tumor with a poor prognosis. Familial glioma is a subset of glioma with a strong genetic predisposition that accounts for approximately 5% of glioma cases. We performed whole-genome sequencing on an exploratory cohort of 203 individuals from 189 families with a history of familial glioma and an additional validation cohort of 122 individuals from 115 families. We found significant enrichment of rare deleterious variants of seven genes in both cohorts, and the most significantly enriched gene was HERC2 (P = 0.0006). Furthermore, we identified rare noncoding variants in both cohorts that were predicted to affect transcription factor binding sites or cause cryptic splicing. Last, we selected a subset of discovered genes for validation by CRISPR knockdown screening and found that DMBT1, HP1BP3, and ZCH7B3 have profound impacts on proliferation. This study performs comprehensive surveillance of the genomic landscape of familial glioma.

Elbow arthroplasty in trauma-current concepts review.

Introduction: Despite advancements in modern locking plate technology, distal humerus fractures in the elderly remain difficult to treat. A subset of fractures in this osteoporotic bone includes multiple, shallow articular fragments that renders fixation unreliable, precluding early motion and acceptable functional outcomes. Arthroplasty, in the form of either Total Elbow Arthroplasty (TEA) or Distal Humeral Hemiarthroplasty (DHH) are alternative treatment options in this cohort and are being increasingly used. Methods: This article reviews the use of TEA or DHH for acute distal humerus fracture, including patient selection, pre-operative planning, surgical approach, implant positioning, rehabilitation, outcomes and complications. Results: Arthroplasties are being increasingly used for acute distal humerus fractures, however they introduce potential complications not seen with fixation. Due care must be employed to correct implant positioning which is a function of implant rotation, implant length and implant sizing. We describe a robust technique for epicondyle repair in DHH and unlinked TEA to avoid instability. Outcomes of DHH and TEA for acute distal humerus fracture are encouraging, however further long-term outcome and comparative data regarding arthroplasty is required. Conclusions: Short to medium term outcomes demonstrate that both DHH and TEA are valuable options for selected patients, although attention to technique is required to minimise potential complications.

Systemic medical complications following joint replacement: a review of the evidence.

INTRODUCTION: Arthroplasty procedures are commonly performed in the UK. Informed consent is required for each procedure. To obtain informed consent the patient and their surgeon should discuss the risks and benefits of the proposed operation. This discussion should include both regional and systemic complication rates. Regional complications of arthroplasty are generally well documented in the literature. Systemic medical complications are less well described. This lack of accurate data could make it difficult for the treating surgeon to obtain valid consent. The aim of this paper was to review and compare the literature regarding the rate of systemic medical complications after common arthroplasty procedures. METHODS: A literature search was conducted using the PubMed, Cochrane Library and MEDLINE databases. Studies regarding the systemic medical complications and mortality rate of joint replacement were included. FINDINGS: We found that systemic complications were more frequent than regional complications following arthroplasty. The systemic complication rates were: hip, 5.1%; knee, 6.9%; ankle, 3.0%; shoulder, 11.2%; elbow, 8.5%; and wrist, 0%. Mortality rates for arthroplasty procedures were: hip, 0.3%; knee, 0.2%; ankle, 0.3%; shoulder, 0.3%; elbow, 0.2%; and wrist, 0%. CONCLUSIONS: The most common systemic medical complication following arthroplasty was venous thromboembolism. Preoperative comorbidity was the most important risk factor for both postoperative mortality and systemic medical complications following arthroplasty procedures. We recommend that to obtain informed consent the given rates of systemic medical complications of joint replacement should be discussed and documented.

Polypharmacy Predicts Onset and Transition of Frailty, Malnutrition, and Adverse Outcomes in Peritoneal Dialysis Patient.

BACKGROUND: Polypharmacy, frailty and malnutrition are known predictors of adverse outcomes in dialysis patients. Little has reported about their interaction and composite prognostic values. We aimed to describe the interaction between polypharmacy, frailty, nutrition, hospitalization, and survival in peritoneal dialysis patients. METHODS: In this prospective cohort study, we recruited 573 peritoneal dialysis patients. Drug burden was measured by medication number and daily pill load. Frailty and nutrition were assessed by the validated Frailty Score (FQ) and Subjective Global Assessment (SGA) respectively. All patients were followed for two years. Primary outcome was all-cause mortality. Secondary outcomes were fall and fracture episodes, hospitalization, change in FQ and SGA. RESULTS: At baseline, each patient took 7.5 ± 2.6 medications with 15.5 ± 8.5 tablets per day. Medication number, but not daily pill load predicted baseline FQ (p = 0.004) and SGA (p = 0.03). Over 2 years, there were 69 fall and 1,606 hospitalization episodes. In addition, 148 (25.8%) patients died, while FQ and SGA changed by 0.73 ± 4.23 and -0.07 ± 1.06 respectively in survivors. Medication number (hospitalization: p = 0.02, survival: p = 0.005), FQ (hospitalization: p < 0.001; survival: p = 0.01) predicted hospitalization and survival. Medication number also predicted fall episodes (p = 0.02) and frailty progression (p = 0.002). Daily pill load did not predict any of these outcomes. CONCLUSIONS: Drug burden is high in peritoneal dialysis patients, and it carries important prognostic implication. Medication number but not pill load significantly predicted onset and progression of frailty, malnutrition, fall, hospitalization, and mortality.

Knowledge and attitudes towards TB among healthcare workers in Yogyakarta, Indonesia.

SETTING: Healthcare workers (HCWs) are at an increased risk of TB worldwide. Individual knowledge and attitudes may influence HCW behaviour, and subsequently, TB risk. Indonesia has the second highest case-load globally. OBJECTIVE: To measure TB knowledge and attitudes among a subsection of HCWs in Yogyakarta, Indonesia, and to explore factors associated with knowledge. DESIGN: A cross-sectional study using an online survey targeting all HCW staff was conducted among HCWs from four pre-selected healthcare facilities in Yogyakarta. Descriptive analysis and a multivariable linear regression were undertaken. RESULTS: Of 792 HCWs, 290 (37%) completed the survey; 64% (n = 185) were medical staff, 33% (n = 95) reported previously being tested for active TB and 8% (n = 24) for latent TB. The mean knowledge score was 7.2/11 (SD 1.5): this was higher among medical staff and those with university education (average score increase: 0.53, 95% CI 0.15 to 0.90; and 0.38, 95% CI 0.01 to 0.74, respectively). Participants agreed that free access to TB screening (93%) and treatment (93%) should be available, and 57% of medical and 77% of non-medical staff would take preventive therapy if eligible. CONCLUSION: Participants had practical understanding of TB; however, gaps were identified in knowledge about TB disease progression and prevention. Prevention programmes were viewed positively. We suggest further TB education and engagement programmes for HCWs.

CONTEXTE: Les travailleurs de la santé (HCW) sont exposés à un risque accru de TB dans le monde entier. Les connaissances et les attitudes individuelles peuvent influencer le comportement des HCW et, par conséquent, le risque de TB. L'Indonésie a le deuxième plus grand nombre de cas dans le monde. OBJECTIF: Mesurer les connaissances et les attitudes à l'égard de la TB parmi un sous-groupe de HCW à Yogyakarta, en Indonésie, et explorer les facteurs associés aux connaissances de la TB. MÉTHODE: Une étude transversale a été menée à l'aide d'un sondage en ligne ciblant tous les HCW de quatre établissements de santé présélectionnés à Yogyakarta. Une analyse descriptive et une régression linéaire multivariable ont été effectuées. RÉSULTATS: Sur 792 HCW, 290 (37%) ont répondu à l'enquête ; 62% (n = 181) étaient des membres du personnel médical, 33% (n = 95) ont déclaré avoir déjà été testés pour la TB active et 8% (n = 24) pour la TB latente. Le score moyen de connaissances était de 7,2/11 (SD 1,5) : il était plus élevé parmi le personnel médical et les personnes ayant une formation universitaire (augmentation moyenne du score : 0,53 ; IC 95% 0,11­0,93 et 0,38 ; IC 95% 0,01­0,74, respectivement). Les participants étaient d'accord pour dire que l'accès au dépistage (93%) et au traitement (93%) de la TB devrait être gratuit, et 57% du personnel médical et 77% du personnel non médical suivraient un traitement préventif s'ils étaient éligibles. CONCLUSION: Les participants avaient une compréhension pratique de la TB ; cependant, des lacunes ont été identifiées dans les connaissances sur la progression de la maladie et la prévention de la TB. Les programmes de prévention ont été perçus positivement. Nous suggérons d'autres programmes d'éducation et d'engagement sur la TB pour les HCW.

Antibiotic resistance genes in the gut microbiota of mothers and linked neonates with or without sepsis from low- and middle-income countries.

Early development of the microbiome has been shown to affect general health and physical development of the infant and, although some studies have been undertaken in high-income countries, there are few studies from low- and middle-income countries. As part of the BARNARDS study, we examined the rectal microbiota of 2,931 neonates (term used up to 60 d) with clinical signs of sepsis and of 15,217 mothers screening for blaCTX-M-15, blaNDM, blaKPC and blaOXA-48-like genes, which were detected in 56.1%, 18.5%, 0% and 4.1% of neonates' rectal swabs and 47.1%, 4.6%, 0% and 1.6% of mothers' rectal swabs, respectively. Carbapenemase-positive bacteria were identified by MALDI-TOF MS and showed a high diversity of bacterial species (57 distinct species/genera) which exhibited resistance to most of the antibiotics tested. Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae/E. cloacae complex, the most commonly found isolates, were subjected to whole-genome sequencing analysis and revealed close relationships between isolates from different samples, suggesting transmission of bacteria between neonates, and between neonates and mothers. Associations between the carriage of antimicrobial resistance genes (ARGs) and healthcare/environmental factors were identified, and the presence of ARGs was a predictor of neonatal sepsis and adverse birth outcomes.

Genome sequencing reveals underdiagnosis of primary ciliary dyskinesia in bronchiectasis.

BACKGROUND: Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60-80% of cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis of PCD has management implications including addressing comorbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments. Diagnostic testing can be complex; however, PCD genetic testing is moving rapidly from research into clinical diagnostics and would confirm the cause of bronchiectasis. METHODS: This observational study used genetic data from severe bronchiectasis patients recruited to the UK 100,000 Genomes Project and patients referred for gene panel testing within a tertiary respiratory hospital. Patients referred for genetic testing due to clinical suspicion of PCD were excluded from both analyses. Data were accessed from the British Thoracic Society audit, to investigate whether motile ciliopathies are underdiagnosed in people with bronchiectasis in the UK. RESULTS: Pathogenic or likely pathogenic variants were identified in motile ciliopathy genes in 17 (12%) out of 142 individuals by whole-genome sequencing. Similarly, in a single centre with access to pathological diagnostic facilities, 5-10% of patients received a PCD diagnosis by gene panel, often linked to normal/inconclusive nasal nitric oxide and cilia functional test results. In 4898 audited patients with bronchiectasis, <2% were tested for PCD and <1% received genetic testing. CONCLUSIONS: PCD is underdiagnosed as a cause of bronchiectasis. Increased uptake of genetic testing may help to identify bronchiectasis due to motile ciliopathies and ensure appropriate management.

Impact of oral abrocitinib on signs, symptoms and quality of life among adolescents with moderate-to-severe atopic dermatitis: an analysis of patient-reported outcomes.

BACKGROUND: A significant improvement in clinical signs was demonstrated with abrocitinib relative to placebo in adolescents with moderate-to-severe atopic dermatitis (AD) in three phase 3, randomized, double-blinded, placebo-controlled studies (JADE TEEN [ClinicalTrials.gov, NCT03796676], JADE MONO-1 [NCT03349060] and JADE MONO-2 [NCT03575871]). OBJECTIVES: To evaluate the impact of abrocitinib on patient-reported signs/symptoms, including sleep loss and quality of life among adolescents with moderate-to-severe AD. METHODS: JADE TEEN, JADE MONO-1 and JADE MONO-2 were conducted in the Asia-Pacific region, Europe and North America and included patients aged 12-17 years with moderate-to-severe AD and inadequate response to ≥ 4 consecutive weeks of topical medication or treatment with systemic therapy for AD. Patients were randomly assigned (1 : 1 : 1, JADE TEEN; 2 : 2 : 1, JADE MONO-1/-2) to receive once-daily oral abrocitinib (200 or 100 mg) or placebo for 12 weeks in combination with topical therapy (JADE TEEN) or as monotherapy (JADE MONO-1/-2). Data from adolescent patients in JADE MONO-1/-2 were pooled for these analyses. RESULTS: At week 12, more adolescents treated with abrocitinib (200 or 100 mg) vs. placebo achieved a ≥ 4-point improvement from baseline in the Patient-Oriented Eczema Measure in JADE TEEN (83.9% and 77.0% vs. 60.2%) and JADE MONO-1/-2 (83.0% and 69.4% vs. 43.5%) and a ≥ 6-point improvement from baseline in the Children's Dermatology Life Quality Index in JADE TEEN (73.8% and 67.5% vs. 56.5%) and JADE MONO-1/-2 (70.0% and 57.1% vs. 19.0%). Significant improvements in SCORing Atopic Dermatitis Visual Analog Scale for sleep loss scores were demonstrated with abrocitinib vs. placebo at weeks 2-12 in JADE TEEN and JADE MONO-1/-2. CONCLUSIONS: Patient-reported signs/symptoms, including reduction of sleep loss and quality of life, were substantially improved with abrocitinib monotherapy or combination therapy relative to placebo in adolescents with moderate-to-severe AD.

Adapting active case-finding for TB during the COVID-19 pandemic in Yogyakarta, Indonesia.

The COVID-19 pandemic and response measures, including lockdowns and the reorientation of health services, have disrupted essential health services for other diseases, including TB, HIV and malaria. For TB, reductions in case detection due to the COVID-19 pandemic are projected to result in increased TB transmission, morbidity and mortality. Active case-finding (ACF) for TB using community-based approaches is a potential strategy to offset reductions in TB detection by obviating the need for patients to seek care at a health facility. A number of approaches can be used to conduct TB ACF safely and screen designated target populations while managing the risks of SARS-CoV-2 transmission for staff, individuals and the community. We present a framework of options for and experience of adapting TB ACF services in response to the challenges of COVID-19 in our programme in Yogyakarta, Indonesia. Key changes have included revised prioritisation of target populations focusing on household contacts, reducing case-finding throughput, implementation of additional infection control measures and precautions, and integration of COVID-19 screening among those being screened for TB. Our approach could inform other programmes seeking to adapt TB ACF services to mitigate the negative impact of COVID-19 on TB case detection.

La pandémie de COVID-19 et les mesures de riposte incluant des confinements et une réorientation des services de santé ont perturbé les services de santé essentiels destinés aux autres maladies comme la TB, le VIH et le paludisme. En ce qui concerne la TB, les réductions de la détection des cas dues à la pandémie de COVID-19 devrait entraîner une augmentation de la transmission, morbidité et mortalité de la TB. La recherche active des cas (ACF) de TB grâce à des approches communautaires est une stratégie potentielle visant à compenser pour les réductions de détection de la TB en écartant le besoin pour les patients de solliciter des soins dans un structure de santé. Plusieurs approches peuvent être utilisées pour réaliser l'ACF TB de façon sûre et de dépister des populations cibles désignées tout en gérant les risques de transmission du SARS-CoV-2 pour le personnel, les individus et la communauté. Nous présentons un cadre d'options et d'expériences d'adaptation des services TB ACF en réponse aux défis du COVID-19 dans notre programme à Yogyakarta, Indonésie. Les changements majeurs ont inclus une révision des priorités des populations cibles focalisée sur les contacts domiciliaires ; une réduction de la cadence de la recherche de cas ; la mise en œuvre de mesures supplémentaires de lutte contre l'infection et de précautions ; et l'intégration du dépistage de COVID-19 parmi ceux dépistés pour la TB. Notre approche pourrait informer d'autres programmes voulant adapter les services TB ACF afin d'atténuer l'impact négatif du COVID-19 sur la détection des cas de TB.