Genetics and Genomics of Pulmonary Fibrosis: Charting the Molecular Landscape and Shaping Precision Medicine.

Recent genetic and genomic advancements have elucidated the complex etiology of idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases (ILDs), emphasizing the contribution of heritable factors. This state-of-the-art review synthesizes evidence on significant genetic contributors to pulmonary fibrosis (PF), including rare genetic variants and common SNPs. The MUC5B promoter variant is unusual, a common SNP that markedly elevates the risk of early and established PF. We address the utility of genetic variation in enhancing understanding of disease pathogenesis and clinical phenotypes, improving disease definitions, and informing prognosis and treatment response. Critical research gaps are highlighted, particularly the underrepresentation of non-European ancestries in PF genetic studies and the exploration of PF phenotypes beyond usual interstitial pneumonia/IPF. We discuss the role of telomere length, often critically short in PF, and its link to progression and mortality, underscoring the genetic complexity involving telomere biology genes (TERT, TERC) and others like SFTPC and MUC5B. In addition, we address the potential of gene-by-environment interactions to modulate disease manifestation, advocating for precision medicine in PF. Insights from gene expression profiling studies and multiomic analyses highlight the promise for understanding disease pathogenesis and offer new approaches to clinical care, therapeutic drug development, and biomarker discovery. Finally, we discuss the ethical, legal, and social implications of genomic research and therapies in PF, stressing the need for sound practices and informed clinical genetic discussions. Looking forward, we advocate for comprehensive genetic testing panels and polygenic risk scores to improve the management of PF and related ILDs across diverse populations.

Pulmonary Fibrosis Stakeholder Summit: A Joint NHLBI, Three Lakes Foundation, and Pulmonary Fibrosis Foundation Workshop Report.

Despite progress in elucidation of disease mechanisms, identification of risk factors, biomarker discovery, and the approval of two medications to slow lung function decline in idiopathic pulmonary fibrosis and one medication to slow lung function decline in progressive pulmonary fibrosis, pulmonary fibrosis remains a disease with a high morbidity and mortality. In recognition of the need to catalyze ongoing advances and collaboration in the field of pulmonary fibrosis, the NHLBI, the Three Lakes Foundation, and the Pulmonary Fibrosis Foundation hosted the Pulmonary Fibrosis Stakeholder Summit on November 8-9, 2022. This workshop was held virtually and was organized into three topic areas: 1) novel models and research tools to better study pulmonary fibrosis and uncover new therapies, 2) early disease risk factors and methods to improve diagnosis, and 3) innovative approaches toward clinical trial design for pulmonary fibrosis. In this workshop report, we summarize the content of the presentations and discussions, enumerating research opportunities for advancing our understanding of the pathogenesis, treatment, and outcomes of pulmonary fibrosis.

Causes and Effects of COVID-19 Vaccine Hesitancy Among Pregnant Women and its Association with Adverse Maternal, Placental, and Perinatal Outcomes.

Populations identified to be severely affected by COVID-19, such as pregnant patients, require special consideration in vaccine counseling, access, and provider education. Maternal infection with COVID-19 poses a significant risk to the maternal-fetal dyad with known adverse placenta destruction [1-5]. Despite the widespread access and availability of vaccinations, vaccine hesitancy continues to persist and is highly prevalent in pregnant populations [6-9]. Addressing the multitude of social ecological factors surrounding vaccine hesitancy can aid in providing holistic counseling [10]. However, such factors are foremost shaped by maternal concern over possible fetal effects from vaccination. While changes in policy can help foster vaccine access and acceptance, increasing global provider education and incorporation of motivational interviewing skills are the first steps towards increasing maternal acceptance.

High Rates of Miscarriage and Stillbirth among Pregnant Women with Clade I Mpox (Monkeypox) Are Confirmed during 2023-2024 DR Congo Outbreak in South Kivu Province.

Mpox (monkeypox) is a neglected tropical disease that has received increased attention since the multi-nation outbreak that began in 2022. The virus is endemic in West and Central Africa, where the Democratic Republic of the Congo (DRC) is the most affected country. Clade I monkeypox virus (MPXV) infection is endemic in the DRC and has an overall case fatality rate of 10.6% among children and adults. A study conducted in Sankuru Province, DRC, from 2007 to 2011 demonstrated that 75% of pregnant women with mpox had miscarriages or stillbirth. Further analysis of a stillborn fetus showed that MPXV could infect both the placenta and fetus, causing congenital infection. No additional cases of Clade I MPXV in pregnant women were reported until a new outbreak occurred in South Kivu Province during 2023 and 2024. Eight pregnant women having Clade I MPXV infection were identified, of whom four had either miscarriages or stillbirth, representing a 50% fetal mortality rate. These reports confirm previous data from the DRC that indicate the capability of Clade I MPXV to affect the fetus, causing congenital infection and fetal loss in a high percentage of cases. In this article, we review both past and new data from the DRC on the effects of Clade I MPXV during pregnancy and discuss the association of mpox with fetal loss.

Enhancing Health Care Accessibility and Equity Through a Geoprocessing Toolbox for Spatial Accessibility Analysis: Development and Case Study.

BACKGROUND: Access to health care services is a critical determinant of population health and well-being. Measuring spatial accessibility to health services is essential for understanding health care distribution and addressing potential inequities. OBJECTIVE: In this study, we developed a geoprocessing toolbox including Python script tools for the ArcGIS Pro environment to measure the spatial accessibility of health services using both classic and enhanced versions of the 2-step floating catchment area method. METHODS: Each of our tools incorporated both distance buffers and travel time catchments to calculate accessibility scores based on users' choices. Additionally, we developed a separate tool to create travel time catchments that is compatible with both locally available network data sets and ArcGIS Online data sources. We conducted a case study focusing on the accessibility of hemodialysis services in the state of Tennessee using the 4 versions of the accessibility tools. Notably, the calculation of the target population considered age as a significant nonspatial factor influencing hemodialysis service accessibility. Weighted populations were calculated using end-stage renal disease incidence rates in different age groups. RESULTS: The implemented tools are made accessible through ArcGIS Online for free use by the research community. The case study revealed disparities in the accessibility of hemodialysis services, with urban areas demonstrating higher scores compared to rural and suburban regions. CONCLUSIONS: These geoprocessing tools can serve as valuable decision-support resources for health care providers, organizations, and policy makers to improve equitable access to health care services. This comprehensive approach to measuring spatial accessibility can empower health care stakeholders to address health care distribution challenges effectively.

Evaluating the effectiveness of a sliding window technique in machine learning models for mortality prediction in ICU cardiac arrest patients.

Extensive research has been devoted to predicting ICU mortality, to assist clinical teams managing critical patients. Electronic health records (EHR) contain both static and dynamic medical data, with the latter accumulating during ICU stays. Existing models often rely on a fixed time window (e.g., first 24 h) for prediction, potentially missing vital post-24-hour data. The present study aims to improve mortality prediction for ICU patients following Cardiac Arrest (CA) using a dynamic sliding window approach that accommodates evolving data characteristics. Our cohort included 2331 CA patients, of whom 684 died in the ICU and 1647 survived. Applying the sliding window technique, we created six different time windows and used each separately for model training and validation. We compared our results to a baseline accumulative window. The different time windows created by the sliding window technique differed in their prediction performance and outperformed the baseline 24-hour window significantly. The XGBoost model outperformed all other models, with the 30-42 h time window achieving the best results (AUC = 0.8, accuracy = 0.77). Our work shows that the sliding window technique is effective in improving mortality prediction. We demonstrated how important time-window selection is and showed that enhancing it can save time and thus improve mortality prediction. These findings promise to improve the clinical team's efficiency in prioritizing patients and giving greater attention to higher-risk patients. To conclude, mortality prediction in the ICU can be improved if we consider alternative time windows instead of the 24-hour window, which is currently the most widely accepted among scoring systems today.

Academic achievement, same- and cross-ethnic positive peer regard among Asian American and Latinx adolescents.

This article presents a short-term longitudinal study examining bidirectional associations between academic achievement and positive peer regard among Asian American and Latinx adolescents. Specifically, our investigation distinguished between positive peer regard within and across different ethnic groups in a diverse school setting. Three hundred and thirty-five middle school students (52.8% girls; 65% Asian American, 35% Latinx; assessment at the first time point Mage = 12.27 years, SD = 0.71) were followed across two consecutive school years. Participants completed a peer-nomination inventory assessing multiple dimensions of positive peer regard (i.e., reciprocal friendship, social acceptance, and respect), and grades were obtained from school records. Academic achievement was predictive of prospective positive peer regard received from same-ethnic peers only for Asian American adolescents. In contrast, academic achievement predicted prospective positive peer regard received from cross-ethnic peers only for Latinx adolescents. These results suggest that academic achievement was linked to social gains with peers from different ethnic backgrounds for Asian American and Latinx students. The findings underscore the importance of disentangling the sources of positive peer regard in multiethnic school environments. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A mixed methods evaluation of family-driven care implementation in juvenile justice agencies in Georgia.

BACKGROUND: Improving family engagement in juvenile justice (JJ) system behavioral health services is a high priority for JJ systems, reform organizations, and family advocacy groups across the United States. Family-driven care (FDC) is a family engagement framework used by youth-serving systems to elevate family voice and decision-making power at all levels of the organization. Key domains of a family-driven system of care include: 1) identifying and involving families in all processes, 2) informing families with accurate, understandable, and transparent information, 3) collaborating with families to make decisions and plan treatments, 4) responding to family diversity and inclusion, 5) partnering with families to make organizational decisions and policy changes, 6) providing opportunities for family peer support, 7) providing logistical support to help families overcome barriers to participation, and 8) addressing family health and functioning. FDC enhances family participation, empowerment, and decision-making power in youth services; ultimately, improving youth and family behavioral health outcomes, enhancing family-child connectedness, and reducing youth recidivism in the JJ setting. METHODS: We evaluated staff-perceived adoption of the eight domains of FDC across detention and community services agencies in the state of Georgia. We collected mixed methods data involving surveys and in-depth qualitative interviews with JJ system administrators, staff, and practitioners between November 2021- July 2022. In total, 140 individuals from 61 unique JJ agencies participated in surveys; and 16 JJ key informants participated in qualitative interviews. RESULTS: FDC domains with the highest perceived adoption across agencies included identifying and involving families, informing families, collaborative decision-making and treatment planning, and family diversity and inclusion. Other domains that had mixed or lower perceived adoption included involving families in organizational feedback and policy making, family peer support, logistical support, and family health and functioning. Adoption of FDC domains differed across staff and organizational characteristics. CONCLUSIONS: Findings from this mixed methods assessment will inform strategic planning for the scale-up of FDC strategies across JJ agencies in the state, and serve as a template for assessing strengths and weaknesses in the application of family engagement practices in systems nationally.

Towards an Explainable AI Platform to Study Interruptions in Cancer Radiation Therapy.

Radiation therapy interruptions drive cancer treatment failures; they represent an untapped opportunity for improving outcomes and narrowing treatment disparities. This research reports on the early development of the X-CART platform, which uses explainable AI to model cancer treatment outcome metrics based on high-dimensional associations with our local social determinants of health dataset to identify and explain causal pathways linking social disadvantage with increased radiation therapy interruptions.

Carbapenem-resistant Acinetobacter baumannii carrier detection: a simple and efficient protocol.

Timely detection of carbapenem-resistant Acinetobacter baumannii (CRAB) carriers is essential to direct infection control measures. In this work, we aimed to develop a practical protocol to detect CRAB from screening samples. To choose a selective medium that detects CRAB with high sensitivity and specificity, 111 A. baumannii clinical isolates were inoculated on three types of agar: mSuperCARBA (SC), CHROMagar Acinetobacter (CaA), and modified CHROMagar Acinetobacter (mCaA) containing 4.5 mg/mL meropenem. SC was non-selective, CaA was the most sensitive (100%), but only moderately specific (72%), and mCaA was highly specific (97%) and sensitive (98%). Confirmation of the carbapenem-resistant phenotype using PCR-based detection of blaOXA-23, blaOXA-24, and blaOXA-58 genes was specific but not sensitive, detecting only 58% of CRAB isolates. Identification of A. baumannii using either gyrB or blaOXA-51 PCR was excellent. Next, we used the same methodology in routine screening for CRAB carriage. mCaA had the best yield, with high sensitivity but moderate specificity to differentiate between CRAB and other carbapenem-resistant organisms. Skin sampling using sponges and 6 hour enrichment was highly sensitive (98%), while other body sites had poor sensitivity (27%- 41%). Shorter incubation had slightly lower yield, and longer incubation did not improve the detection. Performing PCR for blaOXA-51 and gyrB on colonies growing on modified mCaA differentiated between CRAB and other species with high accuracy (98% and 99%, respectively). Based on our results, we present a procedure for easy and reliable detection of CRAB carriage using skin sampling, short enrichment, selection on mCaA, and PCR-based identification. IMPORTANCE: Carbapenem-resistant Acinetobacter baumannii (CRAB) is a substantial cause of nosocomial infections, classified among the most significant multidrug-resistant pathogens by the World Health Organization and by the US Centers for Disease Control. Limiting the spread of CRAB is an important goal of infection control, but laboratory methods for identification of CRAB carriers are not standardized. In this work, we compared different selective agar plates, tested the efficiency of A. baumannii identification by PCR for species-specific genes, and used PCR-based detection of common resistance genes to confirm the carbapenem-resistant phenotype. During a prospective study, we also determined the optimal sample enrichment time. Based on our results, we propose a simple and efficient protocol for the detection of CRAB carriage using skin sampling, short enrichment, selection on appropriate agar plates, and PCR-based identification, resulting in a turn-around time of 24 hours.

Efficacy and Safety of Filgotinib for the Treatment of Perianal Fistulising Crohn's Disease [DIVERGENCE 2]: A Phase 2, Randomised, Placebo-controlled Trial.

BACKGROUND AND AIMS: There is an unmet need in the treatment of perianal fistulising Crohn's disease [PFCD]. This study evaluated the efficacy and safety of the Janus kinase 1 preferential inhibitor, filgotinib, for the treatment of PFCD. METHODS: This phase 2, double-blind, multicentre trial enrolled adults with PFCD and prior treatment failure. Participants were randomised [2:2:1] to receive filgotinib 200 mg, filgotinib 100 mg, or placebo, once daily orally for up to 24 weeks. The primary endpoint was combined fistula response (reduction from baseline of at least one draining external opening determined by physical assessment, and no fluid collections >1 cm on pelvic magnetic resonance imaging [MRI]) at Week 24. RESULTS: Between April 2017 and July 2020, 106 individuals were screened and 57 were randomised. Discontinuations were lowest in the filgotinib 200 mg group (3/17 [17.6%] versus 13/25 [52.0%] for filgotinib 100 mg and 9/15 [60.0%] for placebo). The proportion of participants who achieved a combined fistula response at Week 24 was 47.1% (8/17; 90% confidence interval [CI] 26.0, 68.9%) in the filgotinib 200 mg group, 29.2% [7/24; 90% CI 14.6, 47.9%] in the filgotinib 100 mg group, and 25.0% [3/12; 90% CI 7.2, 52.7%] in the placebo group. Serious adverse events occurred more frequently with filgotinib 200 mg (5/17 [29.4%]) than with placebo (1/15 [6.7%]). There were no treatment-related serious adverse events or deaths. CONCLUSIONS: Filgotinib 200 mg was associated with numerical reductions in the number of draining perianal fistulas based on combined clinical and MRI findings compared with placebo, and was generally well tolerated [NCT03077412].

'Gel-Stacks' gently confine or reversibly immobilize arrays of single DNA molecules for manipulation and study.

Large DNA molecules (>20 kb) are difficult analytes prone to breakage during serial manipulations and cannot be 'rescued' as full-length amplicons. Accordingly, to present, modify and analyze arrays of large, single DNA molecules, we created an easily realizable approach offering gentle confinement conditions or immobilization via spermidine condensation for controlled delivery of reagents that support live imaging by epifluorescence microscopy termed 'Gel-Stacks.' Molecules are locally confined between two hydrogel surfaces without covalent tethering to support time-lapse imaging and multistep workflows that accommodate large DNA molecules. With a thin polyacrylamide gel layer covalently bound to a glass surface as the base and swappable, reagent-infused, agarose slabs on top, DNA molecules are stably presented for imaging during reagent delivery by passive diffusion.

Gel-Stacks technology provides multiple non-covalent molecular presentation modes, coupled with an unusually facile reagent delivery system designed for large-scale analytes, enhancing live imaging and manipulation. Enhanced further by modeling and software, Gel-Stacks technology becomes adaptable to a broad range of experimental applications.

Contextual determinants of family-driven care implementation in juvenile justice settings.

INTRODUCTION: Engaging families in behavioral health services is a high priority for juvenile justice (JJ) systems and family advocacy groups. Family-driven care (FDC) enhances family engagement and decision-making power in youth behavioral health services, ultimately, improving youth and family mental health and substance abuse outcomes. Despite the benefits, there is limited guidance on how to integrate FDC into behavioral health care within the JJ system. Therefore, the goal of this study is to understand factors that promoted adoption of FDC the JJ context. METHODS: JJ staff and leadership across the state of Georgia participated in surveys and interviews to understand contextual implementation determinants related to the adoption of FDC. Between November 2021- July 2022, 140 JJ staff participated in the survey from 61 unique JJ organizations. In addition, 16 staff participated in follow-up key informant interviews to explain quantitative findings. RESULTS: Based on a mixed methods analysis, JJ agencies were more likely to implement FDC if they had the following characteristics: (1) presence of site leaders that were strongly committed to family engagement, (2) a shared understanding that family engagement was a top priority, (3) staff training related to family engagement, (4) external partnerships with organizations that serve families, (5) a workplace culture that was supportive of innovation, and (6) presence of family engagement programs that were easier (or more feasible) for staff to implement. DISCUSSION: This mixed methods study underscores the importance of strengthening these 6 inner and outer setting implementation determinants when preparing to integrate FDC into JJ systems. Findings are used to promote the adoption and delivery of this high priority intervention in a state-level JJ system.

The Comorbidity of Patient-Reported Crohn's Disease Activity and Depression: The Role of Health Behavior Mediators.

Background: Longitudinal research reveals a unidirectional relationship between a nonsomatic symptom of depression, a negative view of the self, and later reported Crohn's disease (CD) activity. We evaluated whether health behaviors mediated this association using a longitudinal design. Methods: We studied 3304 adult volunteers with a self-reported diagnosis of CD who completed a baseline survey that included demographics, CD activity, a symptom-specific index of depression, and measures of physical activity, smoking, and sleep quality. Crohn's disease status and the cognitive index of depression were also measured 6 and 12 months after the baseline evaluation. We specified single-mediator and multiple-mediator models to elucidate the depression-disease activity relationship. Results: Among 2395 females and 909 males, we found a significant mediation effect for activity level (P < .001) after adjusting for age, sex, and body mass index. There was no evidence that sleep quality and smoking are significant single mediators. When we considered multiple mediation models, smoking and less activity partially mediate the depression-CD association. Conclusions: Smoking and lower levels of physical activity are potential mediators of the unidirectional association between a nonsomatic symptom of depression-a negative view of the self-and patient-reported CD activity. Evaluating and treating specific symptoms of depression may reduce the frequency of CD exacerbations.

Impact of SARS-CoV-2 infection during pregnancy on the placenta and fetus.

Pregnant people and their fetuses are vulnerable to adverse health outcomes from coronavirus 2019 disease (COVID-19) due to infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has been associated with higher rates of maternal mortality, preterm birth, and stillbirth. While SARS-CoV-2 infection of the placenta and vertical transmission is rare, this may be due to the typically longer time interval between maternal infection and testing of the placenta and neonate. Placental injury is evident in cases of SARS-CoV-2-associated stillbirth with massive perivillous fibrin deposition, chronic histiocytic intervillositis, and trophoblast necrosis. Maternal COVID-19 can also polarize fetal immunity, which may have long-term effects on neurodevelopment. Although the COVID-19 pandemic continues to evolve, the impact of emerging SARS-CoV-2 variants on placental and perinatal injury/mortality remains concerning for maternal and perinatal health. Here, we highlight the impact of COVID-19 on the placenta and fetus and remaining knowledge gaps.

Piloting delivery of PfSPZ vaccines for malaria through a cryogenic vaccine cold chain to travel and military medicine clinics.

BACKGROUND: PfSPZ vaccines comprising Plasmodium falciparum (Pf) sporozoites (SPZ) have demonstrated > 90% protection against variant Pf malaria infections for at least 12 weeks; they are the only vaccines with the level of efficacy necessary to protect travellers. PfSPZ are eukaryotic cells stabilized by cryopreservation and distributed using a cryogenic (below -150 °C) cold chain. The Ebola vaccine and mRNA vaccines against SARS-CoV-2 pioneered uptake of vaccines requiring non-standard ultra-low temperature cold chains. The cryogenic cold chain using liquid nitrogen (LN2) vapour phase (LNVP) cryoshippers, is simpler, more efficient than -80, -20 or 2-8 °C cold chains, and does not use electricity. This study was conducted to evaluate implementation and integration of a cryogenically distributed vaccine at travel and military immunization clinics. METHODS: We conducted sequential 28-day studies evaluating vaccine shipping, storage, maintenance and accession at two US military and two civilian travel health/immunization clinics. In each clinic, personnel were trained in equipment use, procurement and handling of LN2, temperature monitoring and inventory record keeping by in-person or video instruction. RESULTS: Sites required 2-4 h/person for two persons to assimilate and develop the expertise to manage vaccine storage and LNVP operations. LN2 for recharging cryoshippers was delivered every 1-2 weeks. Vaccine ordering, receipt, storage and inventory control was conducted effectively. Simulated single dose vaccine cryovial retrieval and thawing were performed successfully in different travel clinic settings. Continuous temperature monitoring at each site was maintained with only one short excursion above -150 °C (-145 °C) through shipping, use and reverse logistics. Staff, during and at study conclusion, provided feedback that has been incorporated into our models for cold chain logistics. CONCLUSIONS: These studies demonstrated that the training in delivery, storage, administration and integration of PfSPZ vaccines can be successfully managed in different immunization clinic settings for travellers and military personnel.

Blinatumomab after R-CHOP bridging therapy for patients with Richter transformation: a phase 2 multicentre trial.

Richter transformation (RT) is an aggressive lymphoma occurring in patients with chronic lymphocytic leukaemia. Here we investigated the anti-CD3/anti-CD19 T-cell-engager blinatumomab after R-CHOP (i.e. rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with untreated RT of diffuse large B-cell lymphoma histology (NCT03931642). In this multicentre phase 2 study, patients without complete response (CR) after two cycles of R-CHOP were eligible to receive an 8-week blinatumomab induction via continuous vein infusion with stepwise dosing until 112 µg/day. The primary endpoint was the CR rate after blinatumomab induction and secondary endpoint included safety, response duration, progression-free and overall survival. Thirty-nine patients started the first cycle of R-CHOP, 25 of whom received blinatumomab. After blinatumomab induction, five (20%) patients achieved CR, four (16%) achieved partial response, and six (24%) were stable. Considering the entire strategy, the overall response rate in the full-analysis-set was 46% (n = 18), with CR in 14 (36%) patients. The most common treatment-emergent adverse events of all grades in the blinatumomab-safety-set included fever (36%), anaemia (24%), and lymphopaenia (24%). Cytokine release syndrome (grade 1/2) was observed in 16% and neurotoxicity in 20% of patients. Blinatumomab demonstrated encouraging anti-tumour activity (the trial met its primary endpoint) and acceptable toxicity in patients with RT.

Demographic and Clinical Factors Associated With SARS-CoV-2 Spike 1 Antibody Response Among Vaccinated US Adults: the C4R Study.

This study investigates correlates of anti-S1 antibody response following COVID-19 vaccination in a U.S. population-based meta-cohort of adults participating in longstanding NIH-funded cohort studies. Anti-S1 antibodies were measured from dried blood spots collected between February 2021-August 2022 using Luminex-based microsphere immunoassays. Of 6245 participants, mean age was 73 years (range, 21-100), 58% were female, and 76% were non-Hispanic White. Nearly 52% of participants received the BNT162b2 vaccine and 48% received the mRNA-1273 vaccine. Lower anti-S1 antibody levels are associated with age of 65 years or older, male sex, higher body mass index, smoking, diabetes, COPD and receipt of BNT16b2 vaccine (vs mRNA-1273). Participants with a prior infection, particularly those with a history of hospitalized illness, have higher anti-S1 antibody levels. These results suggest that adults with certain socio-demographic and clinical characteristics may have less robust antibody responses to COVID-19 vaccination and could be prioritized for more frequent re-vaccination.

Genome-wide SNP-sex interaction analysis of susceptibility to idiopathic pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic lung condition that is more prevalent in males than females. The reasons for this are not fully understood, with differing environmental exposures due to historically sex-biased occupations, or diagnostic bias, being possible explanations. To date, over 20 independent genetic variants have been identified to be associated with IPF susceptibility, but these have been discovered when combining males and females. Our aim was to test for the presence of sex-specific associations with IPF susceptibility and assess whether there is a need to consider sex-specific effects when evaluating genetic risk in clinical prediction models for IPF. Methods: We performed genome-wide single nucleotide polymorphism (SNP)-by-sex interaction studies of IPF risk in six independent IPF case-control studies and combined them using inverse-variance weighted fixed effect meta-analysis. In total, 4,561 cases (1,280 females and 2,281 males) and 23,500 controls (8,360 females and 14,528 males) of European genetic ancestry were analysed. We used polygenic risk scores (PRS) to assess differences in genetic risk prediction between males and females. Findings: Three independent genetic association signals were identified. All showed a consistent direction of effect across all individual IPF studies and an opposite direction of effect in IPF susceptibility between females and males. None had been previously identified in IPF susceptibility genome-wide association studies (GWAS). The predictive accuracy of the PRSs were similar between males and females, regardless of whether using combined or sex-specific GWAS results. Interpretation: We prioritised three genetic variants whose effect on IPF risk may be modified by sex, however these require further study. We found no evidence that the predictive accuracy of common SNP-based PRSs varies significantly between males and females.