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Miliary coccidioidomycosis is a severe manifestation of diseases caused by Coccidioides immitis and Coccidioides posadasii that is endemic to the southwestern United States as well as Central and South America. While most cases of coccidioidomycosis present with pulmonary disease, certain risk factors increase the risk for disseminated disease. We present a case of miliary coccidioidomycosis in a 46-year-old patient with uncontrolled diabetes. Additionally, we review the features of thirty-seven cases of patients with miliary coccidioidomycosis.

Objectives Mycophenolate mofetil (MMF) and azathioprine (AZA) are immunomodulatory treatments in interstitial lung disease (ILD). This systematic review aimed to evaluate the efficacy of MMF or AZA on pulmonary function in ILD.Design Population included any ILD diagnosis, intervention included MMF or AZA treatment, outcome was delta change from baseline in per cent predicted forced vital capacity (%FVC) and gas transfer (diffusion lung capacity of carbon monoxide, %DLco). The primary endpoint compared outcomes relative to placebo comparator, the secondary endpoint assessed outcomes in treated groups only.Eligibility criteria Randomised controlled trials (RCTs) and prospective observational studies were included. No language restrictions were applied. Retrospective studies and studies with high-dose concomitant steroids were excluded.Data synthesis The systematic search was performed on 9 May. Meta-analyses according to drug and outcome were specified with random effects, I2 evaluated heterogeneity and Grading of Recommendations, Assessment, Development and Evaluation evaluated certainty of evidence. Primary endpoint analysis was restricted to RCT design, secondary endpoint included subgroup analysis according to prospective observational or RCT design.Results A total of 2831 publications were screened, 12 were suitable for quantitative synthesis. Three MMF RCTs were included with no significant effect on the primary endpoints (%FVC 2.94, 95% CI −4.00 to 9.88, I2=79.3%; %DLco −2.03, 95% CI −4.38 to 0.32, I2=0.0%). An overall 2.03% change from baseline in %FVC (95% CI 0.65 to 3.42, I2=0.0%) was observed in MMF, and RCT subgroup summary estimated a 4.42% change from baseline in %DLCO (95% CI 2.05 to 6.79, I2=0.0%). AZA studies were limited. All estimates were considered very low certainty evidence.Conclusions There were limited RCTs of MMF or AZA and their benefit in ILD was of very low certainty. MMF may support preservation of pulmonary function, yet confidence in the effect was weak. To support high certainty evidence, RCTs should be designed to directly assess MMF efficacy in ILD.PROSPERO registration number CRD42023423223.

Abstract Background Spinal manipulative therapy (SMT) is commonly used to treat musculoskeletal conditions, including thoracic spine pain. Applying patient-specific force-time characteristics are believed to be important to improve SMT’s effectiveness. Investigating SMT as part of a multimodal approach is fundamental to account for the complexity of chiropractic clinical practice. Therefore, pragmatic investigations balancing minimal disruptions to the clinical encounter at the same time as ensuring a robust data quality with rigorous protocols are needed. Consequently, preliminary studies are required to assess the study protocol, quality of data recorded and the sustainability of such investigation. Therefore, this study examined the feasibility of investigating SMT force-time characteristics and clinical outcome measures in a clinical setting. Methods In this mixed-methods study, providers recorded thoracic SMT force-time characteristics delivered to patients with thoracic spinal pain during regular clinical encounters. Self-reported clinical outcomes of pain, stiffness, comfort during the SMT (using an electronic visual analogue scale), and global rating of change scale were measured before and after each SMT application. Feasibility was quantitatively assessed for participant recruitment, data collection and data quality. Qualitative data assessed participants’ perceptions on the impact of data collection on patient management and clinical flow. Results Twelve providers (58% female, 27.3 ± 5.0 years old) and twelve patients (58% female, 37.2 ± 14.0 years old) participated in the study. Enrolment rate was greater than 40%, data collection rate was 49% and erroneous data was less than 5%. Participant acceptance was good with both providers and patients reporting positive experience with the study. Conclusions Recording SMT force-time characteristics and self-reported clinical outcome measures during a clinical encounter may be feasible with specific modification to the current protocol. The study protocol did not negatively impact patient management. Specific strategies to optimize the data collection protocol for the development of a large clinical database are being developed.

Abstract Introduction Adverse drug events (ADEs) are associated with poor outcomes and increased costs but may be prevented with prediction tools. With the National Institute of Health All of Us (AoU) database, we employed machine learning (ML) to predict selective serotonin reuptake inhibitor (SSRI)-associated bleeding. Methods The AoU program, beginning in 05/2018, continues to recruit ≥ 18 years old individuals across the United States. Participants completed surveys and consented to contribute electronic health record (EHR) for research. Using the EHR, we determined participants who were exposed to SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, vortioxetine). Features (n = 88) were selected with clinicians’ input and comprised sociodemographic, lifestyle, comorbidities, and medication use information. We identified bleeding events with validated EHR algorithms and applied logistic regression, decision tree, random forest, and extreme gradient boost to predict bleeding during SSRI exposure. We assessed model performance with area under the receiver operating characteristic curve statistic (AUC) and defined clinically significant features as resulting in > 0.01 decline in AUC after removal from the model, in three of four ML models. Results There were 10,362 participants exposed to SSRIs, with 9.6% experiencing a bleeding event during SSRI exposure. For each SSRI, performance across all four ML models was relatively consistent. AUCs from the best models ranged 0.632–0.698. Clinically significant features included health literacy for escitalopram, and bleeding history and socioeconomic status for all SSRIs. Conclusions We demonstrated feasibility of predicting ADEs using ML. Incorporating genomic features and drug interactions with deep learning models may improve ADE prediction.

Building envelopes are not only the prime element of the exterior aesthetic quality of buildings; they have also become a major driver both for building construction cost and operational performance. The importance of prefabrication is growing in the building industry as it allows faster, high-quality, and cost-effective construction while reducing risks associated with onsite labour. Although prefabrication for structural components is a relatively recent development, it has been widely used in the manufacturing of building envelopes for many years, particularly in the case of unitized curtain wall systems. However, whether using prefabricated components or not, façade design development remains a challenge due to the need for façade engineers to rapidly develop technically viable and financially feasible solutions that achieve the desired architectural design intent. Particularly at the early stages of the design process, the turnaround for multiple iterations is often fast-paced, and abortive work is, therefore, not uncommon. This paper outlines an approach to addressing this challenge, attempting to bridge the gap between façade design, fabrication, and installation. A new design approach and tools are presented that allow designers to iteratively validate concepts based on a pre-engineered system that is optimized for performance and take fabrication, transport, installation costs, maintenance, and circularity into account. As a result, the tool/design workflow will ensure consistent quality, meeting budgets and timelines while enhancing material efficiency and fostering energy-conscious and circular envelope design approaches.

Abstract Background Diagnostic imaging is useful for assessing low back pain (LBP) when a clinician suspects a specific underlying pathology. Evidence-based imaging guidelines assist clinicians in appropriately determining the need for imaging when assessing LBP. A previous study reported high adherence to three clinical guidelines, with utilization rate of 12.3% in imaging of LBP patients attending a chiropractic teaching clinic. A new imaging guideline for spinal disorders has been published and used in teaching. Thus, the aims of our study were to assess the adherence to the new guideline and X-ray utilization in new episodes of LBP. Methods We conducted a historical clinical cohort study using patient electronic health record audits at seven teaching clinics over a period of 20 months. Records of patients who were at least 18 years of age, presented with a new onset of LBP, and consented to data collection were included. Abstracted data included patient demographics, the number and type of red flags, and the decision to image. Rate of guideline adherence (proportion of those not recommended for imaging, given no red flags) and rate of image utilization were descriptively analyzed. Results We included 498 patients in this study. At least 81% of included patients had one or more red flags reported. The most commonly reported individual red flag was age ≥ 50 (43.8%) followed by pain at rest (15.7%). In those referred for imaging, age ≥ 50 (93.3%) was the most frequently reported red flag. No red flag(s) were identified in 93 patient records, and none were referred for imaging of their LBP, yielding an adherence rate of 100% (95% CI 96, 100%). A total of 17 of 498 patients were recommended for imaging for their low back pain, resulting in an imaging utilization rate of 3.4% (95% CI 1.8, 5.0%). Conclusion The imaging utilization rate was 3.4%, lower than 12.3% previously reported at a chiropractic teaching clinic. None without red flags were referred for imaging, yielding a 100%, adherence rate to current LBP imaging guidelines. Future research should consider currency of guideline, accuracy of red flags and factors influencing clinicians’ decision, when assessing imaging adherence rates.

Abstract Background Clinical care pathways may be useful tools to improve the quality of healthcare by facilitating the translation of evidence into practice. Our study is situated within a larger project, whereby end-users co-developed a care pathway for the management of shoulder pain. In this study, we explored end-user perceptions of the usefulness and practicality of implementing a care pathway to manage shoulder pain. We also solicited feedback for the pathway’s improvement. Methods We conducted a qualitative study using a transcendental phenomenological approach seen through a constructivist lens. Clinicians recorded themselves interacting with the care pathway while working through a clinical case. Clinicians described their thoughts and movements aloud as they completed the activity. Second, we conducted individual semi-structured interviews to discuss the usefulness and practicality of pathway implementation. Interview transcripts were coded independently by reviewers. Transcript codes and associated quotes were grouped into themes. Themes were sequenced and linked creating a ‘web’ of thematic connections. Summary statements were developed to synthesize the overall essence of the phenomena. Results Nine clinicians participated. Participants included eight chiropractors and one medical physician. We found that clinicians believed the care pathway could be useful at various levels, including education (students, interns), for early career clinicians, for engaging patients, facilitating interprofessional communication, and as a reminder of information for certain, less familiar conditions. When discussing the practicality of implementing the care pathway into practice settings, clinicians expressed that agreement with the care pathway and its recommendations may influence its acceptability among clinicians. Additionally, integrating recommendations into practice may be a skill requirement included into clinical training. Clinicians described the importance of opinion leaders in the acceptability of new evidence. Various difficulties with the replicability of interventions into clinical care was also discussed. In general, clinicians suggested the layout of the care pathway was manageable, and there was sufficient information for clinical decision-making. Clinicians also made several recommendations for improvement. Conclusions End-user involvement and collaboration provides tangible instruction to improve care pathways themselves, their implementation strategies and helps to support and strengthen future research for overcoming individual, systemic and contextual barriers.

Complex structural variants (CSVs) are genomic alterations that have more than two breakpoints and are considered as the simultaneous occurrence of simple structural variants. However, detecting the compounded mutational signals of CSVs is challenging through a commonly used model-match strategy. As a result, there has been limited progress for CSV discovery compared with simple structural variants. Here, we systematically analyzed the multi-breakpoint connection feature of CSVs, and proposed Mako, utilizing a bottom-up guided model-free strategy, to detect CSVs from paired-end short-read sequencing. Specifically, we implemented a graph-based pattern growth approach, where the graph depicts potential breakpoint connections, and pattern growth enables CSV detection without pre-defined models. Comprehensive evaluations on both simulated and real datasets revealed that Mako outperformed other algorithms. Notably, validation rates of CSVs on real data based on experimental and computational validations as well as manual inspections are around 70%, where the medians of experimental and computational breakpoint shift are 13 bp and 26 bp, respectively. Moreover, the Mako CSV subgraph effectively characterized the breakpoint connections of a CSV event and uncovered a total of 15 CSV types, including two novel types of adjacent segment swap and tandem dispersed duplication. Further analysis of these CSVs also revealed the impact of sequence homology on the formation of CSVs. Mako is publicly available at https://github.com/xjtu-omics/Mako.

Colorectal cancer (CRC) can be demanding for primary caregivers; yet, there is insufficient evidence describing the caregiver-reported outcomes (CROs) that matter most to caregivers. CROs refer to caregivers’ assessments of their own health status as a result of supporting a patient. The study purpose was to describe the emotions that were most impactful to caregivers of patients with CRC, and how the importance caregivers attribute to these emotions changed from diagnosis throughout treatment. Guided by qualitative Interpretive Description, we analyzed 25 caregiver and 37 CRC patient interviews, either as individuals or as caregiver-patient dyads (six interviews), using inductive coding and constant comparative techniques. We found that the emotional aspect of caring for a patient with CRC was at the heart of caregiving. Caregiver experiences that engendered emotions of consequence included: (1) facing the patient’s life-changing diagnosis and an uncertain future, (2) needing to be with the patient throughout the never-ending nightmare of treatment, (3) bearing witness to patient suffering, (4) being worn down by unrelenting caregiver responsibilities, (5) navigating their relationship, and (6) enduring unwanted change. The broad range of emotions important to caregivers contributes to comprehensive foundational evidence for future conceptualization and the use of CROs.

Abstract Background End-user involvement in developing evidence-based tools for clinical practice may result in increased uptake and improved patient outcomes. Understanding end-user experiences and perceptions about the co-production of knowledge is useful to further the science of integrated knowledge translation (iKT) – a strategy for accelerating the uptake and impact of research. Our study had two main objectives: (1) explore end-user (clinician) experiences of co-producing an evidence-based practice tool; and (2) describe end-user perceptions in knowledge development. Methods We used a qualitative study design. We conducted semi-structured interviews with clinicians and used a transcendental phenomenological approach to analyze themes/phenomena. In addition, we explored the interrelated themes between the thematic maps of each objective. Results Four themes emerged from clinicians’ experiences in co-producing the practice tool: ease/convenience of participating, need for support and encouragement, understanding the value of participating, and individual skillsets yield meaningful contributions. Stakeholder roles in knowledge tool development and improving dissemination of evidence and knowledge tools were themes that related to clinician perceptions in knowledge development. The review of interrelated thematic maps depicts an intertwined relationship between stakeholders and dissemination. Conclusions End-users provide invaluable insight and perspective into the development of evidence-based clinical tools. Exploring the experiences and perceptions of end-users may support future research endeavours involving iKT, such as the co-production of clinical resources, potentially improving uptake and patient health outcomes.

Summary: Spinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant disorder caused by an expanded pentanucleotide repeat in the ATXN10 gene. This repeat expansion, when fully penetrant, has a size of 850–4,500 repeats. It has been shown that the repeat composition can be a modifier of disease, e.g., seizures. Here, we describe a Mexican kindred in which we identified both pure (ATTCT)n and mixed (ATTCT)n-(ATTCC)n expansions in the same family. We used amplification-free targeted sequencing and optical genome mapping to decipher the composition of these repeat expansions. We found a considerable degree of mosaicism of the repeat expansion. This mosaicism was confirmed in skin fibroblasts from individuals with ATXN10 expansions with RNAScope in situ hybridization. All affected family members with the mixed ATXN10 repeat expansion showed typical clinical signs of spinocerebellar ataxia and epilepsy. In contrast, individuals with the pure ATXN10 expansion present with Parkinson's disease or are unaffected, even in individuals more than 20 years older than the average age at onset for SCA10. Our findings suggest that the pure (ATTCT)n expansion is non-pathogenic, while repeat interruptions, e.g., (ATTCC)n, are necessary to cause SCA10. This mechanism has been recently described for several other repeat expansions including SCA31 (BEAN1), SCA37 (DAB1), and three loci for benign adult familial myoclonic epilepsy BAFME (SAMD12, TNRC6A, RAPGEF2). Therefore, long-read sequencing and optical genome mapping of the entire genomic structure of repeat expansions are critical for clinical practice and genetic counseling, as variations in the repeat can affect disease penetrance, symptoms, and disease trajectory.

ObjectiveTo determine the prevalence of neuropsychological outcomes in individuals with type 1 diabetes compared to individuals with type 2 diabetes or without diabetes, and to evaluate the association of diabetes status and microvascular/macrovascular complications with neuropsychological outcomes.Patients and MethodsWe used a nationally representative healthcare claims database of privately insured individuals (1/1/2001-12/31/2018) to identify individuals with type 1 diabetes. Propensity score matching was used as a quasi-randomization technique to match type 1 diabetes individuals to type 2 diabetes individuals and controls. Diabetes status, microvascular/macrovascular complications (retinopathy, neuropathy, nephropathy, stroke, myocardial infarction, peripheral vascular disease, amputations), and neuropsychological outcomes (mental health, cognitive, chronic pain, addiction, sleep disorders) were defined using ICD-9/10 codes. Logistic regression determined associations between diabetes status, microvascular/macrovascular complications, and neuropsychological outcomes.ResultsWe identified 184,765 type 1 diabetes individuals matched to 524,602 type 2 diabetes individuals and 522,768 controls. With the exception of cognitive disorders, type 2 diabetes individuals had the highest prevalence of neuropsychological outcomes, followed by type 1 diabetes, and controls. After adjusting for the presence of microvascular/macrovascular complications, type 1 diabetes was not significantly associated with a higher risk of neuropsychological outcomes; however, type 2 diabetes remained associated with mental health, cognitive, and sleep disorders. The presence of microvascular/macrovascular complications was independently associated with each neuropsychological outcome regardless of diabetes status.ConclusionMicrovascular/macrovascular complications are associated with a high risk of neuropsychological outcomes regardless of diabetes status. Therefore, preventing microvascular and macrovascular complications will likely help reduce the likelihood of neuropsychological outcomes either as the result of similar pathophysiologic processes or by preventing the direct and indirect consequences of these complications. For individuals with type 2 diabetes, risk factors beyond complications (such as obesity) likely contribute to neuropsychological outcomes.

Taurine and indicine cattle have different desirable traits making them better adapted to different climates across the world. Here, Low et al. describe a pipeline to produce haplotype-resolved, chromosome-level genomes of Angus and Brahman cattle breeds from a crossbred individual and report on comparisons of the two genomes.

Background The uptake of Self-Management Support (SMS) among clinicians is suboptimal. To date, few studies have tested knowledge translation (KT) interventions to increase the application of SMS in chiropractic teaching clinics. Study objective Evaluate the feasibility of implementing a KT intervention to promote the use of a SMS strategy among chiropractic interns, their supervisors, and individuals with spine pain compared to controls. Methods Mixed methods pilot clustered-clinical trial. Clusters of 16 Patient Management Teams were allocated to a complex KT intervention (online and workshop training). Primary feasibility outcomes for clinicians, interns and patients were rates of recruitment, retention, and adherence to protocol. A nominal group technique and interviews were used to seek end-users’ views on the implementation process, and generate possible solutions. Results In total, 16 (84%) clinicians, 65 (26%) interns and 42 patients agreed to participate. All clinicians in the intervention group completed all KT intervention components, 23 interns (85%) completed the online training and 14 interns (51.8%) attended the workshop training. All clinicians in the intervention and seven (78%) in the control group completed all outcome measures at baseline and 6-month follow-up, while 15 (55.6%) and 23 (60.5%) interns in the intervention and control groups completed the questionnaires at baseline and 6-month follow-up, respectively. Among patients, 10 (52.6%) and 12 (52.2%) in the intervention and control groups respectively completed the questionnaires at the end of the study. Based on interview findings, solutions to improve the feasibility of conducting a full trial include: making SMS a part of the internship, changing the time of introducing the study to the interns, and having more training on SMS. Conclusion Recruitment and retention of chiropractic interns and patients for a larger implementation trial in a single outpatient teaching clinic may be challenging.

Healthcare providers are expected to deliver care improvement solutions that not only provide high quality patient care, but also improve outcomes, reduce costs, ensure safety, and increase patient satisfaction. Human-centered design methodologies, such as design thinking, allow providers to collaboratively ideate solutions with patients and family members. We describe a pilot workshop designed to teach providers the stages of design thinking while working on improving patient-provider communication. Twenty-four providers (physicians, nurses, technical staff, and administrative staff) from multiple cardiovascular units attended the workshop with five former patients and family members from those units. The workshop educated on and guided teams of providers patients and family members through the stages of design thinking (empathy, define, ideate, prototype, test). Pre- and post-event assessments indicated an increase in knowledge of the design thinking methodology and participants’ ability to apply it to a clinical problem. We also present recommendations for designing a successful design thinking workshop.

Abstract Background α3β1 integrin is a promising cancer biomarker and drug target. We previously identified a 9-amino-acid cyclic peptide LXY30 for detecting α3β1 integrin on the surface of live tumor cells. This study was undertaken to characterize LXY30 in the detection, cellular function, imaging, and targeted delivery of in vitro and in vivo non-small cell lung cancer (NSCLC) models. Methods The whole-cell binding assay was performed by incubating NSCLC cells, extracellular vesicles (EVs), and peripheral blood mononuclear cells (PBMCs) with TentaGel resin beads coated with LXY30. In this study, we defined the nanosize EVs as exosomes, which were characterized by flow cytometry, transmission electron microscopy, dynamic light scattering, and Western blots. The function of LXY30 was determined by modulating the epidermal growth factor receptor (EGFR) signaling pathway by growth inhibition and Western blots. For in vivo biodistribution, mice bearing subcutaneous and intracranial NSCLC xenograft tumors were administrated intraveneously with LXY30-biotin/streptavidin-Cy5.5 complex and then analyzed for in vivo and ex vivo optical imaging and histopathology. Results We showed that LXY30 specifically and sensitively detected α3β1 integrin-expressing NSCLC cells and tumor-derived exosomes. Tumor DNA isolated from LXY30-enriched plasma exosomes might be used to detect driver oncogenic mutations in patients with metastatic NSCLC. LXY30 only enriches tumor cells but not neutrophils, macrophages, or monocytes in the malignant pleural effusion of NSCLC patients for detecting genomic alterations by next-generation sequencing. LXY30 detected increased α3β1 integrin expression on the EGFR-mutant NSCLC cells with acquired resistance to erlotinib compared to parental erlotinib-sensitive EGFR-mutant NSCLC cells. We further showed that LXY30 modulated the EGFR signaling pathway independently from another peptide ligand LXW64 targeting αvβ3 integrin in erlotinib-resistant, EGFR-mutant H1975 cells. Analysis of The Cancer Genome Atlas (TCGA) revealed high α3 integrin expression was associated with poor prognosis in lung squamous cell carcinoma. LXY30-biotin/streptavidin-Cy5.5 complex had higher uptakes in the subcutaneous and intracranial xenografts of various α3β1 integrin-expressing lung adenocarcinoma and patient-derived lung squamous cell carcinoma xenografts while sparing the surrounding normal tissues. Conclusion LXY30 is a promising peptide for the cancer diagnosis and in vivo targeted delivery of imaging agents and cancer drugs in NSCLC, independent of histology and tumor genotype.

Structural variants (SVs) in human genomes contribute diversity and diseases. Here, the authors use a multi-platform strategy to generate haplotype-resolved SVs for three human parent–child trios.

BackgroundRenal medullary carcinoma (RMC) is a rare but aggressive tumor often complicated by early lung metastasis with few treatment options and very poor outcomes. There are currently no verified RMC patient-derived xenograft (PDX) mouse models established from metastatic pleural effusion (PE) available to study RMC and evaluate new therapeutic options.MethodsRenal tumor tissue and malignant PE cells from an RMC patient were successfully engrafted into 20 NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. We evaluated the histopathological similarity of the renal tumor and PE PDXs with the original patient renal tumor and PE, respectively. We then evaluated the molecular integrity of the renal tumor PDXs between passages, as well as the PE PDX compared to two generations of renal tumor PDXs, by microarray analysis. The therapeutic efficacy of sunitinib and temsirolimus was tested in a serially-transplanted generation of 27 PE PDX mice.ResultsThe pathologic characteristics of the patient renal tumor and patient PE were retained in the PDXs. Gene expression profiling revealed high concordance between the two generations of renal tumor PDXs (RMC-P0 vs. RMC-P1, r=0.865), as well as between the first generation PE PDX and each generation of the renal tumor PDX (PE-P0 vs. RMC-P0, r=0.919 and PE-P0 vs. RMC-P1, r=0.843). A low number (626) of differentially-expressed genes (DEGs) was seen between the first generation PE PDX and the first generation renal tumor PDX. In the PE-P1 xenograft, sunitinib significantly reduced tumor growth (p

The novel corona virus that is now known as (SARS-CoV-2) has killed more than six million people worldwide. The disease presentation varies from mild respiratory symptoms to acute respiratory distress syndrome and ultimately death. Several risk factors have been shown to worsen the severity of COVID-19 outcomes (such as age, hypertension, diabetes mellitus, and obesity). Since many of these risk factors are known to be influenced by obstructive sleep apnea, this raises the possibility that OSA might be an independent risk factor for COVID-19 severity. A shift in the gut microbiota has been proposed to contribute to outcomes in both COVID-19 and OSA. To further evaluate the potential triangular interrelationships between these three elements, we conducted a thorough literature review attempting to elucidate these interactions. From this review, it is concluded that OSA may be a risk factor for worse COVID-19 clinical outcomes, and the shifts in gut microbiota associated with both COVID-19 and OSA may mediate processes leading to bacterial translocation via a defective gut barrier which can then foster systemic inflammation. Thus, targeting biomarkers of intestinal tight junction dysfunction in conjunction with restoring gut dysbiosis may provide novel avenues for both risk detection and adjuvant therapy.

Cardiac arrhythmia, or irregular heart rhythm, is associated with morbidity and mortality and is described as one of the most important future public health challenges. Therefore, developing new models of cardiac arrhythmia is critical for understanding disease mechanisms, determining genetic underpinnings, and developing new therapeutic strategies. In the last few decades, the zebrafish has emerged as an attractive model to reproduce in vivo human cardiac pathologies, including arrhythmias. Here, we highlight the contribution of zebrafish to the field and discuss the available cardiac arrhythmia models. Further, we outline techniques to assess potential heart rhythm defects in larval and adult zebrafish. As genetic tools in zebrafish continue to bloom, this model will be crucial for functional genomics studies and to develop personalized anti-arrhythmic therapies.

We conducted a post hoc analysis to assess the potential impact of GAP (gender, age, physiology) stage on the treatment effect of nintedanib in patients with idiopathic pulmonary fibrosis. Outcomes were compared in patients at GAP stage I versus II/III at baseline in the INPULSIS® trials. At baseline, 500 patients were at GAP stage I (nintedanib 304, placebo 196), 489 were at GAP stage II (nintedanib 296, placebo 193) and 71 were at GAP stage III (nintedanib 38, placebo 33). In nintedanib-treated patients, the annual rate of decline in forced vital capacity (FVC) was similar in patients at GAP stage I and GAP stage II/III at baseline (−110.1 and −116.6 mL·year−1, respectively), and in both subgroups was lower than in placebo-treated patients (−218.5 and −227.6 mL·year−1, respectively) (treatment-by-time-by-subgroup interaction p=0.92). In the nintedanib group, the number of deaths was 43.8% of those predicted based on GAP stage (35 versus 79.9). In the placebo group, the number of deaths was 59.8% of those predicted based on GAP stage (33 versus 55.2). In conclusion, data from the INPULSIS® trials suggest that nintedanib has a similar beneficial effect on the rate of FVC decline in patients at GAP stage I versus II/III at baseline.