Clinical Outcomes of Collagenase Injections in Management of Dupuytren Contracture of the Proximal Interphalangeal Joint.

Purpose: Dupuytren contracture is characterized by the formation of cords and nodules in the palm. Surgical release has historically been the definitive treatment. Collagenase clostridium histolyticum (CCH) has been used successfully as an alternative to surgery. The treatment of proximal interphalangeal (PIP) contractures is the most challenging. The purpose of this study was to evaluate CCH treatment for Dupuytren contracture of the PIP joint. Methods: A retrospective chart review was performed for CCH treatment of Dupuytren contracture at a single institution from January 2010 to April 2023. Data collected included pretreatment/posttreatment total flexion contracture and adverse events. Contractures were analyzed both by severity (high >40° and low <40°) and type (isolated PIP; combined metacarpophalangeal and PIP). Results: A total of 304 patients with 470 PIP joints treated were included. Digits with isolated and combined contractures each had an average pre-CCH treatment contracture of 51 (±23) degrees. Postmanipulations the contractures were 6 (±13) and 7 (±16) degrees, respectively. Clinical success (<5° residual contracture) and improvement (>50% correction of contracture) were associated with low severity contractures at postmanipulation. There were 256 adverse events recorded (54.5%), including 187 skin tears (39.8%), 68 cases of lymphadenopathy (14.5%), and one injection site infection (0.2%). High severity and combined contractures were independently associated with an increased incidence of skin tears upon manipulation. Conclusions: Collagenase clostridium histolyticum treatment is effective for isolated or combined PIP joint contractures. Adverse events were associated with more severe contractures. Given the degree of improvement based on contracture severity, earlier intervention may provide better correction of contracture. Type of study/level of evidence: Therapeutic III.

Intra-articular corticosteroid injections for osteoarthritis: A qualitative study of patients' and clinicians' experiences.

BACKGROUND: Osteoarthritis is a leading cause of joint pain and disability. Intra-articular corticosteroid injections (IACs) are often used in primary care once other recommended treatments have failed. Evidence shows that IACs provide short-term relief of osteoarthritis symptoms, yet little is known about patients' and primary care clinicians' experiences and beliefs about their use. We explored patients' and primary care clinicians' views about IACs, including the benefits, disadvantages, perceived risks of treatment, when they are used, and factors that affect decision-making. METHODS: We conducted individual interviews with patients and primary care clinicians and used inductive thematic analysis to investigate their views and experiences of intra-articular corticosteroid injections for osteoarthritis (IACs). FINDINGS: We interviewed 38 patients and 19 primary care clinicians. We identified 6 patient themes: variation in access; awareness of IACs; views of risk and trust; effectiveness of IACs; variation in onset and effect duration; and an alternative to undesirable treatments. In the interviews with clinicians, we identified an overarching theme of caution and competence, which included eight subthemes: confidence and (dis)comfort with practical procedures; risk of adverse outcomes; training; uncertainty about evidence and guidelines; technical uncertainties; IACs use on the osteoarthritis pathway; perceived benefits and impacts of IACs; and the possibility of placebo. CONCLUSION: Patients and clinicians valued IACs' potential to relieve symptoms and improve quality of life. Variability in patients' access to treatment appears related to clinicians' confidence in delivering injections and their concerns about the evidence base. Variation in dose frequency and timing reflect clinicians' uncertainty about current guidance. Despite variation in effectiveness patients preferred IACs to other forms of pain medication and to delay or avoid surgery. IACs were mostly used as an adjunct treatment before surgery was offered. These findings can inform further research into the effectiveness of IACs and improvements in information and guidance.

Antidepressants for pain management in adults with chronic pain: a network meta-analysis.

Background: Chronic pain is common and costly. Antidepressants are prescribed to reduce pain. However, there has not been a network meta-analysis examining all antidepressants across all chronic pain conditions, so effectiveness and safety for most antidepressants for pain conditions remain unknown. Objective: To assess the efficacy and safety of antidepressants for chronic pain (except headache) in adults. Our primary outcomes were as follows: substantial pain relief (50%), pain intensity, mood and adverse events. Our secondary outcomes were as follows: moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change, serious adverse events and withdrawal. Design: This was a systematic review with a network meta-analysis. We searched CENTRAL, MEDLINE, EMBASE, CINAHL, LILACS, AMED and PsycINFO databases for randomised controlled trials of antidepressants for chronic pain conditions up until 4 January 2022. The review was registered in PROSPERO (CRD42020171855), and the protocol was published in the Cochrane Library (https://doi.org/10.1002/14651858.CD014682). Setting: We analysed trials from all settings. Participants: We included trials in which participants had chronic pain, defined as longer than 3 months, from any condition excluding headache. Interventions: We included all antidepressants. Main outcome measures: Our primary outcome was substantial pain relief, defined as a reduction ˃ 50%. We also measured pain intensity, mood and adverse events. Secondary measures included moderate pain relief (above 30% reduction), physical function, sleep, quality of life, Global Impression of Change, serious adverse events, and withdrawal from trial. Results: We identified 176 studies with a total of 28,664 participants. Most studies were placebo-controlled (n = 83) and parallel armed (n = 141). The most common pain conditions examined were fibromyalgia (59 studies), neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of randomised controlled trials was 10 weeks. Most studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. Standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that for duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain. Limitations: The evidence for antidepressants other than duloxetine is poor. For duloxetine, it is not clear whether the effect applies to groups with both pain and low mood, since these groups were excluded from trials. There is also insufficient evidence on long-term outcomes and on adverse effects. Conclusions: There is only reliable evidence for duloxetine in the treatment of chronic pain. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Data for all other antidepressants were of low certainty. However, the findings should not be read as an encouragement to prescribe antidepressants where other non-pharmacological intervention could be equally effective, especially in the absence of good evidence on side effects and safety. Future work: There is a need for large, methodologically sound trials testing the effectiveness of antidepressants for chronic pain. These trials should examine long-term outcomes (> 6 months) and include people with low mood. There should also be better reporting of adverse events, tolerance of drugs, and long-term compliance. Study registration: This study is registered as PROSPERO CRD42020171855. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128782) and is published in full in Health Technology Assessment; Vol. 28, No. 62. See the NIHR Funding and Awards website for further award information.

Chronic pain is pain that lasts for more than 3 months. Over one-third of people across the world experience chronic pain. This often has a detrimental impact on people's mood, disability and well-being. Antidepressants are often prescribed to reduce pain, but we are not sure which antidepressants work best for different types of pain, or whether they are safe. We wanted to find out whether antidepressants were effective and safe for management of chronic pain. We searched for studies that had compared any antidepressant with any other treatment for any type of chronic pain (except headache). We compared all the treatments against each other using a statistical method called network meta-analysis. This method allows us to rank the treatments in order of best to worst for each outcome. We found 176 studies that included a total of 28,664 people with chronic pain. Most of the studies (83/176) compared an antidepressant with a placebo (which looks like the real medicine but does not have any medicine in it). The evidence from our analysis suggests that: Duloxetine is the antidepressant that we have the most confidence in. It was the best antidepressant for reducing pain and improving physical function. A standard dose of duloxetine was equally as effective for reducing pain as a high dose of duloxetine. Milnacipran was also effective at reducing pain, but we are not as confident in this result as in the one for duloxetine because there were fewer studies with fewer people involved. Aside from duloxetine and milnacipran, we do not have confidence in the results from any other antidepressant included in this review, and even for duloxetine and milnacipran, we do not know the long-term effects. It is important to recognise that the lack of evidence for the majority of antidepressants in this review does not necessarily equal a lack of benefit. Rather, this means that the large, high-quality trials required for us to be certain of an antidepressant's effectiveness have not been undertaken. Altogether, although duloxetine and milnacipran are effective, the results of this review should not be read as an encouragement to prescribe antidepressants where other non-pharmacological intervention could be equally effective, especially in the absence of good evidence on side effects and safety. These conclusions were informed by our patient and public involvement group.

Music alters heart rate and psychological responses but not muscle activation during light-intensity isometric exercise.

Listening to music manipulates attention to be more externally focused, which has the potential to improve muscular efficiency. This study aimed to determine the effect of listening to music on muscle activation during an isometric exercise task, and compare this effect to those of other attentional focus conditions. Apparently healthy subjects (n = â€‹35; 16 men/19 women) completed an isometric elbow flexion task for 1 â€‹min in three randomized and counterbalanced conditions: internal focus (INT), external focus with a simple distraction task (EXT), or listening to music (MUS). Muscle activation of the biceps and triceps brachii and heart rate (HR) were recorded throughout the exercise tasks. Ratings of perceived exertion (RPE), affective valence, and motivation were measured at the end of each trial. There was no difference in muscle activation measures among the three conditions. HR during MUS was lower than EXT at 15 â€‹s ([89.4 â€‹± â€‹11.8] beats/min vs. [93.1 â€‹± â€‹12.9] beats/min; p â€‹= â€‹0.018) and 30 â€‹s ([90.6 â€‹± â€‹12.4] beats/min vs. [94.2 â€‹± â€‹12.5] beats/min; p â€‹= â€‹0.026), and lower than INT at 60 â€‹s ([93.3 â€‹± â€‹13.3] beats/min vs. [96.7 â€‹± â€‹12.0] beats/min; p â€‹= â€‹0.016). Overall RPE was higher for INT (13.4 â€‹± â€‹2.2) than for MUS ([12.6 â€‹± â€‹2.0]; p â€‹= â€‹0.020) and EXT ([11.94 â€‹± â€‹2.22]; p â€‹< â€‹0.001). Affective valence was higher for MUS than for INT ([2.7 â€‹± â€‹1.4] vs. [2.1 â€‹± â€‹1.5]; p â€‹= â€‹0.011). Manipulating attentional focus did not alter muscle activation for a light-intensity isometric muscular endurance task, though MUS was reported as more positive and requiring less exertion to complete than INT. Using music can therefore be recommended during light-intensity isometric exercise based on the psychological benefits observed.

Impact of Pre-Adolescent Substance Familiarity on Subsequent Use: Longitudinal Analysis of Risk by Latent Classes in the Adolescent Brain Cognitive Development Sample.

BACKGROUND: Predicting substance use in adolescence is a difficult yet important task in developing effective prevention. We aim to extend previous findings on the linear associations between familiarity with (knowledge of) substances in childhood and subsequent substance use in adolescence through a latent class analysis (LCA) to create risk profiles based on substance familiarity. METHOD: Using the ABCD Study® sample, we conducted an LCA using 18 binary substance familiarity variables (n = 11,694 substance-naïve youth). Complementary analyses investigated the relationship between LCA groups and (1) longitudinal use, (2) use initiation, and (3) early use. RESULTS: The optimal LCA resulted in a four-class solution: Naïve, Common, Uncommon, and Rare, with each group increasing in both the number and rarity of known substances. Analysis 1 revealed an increased risk in use over time among both the Uncommon and Rare groups (ORs = 2.08 and 5.55, respectively, p's < 0.001) compared to the Common group. Analysis 2 observed a decreased risk for initiation between the Naïve and Common groups (OR = 0.61, p = 0.009); however, the Uncommon and Rare groups were at an increased risk compared to the Common group (ORs = 2.08 and 3.42, respectively, p's < 0.001). Analysis 3 found an increased risk of early use between the Common and Uncommon groups (OR = 1.92, p < 0.001) with a similar trend between the Common and Rare groups (OR = 1.90, p = 0.06). CONCLUSION: These results highlight distinct risk profiles for adolescent substance use based on substance familiarity in middle childhood. Current work could be applied as an early screening tool for clinicians to identify those at risk for adolescent substance use.

Understanding post-hospitalised patients' experiences of long-COVID - the PELCO study.

Despite significant advances in long COVID research, many aspects of the condition remain unknown. There is a persisting need for further research to improve the management of long COVID symptoms. This study aimed to explore the experiences and psychological needs of patients who were previously hospitalised with COVID-19, and who subsequently developed long COVID symptoms. Twelve patients with long COVID were interviewed between October 2021 and June 2022. Transcripts were analysed thematically. An overarching theme of 'Existential Crisis' was developed, incorporating three interconnecting sub-themes: 'Facing Psychological Threat', 'Seeking Legitimisation' and 'Forging a Path Through Uncertainty'. Findings suggest that the psychological impact of emergency hospitalisation for COVID-19 can be severe, particularly for those with ongoing long COVID symptoms, and that early psychological intervention should be available. Our findings also suggest the importance of further planning for future pandemics to ensure the presence of patient advocates during hospitalisation at points of critical decision-making.

Population-level 5-year event-free survival for children with cancer in Australia.

BACKGROUND: Event-free survival (EFS) considers other adverse events in addition to mortality. It therefore provides a more complete understanding of the effectiveness and consequences of treatment than standard survival measures, but is rarely reported at the population level for childhood cancer. PROCEDURE: Our study cohort (n = 7067) was obtained from the Australian Childhood Cancer Registry, including children aged under 15 diagnosed with cancer between 2006 and 2015, with follow-up potentially available to 31 December 2020. The events of interest were relapse following remission, progressive disease, diagnosis of a second primary cancer or death from any cause. Five-year EFS and all-cause observed survival were both calculated, stratified by type of childhood cancer, remoteness of residence and stage at diagnosis. Differences in EFS were assessed using multivariable flexible parametric models. RESULTS: Approximately one quarter of patients (n = 1605 of 7067, 23%) experienced at least one of the events of interest within 5 years of diagnosis. Relapse was twice as common for children with metastatic/advanced disease (22%) versus children with localised/limited cancers (11%). Overall 5-year EFS was 75.0% (95% confidence interval [CI]: 73.9%-76.0%), compared to 85.8% observed survival (95% CI: 85.0%-86.6%). Patients with other gliomas had the lowest EFS (35.4%, 95% CI: 27.8%-43.1%). EFS was significantly lower among children with acute myeloid leukaemia in outer regional/remote areas compared to major cities (adjusted hazard ratio [HR] = 1.90, 95% CI: 1.20-3.00). CONCLUSIONS: Reporting EFS at a population level provides further insight on a wider range of impacts apart from mortality alone, contributing towards efforts to improve the management and outcomes of childhood cancer.

Analytical code sharing practices in biomedical research.

Data-driven computational analysis is becoming increasingly important in biomedical research, as the amount of data being generated continues to grow. However, the lack of practices of sharing research outputs, such as data, source code and methods, affects transparency and reproducibility of studies, which are critical to the advancement of science. Many published studies are not reproducible due to insufficient documentation, code, and data being shared. We conducted a comprehensive analysis of 453 manuscripts published between 2016-2021 and found that 50.1% of them fail to share the analytical code. Even among those that did disclose their code, a vast majority failed to offer additional research outputs, such as data. Furthermore, only one in ten articles organized their code in a structured and reproducible manner. We discovered a significant association between the presence of code availability statements and increased code availability. Additionally, a greater proportion of studies conducting secondary analyses were inclined to share their code compared to those conducting primary analyses. In light of our findings, we propose raising awareness of code sharing practices and taking immediate steps to enhance code availability to improve reproducibility in biomedical research. By increasing transparency and reproducibility, we can promote scientific rigor, encourage collaboration, and accelerate scientific discoveries. We must prioritize open science practices, including sharing code, data, and other research products, to ensure that biomedical research can be replicated and built upon by others in the scientific community.

Effectiveness and cost-effectiveness of radiofrequency denervation versus placebo for chronic and moderate to severe low back pain: study protocol for the RADICAL randomised controlled trial.

INTRODUCTION: Low back pain (LBP) is the leading global cause of disability. Patients with moderate to severe LBP who respond positively to a diagnostic medial nerve branch block can be offered radiofrequency denervation (RFD). However, high-quality evidence on the effectiveness of RFD is lacking. METHODS AND ANALYSIS: RADICAL (RADIofrequenCy denervAtion for Low back pain) is a double-blind, parallel-group, superiority randomised controlled trial. A total of 250 adults listed for RFD will be recruited from approximately 20 National Health Service (NHS) pain and spinal clinics. Recruitment processes will be optimised through qualitative research during a 12-month internal pilot phase. Participants will be randomised in theatre using a 1:1 allocation ratio to RFD or placebo. RFD technique will follow best practice guidelines developed for the trial. Placebo RFD will follow the same protocol, but the electrode tip temperature will not be raised. Participants who do not experience a clinically meaningful improvement in pain 3 months after randomisation will be offered the alternative intervention to the one provided at the outset without disclosing the original allocation. The primary clinical outcome will be pain severity, measured using a pain Numeric Rating Scale, at 3 months after randomisation. Secondary outcomes will be assessed up to 2 years after randomisation and include disability, health-related quality of life, psychological distress, time to pain recovery, satisfaction, adverse events, work outcomes and healthcare utilisation. The primary statistical analyses will be by intention to treat and will follow a prespecified analysis plan. The primary economic evaluation will take an NHS and social services perspective and estimate the discounted cost per quality-adjusted life-year and incremental net benefit of RFD over the 2-year follow-up period. ETHICS AND DISSEMINATION: Ethics approval was obtained from the London-Fulham Research Ethics Committee (21/LO/0471). Results will be disseminated in open-access publications and plain language summaries. TRIAL REGISTRATION NUMBER: ISRCTN16473239.

In risk we trust? Making decisions about knee replacement.

Risk communication is a key legal and ethical component of shared decision-making. Decisions about total knee replacement, a common surgery, must contend with the fact that a minority of cases result in unintended outcomes, some of which have devastating effects. To understand how risks are communicated during decision-making, we audio-recorded and analysed 62 consultations between surgeons and patients. Various communication methods were evident, including listing risks without elaboration, discussing them in a conversational manner, abrogating discussion of risk, or using decision-tools. Discussion of risks was often brief in nature, and risk communication was sometimes curtailed or deferred by both patients and surgeons. Risks could also be observed to play a part in reinforcing policy norms of the doctor-patient relationship that highlighted patient responsibility. Nevertheless, patients and surgeons in the observed consultations appeared more interested in developing trusting relationships than in discussing risks. Because patients had sometimes experienced considerable deterioration in their knee function before their consultation, were in pain and struggled with mobility, the realities of clinical practice clashed with the policy norms of choice and patient responsibility. Rather, decisions could appear coerced by the disease process rather than being clear-cut examples of self-determination. While policy norms putatively use risk disclosure to frame communication between patients and clinicians as a transaction between customer and technician, the lack of conformity to these norms in the consultations may indicate resistance to this framing. A greater emphasis on determining positive roles for trust and care would help policy to present a nuanced understanding of decision-making. Risk communication could be seen as a factor in the formation of trusting relationships, improving its role in decision-making processes while recognising its inherent tensions with practice.

Identification and transcriptomic assessment of latent profile pediatric septic shock phenotypes.

BACKGROUND: Sepsis poses a grave threat, especially among children, but treatments are limited owing to heterogeneity among patients. We sought to test the clinical and biological relevance of pediatric septic shock subclasses identified using reproducible approaches. METHODS: We performed latent profile analyses using clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock observational cohort to derive phenotypes and trained a support vector machine model to assign phenotypes in an internal validation set. We established the clinical relevance of phenotypes and tested for their interaction with common sepsis treatments on patient outcomes. We conducted transcriptomic analyses to delineate phenotype-specific biology and inferred underlying cell subpopulations. Finally, we compared whether latent profile phenotypes overlapped with established gene-expression endotypes and compared survival among patients based on an integrated subclassification scheme. RESULTS: Among 1071 pediatric septic shock patients requiring vasoactive support on day 1 included, we identified two phenotypes which we designated as Phenotype 1 (19.5%) and Phenotype 2 (80.5%). Membership in Phenotype 1 was associated with ~ fourfold adjusted odds of complicated course relative to Phenotype 2. Patients belonging to Phenotype 1 were characterized by relatively higher Angiopoietin-2/Tie-2 ratio, Angiopoietin-2, soluble thrombomodulin (sTM), interleukin 8 (IL-8), and intercellular adhesion molecule 1 (ICAM-1) and lower Tie-2 and Angiopoietin-1 concentrations compared to Phenotype 2. We did not identify significant interactions between phenotypes, common treatments, and clinical outcomes. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and driven primarily by developing neutrophils among patients designated as Phenotype 1. There was no statistically significant overlap between established gene-expression endotypes, reflective of the host adaptive response, and the newly derived phenotypes, reflective of the host innate response including microvascular endothelial dysfunction. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing patient endophenotypes. CONCLUSIONS: Our research underscores the reproducibility of latent profile analyses to identify pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill.

Preventing adverse events during paediatric cancer treatment: protocol for a multi-site hybrid randomised controlled trial of catheter lock solutions (the CLOCK trial).

INTRODUCTION: Central venous access devices (CVADs) are commonly used for the treatment of paediatric cancer patients. Catheter locking is a routine intervention that prevents CVAD-associated adverse events, such as infection, occlusion and thrombosis. While laboratory and clinical data are promising, tetra-EDTA (T-EDTA) has yet to be rigorously evaluated or introduced in cancer care as a catheter lock. METHODS AND ANALYSIS: This is a protocol for a two-arm, superiority type 1 hybrid effectiveness-implementation randomised controlled trial conducted at seven hospitals across Australia and New Zealand. Randomisation will be in a 3:2 ratio between the saline (heparinised saline and normal saline) and T-EDTA groups, with randomly varied blocks of size 10 or 20 and stratification by (1) healthcare facility; (2) CVAD type and (3) duration of dwell since insertion. Within the saline group, there will be a random allocation between normal and heparin saline. Participants can be re-recruited and randomised on insertion of a new CVAD. Primary outcome for effectiveness will be a composite of CVAD-associated bloodstream infections (CABSI), CVAD-associated thrombosis or CVAD occlusion during CVAD dwell or at removal. Secondary outcomes will include CABSI, CVAD-associated-thrombosis, CVAD failure, incidental asymptomatic CVAD-associated-thrombosis, other adverse events, health-related quality of life, healthcare costs and mortality. To achieve 90% power (alpha=0.05) for the primary outcome, data from 720 recruitments are required. A mixed-methods approach will be employed to explore implementation contexts from the perspective of clinicians and healthcare purchasers. ETHICS AND DISSEMINATION: Ethics approval has been provided by Children's Health Queensland Hospital and Health Service Human Research Ethics Committee (HREC) (HREC/22/QCHQ/81744) and the University of Queensland HREC (2022/HE000196) with subsequent governance approval at all sites. Informed consent is required from the substitute decision-maker or legal guardian prior to participation. In addition, consent may also be obtained from mature minors, depending on the legislative requirements of the study site. The primary trial and substudies will be written by the investigators and published in peer-reviewed journals. The findings will also be disseminated through local health and clinical trial networks by investigators and presented at conferences. TRIAL REGISTRATION NUMBER: ACTRN12622000499785.

Transport and Organization of Individual Vimentin Filaments Within Dense Networks Revealed by Single Particle Tracking and 3D FIB-SEM.

Single-particle tracking demonstrates that individual filaments in bundles of vimentin intermediate filaments are transported in the cytoplasm by motor proteins along microtubules. Furthermore, using 3D FIB-SEM the authors showed that vimentin filament bundles are loosely packed and coaligned with microtubules. Vimentin intermediate filaments (VIFs) form complex, tight-packed networks; due to this density, traditional ensemble labeling and imaging approaches cannot accurately discern single filament behavior. To address this, we introduce a sparse vimentin-SunTag labeling strategy to unambiguously visualize individual filament dynamics. This technique confirmed known long-range dynein and kinesin transport of peripheral VIFs and uncovered extensive bidirectional VIF motion within the perinuclear vimentin network, a region we had thought too densely bundled to permit such motility. To examine the nanoscale organization of perinuclear vimentin, we acquired high-resolution electron microscopy volumes of a vitreously frozen cell and reconstructed VIFs and microtubules within a ~50 µm3 window. Of 583 VIFs identified, most were integrated into long, semi-coherent bundles that fluctuated in width and filament packing density. Unexpectedly, VIFs displayed minimal local co-alignment with microtubules, save for sporadic cross-over sites that we predict facilitate cytoskeletal crosstalk. Overall, this work demonstrates single VIF dynamics and organization in the cellular milieu for the first time.

Immersive Virtual Reality Decreases Work Rate and Manipulates Attentional Focus During Self-Regulated Vigorous Exercise.

To determine the effect of immersive virtual reality use on finishing time of a vigorous-intensity self-regulated exercise task, and on relevant psychological variables. Healthy untrained adults (N = 21; 10 men/11 women; age = 22.9 ± 7.2 years; BMI = 24.0 ± 4.5 kg/m2) completed 1500-m exercise bouts on a rowing ergometer in a counterbalanced and randomized order, with and without use of a headset-delivered virtual reality fitness program. Heart rate, rating of perceived exertion, affective valence, and attentional focus were collected every 300 m, in addition to finishing time. Data were analyzed with repeated measures as appropriate. Intensity of both exercise bouts was considered vigorous according to heart rate results (>77% maximal heart rate). Finishing time was faster in the control condition (449.57 ± 82.39 s) than in the virtual reality condition (463.00 ± 91.78 s), p = .007. Compared to the control condition, the virtual reality condition was characterized by a more external attentional focus (52.38 ± 18.22 vs. 38.76 ± 17.81, p < .001). No differences were observed for remaining variables as a result of condition (p > .05 for all). When a headset-delivered VR program was used during a self-regulated vigorous-intensity exercise task, participants were 13.6 seconds (~3%) slower than in a control condition. Attentional focus was manipulated to be more external with VR use, which may have ultimately distracted from the exercise objective. Recommendations for selecting an appropriate virtual reality experience for a given exercise task are discussed.

Association between emergency department disposition and mortality in patients with COVID-19 acute respiratory distress syndrome.

Objectives: Patients hospitalized for COVID-19 frequently develop hypoxemia and acute respiratory distress syndrome (ARDS) after admission. In non-COVID-19 ARDS studies, admission to hospital wards with subsequent transfer to intensive care unit (ICU) is associated with worse outcomes. We hypothesized that initial admission to the ward may affect outcomes in patient with COVID-19 ARDS. Methods: This was a retrospective study of consecutive adults admitted for COVID-19 ARDS between March 2020 and March 2021 at Stanford Health Care. Mortality scores at hospital admission (Coronavirus Clinical Characterization Consortium Mortality Score [4C score]) and ICU admission (Simplified Acute Physiology Score III [SAPS-III]) were calculated, as well as ROX index for patients on high flow nasal oxygen. Patients were classified by emergency department (ED) disposition (ward-first vs. ICU-direct), and 28- and 60-day mortality and highest level of respiratory support within 1 day of ICU admission were compared. A second cohort (April 2021‒July 2022, n = 129) was phenotyped to validate mortality outcome. Results: A total of 157 patients were included, 48% of whom were first admitted to the ward (n = 75). Ward-first patients had more comorbidities, including lung disease. Ward-first patients had lower 4C and similar SAPS-III score, yet increased mortality at 28 days (32% vs. 17%, hazard ratio [HR] 2.0, 95% confidence interval [95% CI] 1.0‒3.7, p = 0.039) and 60 days (39% vs. 23%, HR 1.83, 95% CI 1.04‒3.22, p = 0.037) compared to ICU-direct patients. More ward-first patients escalated to mechanical ventilation on day 1 of ICU admission (36% vs. 14%, p = 0.002) despite similar ROX index. Ward-first patients who upgraded to ICU within 48 h of ED presentation had the highest mortality. Mortality findings were replicated in a sensitivity analysis. Conclusion: Despite similar baseline risk scores, ward-first patients with COVID-19 ARDS had increased mortality and escalation to mechanical ventilation compared to ICU-direct patients. Ward-first patients requiring ICU upgrade within 48 h were at highest risk, highlighting a need for improved identification of this group at ED admission.

The respiratory system influences flight mechanics in soaring birds.

The subpectoral diverticulum (SPD) is an extension of the respiratory system in birds that is located between the primary muscles responsible for flapping the wing1,2. Here we survey the pulmonary apparatus in 68 avian species, and show that the SPD was present in virtually all of the soaring taxa investigated but absent in non-soarers. We find that this structure evolved independently with soaring flight at least seven times, which indicates that the diverticulum might have a functional and adaptive relationship with this flight style. Using the soaring hawks Buteo jamaicensis and Buteo swainsoni as models, we show that the SPD is not integral for ventilation, that an inflated SPD can increase the moment arm of cranial parts of the pectoralis, and that pectoralis muscle fascicles are significantly shorter in soaring hawks than in non-soaring birds. This coupling of an SPD-mediated increase in pectoralis leverage with force-specialized muscle architecture produces a pneumatic system that is adapted for the isometric contractile conditions expected in soaring flight. The discovery of a mechanical role for the respiratory system in avian locomotion underscores the functional complexity and heterogeneity of this organ system, and suggests that pulmonary diverticula are likely to have other undiscovered secondary functions. These data provide a mechanistic explanation for the repeated appearance of the SPD in soaring lineages and show that the respiratory system can be co-opted to provide biomechanical solutions to the challenges of flight and thereby influence the evolution of avian volancy.

Molecular Endotypes of Idiopathic Pulmonary Fibrosis: A Latent Class Analysis of Two Multicenter Observational Cohorts.

Rationale: Idiopathic pulmonary fibrosis (IPF) causes irreversible fibrosis of the lung parenchyma. Although antifibrotic therapy can slow IPF progression, treatment response is variable. There exists a critical need to develop a precision medicine approach to IPF. Objectives: To identify and validate biologically driven molecular endotypes of IPF. Methods: Latent class analysis (LCA) was independently performed in prospectively recruited discovery (n = 875) and validation (n = 347) cohorts. Twenty-five plasma biomarkers associated with fibrogenesis served as class-defining variables. The association between molecular endotype and 4-year transplant-free survival was tested using multivariable Cox regression adjusted for baseline confounders. Endotype-dependent differential treatment response to future antifibrotic exposure was then assessed in a pooled cohort of patients naive to antifibrotic therapy at the time of biomarker measurement (n = 555). Measurements and Main Results: LCA independently identified two latent classes in both cohorts (P < 0.0001). WFDC2 (WAP four-disulfide core domain protein 2) was the most important determinant of class membership across cohorts. Membership in class 2 was characterized by higher biomarker concentrations and a higher risk of death or transplant (discovery, hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.64-2.48; P < 0.001; validation, HR, 1.95; 95% CI, 1.34-2.82; P < 0.001). In pooled analysis, significant heterogeneity in treatment effect was observed between endotypes (P = 0.030 for interaction), with a favorable antifibrotic response in class 2 (HR, 0.64; 95% CI, 0.45-0.93; P = 0.018) but not in class 1 (HR, 1.19; 95% CI, 0.77-1.84; P = 0.422). Conclusions: In this multicohort study, we identified two novel molecular endotypes of IPF with divergent clinical outcomes and responses to antifibrotic therapy. Pending further validation, these endotypes could enable a precision medicine approach for future IPF clinical trials.

Precision-guided treatment in high-risk pediatric cancers.

Recent research showed that precision medicine can identify new treatment strategies for patients with childhood cancers. However, it is unclear which patients will benefit most from precision-guided treatment (PGT). Here we report consecutive data from 384 patients with high-risk pediatric cancer (with an expected cure rate of less than 30%) who had at least 18 months of follow-up on the ZERO Childhood Cancer Precision Medicine Program PRecISion Medicine for Children with Cancer (PRISM) trial. A total of 256 (67%) patients received PGT recommendations and 110 (29%) received a recommended treatment. PGT resulted in a 36% objective response rate and improved 2-year progression-free survival compared with standard of care (26% versus 12%; P = 0.049) or targeted agents not guided by molecular findings (26% versus 5.2%; P = 0.003). PGT based on tier 1 evidence, PGT targeting fusions or commenced before disease progression had the greatest clinical benefit. Our data show that PGT informed by comprehensive molecular profiling significantly improves outcomes for children with high-risk cancers. ClinicalTrials.gov registration: NCT03336931.

Improving Clinical Practice Through Patient Registries in Allergy and Immunology.

Patient registries are a mechanism for collecting data on allergic and immunologic diseases that provide important information on epidemiology and outcomes that can ultimately improve patient care. Key criteria for establishing effective registries include the use of a clearly defined purpose, identifying the target population and ensuring consistent data collection. Registries in allergic diseases include those for diseases such as inborn errors of immunity (IEI), food allergy, asthma and anaphylaxis, pharmacological interventions in vulnerable populations, and adverse effects of pharmacologic interventions including hypersensitivity reactions to drugs and vaccines. Important insights gained from patient registries in our field include contributions in phenotype and outcomes in IEI, the risk for adverse reactions in food-allergic patients in multiple settings, the benefits and risk of biologic medications for asthma during pregnancy, vaccine safety, and the categorization and genetic determination of risk for severe cutaneous adverse reactions to medications. Impediments to the development of clinically meaningful patient registries include the lack of funding resources for registry establishment and the quality, quantity, and consistency of available data. Despite these drawbacks, high-quality and successful registries are invaluable in informing clinical practice and improving outcomes in patients with allergic and immunological diseases.