Geometric constraint of mechanosensing by modification of hydrogel thickness prevents stiffness-induced differentiation in bone marrow stromal cells.

Extracellular matrix (ECM) stiffness is fundamental in cell division, movement and differentiation. The stiffness that cells sense is determined not only by the elastic modulus of the ECM material but also by ECM geometry and cell density. We hypothesized that these factors would influence cell traction-induced matrix deformations and cellular differentiation in bone marrow stromal cells (BMSCs). To achieve this, we cultivated BMSCs on polyacrylamide hydrogels that varied in elastic modulus and geometry and measured cell spreading, cell-imparted matrix deformations and differentiation. At low cell density BMSCs spread to a greater extent on stiff compared with soft hydrogels, or on thin compared with thick hydrogels. Cell-imparted matrix deformations were greater on soft compared with stiff hydrogels or thick compared with thin hydrogels. There were no significant differences in osteogenic differentiation relative to hydrogel elastic modulus and thickness. However, increased cell density and/or prolonged culture significantly reduced matrix deformations on soft hydrogels to levels similar to those on stiff substrates. This suggests that at high cell densities cell traction-induced matrix displacements are reduced by both neighbouring cells and the constraint imposed by an underlying stiff support. This may explain observations of the lack of difference in osteogenic differentiation as a function of stiffness.

Spatial transcriptomic validation of a biomimetic model of fibrosis enables re-evaluation of a therapeutic antibody targeting LOXL2.

Matrix stiffening by lysyl oxidase-like 2 (LOXL2)-mediated collagen cross-linking is proposed as a core feedforward mechanism that promotes fibrogenesis. Failure in clinical trials of simtuzumab (the humanized version of AB0023, a monoclonal antibody against human LOXL2) suggested that targeting LOXL2 may not have disease relevance; however, target engagement was not directly evaluated. We compare the spatial transcriptome of active human lung fibrogenesis sites with different human cell culture models to identify a disease-relevant model. Within the selected model, we then evaluate AB0023, identifying that it does not inhibit collagen cross-linking or reduce tissue stiffness, nor does it inhibit LOXL2 catalytic activity. In contrast, it does potently inhibit angiogenesis consistent with an alternative, non-enzymatic mechanism of action. Thus, AB0023 is anti-angiogenic but does not inhibit LOXL2 catalytic activity, collagen cross-linking, or tissue stiffening. These findings have implications for the interpretation of the lack of efficacy of simtuzumab in clinical trials of fibrotic diseases.

A trans-eyebrow zig-zag approach for frontal bone fractures✰.

Frontal bone fractures are amongst the most common facial fractures and surgical management, which has traditionally involved access via a coronal flap, can result in unsightly scarring, alopecia, paraesthesia, facial nerve weakness and temporal hollowing. Alternative approaches include use of endoscopically-assisted surgery, often through the eyebrow, which minimises the risk of unsightly scarring but may also sacrifice access in the process. In this technical note, we discuss a surgical technique for open reduction and internal fixation of fractures of the bone overlying the frontal sinus and supra-orbital rim, which the authors have not found in the literature, which involves the making of a "zig-zag" incision through the eyebrow in a trichophytic manner which reduces the risk of unsightly scarring whilst simultaneously allowing for sufficient surgical access to the fracture site.

Low-energy electronic structure in the unconventional charge-ordered state of ScV6Sn6.

Kagome vanadates AV3Sb5 display unusual low-temperature electronic properties including charge density waves (CDW), whose microscopic origin remains unsettled. Recently, CDW order has been discovered in a new material ScV6Sn6, providing an opportunity to explore whether the onset of CDW leads to unusual electronic properties. Here, we study this question using angle-resolved photoemission spectroscopy (ARPES) and scanning tunneling microscopy (STM). The ARPES measurements show minimal changes to the electronic structure after the onset of CDW. However, STM quasiparticle interference (QPI) measurements show strong dispersing features related to the CDW ordering vectors. A plausible explanation is the presence of a strong momentum-dependent scattering potential peaked at the CDW wavevector, associated with the existence of competing CDW instabilities. Our STM results further indicate that the bands most affected by the CDW are near vHS, analogous to the case of AV3Sb5 despite very different CDW wavevectors.

Nerve-Targeted Surgical Treatments for Spasticity: A Narrative Review.

Spasticity is a potentially debilitating symptom of various acquired and congenital neurologic pathologies that, without adequate treatment, may lead to long-term disability, compromise functional independence, and negatively impact mental health. Several conservative as well as non-nerve targeted surgical strategies have been developed for the treatment of spasticity, but these may be associated with significant drawbacks, such as adverse side effects to medication, device dependence on intrathecal baclofen pumps, and inadequate relief with tendon-based procedures. In these circumstances, patients may benefit from nerve-targeted surgical interventions such as (i) selective dorsal rhizotomy, (ii) hyperselective neurectomy, and (iii) nerve transfer. When selecting the appropriate surgical approach, preoperative patient characteristics, as well as the risks and benefits of nerve-targeted surgical intervention, must be carefully evaluated. Here, we review the current evidence on the efficacy of these nerve-targeted surgical approaches for treating spasticity across various congenital and acquired neurologic pathologies.

Integrating smartwatches in community mental health services for severe mental illness for detecting relapse and informing future intervention: A case series.

OBJECTIVE: This case series explored the integration of smartwatches in a community mental health service to support severe mental illness (SMI) management and intervention. We examined whether biometric data provided by smartwatches could help to predict relapse and inform treatment decisions. METHOD: Four Australian SMI outpatients of mixed diagnoses (age range = 19-24) were selected from a prior study. Clinicians accessed patients' biometric data (activity, sleep, heart rate, and electrodermal activity) through smartwatches. RESULTS: Changes in circadian rhythm and electrodermal activity preceded hospitalization in two cases. Additionally, smartwatch data was effectively used to guide targeted interventions, improving patient treatment outcomes. CONCLUSION: Integrating smartwatches in community mental health services offers promise as adjunct tools for SMI management. However, ethical considerations on data privacy and technology reliance require further evaluation. Additionally, as this is a small case series, randomized controlled trials with larger sample sizes are required to provide evidence for generalisability of results.

Updating perspectives on spinal cord function: motor coordination, timing, relational processing, and memory below the brain.

Those studying neural systems within the brain have historically assumed that lower-level processes in the spinal cord act in a mechanical manner, to relay afferent signals and execute motor commands. From this view, abstracting temporal and environmental relations is the province of the brain. Here we review work conducted over the last 50 years that challenges this perspective, demonstrating that mechanisms within the spinal cord can organize coordinated behavior (stepping), induce a lasting change in how pain (nociceptive) signals are processed, abstract stimulus-stimulus (Pavlovian) and response-outcome (instrumental) relations, and infer whether stimuli occur in a random or regular manner. The mechanisms that underlie these processes depend upon signal pathways (e.g., NMDA receptor mediated plasticity) analogous to those implicated in brain-dependent learning and memory. New data show that spinal cord injury (SCI) can enable plasticity within the spinal cord by reducing the inhibitory effect of GABA. It is suggested that the signals relayed to the brain may contain information about environmental relations and that spinal cord systems can coordinate action in response to descending signals from the brain. We further suggest that the study of stimulus processing, learning, memory, and cognitive-like processing in the spinal cord can inform our views of brain function, providing an attractive model system. Most importantly, the work has revealed new avenues of treatment for those that have suffered a SCI.

Pulmonary vein dose and risk of atrial fibrillation in patients with non-small cell lung cancer following definitive radiotherapy: An NI-HEART analysis.

BACKGROUND AND PURPOSE: Symptomatic arrhythmia is common following radiotherapy for non-small cell lung cancer (NSCLC), frequently resulting in morbidity and hospitalization. Modern treatment planning technology theoretically allows sparing of cardiac substructures. Atrial fibrillation (AF) comprises the majority of post-radiotherapy arrhythmias, but efforts to prevent this cardiotoxicity have been limited as the causative cardiac substructure is not known. In this study we investigated if incidental radiation dose to the pulmonary veins (PVs) is associated with AF. MATERIAL AND METHODS: A single-centre study of patients completing contemporary (chemo)radiation for NSCLC, with modern planning techniques. Oncology, cardiology and death records were examined, and AF events were verified by a cardiologist. Cardiac substructures were contoured on planning scans for retrospective dose analysis. RESULTS: In 420 eligible patients with NSCLC treated with intensity-modulated (70%) or 3D-conformal (30%) radiotherapy with a median OS of 21.8 months (IQR 10.8-35.1), there were 26 cases of new AF (6%). All cases were grade 3 except two cases of grade 4. Dose metrics for both the left (V55) and right (V10) PVs were associated with the incidence of new AF. Metrics remained statistically significant after accounting for the competing risk of death and cardiovascular covariables for both the left (HR 1.02, 95%CI 1.00-1.03, p = 0.005) and right (HR 1.01 (95%CI 1.00-1.02, p = 0.033) PVs. CONCLUSION: Radiation dose to the PVs during treatment of NSCLC was associated with the onset of AF. Actively sparing the PVs during treatment planning could reduce the incidence of AF during follow-up, and screening for AF may be warranted for select cases.

Neurological injury following peripheral nerve blocks: a narrative review of estimates of risks and the influence of ultrasound guidance.

BACKGROUND: Peripheral nerve injury or post-block neurological dysfunction (PBND) are uncommon but a recognized complications of peripheral nerve blocks (PNB). A broad range of its incidence is noted in the literature and hence a critical appraisal of its occurrence is needed. OBJECTIVE: In this review, we wanted to know the pooled estimates of PBND and further, determine its pooled estimates following various PNB over time. Additionally, we also sought to estimate the incidence of PBND with or without US guidance. EVIDENCE REVIEW: A literature search was conducted in six databases. For the purposes of the review, we defined PBND as any new-onset sensorimotor disturbances in the distribution of the performed PNB either attributable to the PNB (when reported) or reported in the context of the PNB (when association with a PNB was not mentioned). Both prospective and retrospective studies which provided incidence of PBND at timepoints of interest (>48 hours to <2 weeks; >2 weeks to 6 weeks, 7 weeks to 5 months, 6 months to 1 year and >1 year durations) were included for review. Incidence data were used to provide pooled estimates (with 95% CI) of PBND at these time periods. Similar estimates were obtained to know the incidence of PBND with or without the use of US guidance. Additionally, PBND associated with individual PNB were obtained in a similar fashion with upper and lower limb PNB classified based on the anatomical location of needle insertion. FINDINGS: The overall incidence of PBND decreased with time, with the incidence being approximately 1% at <2 weeks' time (Incidence per thousand (95% CI)= 9 (8; to 11)) to approximately 3/10 000 at 1 year (Incidence per thousand (95% CI)= 0. 3 (0.1; to 0.5)). Incidence of PBND differed for individual PNB with the highest incidence noted for interscalene block. CONCLUSIONS: Our review adds information to existing literature that the neurological complications are rarer but seem to display a higher incidence for some blocks more than others. Use of US guidance may be associated with a lower incidence of PBND especially in those PNBs reporting a higher pooled estimates. Future studies need to standardize the reporting of PBND at various timepoints and its association to PNB.

Effect of In utero Exposure to Air Pollution on Adulthood Hospitalizations.

Empirical analyses have demonstrated that individuals exposed to severe air pollution in utero have worse health outcomes during childhood. However, there is little evidence on the long-term health impacts of air pollution exposure. The objective of this paper is to estimate the effect of in utero exposure to the Great London Smog of 1952 (GLS) on five health outcomes identified through a scoping review to be those most likely affected: respiratory, circulatory, neoplasms, mental health, and nervous system conditions. We use the GLS, an extreme air pollution event in December 1952, as a quasi-natural experiment to estimate the effect of exposure to air pollution in utero on adulthood health. Data from the UK Biobank is analysed for a cohort of participants born from December 1952 to July 1956. Differences in health outcomes between adults exposed and not exposed to the GLS due to their birth dates, born inside and outside London, were explored. Our primary focus is hospitalization events between 1997 and 2020 (corresponding to ages 40 to 69), as recorded in linked administrative data from the National Health Service (NHS). Specifically, the five primary outcomes are binary variables indicating that the individual had at least one hospitalization where the main cause of hospitalization is related to respiratory, circulatory, neoplasms, mental health, or nervous system conditions. The analytical sample comprised 36,281 individuals. A positive effect on adulthood hospitalizations due to respiratory conditions was observed. If exposed to the GLS in utero, the probability of at least one respiratory health-related hospitalization between 1997 and 2020 increased by 2.58 percentage points (95% CI 0.08, 4.30, p = 0.03), a 23% increase relative to the sample mean. Small effects were found for all other outcomes, suggesting that these conditions were not affected by the GLS. We do not find heterogeneous effects by sex or childhood socioeconomic status. This study found that a 5-day pollution exposure event while in utero significantly increased respiratory-related hospitalizations at ages 40 to 69 but had no impact on hospitalizations due to circulatory, neoplasms, mental health, and nervous system conditions.

Unexpected complication after reverse shoulder arthroplasty: Brachial artery pseudoaneurysm: A case report.

Pseudoaneurysm should be acknowledged as a possible but infrequent postoperative complication after shoulder arthroplasty which could be easily misdiagnosed. It is important that the upper-extremity surgeon suspects this problem in the follow-up assessment for appropriate management. In this paper, we present an unusual case of brachial artery pseudoaneurysm in the early postoperative period after reverse shoulder arthroplasty.

Heat and worker health.

Extreme heat negatively impacts cognition, learning, and task performance. With increasing global temperatures, workers may therefore be at increased risk of work-related injuries and illness. This study estimates the effects of temperature on worker health using records spanning 1985-2020 from an Australian mandatory insurance scheme. High temperatures are found to cause significantly more claims, particularly among manual workers in outdoor-based industries. These adverse effects have not diminished across time, with the largest effect observed for the 2015-2020 period, indicating increasing vulnerability to heat. Within occupations, the workers most adversely affected by heat are female, older-aged and higher-earning. Finally, results from firm-level panel analyses show that the percentage increase in claims on hot days is largest at "safer" firms.

Trends in prevalence and implant types in the Nova Scotia Joint Database Registry between 2005 and 2021.

Aims: The aim of this study is to evaluate the change in incidence rate of shoulder arthroplasty, indications, and surgeon volume trends associated with these procedures between January 2003 and April 2021 in the province of Nova Scotia, Canada. Methods: A total of 1,545 patients between 2005 and 2021 were analyzed. Patients operated on between 2003 and 2004 were excluded due to a lack of electronic records. Overall, 84.1% of the surgeries (n = 1,299) were performed by two fellowship-trained upper limb surgeons, with the remainder performed by one of the 14 orthopaedic surgeons working in the province. Results: Total shoulder arthroplasty (TSA) was the most frequent procedure (32.17%; n = 497), followed by stemmed hemiarthroplasty (SHA) (27.7%; n = 428). The most frequent indication for primary shoulder arthroplasty was degenerative osteoarthritis (58.1%; n = 882), followed by acute proximal humerus fracture in 15.11% (n = 245), and rotator cuff arthropathy in 14.18% (n = 220). The overall rate of revision was 7.7% (2.8% to 11.2%). The number of TSAs and reverse shoulder arthroplasties (RSAs) has been increasing since 2016. The amount of revision cases is proportional to the number of operations performed in the same year throughout the study period. Conclusion: The incidence of shoulder arthroplasty in the Maritime Provinces has increased over the last 16 years. Revision rates are similar the those found in other large database registries. Reverse shoulder arthroplasty prevalence has increased since 2016.

Measuring the missing: Knowledge, risk perceptions and self-protection practices of COVID-19 among the Asian population in New Zealand: An online survey.

Aim: Asians are the second largest and fastest growing non-European population in New Zealand but are under-researched in terms of their COVID-19 pandemic response. The paper aims to illustrates Asians' risk perceptions and knowledge of COVID-19, and self-protection practices to avoid infection and prevent community transmission. Subject and methods: An online survey was used to collect data and received 402 valid responses. Data analyses included: 1) a descriptive analysis by using Chi-square tests and a Kruskal-Wallis rank sum tests to explore associations between responses and the four demographic variables (i.e. age, gender, country of origin/ethnicity, and region); and 2) a correlation analysis between different survey objectives. Results: The descriptive analysis of the survey found that while ethnicity (within the Asian category) was the most influential variable that resulted in varying responses to many questions, gender and age were other two important variables in influencing the answering patterns. The correlation analysis found a positive correlation between the perceived 'dangerousness' of COVID-19 and respondents' overall compliance behaviour to New Zealand authorities' recommendations to prevent spread of COVID-19. Conclusion: The majority of the respondents provided correct answers to the questions about the vulnerable populations, symptoms, asymptomatic transmission and potential sequelae of COVID-19; however, their understanding of the availability of a cure for, and the incubation period of COVID-19 was not consistent with the official information. The research also found that the higher perceived dangerousness of COVID-19, the better compliance to self-protection practices among the surveyed population.

Inflammatory Skin Change From a Small 0.9 cm Primary Breast Cancer Not Seen on Initial Imaging: A Case Report.

Most inflammatory breast cancers are caused by invasive ductal cell carcinomas that arise from mammary epithelial cells lining the breast ducts. Typically, in these cancers, radiological signs are conspicuous, and a diagnosis is made after standard mammographic imaging or ultrasound. We report the case of a 54-year-old female who presented to a mammography clinic with right-sided breast pain and swelling. Upon physical examination, there was no palpable mass. Ultrasound and mammogram findings included mild skin thickening, normal-sized but irregularly shaped axillary lymph nodes, and no breast mass. Due to the presence of inflammatory changes (skin thickening) and abnormal lymph nodes but no obvious mass, an MRI was done to find the primary mass after a core needle biopsy of one lymph node showed metastatic ductal disease. In this patient, a 0.9 cm mass was found at the right 8:00 position on MRI. A second-look ultrasound was then performed and the mass was identified, followed by an ultrasound-guided core biopsy. The biopsy showed an invasive ductal cell carcinoma. In most cases, inflammatory breast cancer is associated with larger tumor sizes. However, a subset of patients with inflammatory breast cancer may present with a small primary breast tumor that causes inflammatory changes. Here, we present a rare case of inflammatory breast cancer associated with a small breast mass measuring less than 1 cm in size.

Association between statin therapy dose intensity and radiation cardiotoxicity in non-small cell lung cancer: Results from the NI-HEART study.

INTRODUCTION: Radiation cardiotoxicity is a dose-limiting toxicity and major survivorship issue for patients with non-small cell lung cancer (NSCLC) completing curative-intent radiotherapy, however patients' cardiovascular baseline is not routinely optimised prior to treatment. In this study we examined the impact of statin therapy on overall survival and post-radiotherapy cardiac events. METHODS: Patients treated between 2015-2020 at a regional center were identified. Clinical notes were interrogated for baseline patient, tumor and cardiac details, and both follow-up cancer control and cardiac events. Three cardiologists verified cardiac events. Radiotherapy planning scans were retrieved for application of validated deep learning-based autosegmentation. Pre-specified Cox regression analyses were generated with varying degrees of adjustment for overall survival. Fine and Gray regression for the risk of cardiac events, accounting for the competing risk of death and cardiac covariables was undertaken. RESULTS: Statin therapy was prescribed to 59% of the 478 included patients. The majority (88%) of patients not prescribed a statin had at least one indication for statin therapy according to cardiovascular guidelines. In total, 340 patients (71%) died and 79 patients (17%) experienced a cardiac event. High-intensity (HR 0.68, 95%CI 0.50-0.91, p = 0.012) and medium-intensity (HR 0.70, 95%CI 0.51-0.97, p = 0.033) statin therapy were associated with improved overall survival after adjustment for patient, cancer, treatment, response and cardiovascular clinical factors. There were no consistent differences in the rate or grade of cardiac events according to statin intensity. CONCLUSIONS: Statin therapy is associated with improved overall survival in patients receiving curative-intent radiotherapy for NSCLC, and there is evidence of a dose-response relationship. This study highlights the importance of a pre-treatment cardiovascular risk assessment in this cohort. Further studies are needed to examine if statin therapy is cardioprotective in patients undergoing treatment for NSCLC with considerable incidental cardiac radiation dose and a low baseline cardiac risk.

Long-term health effects of a school construction program.

Non-communicable diseases (NCDs) disproportionately affect people in low- and middle-income countries (LMICs), yet context-specific evidence on policies that impact NCD risk factors is lacking. We estimate the impact of a massive Indonesian primary school expansion program in the 1970s on NCD risk factors in later life using data from two surveys with very large sample sizes. We find that in non-Java regions of Indonesia, the program led to significant increases in the likelihood of overweight and high waist circumference among women, but not among men. The increase for women can be partly explained by increased consumption of high-calorie packaged and take-away meals. We find no meaningful impacts on high blood pressure for either sex. Despite the increase in body weight, the program had a negligible impact on diabetes and cardiovascular disease diagnosis. It led to an improvement in women's self-reported health outcomes in their early-40s, but these benefits largely disappeared once they reached their mid-40s.

Minke whale feeding rate limitations suggest constraints on the minimum body size for engulfment filtration feeding.

Bulk filter feeding has enabled gigantism throughout evolutionary history. The largest animals, extant rorqual whales, utilize intermittent engulfment filtration feeding (lunge feeding), which increases in efficiency with body size, enabling their gigantism. The smallest extant rorquals (7-10 m minke whales), however, still exhibit short-term foraging efficiencies several times greater than smaller non-filter-feeding cetaceans, raising the question of why smaller animals do not utilize this foraging modality. We collected 437 h of bio-logging data from 23 Antarctic minke whales (Balaenoptera bonaerensis) to test the relationship of feeding rates (λf) to body size. Here, we show that while ultra-high nighttime λf (mean ± s.d.: 165 ± 40 lunges h-1; max: 236 lunges h-1; mean depth: 28 ± 46 m) were indistinguishable from predictions from observations of larger species, daytime λf (mean depth: 72 ± 72 m) were only 25-40% of predicted rates. Both λf were near the maxima allowed by calculated biomechanical, physiological and environmental constraints, but these temporal constraints meant that maximum λf was below the expected λf for animals smaller than ~5 m-the length of weaned minke whales. Our findings suggest that minimum size for specific filter-feeding body plans may relate broadly to temporal restrictions on filtration rate and have implications for the evolution of filter feeding.

Cognitive activity at work and the risk of dementia.

Dementia prevalence is projected to rise steeply in coming decades, producing tremendous burdens on families, and health and social services. Motivated by the need for further robust evidence on modifiable risk factors, we investigate the relationship between cognitive activity at work and later-life dementia. Using data from the US Health and Retirement Study matched to the O*NET occupational database, we find that a one standard deviation increase in the cognitive activity associated with one's longest held occupation is associated with a 0.9 percentage point reduction in (predicted) dementia, or a 24% reduction relative to the mean. This relationship is consistently found across model specifications and robustness tests. When controlling for individual fixed-effects we find that the association between dementia and work cognitive activity increases with age. Overall, our results provide some evidence in support of the inclusion of cognitive activity at work as a recognized modifiable risk factor for dementia.

A surplus no more? Variation in krill availability impacts reproductive rates of Antarctic baleen whales.

The krill surplus hypothesis of unlimited prey resources available for Antarctic predators due to commercial whaling in the 20th century has remained largely untested since the 1970s. Rapid warming of the Western Antarctic Peninsula (WAP) over the past 50 years has resulted in decreased seasonal ice cover and a reduction of krill. The latter is being exacerbated by a commercial krill fishery in the region. Despite this, humpback whale populations have increased but may be at a threshold for growth based on these human-induced changes. Understanding how climate-mediated variation in prey availability influences humpback whale population dynamics is critical for focused management and conservation actions. Using an 8-year dataset (2013-2020), we show that inter-annual humpback whale pregnancy rates, as determined from skin-blubber biopsy samples (n = 616), are positively correlated with krill availability and fluctuations in ice cover in the previous year. Pregnancy rates showed significant inter-annual variability, between 29% and 86%. Our results indicate that krill availability is in fact limiting and affecting reproductive rates, in contrast to the krill surplus hypothesis. This suggests that this population of humpback whales may be at a threshold for population growth due to prey limitations. As a result, continued warming and increased fishing along the WAP, which continue to reduce krill stocks, will likely impact this humpback whale population and other krill predators in the region. Humpback whales are sentinel species of ecosystem health, and changes in pregnancy rates can provide quantifiable signals of the impact of environmental change at the population level. Our findings must be considered paramount in developing new and more restrictive conservation and management plans for the Antarctic marine ecosystem and minimizing the negative impacts of human activities in the region.