Slow Fatigue and Highly Delayed Yielding via Shear Banding in Oscillatory Shear.

We study theoretically the dynamical process of yielding in cyclically sheared amorphous materials, within a thermal elastoplastic model and the soft glassy rheology model. Within both models we find an initially slow accumulation, over many cycles after the inception of shear, of low levels of damage in the form strain heterogeneity across the sample. This slow fatigue then suddenly gives way to catastrophic yielding and material failure. Strong strain localization in the form of shear banding is key to the failure mechanism. We characterize in detail the dependence of the number of cycles N^{*} before failure on the amplitude of imposed strain, the working temperature, and the degree to which the sample is annealed prior to shear. We discuss our finding with reference to existing experiments and particle simulations, and suggest new ones to test our predictions.

Optimizing calibration of modern skeletal maturity systems.

Purpose: Greulich and Pyle is the most used system to estimate skeletal maturity but has significant drawbacks, prompting the development of newer skeletal maturity systems, such as the modified Fels skeletal maturity systems based on knee radiographs. To create a new skeletal maturity system, an outcome variable, termed a "skeletal maturity standard," must be selected for calibration of the system. Peak height velocity and 90% of final height are both considered reasonable skeletal maturity standards for skeletal maturity system development. We sought to answer two questions: (1) Does a skeletal maturity system developed using 90% of final height estimate skeletal age as well as it would if it was instead developed using peak height velocity? (2) Does a skeletal maturity system developed using 90% of final height perform as well in lower extremity length prediction as it would if it was instead developed using peak height velocity? Methods: The modified Fels knee skeletal maturity system was recalibrated based on 90% of final height and peak height velocity skeletal maturity standards. These models were applied to 133 serially obtained, peripubertal antero-posterior knee radiographs collected from 38 subjects. Each model was used to estimate the skeletal age of each radiograph. Skeletal age estimates were also used to predict each patient's ultimate femoral and tibial length using the White-Menelaus method. Results: The skeletal maturity system calibrated with 90% of final height produced more accurate skeletal age estimates than the same skeletal maturity system calibrated with peak height velocity (p < 0.05). The 90% of final height and peak height velocity models made similar femoral and tibial length predictions (p > 0.05). Conclusion: Using the 90% of final height skeletal maturity standard allows for simpler skeletal maturity system development than peak height velocity with potentially more accuracy.

Episodic memory assessment: effects of sex and age on performance and response time during a continuous recognition task.

Introduction: Continuous recognition tasks (CRTs) assess episodic memory (EM), the central functional disturbance in Alzheimer's disease and several related disorders. The online MemTrax computerized CRT provides a platform for screening and assessment that is engaging and can be repeated frequently. MemTrax presents complex visual stimuli, which require complex involvement of the lateral and medial temporal lobes and can be completed in less than 2 min. Results include number of correct recognitions (HITs), recognition failures (MISSes = 1-HITs), correct rejections (CRs), false alarms (FAs = 1-CRs), total correct (TC = HITs + CRs), and response times (RTs) for each HIT and FA. Prior analyses of MemTrax CRT data show no effects of sex but an effect of age on performance. The number of HITs corresponds to faster RT-HITs more closely than TC, and CRs do not relate to RT-HITs. RT-HITs show a typical skewed distribution, and cumulative RT-HITs fit a negative survival curve (RevEx). Thus, this study aimed to define precisely the effects of sex and age on HITS, CRs, RT-HITs, and the dynamics of RTs in an engaged population. Methods: MemTrax CRT online data on 18,255 individuals was analyzed for sex, age, and distributions of HITs, CRs, MISSes, FAs, TC, and relationships to both RT-HITs and RT-FAs. Results: HITs corresponded more closely to RT-HITs than did TC because CRs did not relate to RT-HITs. RT-FAs had a broader distribution than RT-HITs and were faster than RT-HITs in about half of the sample, slower in the other half. Performance metrics for men and women were the same. HITs declined with age as RT-HITs increased. CRs also decreased with age and RT-FAs increased, but with no correlation. The group over aged 50 years had RT-HITs distributions slower than under 50 years. For both age ranges, the RevEx model explained more than 99% of the variance in RT-HITs. Discussion: The dichotomy of HITs and CRs suggests opposing cognitive strategies: (1) less certainty about recognitions, in association with slower RT-HITs and lower HIT percentages suggests recognition difficulty, leading to more MISSes, and (2) decreased CRs (more FAs) but faster RTs to HITs and FAs, suggesting overly quick decisions leading to errors. MemTrax CRT performance provides an indication of EM (HITs and RT-HITs may relate to function of the temporal lobe), executive function (FAs may relate to function of the frontal lobe), processing speed (RTs), cognitive ability, and age-related changes. This CRT provides potential clinical screening utility for early Alzheimer's disease and other conditions affecting EM, other cognitive functions, and more accurate impairment assessment to track changes over time.

Pilot evaluation of a behavioral weight loss program for adults with physical disabilities: State of Slim Everybody usability and feasibility.

Background: People with physical disabilities (PWD) have a higher prevalence of obesity than populations without disability, but most evidence-based weight loss programs have not included this population. The State of Slim (SOS) program is an evidence-based weight loss program that has demonstrated success in producing weight loss in populations without disability, but it has not been adapted for or evaluated in PWD. Methods: The SOS program was systematically adapted using the evidence-informed Guidelines, Recommendations, and Adaptations Including Disability (GRAIDs) framework. A total of 35 participants enrolled in the State of Slim Everybody program. The program was offered entirely online. Body weight, attendance, and food log completion were also tracked weekly. The program length was 16.5 h and included weekly group instruction, with optional one-on-one sessions provided upon request. Following completion, participants completed post-evaluation surveys on overall satisfaction with the program. The primary outcomes were program effectiveness (i.e., body weight), usability, and feasibility. Results: Thirty-two out of 35 participants completed the program, representing a retention rate of 91.4%. Average weight loss was 10.9% (9.9 ± 0.7 kg (t (31) = -13.3, p =< 0.0001)). On a 1 (dissatisfied/completely useless) to 5 (very satisfied/completely helpful) Likert scale, the average score for overall program satisfaction was 4.8 ± 0.1 and program helpfulness 4.6 ± 0.1. Conclusion: The State of Slim Everybody program demonstrated significant weight loss and good usability and feasibility in PWD. Existing adaptation frameworks can be used to create inclusive health promotion programs for adults with physical disabilities.

Impact of neoadjuvant chemotherapy on short-term outcomes after simple and complex minimally invasive minor hepatectomy for colorectal liver metastases: A propensity-score matched and coarsened exact matched study.

BACKGROUND: In the last three decades, minimally invasive liver resection has been replacing conventional open approach in liver surgery. More recently, developments in neoadjuvant chemotherapy have led to increased multidisciplinary management of colorectal liver metastases with both medical and surgical treatment modalities. However, the impact of neoadjuvant chemotherapy on the surgical outcomes of minimally invasive liver resections remains poorly understood. METHODS: A multicenter, international, database of 4998 minimally invasive minor hepatectomy for colorectal liver metastases was used to compare surgical outcomes in patients who received neoadjuvant chemotherapy with surgery alone. To correct for baseline imbalance, propensity score matching, coarsened exact matching and inverse probability treatment weighting were performed. RESULTS: 2546 patients met the inclusion criteria. After propensity score matching there were 759 patients in both groups and 383 patients in both groups after coarsened exact matching. Baseline characteristics were equal after both matching strategies. Neoadjuvant chemotherapy was not associated with statistically significant worse surgical outcomes of minimally invasive minor hepatectomy. CONCLUSION: Neoadjuvant chemotherapy had no statistically significant impact on short-term surgical outcomes after simple and complex minimally invasive minor hepatectomy for colorectal liver metastases.

Defining predictors of responsiveness to advanced therapies in Crohn's disease and ulcerative colitis: protocol for the IBD-RESPONSE and nested CD-metaRESPONSE prospective, multicentre, observational cohort study in precision medicine.

INTRODUCTION: Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient's quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments. METHODS AND ANALYSIS: This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk. TRIAL REGISTRATION NUMBER: ISRCTN96296121.

Predicting the presence of infectious virus from PCR data: A meta-analysis of SARS-CoV-2 in non-human primates.

Researchers and clinicians often rely on molecular assays like PCR to identify and monitor viral infections, instead of the resource-prohibitive gold standard of viral culture. However, it remains unclear when (if ever) PCR measurements of viral load are reliable indicators of replicating or infectious virus. The recent popularity of PCR protocols targeting subgenomic RNA for SARS-CoV-2 has caused further confusion, as the relationships between subgenomic RNA and standard total RNA assays are incompletely characterized and opinions differ on which RNA type better predicts culture outcomes. Here, we explore these issues by comparing total RNA, subgenomic RNA, and viral culture results from 24 studies of SARS-CoV-2 in non-human primates (including 2167 samples from 174 individuals) using custom-developed Bayesian statistical models. On out-of-sample data, our best models predict subgenomic RNA positivity from total RNA data with 91% accuracy, and they predict culture positivity with 85% accuracy. Further analyses of individual time series indicate that many apparent prediction errors may arise from issues with assay sensitivity or sample processing, suggesting true accuracy may be higher than these estimates. Total RNA and subgenomic RNA showed equivalent performance as predictors of culture positivity. Multiple cofactors (including exposure conditions, host traits, and assay protocols) influence culture predictions, yielding insights into biological and methodological sources of variation in assay outcomes-and indicating that no single threshold value applies across study designs. We also show that our model can accurately predict when an individual is no longer infectious, illustrating the potential for future models trained on human data to guide clinical decisions on case isolation. Our work shows that meta-analysis of in vivo data can overcome longstanding challenges arising from limited sample sizes and can yield robust insights beyond those attainable from individual studies. Our analytical pipeline offers a framework to develop similar predictive tools in other virus-host systems, including models trained on human data, which could support laboratory analyses, medical decisions, and public health guidelines.

Sensorineural correlates of failed functional recovery after natural regeneration of vestibular hair cells in adult mice.

Vestibular hair cells (HCs) are mechanoreceptors that sense head motions by modulating the firing rate of vestibular ganglion neurons (VGNs), whose central processes project to vestibular nucleus neurons (VNNs) and cerebellar neurons. We explored vestibular function after HC destruction in adult Pou4f3+/DTR (DTR) mice, in which injections of high-dose (50 ng/g) diphtheria toxin (DT) destroyed most vestibular HCs within 2 weeks. At that time, DTR mice had lost the horizontal vestibulo-ocular reflex (aVORH), and their VNNs failed to upregulate nuclear cFos expression in response to a vestibular stimulus (centrifugation). Five months later, 21 and 14% of HCs were regenerated in utricles and horizontal ampullae, respectively. The vast majority of HCs present were type II. This degree of HC regeneration did not restore the aVORH or centrifugation-evoked cFos expression in VNNs. The failure to regain vestibular pathway function was not due to degeneration of VGNs or VNNs because normal neuron numbers were maintained after HC destruction. Furthermore, sinusoidal galvanic stimulation at the mastoid process evoked cFos protein expression in VNNs, indicating that VGNs were able to regulate VNN activity after HC loss. aVORH and cFos responses in VNNs were robust after low-dose (25 ng/g) DT, which compared to high-dose DT resulted in a similar degree of type II HC death and regeneration but spared more type I HCs in both organs. These findings demonstrate that having more type I HCs is correlated with stronger responses to vestibular stimulation and suggest that regenerating type I HCs may improve vestibular function after HC loss.

Curcumin abrogates cobalt-induced neuroinflammation by suppressing proinflammatory cytokines release, inhibiting microgliosis and modulation of ERK/MAPK signaling pathway.

Curcumin, a bioactive polyphenol derived from turmeric, has been reported to have anti-inflammatory properties. The current study investigated the anti-inflammatory effect of curcumin in the hippocampal subfields (CA1 and CA3) after exposure to cobalt (Co) and the impact of ERK protein. Twenty-eight albino Wistar rats were divided into four groups, each with seven randomly selected rats as follows: Control (distilled water), Cobalt (Co) only (40 mg/kg), 120 mg/kg or 240 mg/kg curcumin + Co (40 mg/kg). Treatment was via oral gavage for 28 days. We performed a biochemical investigation to determine the levels of proinflammatory cytokines (TNFα and IL-1ß). Furthermore, we conducted an immunohistochemical evaluation to assess the expression of IBA1 by microglial cells and the immunoexpression of ERK protein in the hippocampus. Results revealed a significant (p<0.05) elevation in the tissue level of TNFα and IL-1ß, an increase in the number of IBA1-positive microglia, and upregulation of ERK protein in the hippocampal subfields of the rats after exposure to cobalt-only. Nevertheless, pretreatment with curcumin restored these parameters to levels comparable to control. In conclusion, our results showed that curcumin abrogated the Co-induced neuroinflammation by suppressing the release of proinflammatory biomarkers, reducing microgliosis, and modulating the ERK/MAPK pathway.

The paradox of haemodialysis: the lived experience of the clocked treatment of chronic illness.

Studies exploring the relationship between time and chronic illness have generally focused on measurable aspects of time, also known as linear time. Linear time follows a predictable, sequential order of past, present and future; measured using a clock and predicated on normative assumptions. Sociological concepts addressing lifecourse disruption following diagnosis of chronic illness have served to enhance the understanding of lived experience. To understand the nuanced relationship between time and chronic illness, however, requires further exploration. Here, we show how the implicit assumptions of linear time meet in tension with the lived experience of chronic illness. We draw on interviews and photovoice work with people with end-stage kidney disease in receipt of in-centre-daytime haemodialysis to show how the clocked treatment of chronic illness disrupts experiences of time. Drawing on concepts of 'crip' and 'chronic' time we argue that clocked treatment and the lived experience of chronic illness converge at a paradox whereby clocked treatment allows for the continuation of linear time yet limits freedom. We use the concept of 'crip time' to challenge the normative assumptions implicit within linear concepts of time and argue that the understanding of chronic illness and its treatment would benefit from a 'cripped' starting point.

Quantum interference enhances the performance of single-molecule transistors.

Quantum effects in nanoscale electronic devices promise to lead to new types of functionality not achievable using classical electronic components. However, quantum behaviour also presents an unresolved challenge facing electronics at the few-nanometre scale: resistive channels start leaking owing to quantum tunnelling. This affects the performance of nanoscale transistors, with direct source-drain tunnelling degrading switching ratios and subthreshold swings, and ultimately limiting operating frequency due to increased static power dissipation. The usual strategy to mitigate quantum effects has been to increase device complexity, but theory shows that if quantum effects can be exploited in molecular-scale electronics, this could provide a route to lower energy consumption and boost device performance. Here we demonstrate these effects experimentally, showing how the performance of molecular transistors is improved when the resistive channel contains two destructively interfering waves. We use a zinc-porphyrin coupled to graphene electrodes in a three-terminal transistor to demonstrate a >104 conductance-switching ratio, a subthreshold swing at the thermionic limit, a >7 kHz operating frequency and stability over >105 cycles. We fully map the anti-resonance interference features in conductance, reproduce the behaviour by density functional theory calculations and trace back the high performance to the coupling between molecular orbitals and graphene edge states. These results demonstrate how the quantum nature of electron transmission at the nanoscale can enhance, rather than degrade, device performance, and highlight directions for future development of miniaturized electronics.

Upadacitinib Achieves Clinical and Endoscopic Outcomes in Crohn's Disease Regardless of Prior Biologic Exposure.

BACKGROUND & AIMS: Upadacitinib, an oral Janus kinase inhibitor, achieved significantly higher rates of clinical remission and endoscopic response vs placebo during induction (U-EXCEL [NCT03345849], U-EXCEED [NCT03345836]) and maintenance (U-ENDURE [NCT03345823]) treatment in patients with moderate-to-severe Crohn's disease. Prior biologic failure is often associated with reduced responses to subsequent therapies. This post hoc analysis assessed upadacitinib efficacy by prior biologic failure status. METHODS: Patients were randomized to placebo or upadacitinib 45 mg (UPA45) for 12 weeks (induction). UPA45 clinical responders were enrolled in U-ENDURE and rerandomized to placebo, upadacitinib 15 mg, or upadacitinib 30 mg (UPA30) for 52 weeks. Assessments were by prior biologic failure. RESULTS: Of 1021 patients, 733 (71.8%) had prior biologic failure. Across outcomes and subgroups, upadacitinib-treated patients achieved higher rates vs placebo. During induction, upadacitinib had higher rates vs placebo for clinical remission based on stool frequency/abdominal pain score (without failure: 54.0% vs 28.3%; with failure: 42.2% vs 14.1%) and endoscopic response (without failure: 52.0% vs 16.2%; with failure: 35.7% vs 5.3%). In maintenance, the greatest treatment effect (upadacitinib vs placebo) was among patients with prior biologic failure treated with UPA30 (clinical remission without failure: 58.5% vs 32.7%; with failure: 42.5% vs 8.7%; endoscopic response without failure: 43.9% vs 17.9%; with failure: 38.9% vs 4.0%). Patients without vs with prior biologic failure had fewer adverse events. CONCLUSIONS: Upadacitinib led to higher absolutes rates of clinical and endoscopic outcomes in patients without vs with prior biologic failure. Patients treated with upadacitinib achieved greater rates of clinical and endoscopic improvements vs placebo, regardless of prior biologic exposure. CLINICALTRIALS: gov: NCT03345849, NCT03345836, NCT03345823.

Intermediate-Term Oncological Outcome Assessment for Robotic Assisted Radical Prostatectomy Comparing Retzius Sparing to Standard Approach in a Randomized Control Cohort.

INTRODUCTION: Retzius sparing prostatectomy was promoted with the early continence result. The long-term oncological outcome is still unknown. In this study, we aimed to compare the Intermediate-term oncologic outcomes of these two approaches in patient's cohort who was treated as part of a randomized controlled trial. METHODS: A total of 120 patients were previously randomized equally to receive retzius sparing (RS-RARP) versus standard robotic assisted laparoscopic radical prostatectomy (S-RARP) between January 2015 to April 2016. Baseline, surgical, and pathological characteristics as well as oncologic outcomes were assessed. The analysis was done based on the treatment received. RESULT: Sixty-three patients underwent S-RARP while 57 patients underwent RS-RARP. There was no statistically significant difference in the baseline nor surgical characteristics. The median follow up was 71.24 (IQR 59.75 - 75.75). There were more pathological T3 diseases in RS-RARP. There was no significant difference in the positive margin status nor the biochemical recurrence rate among both groups. After S-RARP and RS-RARP, 6 and 10 patients had biochemical recurrence and the 5-years biochemical recurrence free survival were 91% and 85%, respectively. (p= 0.21) Conclusion: In this cohort, there was no difference in biochemical recurrence in the patients who received either technique. Further mutli-institutional studies with a larger sample size and longer follow up are required.

Associations Among Environmental Exposures and Physical and Psychiatric Symptoms in a Care-Seeking Sample of U.S. Military Veterans.

INTRODUCTION: Recent research and policy (e.g., the Sergeant First Class (SFC) Heath Robinson Honoring our Promise to Address Comprehensive Toxics (PACT) Act) have highlighted the potential health consequences of toxic environmental exposures. The purpose of the current study was to assess the self-reported prevalence of such exposures among a sample of U.S. military veterans seeking care at a Veterans Affairs facility and to examine associations between exposures and physical and psychiatric symptoms. MATERIALS AND METHODS: Participants were 4,647 newly enrolling post-9/11 veterans at the VA San Diego Healthcare System who completed standard clinical screening processes between January 2015 and April 2019. Electronic health screening data, including demographic information, military history, environmental exposures, and physical and psychiatric symptoms, were assessed. t-Tests for continuous variables and chi-square tests for categorical variables were used to compare exposed to unexposed veterans on demographic and military characteristics as well as physical and psychiatric symptoms. RESULTS: A total of 2,028 veterans (43.6%) reported exposure to environmental toxins during their military service. Analyses revealed a disproportionate burden of exposure on older, male, educated, combat veterans as well as Asian and Native American veterans. Exposure to any type of environmental toxin was associated with more physical symptoms, particularly pain, fatigue, and insomnia, as well as psychiatric symptoms, including moderate depressive symptomology, mild to moderate anxiety, and scores approaching the threshold for likely post-traumatic stress disorder and alcohol misuse. CONCLUSIONS: The high prevalence and detrimental health correlates of environmental exposures underscore the importance of implementing screening for exposures and providing healthcare services that address the multisystemic nature of exposure-related illness.

Should carbohydrate-modified diets be the first option for weight loss in people with impaired glucose metabolism? A scoping review.

While the "precision nutrition" movement is at an early stage of development, several investigations have compared low-fat versus carbohydrate (CHO)-modified diets (i.e., low-or-reduced-CHO, low glycemic index/load diets, and high-fiber) in people with normal versus impaired glucose metabolism. The purpose of this scoping review was to summarize evidence in support of the hypothesis that CHO-modified diets are more effective for weight loss among people with impaired glucose metabolism. Fifteen articles were included in this review: seven retrospective analyses of randomized clinical trials and eight prospective randomized clinical trials with prespecified hypotheses related to a diet (low-fat vs. CHO-modified) × phenotype (normal vs. impaired) interaction. Evidence in support of the hypothesis was identified in six of seven retrospective and three of eight prospective studies, which led to a recommendation of CHO-modified diets as a first-line option for people with impaired glucose metabolism. However, the evidence in support of this recommendation is relatively weak, and dietary prescriptions should consider additional contextual information that may influence overall dietary adherence. Additional and rigorous research using innovative randomized experimental approaches is needed for stronger dietary weight loss recommendations based on pretreatment glycemic status.

Feline radial and ulnar diaphyseal fractures: a retrospective study of 49 cases comparing single bone fixation and dual bone fixation.

OBJECTIVES: The objectives of this study were to report the complications in radial and ulnar diaphyseal fractures in cats and to compare the differences in outcome between single and dual bone internal fixation. METHODS: Medical records between 2004 and 2022 were searched retrospectively for cats with antebrachial diaphyseal fractures treated with internal bone-plate fixation. In total, 49 cases were included from six referral hospitals, including one teaching hospital. Patient information was collated, including fracture configuration, location, repair method and clinical outcome as assessed by veterinary physical examination, radiography and owner questionnaire. RESULTS: A total of 47 cats (mean age 4.2 years) were included. Fractures were located distally (24/49, 49%), proximally (13/49, 26.5%) and mid-diaphyseally (12/49, 24.5%). Dual bone fixation was used in 13/49 (26.5%) cases, with only 1/13 (7.7%) having major complications. By comparison, 4/36 (11.1%) of single plated fractures had major complications. Single bone fixation was 14.25 times more likely (95% confidence interval [CI] 2.07-97.99) to have a successful outcome (veterinarian-assigned score of 0) compared with dual bone fixation (P = 0.007). When evaluating owner-assessed outcomes, single bone fixation was 9.4 times more likely (95% CI 1.4-61.96) to have a successful outcome (owner score of 0) compared with dual bone fixation (P = 0.019). CONCLUSIONS AND RELEVANCE: Fractures that were repaired with single bone fixation had a greater chance of a better outcome. Although the difference was not significant, there was a higher major complication rate and a lower minor complication rate for cases treated with single bone fixation compared with dual bone fixation. The majority of fractures were located in the distal diaphysis. Comminution of the fracture and concurrent orthopaedic issues did not significantly affect the outcome. Further prospective studies with standardised follow-up, radiographic assessment, surgeon and implants are required to truly assess the difference between dual and single bone fixation.

Host and viral determinants of airborne transmission of SARS-CoV-2 in the Syrian hamster.

It remains poorly understood how SARS-CoV-2 infection influences the physiological host factors important for aerosol transmission. We assessed breathing pattern, exhaled droplets, and infectious virus after infection with Alpha and Delta variants of concern (VOC) in the Syrian hamster. Both VOCs displayed a confined window of detectable airborne virus (24-48 hr), shorter than compared to oropharyngeal swabs. The loss of airborne shedding was linked to airway constriction resulting in a decrease of fine aerosols (1-10 µm) produced, which are suspected to be the major driver of airborne transmission. Male sex was associated with increased viral replication and virus shedding in the air. Next, we compared the transmission efficiency of both variants and found no significant differences. Transmission efficiency varied mostly among donors, 0-100% (including a superspreading event), and aerosol transmission over multiple chain links was representative of natural heterogeneity of exposure dose and downstream viral kinetics. Co-infection with VOCs only occurred when both viruses were shed by the same donor during an increased exposure timeframe (24-48 hr). This highlights that assessment of host and virus factors resulting in a differential exhaled particle profile is critical for understanding airborne transmission.

Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial.

BACKGROUND: A previous controlled trial of autologous haematopoietic stem-cell transplantation (HSCT) in patients with refractory Crohn's disease did not meet its primary endpoint and reported high toxicity. We aimed to assess the safety and efficacy of HSCT with an immune-ablative regimen of reduced intensity versus standard of care in this patient population. METHODS: This open-label, multicentre, randomised controlled trial was conducted in nine National Health Service hospital trusts across the UK. Adults (aged 18-60 years) with active Crohn's disease on endoscopy (Simplified Endoscopic Score for Crohn's Disease [SES-CD] ulcer sub-score of ≥2) refractory to two or more classes of biological therapy, with no perianal or intra-abdominal sepsis or clinically significant comorbidity, were recruited. Participants were centrally randomly assigned (2:1) to either HSCT with a reduced dose of cyclophosphamide (intervention group) or standard care (control group). Randomisation was stratified by trial site by use of random permuted blocks of size 3 and 6. Patients in the intervention group underwent stem-cell mobilisation (cyclophosphamide 1 g/m2 with granulocyte colony-stimulating factor (G-CSF) 5 µg/kg) and stem-cell harvest (minimum 2·0 × 106 CD34+ cells per kg), before conditioning (fludarabine 125 mg/m2, cyclophosphamide 120 mg/kg, and rabbit anti-thymocyte globulin [thymoglobulin] 7·5 mg/kg in total) and subsequent stem-cell reinfusion supported by G-CSF. Patients in the control group continued any available conventional, biological, or nutritional therapy. The primary outcome was absence of endoscopic ulceration (SES-CD ulcer sub-score of 0) without surgery or death at week 48, analysed in the intention-to-treat population by central reading. This trial is registered with the ISRCTN registry, 17160440. FINDINGS: Between Oct 18, 2018, and Nov 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and ten (43%) to the control group. In the intervention group, ten (77%) participants underwent HSCT and nine (69%) reached 48-week follow-up; in the control group, nine (90%) reached 48-week follow-up. The trial was halted in response to nine reported suspected unexpected serious adverse reactions in six (46%) patients in the intervention group, including renal failure due to proven thrombotic microangiopathy in three participants and one death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in three (43%) of seven participants in the intervention group and in none of six participants in the control group with available data. Serious adverse events were more frequent in the intervention group (38 in 13 [100%] patients) than in the control group (16 in four [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure. INTERPRETATION: Although HSCT with an immune-ablative regimen of reduced intensity decreased endoscopic disease activity, significant adverse events deem this regimen unsuitable for future clinical use in patients with refractory Crohn's disease. FUNDING: Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.

Connections to the Electrodes Control the Transport Mechanism in Single-Molecule Transistors.

When designing a molecular electronic device for a specific function, it is necessary to control whether the charge-transport mechanism is phase-coherent transmission or particle-like hopping. Here we report a systematic study of charge transport through single zinc-porphyrin molecules embedded in graphene nanogaps to form transistors, and show that the transport mechanism depends on the chemistry of the molecule-electrode interfaces. We show that van der Waals interactions between molecular anchoring groups and graphene yield transport characteristic of Coulomb blockade with incoherent sequential hopping, whereas covalent molecule-electrode amide bonds give intermediately or strongly coupled single-molecule devices that display coherent transmission. These findings demonstrate the importance of interfacial engineering in molecular electronic circuits.