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Abstract Background Cigarette smoking remains the leading cause of preventable disease and death in the United States. Primary care offers an ideal setting to reach adults who smoke cigarettes and improve uptake of evidence-based cessation treatment. Although U.S. Preventive Services Task Force Guidelines recommend the 5As model (Ask, Advise, Assess, Assist, Arrange) in primary care, there are many barriers to its implementation. Automated, comprehensive, and proactive tools are needed to overcome barriers. Our team developed and preliminarily evaluated a proactive electronic visit (e-visit) delivered via the Electronic Health Record patient portal to facilitate evidence-based smoking cessation treatment uptake in primary care, with promising initial feasibility and efficacy. This paper describes the rationale, design, and protocol for an ongoing Hybrid Type I effectiveness-implementation trial that will simultaneously assess effectiveness of the e-visit intervention for smoking cessation as well as implementation potential across diverse primary care settings. Methods The primary aim of this remote five-year study is to examine the effectiveness of the e-visit intervention vs. treatment as usual (TAU) for smoking cessation via a clinic-randomized clinical trial. Adults who smoke cigarettes are recruited across 18 primary care clinics. Clinics are stratified based on their number of primary care providers and randomized 2:1 to either e-visit or TAU. An initial baseline e-visit gathers information about patient smoking history and motivation to quit, and a clinical decision support algorithm determines the best evidence-based cessation treatment to prescribe. E-visit recommendations are evaluated by a patient’s own provider, and a one-month follow-up e-visit assesses cessation progress. Main outcomes include: (1) cessation treatment utilization (medication, psychosocial cessation counseling), (2) reduction in cigarettes per day, and (3) biochemically verified 7-day point prevalence abstinence (PPA) at six-months. We hypothesize that patients randomized to the e-visit condition will have better cessation outcomes (vs. TAU). A secondary aim evaluates e-visit implementation potential at patient, provider, and organizational levels using a mixed-methods approach. Implementation outcomes include acceptability, adoption, fidelity, implementation cost, penetration, and sustainability. Discussion This asynchronous, proactive e-visit intervention could provide substantial benefits for patients, providers, and primary care practices and has potential to widely improve reach of evidence-based cessation treatment. Trial registration NCT05493254.

Abstract Background Many families and individuals do not meet criteria for a known hereditary cancer syndrome but display unusual clusters of cancers. These families may carry pathogenic variants in cancer predisposition genes and be at higher risk for developing cancer. Methods This multi-centre prospective study recruited 195 cancer-affected participants suspected to have a hereditary cancer syndrome for whom previous clinical targeted genetic testing was either not informative or not available. To identify pathogenic disease-causing variants explaining participant presentation, germline whole-genome sequencing (WGS) and a comprehensive cancer virtual gene panel analysis were undertaken. Results Pathogenic variants consistent with the presenting cancer(s) were identified in 5.1% (10/195) of participants and pathogenic variants considered secondary findings with potential risk management implications were identified in another 9.7% (19/195) of participants. Health economic analysis estimated the marginal cost per case with an actionable variant was significantly lower for upfront WGS with virtual panel ($8744AUD) compared to standard testing followed by WGS ($24,894AUD). Financial analysis suggests that national adoption of diagnostic WGS testing would require a ninefold increase in government annual expenditure compared to conventional testing. Conclusions These findings make a case for replacing conventional testing with WGS to deliver clinically important benefits for cancer patients and families. The uptake of such an approach will depend on the perspectives of different payers on affordability.

Abstract Modern scanning microscopes can image materials with up to sub-atomic spatial and sub-picosecond time resolutions, but these capabilities come with large volumes of data, which can be difficult to store and analyze. We report the Fast Autonomous Scanning Toolkit (FAST) that addresses this challenge by combining a neural network, route optimization, and efficient hardware controls to enable a self-driving experiment that actively identifies and measures a sparse but representative data subset in lieu of the full dataset. FAST requires no prior information about the sample, is computationally efficient, and uses generic hardware controls with minimal experiment-specific wrapping. We test FAST in simulations and a dark-field X-ray microscopy experiment of a WSe2 film. Our studies show that a FAST scan of

Gene therapies aim to deliver a therapeutic payload to specified tissues with underlying protein deficiency. Since the 1990s, gene therapies have been explored as potential treatments for chronic conditions requiring lifetime care and medical management. Ocular gene therapies target a range of ocular disorders, but retinal diseases are of particular importance due to the prevalence of retinal disease and the current treatment burden of such diseases on affected patients, as well as the challenge of properly delivering these therapies to the target tissue. The purpose of this review is to provide an update on the most current data available for five different retinal gene therapies currently undergoing clinical trials for use against age-related macular degeneration (AMD) and the development of novel delivery routes for the administration of such therapies. Research has been performed and compiled from PubMed and the select authors of this manuscript on the treatment and effectiveness of five current retinal gene therapies: Luxturna, ADVM-022, RGX-314, GT-005, and HMR59. We present the available data of current clinical trials for the treatment of neovascular and dry age-related macular degeneration with different AAV-based gene therapies. We also present current research on the progress of developing novel routes of administration for ocular gene therapies. Retinal gene therapies offer the potential for life-changing treatment for chronic conditions like age-related macular degeneration with a single administration. In doing so, gene therapies change the landscape of treatment options for these chronic conditions for both patient and provider.

Infectious diseases, also known as transmissible or communicable diseases, are caused by pathogens or parasites that spread in communities by direct contact with infected individuals or contaminated materials, through droplets and aerosols, or via vectors such as insects. Such diseases cause ˜17% of all human deaths and their management and control places an immense burden on healthcare systems worldwide. Traditional approaches for the prevention and control of infectious diseases include vaccination programmes, hygiene measures and drugs that suppress the pathogen, treat the disease symptoms or attenuate aggressive reactions of the host immune system. The provision of vaccines and biologic drugs such as antibodies is hampered by the high cost and limited scalability of traditional manufacturing platforms based on microbial and animal cells, particularly in developing countries where infectious diseases are prevalent and poorly controlled. Molecular farming, which uses plants for protein expression, is a promising strategy to address the drawbacks of current manufacturing platforms. In this review article, we consider the potential of molecular farming to address healthcare demands for the most prevalent and important epidemic and pandemic diseases, focussing on recent outbreaks of high-mortality coronavirus infections and diseases that disproportionately affect the developing world.

The fight against infectious diseases often focuses on epidemics and pandemics, which demand urgent resources and command attention from the health authorities and media. However, the vast majority of deaths caused by infectious diseases occur in endemic zones, particularly in developing countries, placing a disproportionate burden on underfunded health systems and often requiring international interventions. The provision of vaccines and other biologics is hampered not only by the high cost and limited scalability of traditional manufacturing platforms based on microbial and animal cells, but also by challenges caused by distribution and storage, particularly in regions without a complete cold chain. In this review article, we consider the potential of molecular farming to address the challenges of endemic and re-emerging diseases, focusing on edible plants for the development of oral drugs. Key recent developments in this field include successful clinical trials based on orally delivered dried leaves of Artemisia annua against malarial parasite strains resistant to artemisinin combination therapy, the ability to produce clinical-grade protein drugs in leaves to treat infectious diseases and the long-term storage of protein drugs in dried leaves at ambient temperatures. Recent FDA approval of the first orally delivered protein drug encapsulated in plant cells to treat peanut allergy has opened the door for the development of affordable oral drugs that can be manufactured and distributed in remote areas without cold storage infrastructure and that eliminate the need for expensive purification steps and sterile delivery by injection.

Infectious diseases, also known as transmissible or communicable diseases, are caused by pathogens or parasites that spread in communities by direct contact with infected individuals or contaminated materials, through droplets and aerosols, or via vectors such as insects. Such diseases cause ˜17% of all human deaths and their management and control places an immense burden on healthcare systems worldwide. Traditional approaches for the prevention and control of infectious diseases include vaccination programmes, hygiene measures and drugs that suppress the pathogen, treat the disease symptoms or attenuate aggressive reactions of the host immune system. The provision of vaccines and biologic drugs such as antibodies is hampered by the high cost and limited scalability of traditional manufacturing platforms based on microbial and animal cells, particularly in developing countries where infectious diseases are prevalent and poorly controlled. Molecular farming, which uses plants for protein expression, is a promising strategy to address the drawbacks of current manufacturing platforms. In this review article, we consider the potential of molecular farming to address healthcare demands for the most prevalent and important epidemic and pandemic diseases, focussing on recent outbreaks of high-mortality coronavirus infections and diseases that disproportionately affect the developing world.

Introduction: Multimorbidity is the coexistence of two or more chronic medical conditions in a person. The study aims to investigate the immediate cause of death and risk factors of mortality including multimorbidity among patients hospitalized with SARS CoV2 infection in Kasaragod district in Kerala, India. Methods: A record-based case-control study was done using the hospital records and follow-up surveillance system of SARS-COV 2 patients admitted in the Kasaragod district. SARS-COV 2 patients who had expired during the study period from June to December 2020 and reported as COVID-19 deaths (N = 226) were the cases, and an equal number of hospital controls were the study participants. Results: The mean (SD) age of the cases and controls were found to be 64.6 (14.2) years and 61.5 (13.4) years, respectively. Covid pneumonia alone was reported as the cause of death in more than half (52%) of the study participants. This was followed by cardiovascular events (8.5%) and acute kidney injury (6.5%). Among individual comorbidities among people who expired, diabetes mellitus (53%) was the most common, followed by hypertension (46%) and cardiovascular diseases (23%). More than 50% were found to have multimorbidity. Logistic regression showed chronic kidney disease (CKD) (Adjusted odds ratio (AOR) = 2.18 (1.24–3.83)) and malignancy (AOR = 3.05 (1.27–7.32)) to be significantly associated with mortality as individual determinants. Hypertension–diabetes mellitus [AOR = 1.68 (1.02–2.76), P = 0.043] and hypertension–CKD [AOR = 3.49 (1.01–12.01), P = 0.48] dyads were multimorbidities significantly associated with mortality. Conclusion: Combinations of hypertension with diabetes mellitus and CKD were found to be significant determinants for mortality in hospitalized COVID-19 patients. Uniformity in death certification is required to understand the causes and contributors to death in COVID-19.

Abstract Objectives Osteoarthritis (OA) is increasingly recognised as a whole joint disease, with an important role for synovium. However, the repertoire of immune cells and fibroblasts that constitute OA synovium remains understudied. This study aims to characterise the cellular composition of advanced OA synovium and to explore potential correlations between different cell types and patient demographics or clinical scores. Methods Synovium, collected from 10 patients with advanced OA during total knee replacement surgery, was collagenase-digested, and cells were stained for flow cytometry analysis. Formalin-fixed paraffin-embedded synovium was sectioned, stained with immunofluorescence, and imaged using the multiplex Cell DIVE platform. Patient demographics and clinical scores were also collected. Results The proportion of immune cells in OA synovium varied between patients (8–38% of all cells). Macrophages and T cells were the dominant immune cell populations, together representing 76% of immune cells. Age positively correlated with the proportion of macrophages, and negatively correlated with T cells. CCR6+ T cells were found in 6/10 patients; these patients had a higher mean Kellgren-Lawrence grade across the three knee compartments. Immunofluorescence staining showed that macrophages were present in the lining as well as distributed throughout the sublining, while T and B cells were mainly localised near vessels in the sublining. Fibroblast subsets (CD45−PDPN+) based on the expression of CD34/CD90 or FAP/CD90 were identified in all patient samples, and some populations correlate with the percentage of immune cells or clinical scores. Immunofluorescence staining showed that FAP expression was particularly strong in the lining layer, but also present throughout the sublining layer. CD90 expression was exclusively found around vessels in the sublining, while CD34 was mostly found in the sublining but also occasionally in the lining layer. Conclusions There are significant differences in the relative proportions and subsets of immune cells in OA synovium; exploratory correlative analyses suggest that these differences might be correlated with age, clinical scores, or fibroblast subsets. Additional studies are required to understand how different cell types affect OA pathobiology, and if the presence or proportion of cell subsets relates to disease phenotypes.

Abstract Background Cervical traumatic spinal cord injury is a devastating condition. Current management (bony decompression) may be inadequate as after acute severe TSCI, the swollen spinal cord may become compressed against the surrounding tough membrane, the dura. DISCUS will test the hypothesis that, after acute, severe traumatic cervical spinal cord injury, the addition of dural decompression to bony decompression improves muscle strength in the limbs at 6 months, compared with bony decompression alone. Methods This is a prospective, phase III, multicenter, randomized controlled superiority trial. We aim to recruit 222 adults with acute, severe, traumatic cervical spinal cord injury with an American Spinal Injury Association Impairment Scale grade A, B, or C who will be randomized 1:1 to undergo bony decompression alone or bony decompression with duroplasty. Patients and outcome assessors are blinded to study arm. The primary outcome is change in the motor score at 6 months vs. admission; secondary outcomes assess function (grasp, walking, urinary + anal sphincters), quality of life, complications, need for further surgery, and mortality, at 6 months and 12 months from randomization. A subgroup of at least 50 patients (25/arm) also has observational monitoring from the injury site using a pressure probe (intraspinal pressure, spinal cord perfusion pressure) and/or microdialysis catheter (cord metabolism: tissue glucose, lactate, pyruvate, lactate to pyruvate ratio, glutamate, glycerol; cord inflammation: tissue chemokines/cytokines). Patients are recruited from the UK and internationally, with UK recruitment supported by an integrated QuinteT recruitment intervention to optimize recruitment and informed consent processes. Estimated study duration is 72 months (6 months set-up, 48 months recruitment, 12 months to complete follow-up, 6 months data analysis and reporting results). Discussion We anticipate that the addition of duroplasty to standard of care will improve muscle strength; this has benefits for patients and carers, as well as substantial gains for health services and society including economic implications. If the addition of duroplasty to standard treatment is beneficial, it is anticipated that duroplasty will become standard of care. Trial registration IRAS: 292031 (England, Wales, Northern Ireland) - Registration date: 24 May 2021, 296518 (Scotland), ISRCTN: 25573423 (Registration date: 2 June 2021); ClinicalTrials.gov number : NCT04936620 (Registration date: 21 June 2021); NIHR CRN 48627 (Registration date: 24 May 2021).

Abstract Despite the remarkable growth of the global market for robotics, robotic monitoring of habitats is still an understudied topic. This is true, among others, for the species-rich EU Annex I habitat “6210 - Semi-natural grasslands and scrubland facies on calcareous substrates”. This habitat is typically surveyed by human operators. In this work, we present a dataset concerning relevés performed through the quadrupedal robot ANYmal C. The dataset contains information from three plots, which include the robot state, videos, and images acquired to assess the habitat conservation status. Additionally, a collection of videos and pictures about two typical and one early warning species of habitat 6210 is also presented. This database is publicly available in the provided Zenodo repository and will aid researchers in several fields. Robot state information can be used by engineers to validate their algorithms, while data gathered by the robot can be used to design new methodologies and new metrics to assess the habitat conservation status or train/test classifiers (e.g. neural networks) for plant classification.

Abstract Combination of anti-cancer drugs is broadly seen as way to overcome the often-limited efficacy of single agents. The design and testing of combinations are however very challenging. Here we present a uniquely large dataset screening over 5000 targeted agent combinations across 81 non-small cell lung cancer cell lines. Our analysis reveals a profound heterogeneity of response across the tumor models. Notably, combinations very rarely result in a strong gain in efficacy over the range of response observable with single agents. Importantly, gain of activity over single agents is more often seen when co-targeting functionally proximal genes, offering a strategy for designing more efficient combinations. Because combinatorial effect is strongly context specific, tumor specificity should be achievable. The resource provided, together with an additional validation screen sheds light on major challenges and opportunities in building efficacious combinations against cancer and provides an opportunity for training computational models for synergy prediction.

Background Patients with ischemic stroke and concomitant COVID‐19 infection have worse outcomes than those without this infection, but the impact of COVID‐19 on hemorrhagic stroke remains unclear. We aimed to assess if COVID‐19 worsens outcomes in intracerebral hemorrhage (ICH). Methods and Results We conducted an observational study of ICH outcomes using Get With The Guidelines Stroke data. We compared patients with ICH who were COVID‐19 positive and negative during the pandemic (March 2020–February 2021) and prepandemic (March 2019–February 2020). Main outcomes were poor functional outcome (defined as a modified Rankin scale score of 4 to 6 at discharge), mortality, and discharge to a skilled nursing facility or hospice. The first stage included 60 091 patients with ICH who were COVID‐19 negative and 1326 COVID‐19 positive. In multivariable analyses, patients with ICH with versus without COVID‐19 infection had 68% higher odds of poor outcome (odds ratio [OR], 1.68 [95% CI, 1.41–2.01]), 51% higher odds of mortality (OR, 1.51 [95% CI, 1.33–1.71]), and 66% higher odds of being discharged to a skilled nursing facility/hospice (OR, 1.66 [95% CI, 1.43–1.93]). The second stage included 62 743 prepandemic and 64 681 intrapandemic cases with ICH. In multivariable analyses, patients with ICH admitted during versus before the COVID‐19 pandemic had 10% higher odds of poor outcomes (OR, 1.10 [95% CI, 1.07–1.14]), 5% higher mortality (OR, 1.05 [95% CI, 1.02–1.08]), and no significant difference in the risk of being discharged to a skilled nursing facility/hospice (OR, 0.93 [95% CI, 0.90–0.95]). Conclusions The pathophysiology of the COVID‐19 infection and changes in health care delivery during the pandemic played a role in worsening outcomes in the patient population with ICH.

BackgroundSuicide by road vehicle collision in Australia is under-explored with mixed findings. We aimed to address this research gap by examining time trends, different types of vehicle collision, and individual characteristics related to vehicle-collision suicide.MethodWe retrospectively analyzed deaths by suicide between 1st January 2001 and 31st December 2017 in Australia, using coronial records from the National Coronial Information System. The travel mode used and collision counterpart were retrieved from records of death by vehicle-collision suicide using all available information. We conducted negative binomial regression analysis to examine annual changes in suicide rate by vehicle collision on a public road (N = 640) and other methods of suicide (N = 41,890), and logistic regression analysis to examine individual characteristics associated with the likelihood of dying by suicide via road vehicle collision.ResultsOverall, the national suicide rate involving road vehicle collision significantly increased, while the rate by other methods significantly decreased. Drivers accounted for 61% of suicide events by vehicle collision, of which 72% were single-vehicle collisions (commonly involving a tree). For multiple-vehicle collision suicide events, 82% involved collision with a truck. Pedestrians accounted for more than one-third of suicide events, of which 58% involved collision with a truck and 23% involved collision with a car/van. Individuals who were male (odds ratio 1.15; 95% CI 0.88-1.50), aged ConclusionsThis study provides a better understanding of road vehicle collision suicide in Australia and informs future research directions on topic. Our findings can be used to inform suicide prevention initiatives to reduce vehicle-collision suicide deaths.

BackgroundFunctional abdominal pain disorders (FAPD) are the most common chronic pain conditions of childhood and are made worse by co-occurring anxiety. Our research team found that the Aim to Decrease Pain and Anxiety Treatment (ADAPT), a six-session coping skills program using cognitive behavioral therapy strategies, was effective in improving pain-related symptoms and anxiety symptoms compared to standard care. In follow-up, this current randomized clinical trial (RCT) aims to test potential neural mechanisms underlying the effect of ADAPT. Specifically, this two-arm RCT will explore changes in amygdalar functional connectivity (primary outcome) following the ADAPT protocol during the water loading symptom provocation task (WL-SPT). Secondary (e.g., changes in regional cerebral blood flow via pulsed arterial spin labeling MRI) and exploratory (e.g., the association between the changes in functional connectivity and clinical symptoms) outcomes will also be investigated.MethodsWe will include patients ages 11 to 16 years presenting to outpatient pediatric gastroenterology care at a midwestern children's hospital with a diagnosis of FAPD plus evidence of clinical anxiety based on a validated screening tool (the Generalized Anxiety Disorder-7 [GAD-7] measure). Eligible participants will undergo baseline neuroimaging involving the WL-SPT, and assessment of self-reported pain, anxiety, and additional symptoms, prior to being randomized to a six-week remotely delivered ADAPT program plus standard medical care or standard medical care alone (waitlist). Thereafter, subjects will complete a post assessment neuroimaging visit similar in nature to their first visit.ConclusionsThis small scale RCT aims to increase understanding of potential neural mechanisms of response to ADAPT.Trial registrationClinicalTrials.gov registration: NCT03518216.

IntroductionLow-level distal weight bearing in transtibial prosthesis users may help maintain perfusion and improve both proprioception and residual limb tissue health.MethodsThe primary objectives of this research were to develop a sensor to continuously measure distal weight bearing, evaluate how prosthesis design variables affected weight bearing levels, and assess fluctuations in distal weight bearing during at-home and community use.ResultsIn-lab testing on a small group of participants wearing adjustable sockets demonstrated that if distal contact was present, when socket size was increased distal weight bearing increased and when socket size was reduced distal weight bearing decreased. During take-home use, participants accepted the distal weight bearing level set by the research team. It ranged between 1.1% and 6.4% BW for all days tested. The coefficient of variation (standard deviation/mean) ranged from 25% to 43% and was expected due in part to differences in walking style, speed, terrain, direction of ambulation, and bout duration. Two participants commented that they preferred presence of distal weight bearing to non-presence.DiscussionNext steps in this research are to develop clinical practices to determine target distal weight bearing levels and ranges, and to simplify the design of the sensor and weight bearing adjustment mechanism for clinical use.

Chiral phase-transfer catalysis provides high level of enantiocontrol, however no experimental data showed the interaction of catalysts and substrates. 1 H NMR titration was carried out on Cinchona and Maruoka ammonium bromides vs. nitro, carbonyl, heterocycles, and N-F containing compounds. It was found that neutral organic species and quaternary ammonium salts interacted via an ensemble of catalyst + N-C-H and (sp2 )C-H, specific for each substrate studied. The correspondent BArF salts interacted with carbonyls via a diverse set of + N-C-H and (sp2 )C-H compared to bromides. This data suggests that BArF ammonium salts may display a different enantioselectivity profile. Although not providing quantitative data for the affinity constants, the data reported proofs that chiral ammonium salts coordinate with substrates, prior to transition state, through specific C-H positions in their structures, providing a new rational to rationalize the origin of enantioselectivity in their catalyses.

Timing of laparoscopic cholecystectomy, a widely used treatment modality for acute cholecystitis remains controversial. This prospective observational comparative study investigated patient outcomes for early (ELC) and interval laparoscopic cholecystectomy (ILC) in patients with acute cholecystitis admitted to the General Surgery Department at a tertiary care centre in Thrissur, Kerala, between December 2018 and June 2020. Of 67 patients, 34 were assigned to ELC and 33 to ILC groups and followed up for 2 weeks post-surgery. Patient characteristics, clinical features, investigations, intra operative details and post operative outcomes were tabulated. Comparison of age was statistically analyzed using student’s ‘t’ test, demographics and morbidity data using Fisher’s exact test/ Chi-square test and length of hospital stay using Mann Whitney U test. Mean age was significantly higher in the ILC group. 66% of study participants were females with a higher proportion of females observed in the ILC group. Post-surgical complications were not significantly higher in ELC group compared to ILC group. Total length of hospital stay was significantly longer in the ILC group than in ELC group (10.2 ±4.5 vs. 7.1 ±3.0) days, p value: 0.001). Duration of hospital stay for the laparoscopic cholecystectomy procedure taken separately, was longer in ELC group comparatively, 7 ±3.01 versus 4 ±-2.38, (p value: