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Abstract Background Postoperative pain is a common complication following surgery, with severity and duration varying between patients. Chronic postoperative pain after inguinal hernia surgery has an incidence rate of approximately 10%. Risk factors for acute and chronic pain following hernia surgery include age, sex, psychosocial factors, and demographic background. Additionally, genetic polymorphisms in enzymes involved in pain mechanisms, as well as the metabolism of analgesics might influence pain perception, pain development, and response to pain medications. Key enzymes include the catechol-o-methyltransferase (COMT), the µ-opioid receptor 1 (OPRM1), and the cytochrome P450 2D6 (CYP2D6). CYP2D6 plays a crucial role in metabolizing analgesics such as tramadol, codeine, and oxycodone. It is also suspected to be involved in the synthesis of catecholamines and endogenous morphines suggesting a potential role in pathophysiology of pain. We hypothesize that the CYP2D6 activity influences the development of postoperative pain after hernia surgery. Methods This study is a prospective, observational, multicenter association study investigating adult patients scheduled for inguinal hernia surgery using a robotic-assisted (rTAPP) approach. Patients are enrolled during the preoperative surgical consultation. A buccal swab is collected for genetic testing at this time. Pain at the site of the hernia is assessed using the validated EuraHSQoL score preoperatively and at 2, 4, and 6 weeks postoperatively. Additionally, information on co-medication and details of the surgery will be collected. The planned number of participants is 350 patients. The primary objective is to analyze the association between different genotype-predicted CYP2D6 phenotypes and patient-reported pain intensity 6 weeks after surgery. Secondary objectives include the association between further genetic variants, such as the COMT rs4680 and OPRM1 rs1799971 genotype, and pain severity. Additionally, the potential of pharmacogenetic panel testing to optimize analgesic therapy in hernia surgery patients will be explored. Discussion The findings of this study are expected to provide valuable insights into identifying patients at higher risk for postoperative pain before surgery. This knowledge could pave the way for tailored interventions during and after surgery for these specific patients. Trial registration Deutsches Register Klinischer Studien https://www.drks.de/DRKS00034796 Registered on August 07, 2024.

Purpose: This study aims to assess whether water exchange rate (kw), a surrogate for blood–brain barrier (BBB) permeability, is associated with functional outcomes in patients with acute ischemic stroke (AIS). Methods: We studied 22 AIS patients enrolled from 1/2022 to 4/2024 who underwent multi-modal non-contrast imaging on a 3.0-Tesla scanner, including DP-pCASL, DTI, NODDI and MAP imaging. For each parametric map, the intensity and standard deviation (SD) were calculated for the infarcted region. The diffusion maps included were b0, Fractional Anisotropy (FA), Mean Diffusivity (MD), Intra-cellular Volume Fraction (ICVF), Free Water Fraction (FWF), and Orientation Dispersion Index (ODI), q-Space Mean Square Displacement (QMSD), Return-to-Axis Probability (RTAP), Return-to-Plane Probability (RTPP), Return-to-Origin Probability (RTOP), Propagator Anisotropy (PA), and non-Gaussianity (NG). The perfusion-based maps were cerebral blood flow (CBF), arterial transit time (ATT), and kw. The outcome variable was modified Rankin Scale (mRS). Results: Twenty-two patients were included. The average age was 69.5 ± 13.5, the mean NIHSS of 12.4 ± 7.7, and the median infarct of 25.7 (8.4–98.8) ml. Multivariable linear regression identified lower kw (β = −0.029, p = 0.041), longer time to MRI (β = 0.012, p = 0.013) and larger stroke volume (β = 0.014, p = 0.006) as predictive of higher mRS. Higher CBF (β = 0.660, p = 0.003) and RTAP (β = 1.528, p = 0.010), and lower SD RTAP (β = −0.709, p = 0.016), RTPP (β = −2.132, p = 0.006), and NG (β = −1.036, p = 0.011) were identified as most predictive of kw through multivariable linear regression analysis. Conclusions: Lower kw is predictive of higher mRS in patients with AIS. Increasing CBF and RTAP and lower SD RTAP, RTPP, and NG were correlated with higher kw.

Abstract Digital technologies, such as virtual or augmented reality, can potentially support neurocognitive functions of the aging populations worldwide and complement existing intervention methods. However, aging-related declines in the frontal-parietal network and dopaminergic modulation which progress gradually across the later periods of the adult lifespan may affect the processing of multisensory congruence and expectancy based contextual plausibility. We assessed hemodynamic brain responses while middle-aged and old adults experienced car-riding virtual-reality scenarios where the plausibility of vibrotactile stimulations was manipulated by delivering stimulus intensities that were either congruent or incongruent with the digitalized audio-visual contexts of the respective scenarios. Relative to previous findings observed in young adults, although highly plausible vibrotactile stimulations confirming with contextual expectations also elicited higher brain hemodynamic responses in middle-aged and old adults, this effect was limited to virtual scenarios with extreme expectancy violations. Moreover, individual differences in plausibility-related frontal activity did not correlate with plausibility violation costs in the sensorimotor cortex, indicating less systematic frontal context-based sensory filtering in older ages. These findings have practical implications for advancing digital technologies to support aging societies.

Background Atrial fibrillation (AF) is a known risk factor of ischemic stroke, and AF‐related stroke is twice more likely to be fatal. Long‐term cardiac rhythm monitoring using insertable cardiac monitors (ICMs) has greater diagnostic yield compared with conventional monitoring in detecting AF, and the clinical utility of ICMs is established in cryptogenic stroke, strokes attributable to large‐artery atherosclerosis, and strokes attributable to small‐vessel disease. A registry‐based study was conducted to evaluate the inpatient implantation of ICMs and the feasibility of vascular and interventional neurologists as implanters using novel collaborative clinical care pathway for cryptogenic stroke. Methods Multiyear data from a hospital‐based registry at a comprehensive stroke center were reviewed to evaluate inpatient ICM implantation and test feasibility of vascular and interventional neurologists as implanters of ICMs together with cardiology using a novel collaborative care pathway. Reviewed data included the number of ICMs, implantation trend, inpatient versus outpatient setting, time to ICM implantation, inpatient workflow, including defined roles of team members, and AF detection rate. Results A total of 290 ICMs for cryptogenic stroke were implanted when patients were in the hospital and 78 as outpatients after discharge during the study period of 3 years. Most inpatient ICM implants were performed by vascular and interventional neurology (n = 181), and ICM use for cryptogenic stroke increased by 130%. The average time to inpatient ICM implant was 4.1 days, with 77% in 5 days and 95.5% within 10 days poststroke. The average time to out‐patient ICM placement was 57 days. AF detection rate of 36.5% was noted at 24 months with a collaborative care pathway. Conclusion Inpatient implantation of ICMs is feasible and was performed safely and efficiently by vascular and interventional neurology together with cardiology using a collaborative care pathway. An increase in use of ICMs and higher AF detection rates were noted. Findings support innovative efforts to improve access and close the gaps in the delivery of cryptogenic stroke care to ultimately reduce the secondary stroke burden.

The treatment of older patients with cancer is challenging owing to frailty and the presence of comorbidities, which complicate treatment decisions by impacting tolerance to therapeutic interventions, as well as poor representation of this patient population in clinical trials, leading to a lack of evidence-based data, especially in later lines of therapy. There is an urgent need for predictive models that could provide diagnostic and prognostic information relevant to older patients with cancer. Organoid technology has emerged as a promising frontier in cancer treatment, offering a versatile platform for personalized medicine and drug development. By recapitulating the three-dimensional (3D) architecture, cell-matrix interactions and tissue heterogeneity, organoid cultures provide an accurate representation of individual tumor properties, thus enabling the precise modeling of tumor behavior. Clinical trials have demonstrated a high predictive value and statistically significant correlation between the patient’s clinical response and tumor organoid response in different cancer types. The first ongoing Swiss registry study aims to apply organoid-based drug screening technology to identify optimal treatments in older cancer patients in the second or later therapy line setting. This study will help to identify optimal personalized treatment strategies while reducing unnecessary treatment-related toxicity and improving patient outcomes in this patient population. PEER REVIEWED ARTICLE **Peer reviewers:** Dr Andreas Hochstrasser, Hospital Thun, Thun, Switzerland Dr Bich Doan Nguyen-Sträuli, University Hospital Basel, Basel, Switzerland Received on April 22, 2024; accepted after peer review on October 23, 2024; published online on October 30, 2024.

Key Clinical Message Perianal alveolar rhabdomyosarcoma is a rare sarcoma that requires a high index of suspicion along with tissue biopsy for accurate diagnosis. Successful treatment, even in the setting of recurrence, requires a multidisciplinary approach.

Abstract Background Dietary interventions are used for the treatment of hypertension. We evaluated the cost-efficacy of delivering boxes of healthy, culturally tailored foods and checks that can only be spent on produce in a Native American population. Methods We conducted a group randomized controlled trial from 2018 to 2020 with N = 2 treatment counties and N = 2 control counties and a total of N = 160 Native American adults with baseline stage 1 or stage 2 hypertension. Participants in the intervention group received monthly boxes of food that adheres to the Dietary Approaches to Stop Hypertension diet as well as checks that could only be spent on produce for 6 months. We measured blood pressure and quality of life at baseline and at a 6-month follow-up in both intervention and control groups. We used ordered logistic regression to estimate the effect of treatment on probability of blood pressure improvements. We then conducted a cost-efficacy analysis. Results We found that treatment was effective in reducing blood pressure in women with stage 1 hypertension at baseline. Based on this finding, we also estimate that this intervention satisfies normative cost-effectiveness thresholds, even when lifetime treatment is needed to preserve the impact, so long as treatment is only continued in those who respond to treatment. Conclusions Direct delivery of healthy foods and checks that can only be spent on produce are a potentially cost-effective intervention for the management of hypertension among Native American women with stage 1 hypertension. Further research is needed to understand why we found an impact only for this group.

# Background The stigma attached to mental illness impedes diagnosis, treatment, and access to care for people with mental illness. Scalable interventions are needed to enhance attitudes towards seeking treatment, foster community support, and promote acceptance of individuals experiencing mental illness. We worked with community health workers in the Busoga region of eastern Uganda to develop a radio program aimed at reducing mental illness stigma. We piloted the radio program in focus groups, purposively sampling people with families affected by mental illness and people with families unaffected by mental illness, to understand their perspectives about the program’s acceptability and potential effectiveness. # Methods The 45-minute radio program was adapted from a previously studied community-led theater intervention, produced by community health workers, that demonstrated an individual’s recovery from mental illness. Afterward, we conducted 2 focus group discussions, each involving six participants: n=12; and 17 one-on-one, in-depth interviews. We employed the framework method to inductively identify themes and sub-themes. # Results Participants reported greater understanding of causes of mental illness, treatment options, and greater acceptance of those with mental illness as a result of listening to the program. # Conclusions This radio program intervention showed potential to change healthcare seeking behavior for mental illness and to decrease mental illness stigma in rural Uganda. Further investigation is needed to assess the broader applicability of this approach.

Objectives Home blood pressure monitoring (HBPM) is crucial for managing hypertension, but there is a potential trade-off between measurement accuracy and health/economic outcomes due to asymmetric costs associated with misclassifying an individual as having hypertension or not. We assessed whether adjustments to device readings that increased overall accuracy produced net health and economic benefits. Methods We analyzed data from N = 89 Alaska Native individuals who used 2 HBPM devices and a standard aneroid sphygmomanometer. We modeled changes in expected costs associated with individuals being misclassified as hypertensive or not under 3 different models of adjusting HBPM device readings. Results The gains in accuracy produced by adjusting HBPM readings decreased the overall rate of hypertension misclassification but increased the rate of false-negative readings. Adjusting readings led to a net increase in expected health and economic costs. Discussion Ignoring asymmetric costs of misclassification can escalate overall costs and worsen uncontrolled hypertension. Home blood pressure monitoring algorithms must be cautiously designed, considering both false negatives and positives. Greater transparency in HBPM algorithms is needed for effective coordination among manufacturers, clinicians, and patients.

Noise and whole-body vibrations (WBV) inside commercial vehicles can lead to annoyance and reduced comfort. As a result, negative effects on the driver can occur even below the legal exposure limits. In order to understand the annoyance perception and the interaction between noise and WBV, two perception experiments were conducted. For both experiments, recorded signals inside different commercial vehicles were used. Sound pressure and acceleration levels varied. In addition, the frequency content of the recorded vertical seat vibrations was reproduced in different modified variants. The varied parameters (sound pressure level, acceleration level and vibration frequency) were investigated within a three-factorial experimental design. It was found that noise and vibration levels, as well as the vibration spectrum, had a significant effect on total annoyance. Furthermore, an interaction between noise and vibration levels in both experiments could be observed. The results show that for the highest noise level, changing vibration exposure influences annoyance ratings less than the lowest noise level. The results also show that despite the same Wk-weighted RMS level of the WBV according to ISO 2631-1, vibration spectra with sinusoidal components or narrowband vibrations below

Abstract Background Low- and middle-income countries (LMICs) bear a disproportionate burden of mental illness, with limited access to biomedical care. This study examined pathways to care for psychosis in rural Uganda, exploring factors influencing treatment choices. Methods We conducted a mixed-methods study in Buyende District, Uganda, involving 67 in-depth interviews and 4 focus group discussions (data collection continued until thematic saturation was reached) with individuals with psychotic disorders, family members, and local leaders. Structured questionnaires were administered to 41 individuals with psychotic disorders. Results Three main themes emerged: (1) Positive attitudes towards biomedical providers, (2) Barriers to accessing biomedical care (3) Perceived etiologies of mental illness that influenced care-seeking behaviors. While 81% of participants eventually accessed biomedical care, the median time to first biomedical contact was 52 days, compared to 7 days for any care modality. Conclusions Despite a preference for biomedical care, structural barriers and diverse illness perceptions led many to seek pluralistic care pathways. Enhancing access to biomedical services and integrating traditional and faith healers could improve mental health outcomes in rural Uganda.

Background and purpose: While mechanical thrombectomy (MT) achieves restoration of cerebral blood flow to the area at risk in patients with acute ischemic stroke (AIS), the influx of blood flow may exacerbate the blood–brain barrier (BBB) disruption and extravasation across the BBB, and it therefore remains unclear how reperfusion impacts the blood–brain barrier integrity. In this study, we use diffusion-prepared pseudocontinuous ASL (DP-pCASL) and Neurite Orientation Dispersion and Density Imaging (NODDI) sequence to measure the water exchange rate (kw) in patients who underwent either MT or medical management and determine its impact on the brain tissue microstructure in order to elucidate the impact of MT on BBB complex integrity. Materials and methods: We prospectively enrolled 21 patients with AIS treated at our institution from 10/2021 to 6/2023 who underwent MR imaging at a 3.0-Tesla scanner. Patients underwent DP-pCASl and NODDI imaging in addition to the standard stroke protocol which generated cerebral blood flow (CBF), arterial transit time (ATT), water exchange rate (kw), orientation dispersion index (ODI), intracellular volume fraction (ICVF), and free water fraction (FWF) parametric maps. Results: Of the 21 patients, 11 underwent MT and 10 were treated non-operatively. The average age and NIHSS for the MT cohort and non-MT cohorts were 69.3 ± 16.6 years old and 15.0 (12.0–20.0), and 70.2 ± 10.7 (p = 0.882) and 6.0 (3.8–9.0, p = 0.003) respectively. The average CBF, ATT, and kw in the infarcted territory of the MT cohort were 38.2 (18.4–59.6), 1347.6 (1182.5–1842.3), and 107.8 (79.2–140.1) respectively. The average CBF, ATT, and kw in the stroke ROI were 16.0 (8.8–36.6, p = 0.036), 1090.8 (937.1–1258.9, p = 0.013), 89.7 (68.0–122.7, p = 0.314) respectively. Linear regression analysis showed increasing CBF (p = 0.008) and undergoing mechanical thrombectomy (p = 0.048) were significant predictors of increased kw. Conclusion: Using our multimodal non-contrast MRI protocol, we demonstrate that increased CBF and mechanical thrombectomy increased kw, suggesting a better functioning BBB complex. Higher kw suggests less disruption of the BBB complex in the MT cohort.

Objectives: Detoxification clinics manage acute intoxication and withdrawal from alcohol and other drugs. At discharge, patients are referred to treatment, yet many are readmitted to detoxification, creating a “revolving door” of discharges and admissions. This pattern disproportionately affects some groups such as Alaska Native and American Indian (AN/AI) people. The primary goals of this study are to: 1) test the effectiveness of a patient navigation intervention to increase rates of transition to alcohol treatment following detoxification, and 2) prevent readmission to detoxification within 12-months. The secondary goal is a cost-effectiveness and cost-benefit evaluation of patient navigation. Study design: This randomized controlled comparative effectiveness trial plans to recruit 440 patients (∼70% AN/AI) admitted to alcohol detoxification. We collaborated with Fairbanks Native Association (FNA) to select an appropriate intervention, control condition, and other study-related decisions. Here, we describe intervention development, study design, challenges encountered during implementation, and collaborative processes to identify solutions. Methods: Participants are equally randomized to the control (one motivational interviewing session) or intervention (one motivational interviewing session plus up to four weeks of patient navigation). The primary outcomes are successful transition to alcohol treatment within 30-days after discharge and detoxification readmission within 12-months. The secondary outcome is health-related quality of life. Conclusion: Patient navigation is successful in other settings and for other health conditions. It may assist in overcoming barriers to successful transition to substance use treatment and may augment interventions, such as motivational interviewing, that are less resource-intensive but may not be optimally effective by themselves. ClinicalTrials.gov Identifier: NCT03737864.

The biological plausibility of backpropagation and its relationship with synaptic plasticity remain open questions. The authors propose a meta-learning approach to discover interpretable plasticity rules to train neural networks under biological constraints. The meta-learned rules boost the learning efficiency via bio-inspired synaptic plasticity.

Abstract Background Multisite practical clinical trials evaluate treatments in real-world practice. A multisite randomized Veterans Health Administration (VHA) cooperative study (CSP#555) published in 2011 compared the first long-acting injectable (LAI) second-generation antipsychotic (SGA), Risperidone Consta®, in veterans with a diagnosis of schizophrenia or schizoaffective disorder, to oral antipsychotics, with unexpected null results for effectiveness and cost-effectiveness. Whether null results of this type could change VHA practice has not been studied. Methods A longitudinal observational analysis was used to evaluate the impact of the trial findings on VHA clinical practices. National administrative data compared new starts on LAI risperidone during the 4 years before the publication of CSP#555 in 2011 to new starts on LAI risperidone during the 4 years after. Results Among 119,565 Veterans with the indicated diagnoses treated with antipsychotics from 2007 to 2015, the number and proportion of new starts on LAI risperidone declined significantly following the study publication, as did the total number of annual users and drug expenditures. However, data from 2007 to 2010 showed the decline in new starts actually preceded the publication of CSP#555. This change was likely explained by the increase in new starts, total use, and expenditures on a newer medicine, LAI paliperidone, a 4-week LAI treatment, in the 2 years prior to the publication of CSP#555. Conclusions The declining use of LAI risperidone likely primarily reflects the substitution of a longer-acting LAI SGA, paliperidone, that came to market 2 years before the study publication, a substitution that may have been reinforced by null CSP#555 study results for LAI risperidone.

In this article, we present a comprehensive sensitivity analysis and geophysical retrieval product demonstration to assess the enhanced information content in atmospheric temperature and water vapor, harnessed in hyperspectral microwave measurements. A particular focus of this study is devoted to quantifying and comparing the impact on retrieval performance resulting from novel spectral bands of the microwave thermal spectrum, by means of data addition and data denial trade studies. Various spectral configurations are assessed, each reflecting specific technology solutions intended to maximize geophysical product performance within feasible size, weight, power, and cost constraints. Our results indicate that the use of a hyperspectral sampling in the oxygen and water vapor sounding lines alone provides significant improvements in the lower and free tropospheric thermodynamic fields (up to $\sim$40%), when compared against the program of record (i.e., the Advanced Technology Microwave Sounder, ATMS). Our experiments also demonstrate the essential role played by extending the coverage in the window regions, leading to an overall improvement of up to $\sim$50% in the Earth's planetary boundary layer thermodynamic fields. This work concludes with an overview on the state of the art in hyperspectral microwave technology and a discussion on future applications of interest to numerical weather prediction and climate science. The work presented in this study focuses on ocean, clear-sky demonstrations. All-sky, all-surface investigations will be the focus of a follow-up study, as we advance our capability to simulate more complex scenarios and improve scene variability.

The effect of trimodal visuo-audio-tactile stimulations on perceptual realism during vehicle riding simulations in virtual reality reveals that multisensory plausibility engages cortical activities in the frontal-parietal and sensorimotor regions.

Ventriculoperitoneal (VP) shunts represent a surgical option for patients affected by increased intracranial hypertension when medical management fails or is contraindicated. Complications following implantation include shunt obstruction, infection, over and under drainage, migration or disconnection of the tube, formation of a pseudocyst, and allergy to the silicone tube. We report the case of a 31-year-old woman who presented to the emergency room with nausea and generalized malaise, found to have the distal segment of the VP catheter perforating her gastric wall into the stomach lumen which required surgical intervention. In this report, we describe a rare complication associated with the implantation of ventriculoperitoneal shunt (VPS) catheters and the subsequent management plan.

Introduction The role of artificial intelligence (AI) in clinical medicine is ever‐increasing and in time‐dependent, tissue‐based evaluation and treatment of ischemic stroke, AI is clearly proving its utility. In the past decade, scientific publications evaluating the use of AI in stroke care have increased exponentially and information on level of evidence is limited.We aim to systematically review the use of AI in different areas of stroke care, evaluate the level of evidence, and demonstrate the trend of scientific publications in the past decade. Methods A systematic search of electronic scientific databases from 2013 to 2022 was conducted with inclusion of published studies that incorporated AI in all areas of stroke care: prevention, diagnosis, acute care and rehabilitation. Studies published in languages other than English, not directly relevant to stroke care and AI, and any duplicate studies were excluded. Results Our study comprised of 623 studies divided into 101 (16.2%) review studies, 9 (1.4%) meta‐analyses, 140 (22.5%) methodology articles, 2 (0.3%) case reports, 2 (0.3%) case series, 31 (5%) case‐control studies, 277 (44.5%) cohort studies, 16 (2.6%) cross‐sectional studies, and 45 (7.2%) experimental studies. Role of AI in stroke diagnosis was the most frequently explored areas in the published literature (n=275, 44.1%). Our trend analysis showed that the number of studies focusing on AI in stroke significantly increased in the past decade from 1 study in 2012 to 242 studies in 2022 (p=0.0001). Conclusion Majority research focused on role of AI in stroke diagnosis and rehabilitation with more data and input needed in stroke treatment. Although several articles demonstrate AI’s precision and efficacy, utility across the spectrum of stroke care remains to be seen.

BackgroundMachine learning (ML) is an inquiry domain that aims to establish methodologies that leverage information to enhance performance of various applications. In the healthcare domain, the ML concept has gained prominence over the years. As a result, the adoption of ML algorithms has become expansive. The aim of this scoping review is to evaluate the application of ML in pancreatic surgery.MethodsWe integrated the preferred reporting items for systematic reviews and meta-analyses for scoping reviews. Articles that contained relevant data specializing in ML in pancreas surgery were included.ResultsA search of the following four databases PubMed, Cochrane, EMBASE, and IEEE and files adopted from Google and Google Scholar was 21. The main features of included studies revolved around the year of publication, the country, and the type of article. Additionally, all the included articles were published within January 2019 to May 2022.ConclusionThe integration of ML in pancreas surgery has gained much attention in previous years. The outcomes derived from this study indicate an extensive literature gap on the topic despite efforts by various researchers. Hence, future studies exploring how pancreas surgeons can apply different learning algorithms to perform essential practices may ultimately improve patient outcomes.

Cancer is a common health problem in the older population. In Switzerland, more than 40,000 patients are diagnosed with cancer every year, with the majority older than 65 years. Because older patients are often excluded from clinical trials, optimal treatment for this population needs to be considered to prevent over- or under-treatment. Several international guidelines provide recommendations for special care of older and frail patients, with a focus on addressing comorbidities in cancer care. In many countries, including the USA, Belgium, France and the Netherlands, special geriatric oncology units are established for this huge group of cancer patients. Currently, such units have not been routinely established in Switzerland, so we were interested in assessing viewpoints and opinions about such a future geriatric oncology unit at our institution. This article discusses the outcome of an online questionnaire within a midsize cancer center in Switzerland. The survey focused on preferences among members of the interdisciplinary cancer diagnostic and treatment team regarding screening for frailty, decision tools and instruments, while also accounting for each individuals level of healthcare experience. The response rate was 54% (22 out of 41 responses within 4 weeks). The majority (94%) voted for a clear benefit from a regular geriatric oncology multidisciplinary team meeting (MDT) and 54.5% voted to use the G8 form as the preferred screening tool for frailty. In order to optimize treatment, most participants stressed the importance of adjusting all factors according to co-morbidities and nutrition. This questionnaire, however, represents only a small group of healthcare professionals working in the cancer center who are in favor of implementing a geriatric oncology unit. PEER REVIEWED ARTICLE

Abstract Background China’s Mental Health Law (MHL) implemented in 2013 required increased consideration of the rights of people with mental illness and was expected to lead to a reduction in involuntary hospitalization (IH). This study aimed to examine the rates and correlates of IH in a large psychiatric hospital in Guangzhou from 2014 to 2017 after the implementation of MHL and a structured assessment of the need for IH. Methods Unduplicated electronic medical records concerning all inpatients admitted to the hospital with a primary psychiatric diagnose were examined. Diagnostic, sociodemographic and socioeconomic data were used to identify correlates of IH using bivariate chi-square tests followed by logistic regression analysis. Results Of 10, 818 hospitalized patients, there was a significant but small increase, from 71.6 to 74.9% in rates of IH in the years after a structured assessment of need for IH was implemented. Logistic regression analysis showed IH was positively associated with being younger, having a local residence, and a diagnosis of bipolar disorder, schizophrenia spectrum disorders or a substance abuse disorder as compared to those diagnosed with major depressive disorder. Conclusions IH did not decrease over the first four years after the implementation of China’s MHL and a structured assessment in 2013 perhaps, reflecting the initiation of a systematic assessment of the need for IH and the relatively low number of psychiatric beds in this area.

Abstract Background Home blood pressure monitoring (HBPM) is an effective tool in treatment and long-term management of hypertension. HBPM incorporates more data points to help patients and providers with diagnosis and management. The characteristics of HBPM devices matter to patients, but the relative importance of the characteristics in choosing a device remains unclear. Methods We used data from a randomized cross-over pilot study with 100 Alaska Native and American Indian (ANAI) people with hypertension to assess the choice of a wrist or arm HBPM device. We use a random utility framework to evaluate the relationship between stated likely use, perceived accuracy, ease of use, comfort, and participant characteristics with choice of device. Additional analyses examined willingness to change to a more accurate device. Results Participants ranked the wrist device higher compared to the arm on a 5-point Likert scale for likely use, ease of use, and comfort (0.3, 0.5, 0.8 percentage points, respectively). Most participants (66%) choose the wrist device. Likely use (wrist and arm devices) was related to the probability of choosing the wrist (0.7 and − 1.4 percentage points, respectively). Independent of characteristics, 75% of participants would be willing to use the more accurate device. Ease of use (wrist device) and comfort (arm device) were associated with the probability of changing to a more accurate device (− 1.1 and 0.5 percentage points, respectively). Conclusion Usability, including comfort, ease, and likely use, appeared to discount the relative importance of perceived accuracy in the device choice. Our results contribute evidence that ANAI populations value accurate HBPM, but that the devices should also be easy to use and comfortable to facilitate long-term management.

Abstract Background To address the US opioid epidemic, there is an urgent clinical need to provide persons with opioid use disorder (OUD) with effective medication treatments for OUD (MOUD). Formulations of sublingual buprenorphine/naloxone (SL-BUP/NLX) are considered the standard of care for OUD including within the Veterans Healthcare Administration (VHA). However, poor retention on MOUD undermines its effectiveness. Long-acting injectable monthly buprenorphine (INJ-BUP) (e.g., Sublocade®) has the potential to improve retention and therefore reduce opioid use and overdose. Designing and conducting studies for OUD pose unique challenges. The strategies and solutions to some of these considerations in designing Cooperative Studies Program (CSP) 2014, Buprenorphine for Treating Opioid Use Disorder in Veterans (VA-BRAVE), a randomized, 20-site, clinical effectiveness trial comparing INJ-BUP to SL-BUP/NLX conducted within the VHA may provide valuable guidance for others confronted with similar investigation challenges. Methods This 52-week, parallel group, open-label, randomized controlled trial (RCT) evaluates the comparative effectiveness of two current FDA-approved formulations of buprenorphine: (1) daily SL-BUP/NLX vs. (2) monthly (28-day) INJ-BUP for Veterans with moderate to severe OUD (n = 952). The primary outcomes are (1) retention in MOUD and (2) opioid abstinence. Secondary outcomes include measures of other drug use, psychiatric symptoms, medical outcomes including prevalence rates of HIV, hepatitis B and C as well as social outcomes (housing instability, criminal justice involvement), service utilization and cost-effectiveness. Special considerations in conducting a comparative effectiveness trial with this population and during COVID-19 pandemic were also included. Discussion The evaluation of the extended-release formulation of buprenorphine compared to the standard sublingual formulation in real-world VHA settings is of paramount importance in addressing the opioid epidemic. The extent to which this new treatment facilitates retention, decreases opioid use, and prevents severe sequelae of OUD has not been studied in any long-term trial to date. Positive findings in this trial could lead to widespread adoption of MOUD, and, if proven superior INJ-BUP, by clinicians throughout the VHA and beyond. This treatment has the potential to reduce opioid use among Veterans, improve medical, psychological, and social outcomes, and save lives at justifiable cost. Trial registration Registered at Clinicaltrials.gov NCT04375033

Background Next-generation cancer immunotherapies are designed to broaden the therapeutic repertoire by targeting new immune checkpoints including lymphocyte-activation gene 3 (LAG-3) and T cell immunoglobulin and mucin-domain containing-3 (TIM-3). Yet, the molecular and cellular mechanisms by which either receptor functions to mediate its inhibitory effects are still poorly understood. Similarly, little is known on the differential effects of dual, compared with single, checkpoint inhibition.Methods We here performed in-depth characterization, including multicolor flow cytometry, single cell RNA sequencing and multiplex supernatant analysis, using tumor single cell suspensions from patients with cancer treated ex vivo with novel bispecific antibodies targeting programmed cell death protein 1 (PD-1) and TIM-3 (PD1-TIM3), PD-1 and LAG-3 (PD1-LAG3), or with anti-PD-1.Results We identified patient samples which were responsive to PD1-TIM3, PD1-LAG3 or anti-PD-1 using an in vitro approach, validated by the analysis of 659 soluble proteins and enrichment for an anti-PD-1 responder signature. We found increased abundance of an activated (HLA-DR+CD25+GranzymeB+) CD8+ T cell subset and of proliferating CD8+ T cells, in response to bispecific antibody or anti-PD-1 treatment. Bispecific antibodies, but not anti-PD-1, significantly increased the abundance of a proliferating natural killer cell subset, which exhibited enrichment for a tissue-residency signature. Key phenotypic and transcriptional changes occurred in a PD-1+CXCL13+CD4+ T cell subset, in response to all treatments, including increased interleukin-17 secretion and signaling toward plasma cells. Interestingly, LAG-3 protein upregulation was detected as a unique pharmacodynamic effect mediated by PD1-LAG3, but not by PD1-TIM3 or anti-PD-1.Conclusions Our in vitro system reliably assessed responses to bispecific antibodies co-targeting PD-1 together with LAG-3 or TIM-3 using patients’ tumor infiltrating immune cells and revealed transcriptional and phenotypic imprinting by bispecific antibody formats currently tested in early clinical trials.

Artificial neural networks are often interpreted as abstract models of biological neuronal networks, but they are typically trained using the biologically unrealistic backpropagation algorithm and its variants. Predictive coding has been proposed as a potentially more biologically realistic alternative to backpropagation for training neural networks. This manuscript reviews and extends recent work on the mathematical relationship between predictive coding and backpropagation for training feedforward artificial neural networks on supervised learning tasks. Implications of these results for the interpretation of predictive coding and deep neural networks as models of biological learning are discussed along with a repository of functions, Torch2PC, for performing predictive coding with PyTorch neural network models.

Spine posture during repetitive lifting is one of the main risk factors for low-back injuries in the occupational sector. It is thus critical to design appropriate intervention strategies for training workers to improve their posture, reducing load on the spine during lifting. The main approach to train safe lifting to workers has been educational; however, systematic reviews and meta-analyses have shown that this approach does not improve lifting movement nor reduces the risk of low back injury. One of the main limitations of this approach lies in the amount, quality and context of practice of the lifting movement. In this article, first we argue for integrating psychologically-grounded perspectives of practice design in the development of training interventions for safe lifting. Principles from deliberate practice and motor learning are combined and integrated. Given the complexity of lifting, a training intervention should occur in the workplace and invite workers to repeatedly practice/perform the lifting movement with the clear goal of improving their lifting-related body posture. Augmented feedback has a central role in creating the suitable condition for achieving such intervention. Second, we focus on spine bending as risk factor and present a pilot study examining the benefits and boundary conditions of different feedback modalities for reducing bending during lifting. The results showed how feedback modalities meet differently key requirements of deliberate practice conditions, i.e., feedback has to be informative, individualized and actionable. Following the proposed approach, psychology will gain an active role in the development of training interventions, contributing to finding solutions for a reduction of risk factors for workers.

Introduction: Atrial fibrillation (AF) is a recognized risk factor of ischemic stroke and AF‐related stroke is twice more likely to prove fatal. Long‐term cardiac rhythm monitoring has greater diagnostic yield compared to conventional monitoring in detecting AF. Utility of implantable loop recorder (ILR) in detecting AF was established not only in patients with cryptogenic stroke but more recently in strokes due large artery atherosclerosis and small vessel disease Stroke AF trial. We present a collaborative care pathway and share multi‐year data on ILR implantation. Methods: A review of prospectively collected registry of ILR implantations performed at a Comprehensive stroke center was conducted. Data from 2017–2019 of in‐patient and out‐patient implantation was analyzed. Eligible patients identified by vascular neurology (VN) underwent in‐patient implantation primarily by interventional neurology (IN) and as out‐patient by electrophysiology Cardiology. In‐patient implant and programming were done on the day of discharge. Continuous monitoring was followed by EP Cardiology. AF detection was urgently communicated by EP Cardiology and anticoagulation initiated by VN. Patients lost to follow up or lacking information in medical records were excluded from analysis. Results: Total of 428 ILR implantations were performed over a period of 3 years (1/2017 ‐ 12/2019) with majority implants as in‐patient prior to discharge 290 (67.8%) and out‐patient 78 (32.2%). Inpatient ILR placement was noted to be 75% in 2017, 78% in 2018 and 80% in 2019. 57.2% of in‐patient ILRs were placed by IN and 42.8% by EP. Average time to in‐patient ILR was 4.1 days with 77% within 5, 18.5% within 10, and

Introduction: Neuroendovascular procedures are becoming more routine in the treatment of intracranial conditions such as aneurysms, arterial stenosis, and ischemic stroke. These patients are frequently treated with antiplatelet agents prior to the procedure to prevent thrombotic complications. The combination of aspirin and a P2Y12 inhibitor such as clopidogrel is often initiated days before elective procedures or as loading doses for emergent procedures. However, some patients may still experience post procedural thrombotic or hemorrhagic complications which may be related to platelet inhibition. Methods: A retrospective review of patients who underwent a neuroendovascular procedure from 1/2017 to 12/2019 in a single tertiary care academic hospital. Procedures included flow‐diverting stent placement for aneurysms, intracranial, and cervical carotid artery stenting. Patients undergoing elective procedure were started on Aspirin and Clopidogrel 75 mg daily. Patients undergoing emergent procedures were given loading doses of Aspirin (650 mg) and Clopidogrel (600 mg). P2Y12 assay was checked prior to receiving Platelet inhibitor and from 3–6 hours after Clopidogrel loading dose. Optimal platelet inhibition was classified as reduction in P2Y12 assay by at least 60%. Patients with suboptimal platelet inhibition 70% platelet inhibition was noted in 14 patients with mean P2Y12 value of 59. Conclusions: Patients receiving P2Y12 ADP antiplatelet therapy may have suboptimal platelet inhibition which results in increased thrombotic risk. Patients who have significant platelet inhibition (>70%) after loading dose are at increased risk for hemorrhagic complications. Better platelet inhibition was achieved with Ticagrelor in Clopidogrel hypo‐response patients. In patients with Clopidogrel hyper‐response, dosing was changed to half the dose or alternate day to reduce hemorrhagic complications. As the use of endovascular therapies requiring dual anti‐platelet agents becomes more established, there is an increasing need to develop titration protocols that minimize the risk of thrombotic and hemorrhagic events based on platelet inhibition.

Objective: To assess current management of diverticulitis in Switzerland.Methods: Prospective observational study of diverticulitis management and outcomes in surgical departments over a 3-month time period. Hospital category was graded according to the Swiss Medical Association (FMH) as: U: University; A: Cantonal; B: Regional; P: Private.Results: 75 participating hospitals treated 1,015 patients, among whom 214 patients (21%) had elective sigmoid resections in 49 hospitals. Indication for elective resection were recurrent diverticulitis, previous complicated diverticulitis, fistulas, and stenosis. Surgeries were performed completely laparoscopically in 185 cases (86%) and required conversion to open in 19 cases (9%). Overall postoperative complication rate was 18% (n = 39) and no mortality was observed. Operation time, surgeons experience and hospital stay differed considerably between hospital categories.Conclusions: Elective sigmoid resection for diverticulitis in Switzerland was mainly performed laparoscopically with low postoperative morbidity. Different practices and outcomes between institutions were observed.

RESUMO Objetivo Avaliar o efeito do internato em saúde mental nas atitudes dos alunos de medicina quanto ao portador de transtorno mental (PTM). Métodos Atitudes foram avaliadas por questionário antes e depois do internato, por meio dos fatores: “aceitação social de PTM” (F1), “não acreditar em causas sobrenaturais para doença mental” (F2), “papéis sociais comuns para PTM” (F3), “acreditar em causas psicossociais para doença mental” (F4), “intimidade” (F5). Diferenças foram avaliadas por meio de testes t, fatores confundidores por ANOVA e correlações entre expectativa de melhora e fatores por Pearson. Resultados 74 de 85 alunos responderam ao questionário. Houve redução significativa em quatro fatores avaliados (F1, p < 0,001, F2, p = 0,002, F3, p = 0,04, F5, p < 0,001). Uma associação entre ter um amigo PTM e F3 foi identificada antes do curso (p = 0,04), porém não após (p = 0,13). Houve correlação positiva entre crenças de melhora e atitudes negativas com o F2 antes do curso (p = 0,01), mas não após. F5 esteve relacionado com a expectativa de melhora (p < 0,001) após o curso, indicando melhores atitudes quando melhor expectativa. Observou-se a melhora da expectativa quanto a resposta ao tratamento da esquizofrenia (p = 0,02), transtorno bipolar (p = 0,03) e transtorno de ansiedade (p = 0,03). Conclusões O internato esteve associado à redução de atitudes negativas com relação aos PTMs. O contato direto com o paciente parece ter influência direta nessa redução. Acreditamos que, mais importante do que possíveis efeitos de esclarecimento sobre causas do adoecimento, a desconstrução do mito sobre o louco violento é essencial para a melhora das atitudes. Estudos com populações de outras regiões do Brasil e voltadas para avaliação do medo de violência são necessários para a confirmação dessa hipótese e do efeito do internato sobre os alunos.

The dynamics of local cortical networks are irregular, but correlated. Dynamic excitatory-inhibitory balance is a plausible mechanism that generates such irregular activity, but it remains unclear how balance is achieved and maintained in plastic neural networks. In particular, it is not fully understood how plasticity induced changes in the network affect balance, and in turn, how correlated, balanced activity impacts learning. How do the dynamics of balanced networks change under different plasticity rules? How does correlated spiking activity in recurrent networks change the evolution of weights, their eventual magnitude, and structure across the network? To address these questions, we develop a theory of spike-timing dependent plasticity in balanced networks. We show that balance can be attained and maintained under plasticity-induced weight changes. We find that correlations in the input mildly affect the evolution of synaptic weights. Under certain plasticity rules, we find an emergence of correlations between firing rates and synaptic weights. Under these rules, synaptic weights converge to a stable manifold in weight space with their final configuration dependent on the initial state of the network. Lastly, we show that our framework can also describe the dynamics of plastic balanced networks when subsets of neurons receive targeted optogenetic input.

Task-related activity in the ventral thalamus, a major target of basal ganglia output, is often assumed to be permitted or triggered by changes in basal ganglia activity through gating- or rebound-like mechanisms. To test those hypotheses, we sampled single-unit activity from connected basal ganglia output and thalamic nuclei (globus pallidus-internus [GPi] and ventrolateral anterior nucleus [VLa]) in monkeys performing a reaching task. Rate increases were the most common peri-movement change in both nuclei. Moreover, peri-movement changes generally began earlier in VLa than in GPi. Simultaneously recorded GPi-VLa pairs rarely showed short-time-scale spike-to-spike correlations or slow across-trials covariations, and both were equally positive and negative. Finally, spontaneous GPi bursts and pauses were both followed by small, slow reductions in VLa rate. These results appear incompatible with standard gating and rebound models. Still, gating or rebound may be possible in other physiological situations: simulations show how GPi-VLa communication can scale with GPi synchrony and GPi-to-VLa convergence, illuminating how synchrony of basal ganglia output during motor learning or in pathological conditions may render this pathway effective. Thus, in the healthy state, basal ganglia-thalamic communication during learned movement is more subtle than expected, with changes in firing rates possibly being dominated by a common external source.

Background The costimulatory receptor 4-1BB (CD137, TNFRSF9) plays an important role in sustaining effective T cell immune responses and is investigated as target for cancer therapy. Systemic 4-1BB directed therapies elicit toxicity or low efficacy, which significantly hampered advancement of 4-1BB-based immunotherapy. Therefore, targeted delivery of 4-1BB agonist to the tumor side is needed for eliciting antitumor efficacy while avoiding systemic toxicity.Methods We analyzed the immunostimulatory properties of a fibroblast activation protein (FAP)-targeted 4-1BB agonist (FAP-4-1BBL) by assessing tumor-infiltrating lymphocytes’ (TIL) activity from patients with non-small cell lung cancer and epithelial ovarian cancer.Results Combination treatment with FAP-4-1BBL and T cell receptor stimulation by either anti-CD3 or T cell bispecific antibodies significantly enhanced TIL activation and effector functions, including T cell proliferation, secretion of proinflammatory cytokines and cytotoxicity. Notably, costimulation with FAP-4-1BBL led to de novo secretion of interleukin (IL)−13. This was associated with cytokine-mediated tumor cell apoptosis, which was partially dependent on IL-13 alpha 1/2 receptors and STAT6 phosphorylation.Conclusions Our study provides mechanistic insights into T cell stimulation induced by FAP-4-1BBL in primary human tumors and supports the investigation of FAP-4-1BBL compound in early clinical trials.

Balanced excitation and inhibition is widely observed in cortex. How does this balance shape neural computations and stimulus representations? This question is often studied using computational models of neuronal networks in a dynamically balanced state. But balanced network models predict a linear relationship between stimuli and population responses. So how do cortical circuits implement nonlinear representations and computations? We show that every balanced network architecture admits stimuli that break the balanced state and these breaks in balance push the network into a "semi-balanced state" characterized by excess inhibition to some neurons, but an absence of excess excitation. The semi-balanced state produces nonlinear stimulus representations and nonlinear computations, is unavoidable in networks driven by multiple stimuli, is consistent with cortical recordings, and has a direct mathematical relationship to artificial neural networks.

Abstract Introduction Electroconvulsive therapy (ECT) is an effective treatment for patients with mood disorders and is most often used for treatment‐resistant cases. This study aimed to examine the effectiveness of ECT in a real‐world treatment sample in a Chinese psychiatric hospital which included both treatment‐resistant and nontreatment‐resistant patients. Methods An observational study of symptom outcomes from admission to the time of discharge was conducted with 37 inpatients diagnosed with unipolar or bipolar depression treated with ECT. Symptom severity was assessed with the 17‐item Hamilton Rating Scales for Depression (HRSD‐17) and treatment‐resistance with the Maudsley Staging Model (MSM). Stratifying at the MSM median admission characteristics and symptom change was compared between patients who were treatment‐resistant (n = 18) and who were not (n = 19). The outcome difference between groups was compared using analyses of covariance adjusted for baseline characteristics including symptom severity, followed by linear regression to identify factors associated symptom improvement in the entire sample. Results The sample (n = 37) showed moderate treatment‐resistance (MSM = 7.30 ± 1.13) at admission and both groups received 8.3 ± 2 ECT sessions. The treatment‐resistant group had a smaller proportion of bipolar patients and more severe symptoms, but showed no significant difference from the nontreatment‐resistant group in HDRS‐17 scores at the time of discharge (adjusted means = 6.23 ± 1.00 vs. 5.94 ± 0.97, Partial η2 = 0.001, p = .845). Baseline symptom severity was the strongest correlate of reduction in HDRS‐17 scores (β = 0.891, p

Stroke patients are at increased risk for recurrent stroke and development of post-stroke dementia. In this study, we investigated the effects of recurrent stroke on adult brain neurogenesis using a novel rat model of recurrent middle cerebral artery occlusion (MCAO) developed in our laboratory. Using BrdU incorporation, activation and depletion of stem cells in the subgranular zone (SGZ) and subventricular zone (SVZ) were assessed in control rats and rats after one or two strokes. In vitro neurosphere assay was used to assess the effects of plasma from normal and stroke rats. Also, EM and permeability studies were used to evaluate changes in the blood-brain-barrier (BBB) of the SGZ after recurrent stroke. We found that proliferation and neurogenesis was activated 14 days after MCAO. This was correlated with increased permeability in the BBB to factors which increase proliferation in a neurosphere assay. However, with each stroke, there was a stepwise decrease of proliferating stem cells and impaired neurogenesis on the ipsilateral side. On the contralateral side, this process stabilized after a first stroke. These studies indicate that stem cells are activated after MCAO, possibly after increased access to systemic stroke-related factors through a leaky BBB. However, the recruitment of stem cells for neurogenesis after stroke results in a stepwise ipsilateral decline with each ischemic event, which could contribute to post-stroke dementia.