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Background: Anxiety disorders and treatment-resistant major depressive disorder (TRD) are often comorbid. Studies suggest ketamine has anxiolytic and antidepressant properties., Aims: To investigate if subcutaneous racemic ketamine, delivered twice weekly for 4 weeks, reduces anxiety in people with TRD., Method: The Ketamine for Adult Depression Study was a multisite 4-week randomised, double-blind, active (midazolam)-controlled trial. The study initially used fixed low dose ketamine (0.5 mg/kg, cohort 1), before protocol revision to flexible, response-guided dosing (0.5-0.9 mg/kg, cohort 2). This secondary analysis assessed anxiety using the Hamilton Anxiety (HAM-A) scale (primary measure) and 'inner tension' item 3 of the Montgomery-Åsberg Depression Rating Scale (MADRS), at baseline, 4 weeks (end treatment) and 4 weeks after treatment end. Analyses of change in anxiety between ketamine and midazolam groups included all participants who received at least one treatment ( n = 174), with a mixed effects repeated measures model used to assess the primary anxiety measure. The trial was registered at www.anzctr.org.au (ACTRN12616001096448)., Results: In cohort 1 ( n = 68) the reduction in HAM-A score was not statistically significant: -1.4 (95% CI [-8.6, 3.2], P = 0.37), whereas a significant reduction was seen for cohort 2 ( n = 106) of -4.0 (95% CI [-10.6, -1.9], P = 0.0058), favouring ketamine over midazolam. These effects were mediated by total MADRS and were not maintained at 4 weeks after treatment end. MADRS item 3 was also significantly reduced in cohort 2 ( P = 0.026) but not cohort 1 ( P = 0.96)., Conclusion: Ketamine reduces anxiety in people with TRD when administered subcutaneously in adequate doses.

Background: Time to reorientation after electroconvulsive therapy (ECT) has been shown to predict retrograde amnesia and is a useful measure for monitoring patients over the acute treatment course. This study investigated the effects of treatment, clinical and demographic factors on the recovery of orientation after ECT., Methods: Data from 555 ECT patients across two different clinical CARE Network sites were analysed. The main outcome variable was recovery of orientation on the 10-Item Orientation Questionnaire assessed after every ECT treatment. A linear mixed-effects repeated measures model was used to predict the recovery of orientation across the ECT course based on multiple factors, including age, gender, electrode montage, ECT number and frequency, diagnosis, and baseline cognitive impairment., Results: Type of ECT demonstrated a significant effect (F(2, 2341) = 48.414, p = 0.000): individuals who received right unilateral (RUL) ultrabrief ECT or bifrontal ECT had higher orientation scores compared to those who received RUL brief pulse ECT. Older age groups and female patients had lower orientation scores. Baseline global cognitive functioning significantly influenced orientation scores (F(3, 2339) = 43.597, p = 0.000), with individuals with no or mild cognitive impairment exhibiting higher scores., Limitations: The study involved a retrospective analysis of de-identified data, which may have introduced inherent biases with missing data., Conclusions: This large-scale retrospective, real-world study showed that recovery of orientation after ECT was most affected by ECT type, though age, gender, and baseline level cognitive impairment also affected outcomes. These findings can inform the interpretation of post ECT orientation scores, facilitating its monitoring and optimisation of patient outcomes., Competing Interests: Declaration of competing interest None of the authors of this manuscript have conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: Women with gestational diabetes mellitus (GDM) have a high risk of developing type 2 diabetes (T2D). Readiness for behaviour change to mitigate this risk may be low after pregnancy and may further decrease over time without appropriate interventions. This study aimed to evaluate readiness for behaviour change in the first and second postpartum years in women with recent GDM to determine the best timing for lifestyle interventions to prevent T2D., Methods: This study included a subset of women with GDM between 2009 and 2013 in Ontario, Canada from a larger prospective cohort study who completed a survey in the first and second postpartum years (N = 329). The primary outcome was stage of readiness for behaviour change for diet and physical activity, compared between the first and second postpartum years., Results: The mean age was 34.3 ± 4.4 standard deviation (SD) years and mean pre-pregnancy body-mass index (BMI) was 26.7 ± 6.9 kg/m 2 . In the first postpartum year, 86% of women reported a pre-action stage of change, which was 87% by the second postpartum year (p = 0.646). Non-Caucasian ethnicity was associated with lower odds of being in the action stage of readiness for behaviour change overall and for physical activity in both time periods., Conclusions: Most postpartum women with recent GDM are in a pre-action stage of change after delivery, which does not increase by the second postpartum year. Behavioural interventions should continue to be prioritized in postpartum women with GDM to optimize this slim window of opportunity for T2D prevention., (© 2024 Diabetes UK.)

Exercise intolerance is common in patients with heart failure with preserved ejection fraction. This review will discuss the utility of exercise hemodynamics under both diagnostic and prognostic circumstances and highlight challenges associated with making and interpreting measures taken during exercise., Competing Interests: Disclosure The author has nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The amount of data collected for sensing tasks in scientific computing is based on the Shannon-Nyquist sampling theorem proposed in the 1940s. Sensor data generation will surpass 73 trillion GB by 2025 as we increase the high-fidelity digitization of the physical world. Skyrocketing data infrastructure costs and time to maintain and compute on all this data are increasingly common. To address this, we introduce a selective learning approach, where the amount of data collected is problem dependent. We develop novel shift-invariant and spectrally stable neural networks to solve real-time sensing problems formulated as classification or regression problems. We demonstrate that (i) less data can be collected while preserving information, and (ii) test accuracy improves with data augmentation (size of training data), rather than by collecting more than a certain fraction of raw data, unlike information theoretic approaches. While sampling at Nyquist rates, every data point does not have to be resolved at Nyquist and the network learns the amount of data to be collected. This has significant implications (orders of magnitude reduction) on the amount of data collected, computation, power, time, bandwidth, and latency required for several embedded applications ranging from low earth orbit economy to unmanned underwater vehicles., Competing Interests: Declarations. Competing interests: AV and SK have filed two provisional patent applications on some implementations of the above technology, on April 13th, 2022 (U.S. Prov. Pat. App. No. 63330669), and on September 22nd, 2022 (U.S. Prov. Pat. App. No. 63408961). AV, AG, and SK have filed a provisional patent application on some implementations of the above technology, on January 4th, 2024 (U.S. Prov. Pat. App. No. 63/617,463), and on December 17th, 2024 (PCT/US24/60489). AV, AG, and SK have financial interests in Lightscline. SS has no competing interests to declare. As of May, and June 2024, AV and AG respectively are employed with Lightscline Inc., (© 2024. The Author(s).)

Aims: To identify factors associated with use of novel diabetes medications among patients hospitalized under general internal medicine., Methods: We conducted a cohort study of patients with type 2 diabetes mellitus (T2DM) hospitalized in Ontario, Canada between 2015 and 2020. We evaluated the patient- and physician-level factors associated with sodium-glucose cotransporter 2 inhibitor (SGLT2) and glucagon-like peptide 1 receptor agonist (GLP1R) use using a multivariable logistic regression model., Results: There were 253,152 hospitalizations and 68,126 involved patients who had T2DM. Prior to discharge, 3.7 % (N = 2490) of patients with T2DM received an SGLT2 and 0.2 % (N = 121) received a GLP1R. The strongest predictors for receiving a novel diabetes medication were hemoglobin A1C > 9.0 % (Odds Ratio (OR) = 1.81, 95 % Confidence Interval (CI) 1.28, 2.60) and patients aged 40-60 compared with patients <40 years old (OR = 1.81, 95 % CI 1.33, 2.68). The strongest predictors for not receiving a novel diabetes medication were dementia (OR = 0.47, 95 % CI 0.39, 0.56) and creatinine ≥200 μmol/L (OR = 0.11, 95 % CI 0.08, 0.15). Overall, 46.8 % of patients hospitalized with T2DM not receiving a novel diabetes medication would potentially benefit from an SGLT2 inhibitor., Conclusions: Novel diabetes medications were rarely continued or initiated during hospitalization despite a high prevalence of cardiovascular disease, raising the concern for systematic under-utilization after discharge., Competing Interests: Declaration of competing interest Michael Fralick was a consultant for ProofDx, a start-up company creating a point of care diagnostic test for COVID-19. Michael Fralick is an advisor for SIGNAL1, a start-up company deploying machine learned models to improve inpatient care. Tor Biering-Sørensen discloses the following relationships: steering committee member of the Amgen-financed GALACTIC-HF trial, of the Boehringer Ingelheim financed SHARP3 trial, of “LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific's Investigational ICM System” trial; advisory board: Amgen, CSL Seqirus and GSK; chief investigator of the Sanofi Pasteur financed “NUDGE-FLU”, “DANFLU-1”, and “DANFLU-2” trials; speaker honorarium: Bayer, Novartis, Sanofi Pasteur, GE healthcare and GSK; consultant appointments: Novo Nordisk, IQVIA and Parexel; and research grants: GE Healthcare, AstraZeneca, Novo Nordisk and Sanofi Pasteur. Fahad Razak is a part-time employee of Ontario Health. The development of the GEMINI data platform has been supported with funding from sources such as the Canadian Cancer Society, the Canadian Frailty Network, the Canadian Institutes of Health Research, the Canadian Medical Protective Agency, Green Shield Canada Foundation, the Natural Sciences and Engineering Research Council of Canada, Ontario Health, the St. Michael's Hospital Association Innovation Fund, the University of Toronto Department of Medicine, and in-kind support from partner hospitals and the Vector Institute. Fahad Razak holds a salary award from Canada Research Chairs Program, University of Toronto and the PSI Graham Farquharson Knowledge Translation Fellowship. No funding sources from Fahad Razak influenced the writing of this manuscript. Outside of the submitted work, Amol Verma is a part-time employee of Ontario Health and a co-inventor of an AI-based early warning system for patient deterioration that was acquired by the start-up company Signal1. Magnus Thorsten Jensen is the CEO of Steno Diabetes Center Copenhagen which is funded through a partnership between the Capital Region of Denmark and the Novo Nordisk Foundation. Bruce A. Perkins has received honoraria for educational events from Medtronic, Novo Nordisk, Sanofi, Insulet and Abbott. His research institute has received funding from BMO Bank of Montreal and Novo Nordisk for research support. He has served as an advisor to Boehringer Ingelheim, Sanofi, Insulet, Abbott, and Vertex. Ashley Raudanskis, Shohinee Sarma, Katarina Zorcic, and Michael Colacci have no reported conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The scientific community has achieved a remarkable milestone by creating efficacious vaccines against the SARS-CoV-2 virus. The treatment alternatives are still restricted, though. The bioactive ingredients present in natural plants are known to exhibit diverse pharmacological effects against many diseases. Using computational techniques such as molecular docking, drug-likeness, ADMET study, MD simulation, and our own N-layered Integrated molecular Orbital and Molecular mechanics (ONIOM) calculations, this study aimed to investigate essential oil constituents of Lindera neesiana , Litsea cubeba and Zanthoxylum armatum DC plants as a potential natural inhibitor of SARS-CoV-2 main protease (M pro ). To determine their binding affinity, 107 phytochemical substances in total were docked inside the binding pocket of M pro . Copaene showed the highest binding affinity among the 107 compounds, with an energy of -7.90 kcal/mol. Furthermore, physiochemical and ADMET properties were evaluated for the top five phytocompounds. The studied phytocompounds showed good physiochemical and pharmacokinetic behaviour with no associated toxicity. MD simulation further provided evidence for stable interaction of phytocompounds within the binding pocket of M pro . Subsequently, ONIOM calculation was done on the best-hit complex, wherein the hydrogen bonding interactions were retained with appreciable negative energy. These in silico results indicate that the specific phytocompounds present in essential oils of L. neesiana, L. cubeba, and Z. armatum DC have significant inhibitor ability against SARS-CoV-2 main protease and could be explored for future therapeutic investigations.

Health care reforms introduced interprofessional team-based primary care to optimize access to health care and preventive services. In this context, preventive cancer screening represents an important measure as it is essential for the early detection of cancer and treatment. We investigated the effects of Family Health Teams (FHTs), an interprofessional team-based primary care practice setting, on cancer screening rates in Ontario, Canada. By utilizing comprehensive health administrative data from April 1st 2011 to March 31st 2023, we determined the effect of FHT on screening rates for breast, cervical, and colorectal cancer while controlling for relevant physician and patient characteristics. Our analytical framework employs fractional probit models, including the Mundlak procedure, and generalized estimating equations to assess the impact of practicing in FHTs on cancer screening rates, while accounting for unobserved physician heterogeneity. Our results indicate that compared to non-FHTs, physicians practicing in FHTs have higher breast (2.4%), cervical (2%), and colon (0.8%) cancer screening rates per physician per year. The effectiveness of FHTs in promoting cancer screenings is particularly pronounced in smaller practices and among populations in rural and economically deprived areas. Our findings highlight the role of teams in enhancing preventive health care services potentially through task shifting mechanisms and suggest that such models may offer a pathway to improving access to preventive health care, especially in marginalized populations. Our research contributes to the literature by providing empirical evidence on the benefits of interprofessional team-based primary care in improving cancer screening., Competing Interests: Declarations. Conflict of interest: None. Ethics statement: We used confidential health administrative data for all Ontario residents with a valid OHIP card without any patient identifiable information. This study was approved under Sect. 45 of Ontario's Personal Health Information Protection Act, eliminating the need for a Research Ethics Board review., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: The "2024 Guideline for the Primary Prevention of Stroke" replaces the 2014 "Guidelines for the Primary Prevention of Stroke." This updated guideline is intended to be a resource for clinicians to use to guide various prevention strategies for individuals with no history of stroke., Methods: A comprehensive search for literature published since the 2014 guideline; derived from research involving human participants published in English; and indexed in MEDLINE, PubMed, Cochrane Library, and other selected and relevant databases was conducted between May and November 2023. Other documents on related subject matter previously published by the American Heart Association were also reviewed., Structure: Ischemic and hemorrhagic strokes lead to significant disability but, most important, are preventable. The 2024 primary prevention of stroke guideline provides recommendations based on current evidence for strategies to prevent stroke throughout the life span. These recommendations align with the American Heart Association's Life's Essential 8 for optimizing cardiovascular and brain health, in addition to preventing incident stroke. We also have added sex-specific recommendations for screening and prevention of stroke, which are new compared with the 2014 guideline. Many recommendations for similar risk factor prevention were updated, new topics were reviewed, and recommendations were created when supported by sufficient-quality published data.

Competing Interests: This trial involves no commercial input: the findings from this trial will not benefit any commercial manufacturers/suppliers of clinical ECT devices. GLS has collaborated with MagVenture and MECTA as part of investigator-initiated trials, consults for and has equity in the company Trial Catalyst, and has provided consultation to Indivior. Dr Harold A. Sackeim serves as a scientific adviser and receives consulting fees from Cerebral Therapeutics Inc, Holmusk Technologies Inc, LivaNova PLC, MECTA Corporation, Neurolief Ltd, Neuronetics Inc, Parow Entheobiosciences LLC, and SigmaStim LLC. He receives honoraria and royalties from Elsevier Inc and Oxford University Press. He is the inventor on nonremunerative US patents for Focal Electrically Administered Seizure Therapy (FEAST), titration in the current domain in ECT, and the adjustment of current in ECT devices, each held by Balance Point LLC. He is also the originator of magnetic seizure therapy (MST). In the last 3 years PBF has received equipment for research from Neurosoft, Nexstim, and Brainsway Ltd. He has served on scientific advisory boards for Magstim and LivaNova and received speaker fees from Otsuka. He has also acted as a founder and board member for TMS Clinics Australia and Resonance Therapeutics. PBF is supported by a National Health and Medical Research Council of Australia Investigator grant (1193596). The other authors have no conflicts of interest or financial disclosures to report.

Competing Interests: Conflict of interest: C.L. and D.M. have received institutional NHMRC grant funding for the CARE Network. The authors have no conflicts of interest or financial disclosures to report.

Effective diabetes management can prevent avoidable diabetes-related hospitalizations. This review examines the impact of financial incentives for diabetes management in primary care settings on diabetes-related hospitalizations, hospitalization costs, and premature mortality. To assess the evidence, we conducted a literature search of studies using five databases: Medline, Embase, Scopus, CINAHL and Web of Science. We examined the results by health insurance system, study quality or diabetes population (newly diagnosed diabetes). We identified 32 articles ranging from fair- to high-quality: 19 articles assessed the relationship between financial incentives for diabetes management and hospitalizations, 8 assessed hospitalization costs, and 15 assessed mortality. Many studies found that financial incentives for diabetes management reduced hospitalizations, while a few found no effects. Similar findings were evident for hospitalization costs and mortality. The results did not differ by the type of health insurance system, but the quality of the studies did matter; most high-quality studies reported reduced hospitalizations and/or mortality. We also found that financial incentives tend to be beneficial for patients with newly diagnosed diabetes. We conclude that well-designed diabetes management incentives can reduce diabetes-related hospitalizations, especially for newly diagnosed diabetes patients., Competing Interests: Declaration of competing interest Nome of the authors have any conflicts of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Type 2 diabetes mellitus and lower weight are both associated with osteoporotic fractures, but the roles of variability and trajectory are less clear. The associations of these factors among older adults with dysglycemia, who are at highest risk of fracture, with fracture risk and BMD remain uncertain. We followed 775 men and 1080 women from the Cardiovascular Health Study (mean age 77.4 years) with abnormal oral glucose tolerance testing in 1989-1990. We measured their weights yearly through 1994-1995 and derived intra-individual mean weight, weight slope, and weight variability. We also used growth mixture modeling to derive 4 latent BMI trajectories over time. We used Cox proportional hazards models to calculate hazard ratios (HRs) and 95% CI for subsequent hip fracture through 2015 and linear regression models to estimate cross-sectional associations with BMD of the hip. Each 10 kg higher mean weight was associated with a lower risk of subsequent hip fracture overall (HR 0.81; CI, 0.70-0.94) and among women (HR 0.76; CI, 0.64-0.91) and with higher BMD (p <.001). Higher weight variability was directly associated with incident hip fracture among women (HR 1.18; CI, 1.03-1.35). Compared with a stable trajectory, a "progressive overweight" trajectory was associated with lower risk of hip fracture (HR 0.66; CI, 0.44-0.99). An uncommon trajectory of "accelerating obesity" was associated with higher BMD. Among older adults with dysglycemia at high risk for fracture, lower mean weight is associated with higher fracture risk, but variability and trajectory may also contribute. These results highlight the complex effects of weight in older age., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Trials of GLP-1 (glucagon-like peptide-1) medicines have changed the paradigm of obesity treatment. Diversity in trial participation is imperative considering that obesity disproportionately impacts marginalised populations worldwide. We performed a systematic review and meta-analyses to evaluate the representation of racialised and ethnically diverse populations in randomised controlled trials (RCTs) of GLP-1 medicines for obesity., Methods: We searched PubMed/Embase/ClinicalTrials.gov. Prevalence of each racial/ethnic group was compared in relation to the USA, Canada, the UK, Brazil and South Africa. The geographical locations of the trial sites were extracted., Results: 27 RCTs were identified (n=21 547 participants). Meta-analyses of prevalence demonstrated the vast predominance of white/Caucasians (79%) with smaller proportion of blacks (9%), Asians (13%), Indigenous (2%) and Hispanics (22%). The gaps in representation were evidenced by the significantly under-represented proportion of non-white individuals in these RCTs as compared with the prevalence of non-white individuals in the general population of the USA (-23%, p=0.002) and Canada (-34%, p<0.0001), reaching an alarming gap of -58% in relation to Brazil and striking under-representation of -68% as compared with South Africa. Similar discrepancies in proportions of blacks, Asians and Indigenous peoples as compared with reference nations were found. Moreover, the trial sites (n=1859) were predominately located in high-income countries (84.2%), in sharp contrast to the global prevalence of obesity that is predominantly in low-income and middle-income countries., Conclusion: There are discrepancies in representation of racialised and ethnically diverse populations in obesity trials as compared with multiethnic populations worldwide. These data highlight the need for broader reform in the research process in order to ultimately address health inequities., Competing Interests: Competing interests: YJ has no conflict of interest. LR has no conflict of interest. SS received salary support from the University of Toronto. RR reports grants from Boehringer Ingelheim, grants and personal fees from Novo Nordisk, personal fees from Sanofi, personal fees from Eli Lilly, outside the submitted work. CKK reports research grant (investigator initiated) from Boehringer Ingelheim outside of the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Targeted electrical stimulation to specific thalamic regions offers a therapeutic approach for patients with refractory focal and generalized epilepsy who are not candidates for resective surgery. However, clinical outcome varies significantly, in particular for focal epilepsy, influenced by several factors, notably the precise anatomical and functional alignment between cortical regions generating epileptic discharges and the targeted thalamic stimulation sites. Here we hypothesized that targeting thalamic nuclei with precise anatomical and functional connections to epileptic cortical areas (an approach that we refer to as hodological matching) could enhance neuromodulatory effects on focal epileptic discharges. To investigate this, we examined three thalamic subnuclei (pulvinar nucleus, anterior nucleus, and ventral intermediate nucleus/ventral oral posterior nuclei) in a retrospective study involving 32 focal epilepsy patients. Specifically, we first identified hodologically organized thalamocortical fibers connecting these nuclei to individual seizure onset zones (SOZs), combining neuroimaging and electrophysiological techniques. Further, analysis of 216 spontaneous seizures revealed the critical role of matched thalamic nuclei in seizure development and termination. Importantly, electrical stimulation of hodologically-matched thalamic nuclei immediately suppressed intracortical interictal epileptiform discharges, contrasting with ineffective outcomes from stimulation of unmatched targets. Finally, we retrospectively evaluated 7 patients with a chronic hodologically-matched neurostimulation system, which led to a clinically relevant reduction in seizure frequency (median reduction 86.5%), that outstands the current clinical practice of unmatched targets (39%). Our results underscore the potential of hodological thalamic targeting to modulate epileptiform activity in specific cortical regions, highlighting the promise of precision medicine in thalamic neuromodulation for focal refractory epilepsy., Competing Interests: Competing interests The authors declare no conflicts of interests in relation to this work.

The present study aimed to investigate the episodes of per-acute mortality due to peste des petits ruminants (PPR) that resulted in the death of 30 animals of different species of cervids, namely, barking deer, four-horned antelope, hog deer, thamin, and mouse deer in the State Zoo of Assam, a northeastern state of India. The affected animals showed no to limited clinical signs. However, the necropsy and histopathological findings were highly suggestive of PPR virus (PPRV) infection observed in domestic small ruminants. Representative tissue samples were screened for the presence of PPRV along with blue tongue virus (BTV) and epizootic hemorrhagic disease virus (EHDV) using RT-PCR or RT-qPCR and were found to be positive for PPRV. Considering the sudden outbreak of PPR in captive cervids, we sought to determine the role of domestic goats as the potential spillover host. To verify that, archived tissue samples of domestic goats collected during PPRV outbreaks in nearby localities and slaughtered goats used as meat for Carnivorous animals in the State Zoo were also screened and found to be positive for PPRV in RT-PCR. Phylogenetic analysis based on the Nucleocapsid (N) protein gene of PPRV from infected cervids, domestic goats, and goat meat revealed the virus to be of Lineage IV origin. Our findings provide evidence of probable spillover of PPRV from domestic goats to captive endangered cervids and circulation of Lineage IV PPRV strains among the small-ruminant population of this region.

Introduction: The prevalence of peripheral neuropathy (PN) in the lower limb increases with age and with the presence of diabetes. Studies show an association of PN with advanced cognitive impairment. Here we examine the association of PN with measures of early cognitive deficits in a cohort of older adults without apparent cognitive impairment, with or without diabetes., Methods: A total of 2,798 participants from the Cardiovascular Health Study were examined, mean age 80 years. All underwent tests of overall cognition (3MSE), executive function (DSST), and visual memory (BVRT). Impairment of vibration sensation in the toes, ankles, and tibial tuberosities was ascertained. Participants were graded according to the extent of impairment. Adjusted linear regression analyses of the extent of impaired vibration sensation with cognitive tests were performed. Results were further categorized by the presence or absence of diabetes., Results: 70% of participants had intact vibration sensation in the toes; 8% had no vibration sensation in the tibial tuberosities or below. Compared to participants with intact vibration sensation in the toes, those with no vibration sensation in the tibial tuberosities had lower 3MSE scores. Tests of executive function were lower in a stepwise manner with greater impaired vibration sensation. Visual memory was less strongly associated with impaired vibration sensation. Findings did not differ significantly by diabetes status., Conclusion: In older adults, impaired vibration sensation in the lower limb is associated with impaired executive function and visual memory. These findings did not differ by diabetes status., (© 2024 S. Karger AG, Basel.)

The integration of biomolecules into supramolecular nanostructures forms the basis of the natural world. Naturally occurring liquid-liquid phase separation resulting in biomolecular condensates has inspired the formation of biomolecule-based smart materials with multi-dimensional applications. A non-covalent bio-condensation between biomass DNA and guanosine monophosphate (GMP) has been described, mimicking chromatin folding and creating a unique "all-nucleic" DNA-GMP condensates. These condensates initiate the formation of G-quadruplex-based superstructures, assembling into super-helical fibres driven by synergistic hydrogen bonding and stacking, which have been thoroughly investigated. This simple, one-step method for the bio-condensation of biomass DNA leads to an "all-nucleic" hydrogel with higher-order self-assembly and excellent mechanical properties. While most of the reported DNA based biomaterials, including hydrogels, require precisely sequenced and molecularly architectured DNA building blocks, we have developed a simple, universal, and facile bio-condensation method that utilizes biomass DNA acquired from any bio-resource to fabricate DNA hydrogels. The hydrogel efficiently encapsulates and sustains the release of both hydrophilic and hydrophobic drugs, demonstrating its competency as a drug carrier. We believe this energy-efficient and low-cost method represents a new technique for using biomass DNA as building blocks for the next generation of soft materials., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Exercise pulmonary hypertension (ePH), defined as a mean pulmonary artery pressure (mPAP)/cardiac output (Qc) slope >3 WU during exercise, is common in patients with heart failure with preserved ejection fraction (HFpEF). However, the pulmonary gas exchange-related effects of an exaggerated ePH (EePH) response are not well-defined, especially in relation to dyspnea on exertion (DOE) and exercise intolerance., Methods: 48 HFpEF patients underwent invasive (pulmonary and radial artery catheters) constant-load (20W) and maximal incremental cycle testing. Hemodynamic measurements (mPAP and Qc), arterial blood and expired gases, and ratings of breathlessness (RPB, Borg 0-10) were obtained. The mPAP/Qc slope was calculated from rest-to-20W. Those with a mPAP/Qc slope >4.2 (median) were classified as HFpEF+EePH (n=24) and those with a mPAP/Qc slope <4.2 were classified as HFpEF (without EePH) (n=24). The A-aDO 2 , V D /V T (Bohr equation), and the V E /VCO 2 slope (from rest-to-20W) were calculated., Results: PaO 2 was lower (p=0.03), and V D /V T was higher (p=0.03) at peak exercise in HFpEF+EePH compared with HFpEF. A-aDO 2 was similar at peak exercise between groups (p=0.14); however, HFpEF+EePH achieved the peak A-aDO 2 at a lower peak work rate (p<0.01). The V E /VCO 2 slope was higher in HFpEF+EePH compared with HFpEF (p=0.01). RPB was ≥1-unit higher at 20W and VO 2peak was lower (p<0.01) in HFpEF+EePH compared with HFpEF., Conclusions: These data suggest that EePH contributes to pulmonary gas exchange impairments during exercise by causing a V/Q mismatch that provokes both ventilatory inefficiency and hypoxemia, both of which seem to contribute to DOE and exercise intolerance in patients with HFpEF., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Improving access to primary care physicians' services may help reduce hospitalizations due to Ambulatory Care Sensitive Conditions (ACSCs). Ontario, Canada's most populous province, introduced blended payment models for primary care physicians in the early- to mid-2000s to increase access to primary care, preventive care, and better chronic disease management. We study the impact of payment models on avoidable hospitalizations due to two incentivized ACSCs (diabetes and congestive heart failure) and two non-incentivized ACSCs (angina and asthma). The data for our study came from health administrative data on practicing primary care physicians in Ontario between 2006 and 2015. We employ a two-stage estimation strategy on a balanced panel of 3710 primary care physicians (1158 blended-fee-for-service (FFS), 1388 blended-capitation models, and 1164 interprofessional team-based practices). First, we account for the differences in physician practices using a generalized propensity score based on a multinomial logit regression model, corresponding to three primary care payment models. Second, we use fractional regression models to estimate the average treatment effects on the treated outcome (i.e., avoidable hospitalizations). The capitation-based model sometimes increases avoidable hospitalizations due to angina (by 7 per 100,000 patients) and congestive heart failure (40 per 100,000) relative to the blended-FFS-based model. Switching capitation physicians into interprofessional teams mitigates this effect, reducing avoidable hospitalizations from congestive heart failure by 30 per 100,000 patients and suggesting better access to primary care and chronic disease management in team-based practices., (© 2024 The Author(s). Health Economics published by John Wiley & Sons Ltd.)

The French National Authority for Health (HAS) recently issued guidelines for patient blood management (PBM) in surgical procedures. These recommendations are based on three usual pillars of PBM: optimizing red cell mass, minimizing blood loss and optimizing anemia tolerance. In the preoperative period, these guidelines recommend detecting anemia and iron deficiency and taking corrective measures well in advance of surgery, when possible, in case of surgery with moderate to high bleeding risk or known preoperative anemia. In the intraoperative period, the use of tranexamic acid and some surgical techniques are recommended to limit bleeding in case of high bleeding risk or in case of hemorrhage, and the use of cell salvage is recommended in some surgeries with a major risk of transfusion. In the postoperative period, the limitation of blood samples is recommended but the monitoring of postoperative anemia must be carried out and may lead to corrective measures (intravenous iron in particular) or more precise diagnostic assessment of this anemia. A "restrictive" transfusion threshold considering comorbidities and, most importantly, the tolerance of the patient is recommended postoperatively. The implementation of a strategy and a program for patient blood management is recommended throughout the perioperative period in healthcare establishments in order to reduce blood transfusion and length of stay. This article presents an English translation of the HAS recommendations and a summary of the rationale underlying these recommendations., (Copyright © 2024 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.)

Nanotechnology presents an exciting opportunity in cancer research by offering significant advancements in therapies, diagnosis, and management. It possesses unparalleled potential to enhance the accuracy and effectiveness of cancer therapy while simultaneously reducing adverse effects, owing to its distinctive capability to manipulate matter at a molecular level. Using nanoparticle carriers has facilitated the precise administration of therapeutic agents to afflicted areas within the human body through customized drug delivery systems, resulting in improved treatment accuracy and efficacy while reducing adverse effects. These techniques improve drug solubility and stability, leading to elevated levels of biochemical availability and improved efficacy outcomes for patients with minimal negative effects during treatment cycles. Another use case for nanoparticles includes tumor imaging; functionalized with targeting ligands containing diagnostic agents, they foster early detection, making quicker remedial action plans possible. Overall, the incorporation of nanotechnology ensures a promising future, although it stresses the need to address regulatory hurdles and safety concerns before widespread clinical implementation. Despite the complexity of cancer research and patient care, nanotechnology shows promise in transforming both fields., (© 2024 Institute of Bioorganic Chemistry, Polish Academy of Sciences.)

Diffusion models have shown promise in addressing the protein docking problem. Traditionally, these models are used solely for sampling docked poses, with a separate confidence model for ranking. We introduce DFMDock (Denoising Force Matching Dock), a diffusion model that unifies sampling and ranking within a single framework. DFMDock features two output heads: one for predicting forces and the other for predicting energies. The forces are trained using a denoising force matching objective, while the energy gradients are trained to align with the forces. This design enables our model to sample using the predicted forces and rank poses using the predicted energies, thereby eliminating the need for an additional confidence model. Our approach outperforms the previous diffusion model for protein docking, DiffDock-PP, with a sampling success rate of 44% compared to its 8%, and a Top- 1 ranking success rate of 16% compared to 0% on the Docking Benchmark 5.5 test set. In successful decoy cases, the DFMDock Energy forms a binding funnel similar to the physics-based Rosetta Energy, suggesting that DFMDock can capture the underlying energy landscape.

Background: Rigorous antibiotic stewardship is advised by international societies to combat rising antibiotic resistance. A major component of these programs is the metric used for antibiotic consumption measurement. A method for standardized antimicrobial administration ratio (SAAR) is suggested by the Centre for Disease Control & Prevention-National Healthcare Safety Network (NHSN)., Objectives: We applied the SAAR method to calculate antibiotic consumption in a tertiary care hospital in India. We also validated a limited sampling approach to calculate SAAR., Method: The prospective study was conducted in three medical intensive care units over a period of 12 months. Monthly antibiotic consumption was measured by the hospital electronic records. Limited sampling was performed by weekly bedside review of the antibiotic orders. Formulae for SAAR calculation were derived from the NHSN guide. SAAR obtained by electronic records and limited sampling were compared to validate this approach., Results: SAAR was calculated as >1 for an Indian hospital (1.49 by electronic records and 1.43 by limited sampling approach). The difference between the two ratios was not statistically significant ( P = .47)., Conclusions: SAAR in our setting is 1.49, which is slightly higher than the NHSN benchmark. Antibiotic usage (AU) risk adjustment based on data from the NHSN might not be adequate for calculating SAAR for Indian hospitals. There is a need to perform AU risk factor analysis for Indian settings for better defining SAAR in Indian context. The limited sampling approach can be adapted for calculation of SAAR in settings with limited resources., Competing Interests: The authors have no competing interests.Human Ethics and Consent to Participate declarations: not applicable., (© The Author(s) 2024.)

Introduction: Sodium glucose co-transporter-2 inhibitors (SGLT-2i) are increasingly being used among hospitalized patients. Our objective was to assess the risk of diabetic ketoacidosis (DKA) among hospitalized patients receiving an SGLT-2i., Research Design and Methods: We conducted a multicentre cohort study of patients hospitalized at 19 hospitals. We included patients over 18 years of age who received an SGLT-2i or a dipeptidyl peptidase-4 inhibitor (DPP-4i) in hospital. The primary outcome was the risk of DKA during their hospitalization., Results: 61,517 patients received a DPP-4i and 11,061 received an SGLT-2i. The risk of inpatient DKA was 0.07 % (N = 41 events) among adults who received a DPP-4i and 0.18 % (N = 20 events) among adults who received an SGLT-2i; adjusted odds ratio of 3.30 (95 % CI: 1.85-5.72)., Conclusions: In hospitalized patients, the absolute risk of DKA was 0.2 %, which corresponded to a three-fold higher relative risk., Competing Interests: Declaration of competing interest MF was a consultant for ProofDx, a start-up company creating point of care diagnostic tests for COVID-19 using CRISPR. MF is an advisor for SIGNAL1, a start-up company deploying machine learned models to improve inpatient care. MF has been paid for medicolegal cases unrelated to the content of this study. FR is a provincial clinical lead for quality improvement at Ontario Health (as a part-time salaried employee). This research was undertaken, in part, with funding from the Canada Research Chairs Program. AV is a part-time employee of Ontario Health and is supported by the Temerty Professorship of AI Research and Education in Medicine at the University of Toronto., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Our objective was to identify central line (CL)-associated bloodstream infections (CLABSI) rates and risk factors (RF) in Asia., Methods: From 03/27/2004 to 02/11/2022, we conducted a multinational multicenter prospective cohort study in 281 ICUs of 95 hospitals in 44 cities in 9 Asian countries (China, India, Malaysia, Mongolia, Nepal, Pakistan, Philippines, Sri Lanka, Thailand, and Vietnam). For estimation of CLABSI rate we used CL-days as denominator and number of CLABSI as numerator. To estimate CLABSI RF for we analyzed the data using multiple logistic regression, and outcomes are shown as adjusted odds ratios (aOR)., Results: A total of 150,142 patients, hospitalized 853,604 days, acquired 1514 CLABSIs. Pooled CLABSI rate per 1000 CL-days was 5.08; per type of catheter were: femoral: 6.23; temporary hemodialysis: 4.08; jugular: 4.01; arterial: 3.14; PICC: 2.47; subclavian: 2.02. The highest rates were femoral, temporary for hemodialysis, and jugular, and the lowest PICC and subclavian. We analyzed following variables: Gender, age, length of stay (LOS) before CLABSI acquisition, CL-days before CLABSI acquisition, CL-device utilization ratio, CL-type, tracheostomy use, hospitalization type, ICU type, facility ownership and World Bank classifications by income level. Following were independently associated with CLABSI: LOS before CLABSI acquisition, rising risk 4% daily (aOR = 1.04; 95% CI = 1.03-1.04; p  < 0.0001); number of CL-days before CLABSI acquisition, rising risk 5% per CL-day (aOR = 1.05; 95% CI 1.05-1.06; p  < 0.0001); medical hospitalization (aOR = 1.21; 95% CI 1.04-1.39; p  = 0.01); tracheostomy use (aOR = 2.02;95% CI 1.43-2.86; p  < 0.0001); publicly-owned facility (aOR = 3.63; 95% CI 2.54-5.18; p  < 0.0001); lower-middle-income country (aOR = 1.87; 95% CI 1.41-2.47; p  < 0.0001). ICU with highest risk was pediatric (aOR = 2.86; 95% CI 1.71-4.82; p  < 0.0001), followed by medical-surgical (aOR = 2.46; 95% CI 1.62-3.75; p  < 0.0001). CL with the highest risk were internal-jugular (aOR = 3.32; 95% CI 2.84-3.88; p  < 0.0001), and femoral (aOR = 3.13; 95% CI 2.48-3.95; p  < 0.0001), and subclavian (aOR = 1.78; 95% CI 1.47-2.15; p  < 0.0001) showed the lowest risk., Conclusions: The following CLABSI RFs are unlikely to change: country income level, facility-ownership, hospitalization type, and ICU type. Based on these findings it is suggested to focus on reducing LOS, CL-days, and tracheostomy; using subclavian or PICC instead of internal-jugular or femoral; and implementing evidence-based CLABSI prevention recommendations., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: All authors declare that don’t have any financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work. All authors declare that don’t have potential competing interests, such as employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. Submission of this article implies that the work described has not been published previously, that it is not under consideration for publication elsewhere, that its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in English or in any other language, including electronically without the written consent of the copyright-holder.

Background: In Canada, one in seven adults has diabetes (i.e., 2.3 million) and the lifetime risk of developing diabetes is approximately 30% by age 65. Although 30% of patients admitted to the hospital have diabetes, data from inpatient hospitalizations for patients with diabetes are lacking, both in Canada and globally., Objective: To validate International Classification of Diseases 10th edition Canadian version (ICD-10-CA) codes for the identification of patients with diabetes, to create a multicenter database of patients with diabetes hospitalized under internal medicine in Ontario, and to determine their baseline characteristics, medication use, and admission characteristics., Study Design: We created a database of people who had diabetes and were hospitalized between 2010 and 2020 at 8 hospitals in Ontario that were part of the General Medicine Inpatient Initiative (GEMINI) hospital data-sharing network. Patients who had diabetes were identified using chart review, based upon either (i) a previous physician diagnosis of diabetes, (ii) a recorded hemoglobin A1c ≥ 6.5% or (iii) outpatient prescription of a diabetes medication preceding the hospitalization. The test characteristics of ICD-10-CA codes for diabetes were evaluated. We compared baseline demographics, medication use and hospitalization details among patients with and without diabetes. For hospitalization details, we collected information on the admission diagnosis, comorbidity index, length of stay, receipt of ICU-level care, and inpatient mortality., Results: There were 384,588 admissions within the total study cohort, of which 118,987 (30.9%) had an ICD-10-CA diagnosis code of diabetes (E10.x, E11.x, E13.x, E14.x). The sensitivity and specificity of ICD-10-CA diagnostic codes was 95.9% and 98.8%, respectively. Most patients with an ICD-10-CA code for diabetes had a code for type 2 diabetes (93.9%) and a code for type 1 diabetes was rare (6.1%). The mean age was 66.4 years for patients without diabetes and 71.3 years for those with an ICD-10-CA diagnosis code for diabetes. Patients with diabetes had a higher prevalence of hypertension (64% vs. 37.9%), coronary artery disease (28.7% vs. 15.3%), heart failure (24.5% vs. 12.1%) and renal failure (33.8% vs. 17.3%) in comparison to those without diabetes. The most prevalent diabetes medications received in hospital were metformin (43%), DPP4 inhibitors (22.7%) and sulfonylureas (18.8%). The most common reason for admission among patients with diabetes was heart failure (9.0%), and among patients without diabetes was pneumonia (7.8%). Median length of stay was longer for patients with diabetes (5.5 vs. 4.5 days) and in-hospital mortality was similar between groups (6.8% with diabetes vs. 6.5% without diabetes)., Importance: Diabetes is one of the most prevalent chronic medical conditions, affecting roughly one third of all patients hospitalized on an internal medicine ward and is associated with other comorbidities and longer hospital stays. ICD-10-CA codes were highly accurate in identifying patients with diabetes. The development of an inpatient cohort will allow for further study of in-hospital practices and outcomes among patients with diabetes., Competing Interests: MF was a consultant for ProofDx, a start-up company creating a point of care diagnostic test for COVID-19. MF is an advisor for Signal1, a start-up company deploying machine learned models to improve inpatient care. TBS was a steering committee member of the Amgen-financed GALACTIC-HF trial, of the Boehringer Ingelheim financed SHARP3 trial, of “LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific's Investigational ICM System” trial; advisory board: Amgen, CSL Seqirus and GSK; chief investigator of the Sanofi Pasteur financed “NUDGE-FLU”, “DANFLU-1”, and “DANFLU-2” trials; speaker honorarium: Bayer, Novartis, Sanofi Pasteur, GE healthcare and GSK; consultant appointments: Novo Nordisk, IQVIA and Parexel; and research grants: GE Healthcare, AstraZeneca, Novo Nordisk and Sanofi Pasteur. Outside of the submitted work, AV is a part-time employee of Ontario Health and a co-inventor of an AI-based early warning system for patient deterioration that was acquired by the start-up company Signal1. FR is a part-time employee of Ontario Health. The development of the GEMINI data platform has been supported with funding from sources such as the Canadian Cancer Society, the Canadian Frailty Network, the Canadian Institutes of Health Research, the Canadian Medical Protective Agency, Green Shield Canada Foundation, the Natural Sciences and Engineering Research Council of Canada, Ontario Health, the St. Michael’s Hospital Association Innovation Fund, the University of Toronto Department of Medicine, and in-kind support from partner hospitals and the Vector Institute. FR holds a salary award from Canada Research Chairs Program, University of Toronto and the PSI Graham Farquharson Knowledge Translation Fellowship. No funding sources from FR influenced the writing of this manuscript. There are no patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have no reported conflicts of interest., (Copyright: © 2024 Colacci et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A 39-year-old male patient presented with grossly reduced vision in the left eye for the past three months. Fundus evaluation revealed multiple discrete grayish-white deep chorioretinal lesions in the macular area. An optical coherence tomography (OCT) scan in the affected area was normal. Following investigations, a specific diagnosis of syphilitic macular chorioretinitis was made. A repeat OCT on day eight revealed cystic macular edema, consistent with a Jarisch-Herxheimer reaction (JHR). He was started on oral prednisolone in tapering doses and followed up till resolution. The ocular correlates of JHR are rare, and physicians should be aware of the potential of this phenomenon., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Mehta et al.)

Objectives: To provide guidance for the optimal administration of repetitive transcranial magnetic stimulation, based on scientific evidence and supplemented by expert clinical consensus., Methods: Articles and information were sourced from existing guidelines and published literature. The findings were then formulated into consensus-based recommendations and guidance by the authors. The guidelines were subjected to rigorous successive consultation within the RANZCP, involving the Section of ECT and Neurostimulation (SEN) Committee, its broader membership and expert committees., Results: The RANZCP professional practice guidelines (PPG) for the administration of rTMS provide up-to-date advice regarding the use of rTMS in clinical practice. The guidelines are intended for use by psychiatrists and non-psychiatrists engaged in the administration of rTMS to facilitate best practice to optimise outcomes for patients. The guidelines strive to find the appropriate balance between promoting best evidence-based practice and acknowledging that evidence for rTMS use is a continually evolving., Conclusion: The guidelines provide up-to-date advice for psychiatrists and non-psychiatrists to promote optimal standards of rTMS practice., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: Members of the working group of the Section of Electroconvulsive Therapy and Neurostimulation (SEN) who developed these guidelines signed a deed of undertaking at the time of appointment to the SEN in which they agreed to declare any conflict, whether actual, potential, perceived or likely to arise. To manage conflicts of interest during the development process, a standing item at all SEN Executive meetings asked all members to declare their conflicts of interest. All working group members are providers of rTMS treatment. Working group members’ individual declarations of interest are listed. In the last 3 years PBF has received equipment for research from Neurosoft, Nexstim and Brainsway Ltd. He has served on scientific advisory boards for Magstim and LivaNova and received speaker fees from Otsuka. He has also acted as a founder and board member for TMS Clinics Australia and Resonance Therapeutics. PBF is supported by a National Health and Medical Research Council of Australia Investigator grant (1193596). CKL is supported by a National Health and Medical Research Council of Australia Investigator grant (1195651). S.H., S.C., A.G., S.G. and S.S. declare no conflict of interest.

Background: We identified peripherally limited patients using cardiopulmonary exercise testing and measured skeletal muscle oxygen transport and utilization during invasive single leg exercise testing to identify the mechanisms of the peripheral limitation., Methods: Forty-five patients with heart failure with preserved ejection fraction (70±7 years, 27 females) completed seated upright cardiopulmonary exercise testing and were defined as having a (1) peripheral limitation to exercise if cardiac output/oxygen consumption (VO 2 ) was elevated (≥6) or 5 to 6 with a stroke volume reserve >50% (n=31) or (2) a central limitation to exercise if cardiac output/VO 2 slope was ≤5 or 5 to 6 with stroke volume reserve <50% (n=14). Single leg knee extension exercise was used to quantify peak leg blood flow (Doppler ultrasound), arterial-to-venous oxygen content difference (femoral venous catheter), leg VO 2 , and muscle oxygen diffusive conductance. In a subset of participants (n=36), phosphocreatine recovery time was measured by magnetic resonance spectroscopy to determine skeletal muscle oxidative capacity., Results: Peak VO 2 during cardiopulmonary exercise testing was not different between groups (central: 13.9±5.7 versus peripheral: 12.0±3.1 mL/min per kg; P =0.135); however, the peripheral group had a lower peak arterial-to-venous oxygen content difference (central: 13.5±2.0 versus peripheral: 11.1±1.6 mLO 2 /dL blood; P <0.001). During single leg knee extension, there was no difference in peak leg VO 2 ( P =0.306), but the peripherally limited group had greater blood flow/VO 2 ratio ( P =0.024), lower arterial-to-venous oxygen content difference (central: 12.3±2.5 versus peripheral: 10.3±2.2 mLO 2 /dL blood; P =0.013), and lower muscle oxygen diffusive conductance ( P =0.021). A difference in magnetic resonance spectroscopy-derived phosphocreatine recovery time was not detected ( P =0.199)., Conclusions: Peripherally limited patients with heart failure with preserved ejection fraction identified by cardiopulmonary exercise testing have impairments in oxygen transport and utilization at the level of the skeletal muscle quantified by invasive knee extension exercise testing, which includes an increased blood flow/V̇O 2 ratio and poor muscle diffusive capacity., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04068844., Competing Interests: None.

Intervention: Electroconvulsive therapy (ECT) is a commonly used treatment for severe psychiatric illness in older adults, including in the 'older old' population aged 80 years and above. However, there can sometimes be a reluctance to treat the 80+ year old age group with ECT due to medical comorbidities, frailty, and concerns about cognition., Objective, Design, Setting, and Participants: This multi-site, longitudinal Australian study aimed to investigate the effectiveness and safety of ECT in older old people compared with younger age groups. Data from 310 people receiving ECT for depression at three participating hospitals was collected in a naturalistic setting, between 2015 and 2022., Measurements: Clinical ratings were conducted pre-ECT and end-acute ECT using the Montgomery-Åsberg Depression Rating Scale (MADRS). Cognitive outcomes were assessed using the Montreal Cognitive Assessment (MoCA)., Results: Older old adults demonstrated a significant reduction MADRS scores at post-treatment. They were more likely to meet remission criteria compared with the younger age groups. Older old adults were also less likely to show clinically significant cognitive decline post-ECT, and were more likely to show clinically significant cognitive improvement post-ECT compared with younger age groups., Conclusions: ECT is highly effective in treating severe psychiatric illness in older old adults. Relative to the younger age groups, the older old group were more likely to remit with ECT and a greater proportion showed cognitive improvement post-ECT. These findings suggest that ECT should be considered as a valuable and safe treatment option for older old individuals with depression., (© 2024 The Author(s). International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Hyperthermia is known as a hyperadrenergic state, yet there is a lack of data on the sympathetic responses to ambient heat stress in humans. Therefore, we investigated the plasma epinephrine and norepinephrine concentrations of healthy young and older adults exposed to 3 h of very hot and dry, as well as hot and humid, heat, both with accompanying activities of daily living. We hypothesized that older adults, compared with young adults, would have augmented increases in epinephrine and norepinephrine concentrations secondary to increased thermal strain. Young ( n = 20) and older ( n = 18) participants underwent two 3-h heat exposures on different days: very hot and dry [47°C and 15% relative humidity (RH)] and hot and humid (41°C and 40% RH). To mimic heat generation comparable to activities of daily living, participants performed seven 5-min bouts of light cycling (approximately 3 METS) dispersed throughout the heat exposure. We measured plasma concentrations of epinephrine and norepinephrine at baseline, end, and 2-h postheat exposure. There was a group-wide increase in epinephrine from baseline to the end of the heat exposure (Δ19 ± 27 pg/mL; P < 0.001) in the hot and humid condition, but not in the very hot and dry condition (Δ6 ± 19 pg/mL; P = 0.10). There were group-wide decreases in norepinephrine concentrations from baseline to the end of the heat exposure in both the very hot and dry (Δ-131 ± 169 pg/mL; P < 0.001) and the hot and humid (Δ-138 ± 157 pg/mL; P < 0.001) conditions, with both returning to near baseline at 2-h postexposure. These data suggest that ambient heating with accompanying bouts of light intermittent exercise may lead to decreases in circulating concentrations of norepinephrine. NEW & NOTEWORTHY Herein we present plasma epinephrine and norepinephrine concentrations to 3 h of very hot and dry, as well as hot and humid, heat exposures with accompanying activities of daily living in young and older participants. We found 1 ) increased plasma concentrations of epinephrine in young and older adults following the hot and humid, but not the very hot and dry exposures and 2 ) decreased concentrations of norepinephrine in both groups following exposure to both conditions.

Peptide self-assembly into amyloid fibrils provides numerous applications in drug delivery and biomedical engineering applications. We augment our previously-established computational screening technique along with experimental biophysical characterization to discover 7-mer peptides that self-assemble into "parallel β-sheets", that is, β-sheets with N-terminus-to-C-terminus 𝛽-strand vectors oriented in parallel. To accomplish the desired β-strand organization, we applied the PepAD amino acid sequence design software to the Class-1 cross-β spine defined by Sawaya et al. This molecular configuration includes two layers of parallel β-sheets stacked such that N-terminus-to-C-terminus vectors are oriented antiparallel for molecules on adjacent β-sheets. The first cohort of PepAD identified peptides were examined for their fibrillation behavior in DMD/PRIME20 simulations, and the top performing sequence was selected as a prototype for a subsequent round of sequence refinement. The two rounds of design resulted in a library of eight 7-mer peptides. In DMD/PRIME20 simulations, five of these peptides spontaneously formed fibril-like structures with a predominantly parallel 𝛽-sheet arrangement, two formed fibril-like structure with <50% in parallel 𝛽-sheet arrangement and one remained a random coil. Among the eight candidate peptides produced by PepAD and DMD/PRIME20, five were synthesized and purified. All five assembled into amyloid fibrils composed of parallel β-sheets based on Fourier transform infrared spectroscopy, circular dichroism, electron microscopy, and thioflavin-T fluorescence spectroscopy measurements., (© 2024 The Author(s). Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

Decision-making is a cognitive process involving working memory, executive function, and attention. However, the connectivity of large-scale brain networks during decision-making is not well understood. This is because gaining access to large-scale brain networks in humans is still a novel process. Here, we used SEEG (stereoelectroencephalography) to record neural activity from the default mode network (DMN), dorsal attention network (DAN), and frontoparietal network (FN) in ten humans while they performed a gambling task in the form of the card game, "War". By observing these networks during a decision-making period, we related the activity of and connectivity between these networks. In particular, we found that gamma band activity was directly related to a participant's ability to bet logically, deciding what betting amount would result in the highest monetary gain or lowest monetary loss throughout a session of the game. We also found connectivity between the DAN and the relation to a participant's performance. Specifically, participants with higher connectivity between and within these networks had higher earnings. Our preliminary findings suggest that connectivity and activity between these networks are essential during decision-making.

This review seeks to assess the potential of nanomaterials, specifically Nano-struc-tured Lipid Carriers (NLCs), in mitigating challenges associated with inflammation-related disorders, with a particular emphasis on chronic ailments like arthritis. A comprehensive lit-erature review spanning Web of Science, PubMed, and other scholarly repositories from 2000 to 2023 is conducted. Articles are selected based on their focus on NLCs and inflammation management, utilizing keywords, such as "nanomaterials," "targeted drug delivery," and "ar-thritis." Exclusion criteria involve non-English studies or those lacking adequate detail on NLCs. Synthesized data provide an overview of the advantages, challenges, and prospects of NLCs in addressing chronic inflammatory disorders. This review also examines the therapeu-tic applications of nanotechnology, including targeted drug delivery and tissue engineering, particularly focusing on the intricate biological responses in chronic inflammation, often in-volving Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). Moreover, the exploration ex-tends to topical delivery methods to enhance control over medication concentration, with a review of lipid nanoparticles, such as liposomes and solid-lipid nanoparticles, highlighting their potential in augmenting drug permeation while addressing challenges like inadequate drug loading. NLCs have emerged as promising candidates for overcoming drug delivery challenges, par-ticularly in arthritis treatment, with a focus on their advantages across diverse lipid composi-tions. The review underscores significant strides in inflammation management through NLC utilization, offering insights into future research directions. Moreover, it contributes to ongoing advancements in nanomedicine, emphasizing the pivotal role of NLCs in developing innovative therapeutic approaches for inflammation-related dis-orders, particularly arthritis. NLCs represent a promising avenue for effective interventions, signaling progress in nanotechnology-enabled therapeutics., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Leucaena leucocephala. (Lam.) de Wit, a traditional medicinal plant, has been reported among the ethnic communities of Mexico, Indonesia, China, and India for the treatment of diabetes, obesity, and related complications. This study investigates the antihyperglycemic activity of the plant and its isolated active compound quercetin-3-glucoside. Further, bioactivity guided marker assisted development of an enriched bioactive fraction toward enhancing insulin sensitization was carried out. The enriched fraction was also found to contain 397.96 mg/g of quercetin-3-glucoside along with three other marker compounds, which were also isolated and identified. Quercetin-3-glucoside, out of the four isolated marker compounds from the plant, showed the most significant bioactivity when tested in palmitate-induced insulin-resistant C2C12 myotubes. The compound also showed significant upregulation of sirtuin1 (SIRT1) followed by enhancement of insulin-dependent signaling molecules SIRT1/AMPK/PGC1-α and GLUT4 translocation. Molecular dynamics studies showed the compound having stable interactions with the SIRT1 protein. SIRT1 upregulation has been associated with enhanced insulin sensitivity in skeletal muscle, increasing the glucose uptake by muscle cells. The prepared enriched fraction also modulated the SIRT1/AMPK/GLUT4 pathway. The findings of the present study may find future application toward the development of botanical or phytopharmaceutical drugs from the traditionally important plant L. leucocephala against type II diabetes., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

We investigated whether central or peripheral limitations to oxygen uptake elicit different respiratory sensations and whether dyspnea on exertion (DOE) provokes unpleasantness and negative emotions in patients with heart failure with preserved ejection fraction (HFpEF). 48 patients were categorized based on their cardiac output (Q̇c)/oxygen uptake (V̇O 2 ) slope and stroke volume (SV) reserve during an incremental cycling test. 15 were classified as centrally limited and 33 were classified as peripherally limited. Ratings of perceived breathlessness (RPB) and unpleasantness (RPU) were assessed (Borg 0-10 scale) during a 20 W cycling test. 15 respiratory sensations statements (1-10 scale) and 5 negative emotions statements (1-10) were subsequently rated. RPB (Central: 3.5±2.0 vs. Peripheral: 3.4±2.0, p=0.86), respiratory sensations, or negative emotions were not different between groups (p>0.05). RPB correlated (p<0.05) with RPU (r=0.925), "anxious" (r=0.610), and "afraid" (r=0.383). While DOE provokes elevated levels of negative emotions, DOE and respiratory sensations seem more related to a common mechanism rather than central and/or peripheral limitations in HFpEF., Competing Interests: Declaration of Competing Interest No conflicts of interest, financial or otherwise, are declared by the authors., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: International Classification of Diseases (ICD) codes are commonly used to identify cases of diabetic ketoacidosis (DKA) in health services research, but they have not been validated. Our aim in this study was to assess the accuracy of ICD, 10th revision (ICD-10) diagnosis codes for DKA., Methods: We conducted a multicentre, cross-sectional study using data from 5 hospitals in Ontario, Canada. Each hospitalization event has a single most responsible diagnosis code. We identified all hospitalizations assigned diagnosis codes for DKA. A true case of DKA was defined using laboratory values (serum bicarbonate ≤18 mmol/L, arterial pH ≤7.3, anion gap ≥14 mEq/L, and presence of ketones in urine or blood). Chart review was conducted to validate DKA if laboratory values were missing or the diagnosis of DKA was unclear. Outcome measures included positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity of ICD-10 codes in patients with laboratory-defined DKA., Results: We identified 316,517 hospitalizations. Among these, 312,948 did not have an ICD-10 diagnosis code for DKA and 3,569 had an ICD-10 diagnosis code for DKA. Using a combination of laboratory and chart review, we identified that the overall PPV was 67.0%, the NPV was 99.7%, specificity was 99.6%, and sensitivity was 74.9%. When we restricted our analysis to hospitalizations in which DKA was the most responsible discharge diagnosis (n=3,374 [94.5%]), the test characteristics were PPV 69.8%, NPV 99.7%, specificity 99.7%, and sensitivity 71.9%., Conclusion: ICD-10 codes can identify patients with DKA among those admitted to general internal medicine., (Copyright © 2024 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Background: In patients with hypertrophic cardiomyopathy (HCM), impaired augmentation of stroke volume and diastolic dysfunction contribute to exercise intolerance. Systolic-diastolic (S-D) coupling characterizes how systolic contraction of the left ventricle (LV) primes efficient elastic recoil during early diastole. Impaired S-D coupling may contribute to the impaired cardiac response to exercise in patients with HCM., Methods: Patients with HCM (n = 25, age = 47 ± 9 years) and healthy adults (n = 115, age = 49 ± 10 years) underwent a cardiopulmonary exercise testing (CPET) and echocardiogram. S-D coupling was defined as the ratio of LV longitudinal excursion of the mitral annulus during early diastole (ED exc ) and systole (S exc ) and compared between groups. Peak oxygen uptake (peak V̇O 2 ) (Douglas bags), cardiac index (C 2 H 2 rebreathe), and stroke volume index (SVi) were assessed during CPET. Linear regression was performed between S-D coupling and peak V̇O 2 , peak cardiac index, and peak SVi., Results: S-D coupling was lower in HCM (Controls: 0.63 ± 0.08, HCM: 0.56 ± 0.10, p < 0.001). Peak V̇O 2 and stroke volume reserve were lower in patients with HCM (Peak VO 2 Controls: 28.5 ± 5.5, HCM: 23.7 ± 7.2 mL/kg/min, p < 0.001, SV reserve: Controls 39 ± 16, HCM 30 ± 18 mL, p = 0.008). In patients with HCM, S-D coupling was associated with peak V̇O 2 (r = 0.47, p = 0.018), peak cardiac index (r = 0.60, p = 0.002), and peak SVi (r = 0.63, p < 0.001)., Conclusion: Systolic-diastolic coupling was impaired in patients with HCM and was associated with fitness and the cardiac response to exercise. Inefficient S-D coupling may link insufficient stroke volume generation, diastolic dysfunction, and exercise intolerance in HCM., (© 2024 The Author(s). Echocardiography published by Wiley Periodicals LLC.)

Background: Due to its rapid antidepressant effect, ketamine has recently been clinically translated for people with treatment-resistant depression. However, its cognitive profile remains unclear, particularly with repeated and higher doses. In the present study, we report the cognitive results from a recent large multicentre randomised controlled trial, the Ketamine for Adult Depression Study (KADS)., Methods: In this randomised, double-blind, active-controlled, parallel group, multicentre phase 3 trial study we investigated potential cognitive changes following repeated treatment of subcutaneous racemic ketamine compared to an active comparator, midazolam, over 4 weeks, which involved two cohorts; Cohort 1 involved a fixed dose treatment protocol (0.5 mg/kg ketamine), Cohort 2 involved a dose escalation protocol (0.5-0.9 mg/kg) based on mood outcomes. Participants with treatment-resistant Major Depressive Disorder (MDD) were recruited from 7 mood disorder centres and were randomly assigned to receive ketamine (Cohort 1 n = 33; Cohort 2 n = 53) or midazolam (Cohort 1 n = 35; Cohort 2 n = 53) in a 1:1 ratio. Cognitive measurements were assessed at baseline and at the end of randomised treatment., Results: Results showed that in Cohort 1, there were no differences between ketamine and midazolam in cognitive outcomes. For Cohort 2, there was similarly no difference between conditions for cognitive outcomes., Limitations: The study included two Cohorts with different dosing regimes., Conclusions: The findings support the cognitive safety of repeated fixed and escalating doses at least in the short-term in people with treatment resistant MDD., Competing Interests: Declaration of competing interest Dr. Loo is supported by a NHMRC Investigator Grant (1195651), is on the Clinical Advisory Board for Douglas Pharmaceuticals, and has received fees for the following: Janssen Cilag advisory board, Medical Director of Neurostimulation and Interventional Psychiatry at Ramsay Health Care, book royalties from Springer, speaker fees from the Australian Private Hospitals Association, Wesley Hospital ECT course, Royal Australian and New Zealand College of Psychiatrists Congress, Spanish Psychiatric Hospitalisation Units Conference, Japanese Society of Psychiatry and Neurology conference. In the last 36 months, Dr. Glozier has received speaker's bureau honoraria from Servier Laboratories, Janssen and Lundbeck, and served on Advisory Boards for Servier Laboratories, Esia, Seqirus and Lundbeck. Dr. Baune has received grants and served as consultant, advisor or CME speaker for the following entities: AstraZeneca, Bristol-Myers Squibb, Janssen, Lundbeck, Otsuka, Servier, the National Health and Medical Research Council, the Fay Fuller Foundation, the James and Diana Ramsay Foundation. He is supported by research grants from European Union, DFG (Germany) and NHMRC (Australia). Within the last 36 months, Dr. Glue has attended a Janssen New Zealand advisory board, and is named on a patent for a controlled release ketamine tablet developed by Douglas Pharmaceuticals. In the last 36 months, Dr. Martin has received research consulting fees from Douglas Pharmaceuticals for a clinical trial involving ketamine. Dr. Berk is supported by a NHMRC Senior Principal Research Fellowship [1156072]. In the last 3 years he received grant/research support from National Health and Medical Research Council, Wellcome Trust, Medical Research Future Fund, Victorian Medical Research Acceleration Fund, Centre for Research Excellence CRE, Victorian Government Department of Jobs, Precincts and Regions and Victorian COVID-19 Research Fund. He received honoraria/royalties from Springer, Oxford University Press, Cambridge University Press, Allen and Unwin, EPA Warsaw, Lundbeck, Controversias Barcelona, Servier, Medisquire, HealthEd, ANZJP, European Psychiatric Association, Janssen, Medplan, Milken Institute, RANZCP, Abbott India, ASCP, Headspace, Allori for Eisai, Otsuka, Global Congress of Biological Psychiatry India, St Bio Pharma and Sandoz. Dr. Carter has received educational and travel support from Servier, Astra Zeneca, Otsuka Australia, Merck Sharp & Dohme, and Janssen-Cilag in the past five years. He also served on an advisory board for the AFFINITY trial. Dr. Hackett was supported by an NHMRC fellowship from 2018 to 2021 (APP1141328) and was a named investigator on the NHMRC grant for this study (APP1105089). Dr. Hood has received speaker and consultancy fees from Janssen & Servier, served on advisory boards for Janssen and Lundbeck, and is a board member of UWA Young Lives Matter Foundation, International Master in Affective Neuroscience, and Journal of Psychopharmacology. Dr. Somogyi is a director of the Australian Medicines Handbook Pty Ltd. (unpaid) and has received funding support by the Australian and New Zealand College of Anaesthetists to investigate ketamine for chronic postsurgical pain. The following authors report no financial relationships with commercial interests: Ania Harvey, Dr. Natalie Mills, Dr. Shanthi Sarma, Mr. Dusan Hadzi-Pavlovic, Ms. Vanessa Dong, and Dr. Anthony Rodgers., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Non-valvular atrial fibrillation (AF) is a common heart arrhythmia in the elderly population. AF patients are at high-risk of ischemic strokes, but oral anticoagulant (OAC) therapy reduces such risks. Warfarin had been the standard OAC for AF patients, however its effectiveness is highly variable and dependent on close monitoring of the anticoagulant response. Newer OACs such as rivaroxaban and apixaban address these drawbacks but are more costly. It is uncertain which OAC therapy for AF is cost-saving from the healthcare system perspective., Methods: We followed a cohort of patients in Ontario, Canada, aged ≥ 66 who were newly diagnosed with AF and prescribed OACs between 2012 and 2017. We used a two-stage estimation procedure. First, we account for the patient selection into OACs using a multinomial logit regression model and estimated propensity scores. Second, we used an inverse probability weighted regression adjustment approach to determine cost-saving OAC options. We also examined component-specific costs (i.e., drug, hospitalization, emergency department and physician) to understand the drivers of cost-saving OACs., Results: We found that compared to warfarin, rivaroxaban and apixaban treatments were cost-saving options, with per-patient 1-year healthcare cost savings at $2436 and $1764, respectively. These savings were driven by cost-savings in hospitalization, emergency department visits, and physician visits, outweighing higher drug costs. These results were robust to alternative model specifications and estimation procedures., Conclusions: Treating AF patients with rivaroxaban and apixaban than warfarin reduces healthcare costs. OAC reimbursement policies for AF patients should consider rivaroxaban or apixaban over warfarin as the first-line treatment., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: We tested the hypothesis that patients with heart failure with preserved ejection fraction (HFpEF) would have greater muscle sympathetic nerve activity (MSNA) at rest and sympathetic reactivity during a cold pressor test compared with non-heart failure controls. Further, given the importance of the baroreflex modulation of MSNA in the control of blood pressure (BP), we hypothesized that patients with HFpEF would exhibit a reduced sympathetic baroreflex sensitivity., Methods: Twenty-eight patients with HFpEF and 44 matched controls (mean±SD: 71±8 versus 70±7 years; 9 men/19 women versus 16 men/28 women) were studied. BP, heart rate, and MSNA (microneurography) were measured during 6 to 10 minutes of supine rest and the 2-minute cold pressor test. Spontaneous sympathetic baroreflex sensitivity was assessed during supine rest., Results: Patients with HFpEF had higher resting MSNA burst frequency (39±14 versus 31±12 bursts/min; P =0.020) and lower sympathetic baroreflex sensitivity (-2.83±0.76 versus -3.57±1.19 bursts/100 heartbeats/mm Hg; P =0.019) than controls, but burst incidence was not different between groups (56±19 versus 50±20 bursts/100 heartbeats; P =0.179). During the cold pressor test, increases in MSNA indices did not differ between groups ( P =0.135-0.998), but patients had a smaller increase in diastolic BP (Δ4±6 versus Δ14±11 mm Hg; P <0.001) compared with controls., Conclusions: Despite augmented resting MSNA burst frequency, burst incidence was not significantly different between groups, and sympathetic baroreflex sensitivity was reduced in patients with HFpEF. Furthermore, patients had preserved sympathetic reactivity but attenuated diastolic BP responses during the cold pressor test. These data suggest that, during physiological stress, sympathetic reactivity is intact, but the peripheral pathway for sympathetic vasoconstriction may be impaired in HFpEF., Competing Interests: None.

Spontaneous intracranial hypotension (SIH) is a condition characterized by orthostatic headache associated with nausea, vomiting, tinnitus, vertigo, hypoacusis, neck pain/stiffness, and photophobia. Usual treatment includes bed rest, hydration, caffeine, analgesics, epidural blood patch, steroids, fibrin glue (N-butyl-cyanoacrylate), and surgical repair. In this series, we report two cases, who presented to us with features of SIH and were managed successfully with sphenopalatine ganglion block. This is a novel modality of management of SIH and has not been reported before., Competing Interests: There are no conflicts of interest., (© 2024 Published by Scientific Scholar on behalf of Journal of Neurosciences in Rural Practice.)