PPARs (Peroxisome Proliferator-activated Receptors) and Their Agonists in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease leading to dementia because of complex phathomechanisms like amyloid ß (Aß) aggregation, tau aggregates, and neurofibrillary tangles. Peroxisome proliferator-activated receptor (PPAR) agonists have been reported recently with neuroprotective and anti-inflammatory properties. PPARs belong to the superfamily of nuclear hormone receptors and function as ligand-activated transcription factors. These have emerged as crucial players in the pathogenesis of AD. This review presented the potential of PPARs and their agonists in treating neurodegenerative diseases like AD.

Sepsis and case fatality rates and associations with deprivation, ethnicity, and clinical characteristics: population-based case-control study with linked primary care and hospital data in England.

PURPOSE: Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. The purpose of the study was to measure the associations of specific exposures (deprivation, ethnicity, and clinical characteristics) with incident sepsis and case fatality. METHODS: Two research databases in England were used including anonymized patient-level records from primary care linked to hospital admission, death certificate, and small-area deprivation. Sepsis cases aged 65-100 years were matched to up to six controls. Predictors for sepsis (including 60 clinical conditions) were evaluated using logistic and random forest models; case fatality rates were analyzed using logistic models. RESULTS: 108,317 community-acquired sepsis cases were analyzed. Severe frailty was strongly associated with the risk of developing sepsis (crude odds ratio [OR] 14.93; 95% confidence interval [CI] 14.37-15.52). The quintile with most deprived patients showed an increased sepsis risk (crude OR 1.48; 95% CI 1.45-1.51) compared to least deprived quintile. Strong predictors for sepsis included antibiotic exposure in prior 2 months, being house bound, having cancer, learning disability, and diabetes mellitus. Severely frail patients had a case fatality rate of 42.0% compared to 24.0% in non-frail patients (adjusted OR 1.53; 95% CI 1.41-1.65). Sepsis cases with recent prior antibiotic exposure died less frequently compared to non-users (adjusted OR 0.7; 95% CI 0.72-0.76). Case fatality strongly decreased over calendar time. CONCLUSION: Given the variety of predictors and their level of associations for developing sepsis, there is a need for prediction models for risk of developing sepsis that can help to target preventative antibiotic therapy.

Evaluation of two doses (20 mL and 15 mL) of 0.25% bupivacaine in pericapsular nerve group block for patient positioning for sub-arachnoid block during hip fracture surgery: A single-centre, randomised comparative trial.

Background and Aims: Peri-capsular nerve group (PENG) block is a novel ultrasound (US)-guided technique to achieve regional analgesia in hip fractures. We compared the effectiveness of two doses of 0.25% bupivacaine (20 mL and 15 mL) in the US-guided PENG block for positioning patients for sub-arachnoid block (SAB) during hip fracture surgery. Methods: The randomised trial included 60 patients aged 40-90 years undergoing hip fracture surgery under SAB. PENG block was given by a US-guided approach with the patient in a supine position 20 minutes before SAB, and a total of 20 mL and 15 mL of bupivacaine (0.25%) were given in groups A and B, respectively. The primary outcome was to measure and compare the ease of positioning (EOP) of patients for the conduct of SAB. The secondary outcome was the pain assessment at rest and 15° leg raise position at baseline and 10 and 20 minutes post block using the verbal analogue scale (VAS). Continuous variables were compared using the t-test, and categorical variables were analysed using Pearson's Chi-square test or Fisher's exact test. Results: The mean (standard deviation) grade of EOP for SAB was significantly better in group A (2.47 (0.73) (95% confidence interval [CI]: 2.19-2.69)) than in group B (1.86 (0.62) (95% CI: 1.65-2.1)) (P = 0.001). The decrease in VAS scores was significantly higher in group A compared to group B at resting and 15° leg raise position at all-time points (P < 0.05). Conclusion: A dose of 20 mL of 0.25% bupivacaine shows better outcomes than 15 mL regarding the patient's positioning during the SAB.

The Association Between Short-Acting ß2-Agonist Over-Prescription, and Patient-Reported Acquisition and Use on Asthma Control and Exacerbations: Data from Australia.

INTRODUCTION: In Australia, short-acting ß2-agonists (SABA) are available both over the counter (OTC) and on prescription. This ease of access may impact SABA use in the Australian population. Our aim was to assess patterns and outcome associations of prescribed, acquired OTC and reported use of SABA by Australians with asthma. METHODS: This was a cross-sectional study, using data derived from primary care electronic medical records (EMRs) and patient completed questionnaires within Optimum Patient Care Research Database Australia (OPCRDA). A total of 720 individuals aged ≥ 12 years with an asthma diagnosis in their EMRs and receiving asthma therapy were included. The annual number of SABA inhalers authorised on prescription, acquired OTC and reported, and the association with self-reported exacerbations and asthma control were investigated. RESULTS: 92.9% (n = 380/409) of individuals issued with SABA prescription were authorised ≥ 3 inhalers annually, although this differed from self-reported usage. Of individuals reporting SABA use (n = 546) in the last 12 months, 37.0% reported using ≥ 3 inhalers. These patients who reported SABA overuse experienced 2.52 (95% confidence interval [CI] 1.73-3.70) times more severe exacerbations and were 4.51 times (95% CI 3.13-6.55) more likely to have poor asthma control than those who reported using 1-2 SABA inhalers. Patients who did not receive SABA on prescription (43.2%; n = 311/720) also experienced 2.71 (95% CI 1.07-7.26) times more severe exacerbations than those prescribed 1-2 inhalers. Of these patients, 38.9% reported using OTC SABA and other prescription medications, 26.4% reported using SABA OTC as their only asthma medication, 13.2% were prescribed other therapies but not SABA OTC and 14.5% were not using any medication. CONCLUSION: Both self-reported SABA overuse and zero SABA prescriptions were associated with poor asthma outcomes. The disconnect between prescribing authorisation, OTC availability and actual use, make it difficult for clinicians to quantify SABA use.

Adverse drug reactions and hospital admissions: Large case-control study of patients aged 65-100 years using linked English primary care and hospital data.

BACKGROUND: Adverse drug reactions (ADRs) are common and a leading cause of injury. However, information on ADR risks of individual medicines is often limited. The aim of this hypothesis-generating study was to assess the relative importance of ADR-related and emergency hospital admission for large group of medication classes. METHODS: This study was a propensity-matched case-control study in English primary care. Data sources were Clinical Practice Research Databank and Aurum with longitudinal, anonymized, patient level electronic health records (EHRs) from English general practices linked to hospital records. Cases aged 65-100 with ADR-related or emergency hospital admission were matched to up to six controls by age, sex, morbidity and propensity scores for hospital admission risk. Medication groups with systemic administration as listed in the British National Formulary (used by prescribers for medication advice). Prescribing in the 84 days before the index date was assessed. Only medication groups with 50+ cases exposed were analysed. The outcomes of interest were ADR-related and emergency hospital admissions. Conditional logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CI). RESULTS: The overall population included 121 546 cases with an ADR-related and 849 769 cases with emergency hospital admission. The percentage of hospitalizations with an ADR-related code for admission diagnosis was 1.83% and 6.58% with an ADR-related code at any time during hospitalization. A total of 137 medication groups was included in the main ADR analyses. Of these, 13 (9.5%) had statistically non-significant adjusted ORs, 58 (42.3%) statistically significant ORs between 1.0 and 1.5, 37 (27.0%) between 1.5-2.0, 18 (13.1%) between 2.0-3.0 and 11 (8.0%) 3.0 or higher. Several classes of antibiotics (including penicillins) were among medicines with largest ORs. Evaluating the 14 medications most often associated with ADRs, a strong association was found between the number of these medicines and the risk of ADR-related hospital admission (adjusted OR of 7.53 (95% CI 7.15-7.93) for those exposed to 6+ of these medicines). CONCLUSIONS AND RELEVANCE: There is a need for a regular systematic assessment of the harm-benefit ratio of medicines, harvesting the information in large healthcare databases and combining it with causality assessment of individual case histories.

Exploring microbial diversity responses in agricultural fields: a comparative analysis under pesticide stress and non-stress conditions.

Exposure to pesticides changes the microbial community structure in contaminated agricultural fields. To analyze the changes in the native microbial composition qRT-PCR, a metagenomic study was conducted. The qRT-PCR results exhibited that the uncontaminated soil has a higher copy number of 16S rDNA relative to the soil contaminated with pesticide. Metagenome analysis interprets that uncontaminated soil is enriched with proteobacteria in comparison with pesticide-contaminated soil. However, the presence of Actinobacteria, Firmicutes, and Bacteroides was found to be dominant in the pesticide-spiked soil. Additionally, the presence of new phyla such as Chloroflexi, Planctomycetes, and Verrucomicrobia was noted in the pesticide-spiked soil, while Acidobacteria and Crenarchaeota were observed to be extinct. These findings highlight that exposure to pesticides on soil significantly impacts the biological composition of the soil. The abundance of microbial composition under pesticide stress could be of better use for the treatment of biodegradation and bioremediation of pesticides in contaminated environments.

Knowledge support for optimising antibiotic prescribing for common infections in general practices: evaluation of the effectiveness of periodic feedback, decision support during consultations and peer comparisons in a cluster randomised trial (BRIT2) - study protocol.

INTRODUCTION: This project applies a Learning Healthcare System (LHS) approach to antibiotic prescribing for common infections in primary care. The approach involves iterations of data analysis, feedback to clinicians and implementation of quality improvement activities by the clinicians. The main research question is, can a knowledge support system (KSS) intervention within an LHS implementation improve antibiotic prescribing without increasing the risk of complications? METHODS AND ANALYSIS: A pragmatic cluster randomised controlled trial will be conducted, with randomisation of at least 112 general practices in North-West England. General practices participating in the trial will be randomised to the following interventions: periodic practice-level and individual prescriber feedback using dashboards; or the same dashboards plus a KSS. Data from large databases of healthcare records are used to characterise heterogeneity in antibiotic uses, and to calculate risk scores for clinical outcomes and for the effectiveness of different treatment strategies. The results provide the baseline content for the dashboards and KSS. The KSS comprises a display within the electronic health record used during the consultation; the prescriber (general practitioner or allied health professional) will answer standard questions about the patient's presentation and will then be presented with information (eg, patient's risk of complications from the infection) to guide decision making. The KSS can generate information sheets for patients, conveyed by the clinicians during consultations. The primary outcome is the practice-level rate of antibiotic prescribing (per 1000 patients) with secondary safety outcomes. The data from practices participating in the trial and the dashboard infrastructure will be held within regional shared care record systems of the National Health Service in the UK. ETHICS AND DISSEMINATION: Approved by National Health Service Ethics Committee IRAS 290050. The research results will be published in peer-reviewed journals and also disseminated to participating clinical staff and policy and guideline developers. TRIAL REGISTRATION NUMBER: ISRCTN16230629.

Preventing Risks of Infections and Medication Errors in IV therapy (PRIME): a patient safety initiative.

BACKGROUND: Two major avoidable reasons for adverse events in hospital are medication errors and intravenous therapy-induced infections or complications. Training for clinical staff and compliance to patient safety principles could address these. METHODS: Joint Commission International (JCI) consultants created a standardised, 6-month training programme for clinical staff in hospitals. Twenty-one tertiary care hospitals from across south-east Asia took part. JCI trained the clinical consultants, who trained hospital safety champions, who trained nursing staff. Compliance and knowledge were assessed, and monthly audits were conducted. RESULTS: There was an overall increase of 29% in compliance with parameters around medication preparation and vascular access device management. CONCLUSION: The programme improved safe practice around preparing medications management and managing vascular access devices. The approach could be employed as a continuous quality improvement initiative for the prevention of medication errors and infusion-associated complications.

Functional outcome and frailty in colorectal surgery patients.

BACKGROUND: Frailty is a recognized risk and predictor of poor health outcomes in older patients undergoing surgery. A significant proportion of elderly patients undergoing colorectal cancer-related surgery are nevertheless not routinely assessed for frailty in current clinical practice in Australia. We examined the preoperative use of the Clinical Frailty Scale (CFS) to predict post-operative functional outcomes in geriatric patients undergoing colorectal cancer surgery. METHODS: This retrospective observational cohort study included elderly colorectal cancer patients (n = 227) who underwent elective major colorectal surgery from 2016 to 2020 at Nepean Hospital, Australia. CFS was calculated retrospectively from medical records and the relationship between CFS and functional outcome factors was analysed. RESULTS: Frail patients (n = 111) had a significant postoperative functional decline as demonstrated by discharge to supported care (57% vs. 0.9%), Barthel Index change (P<0.05) and inability to self-manage stoma (P<0.05) compared to non-frail patients (n = 116). Multivariate analysis with adjustment for age, comorbidities as measured by Charlson Comorbidities Index (CCI), and cognitive impairment, demonstrated frailty was the most significant independent predictor of discharge to supported care (OR 109.3). Cognitive impairment and an increased CCI were also found to be important predictors. CONCLUSION: Preoperative frailty is significantly associated with postoperative functional decline and postoperative adverse outcomes, highlighting the potential utility of CFS in preoperative frailty assessment.

Perspective Toward Complementary & Alternative Medicines in the Prevention of COVID-19 Infection.

Background: Across the globe, people are seeking integrative and holistic measures to prevent coronavirus (COVID-19) infection in the form of complementary and alternative medicines (CAM) with or without conventional medicines. This study was done to know the extent of CAM use for COVID-19 prophylaxis and to know beliefs and attitudes of people related to CAM use in India. Methodology: A pretested and prevalidated questionnaire was circulated on social media. Participants, who completed the online form and gave voluntary consent, were included. The questionnaire included demographic details and questions related to CAM use, preferences with reasons, preparations used, perceived role of CAM in prevention, immunity boosting and side effects, sources of information, etc. Results: Out of 514 responses, 495 were analyzed. 47.07% of respondents were males and 52.93% were females. 66.9% were using CAM for COVID-19 prophylaxis. The association between age, gender, and profession with CAM use was statistically significant (P < 0.05). 41.1% reported CAM use in the past. 36.6% of CAM users were taking "Kadha" and 33% were using ayurvedic medicines. Other frequently used CAM preparations were chyavanprash, giloy, tulsi, ginger, pepper, cloves, honey, sudarshanghanvati, arsenic-30, lemon juice, cinnamon, steam inhalation, ashwagandha, swasarivati, coronil, and warm saline water gargles. 46.9% of the CAM users were on self-medication and 52.3% preferred CAM over allopathy. Conclusion: Complementary and alternative medicine utilization for COVID-19 prophylaxis is widespread and self-medication is prevalent. As no specific cure is available in conventional systems, people believe in traditional medicines more than conventional, yet confusion exists. There is a need of increasing awareness regarding side effects, drug-drug interactions, and self-medication.

Esterase and ALDH dehydrogenase-based pesticide degradation by Bacillus brevis 1B from a contaminated environment.

The isolated bacterial strain (Bacillus brevis strain 1 B) showed a maximum tolerated level of 450 mg L-1 of the selected pesticides namely: imidacloprid, fipronil, cypermethrin, and sulfosulfuron. Within 15 days of the experiment, strain 1 B was able to reduce up to 95% of a pesticide mixture (20 mg L-1) in a carbon-deficient medium (minimal medium). The optimal conditions obtained using Response Surface Methodology (RSM) were: inoculums; 2.0 × 107 CFU mL-1, shaking speed; 120 rpm, and pesticide concentration; 80 mg L-1. After 15 days of soil-based bioremediation using strain 1 B, the degradation pattern for imidacloprid, fipronil, cypermethrin, sulfosulfuron, and control was 99, 98.5, 94, 91.67, and 7%, respectively. Gas chromatography-mass spectrometry (GC-MS) analysis was used to determine the intermediate metabolites of cypermethrin with bacterial 1 B as 2-cyclopenten-1-one, 2-methylpyrrolidine, 2-oxonanone, 2-pentenoic acid, 2-penten-1-ol, hexadecanoic acid or palmitic acid, pentadecanoic acid, 3-cyclopentylpropionic acid, and 2-dimethyl. Furthermore, genes encoding aldehyde dehydrogenase (ALDH) and esterase were expressed under stress conditions and connected to pesticide bioremediation. Hence the efficacy of Bacillus brevis (1 B) could be employed for the bioremediation of pesticide mixtures and other toxic substances (dye, polyaromatic hydrocarbon, etc.) from contaminated sites.

The Impact of Maternal Probiotics on Intestinal Vitamin D Receptor Expression in Early Life.

Vitamin D signaling via the Vitamin D Receptor (VDR) has been shown to protect against intestinal inflammation. Previous studies have also reported the mutual interactions of intestinal VDR and the microbiome, indicating a potential role of probiotics in modulating VDR expression. In preterm infants, although probiotics have been shown to reduce the incidence of necrotizing enterocolitis (NEC), they are not currently recommended by the FDA due to potential risks in this population. No previous studies have delved into the effect of maternally administered probiotics on intestinal VDR expression in early life. Using an infancy mouse model, we found that young mice exposed to maternally administered probiotics (SPF/LB) maintained higher colonic VDR expression than our unexposed mice (SPF) in the face of a systemic inflammatory stimulus. These findings indicate a potential role for microbiome-modulating therapies in preventing diseases such as NEC through the enhancement of VDR signaling.

Combinations of medicines in patients with polypharmacy aged 65-100 in primary care: Large variability in risks of adverse drug related and emergency hospital admissions.

BACKGROUND: Polypharmacy can be a consequence of overprescribing that is prevalent in older adults with multimorbidity. Polypharmacy can cause adverse reactions and result in hospital admission. This study predicted risks of adverse drug reaction (ADR)-related and emergency hospital admissions by medicine classes. METHODS: We used electronic health record data from general practices of Clinical Practice Research Datalink (CPRD GOLD) and Aurum. Older patients who received at least five medicines were included. Medicines were classified using the British National Formulary sections. Hospital admission cases were propensity-matched to controls by age, sex, and propensity for specific diseases. The matched data were used to develop and validate random forest (RF) models to predict the risk of ADR-related and emergency hospital admissions. Shapley Additive eXplanation (SHAP) values were calculated to explain the predictions. RESULTS: In total, 89,235 cases with polypharmacy and hospitalised with an ADR-related admission were matched to 443,497 controls. There were over 112,000 different combinations of the 50 medicine classes most implicated in ADR-related hospital admission in the RF models, with the most important medicine classes being loop diuretics, domperidone and/or metoclopramide, medicines for iron-deficiency anaemias and for hypoplastic/haemolytic/renal anaemias, and sulfonamides and/or trimethoprim. The RF models strongly predicted risks of ADR-related and emergency hospital admission. The observed Odds Ratio in the highest RF decile was 7.16 (95% CI 6.65-7.72) in the validation dataset. The C-statistics for ADR-related hospital admissions were 0.58 for age and sex and 0.66 for RF probabilities. CONCLUSIONS: Polypharmacy involves a very large number of different combinations of medicines, with substantial differences in risks of ADR-related and emergency hospital admissions. Although the medicines may not be causally related to increased risks, RF model predictions may be useful in prioritising medication reviews. Simple tools based on few medicine classes may not be effective in identifying high risk patients.

Closing the gap in osteoporosis management: the critical role of primary care in bone health.

OBJECTIVE: The World Health Organization issued a call to action for primary care to lead efforts in managing noncommunicable diseases, including osteoporosis. Although common, osteoporosis remains underdiagnosed and undertreated. Primary care practitioners (PCPs) are critical in identifying individuals at risk for osteoporosis and osteoporotic fractures; however, recent advances in assessment, diagnosis, and treatment of osteoporosis have not been incorporated into clinical practice in primary care due to numerous reasons including time constraints and insufficient knowledge. To close this gap in clinical practice, we believe PCPs need a practical strategy to facilitate osteoporosis assessment and management that is easy to implement. METHODS: In this article, we consolidate information from various global guidelines and highlight areas of agreement to create a streamlined osteoporosis management strategy for a global audience of PCPs. RESULTS: We present a systematic approach to facilitate osteoporosis assessment and management that includes four steps: (1) identifying patients at risk through proactive screening strategies, (2) investigating and diagnosing patients, (3) intervening with personalized treatment plans, and (4) implementing patient-centered strategies for long-term management and monitoring of patients. CONCLUSION: Primary care has a central role in ensuring the incorporation of key elements of holistic care as outlined by the World Health Organization in managing noncommunicable diseases including osteoporosis; namely, a people-centered approach, incorporation of specialist services, and multidisciplinary care. This approach is designed to strengthen the health system's response to the growing osteoporosis epidemic.

Osteoporosis is a chronic condition associated with aging in which bones become "porous" and weak, and are more likely to break (i.e., fracture) even with minimal trauma such as tripping or falling from a standing height. A broken bone is a serious condition that not only affects daily activities, but can also lead to reduced quality of life, need for caregiver support, work loss, hospital and rehabilitation costs, nursing home costs, and increased mortality. Although osteoporosis is common, it is often undiagnosed or untreated, leaving many people at risk for experiencing broken bones. A broken bone increases the risk of more broken bones. Given the growing size of the aging global population, osteoporosis and the risk of broken bones represent an urgent problem and growing burden. We need ways to make it easier for primary care practitioners (PCPs), such as family physicians, internists, physician assistants, nurse practitioners, and nurses, to include osteoporosis care as part of routine clinical visits. In this article, we discuss the critical role of PCPs in early detection, diagnosis, and treatment of osteoporosis as they are often the first point of contact for at-risk patients. We present a simple, four-step approach to help PCPs and patients navigate the journey from osteoporosis diagnosis to a treatment plan. The four steps are to: (1) identify at-risk patients by screening for weak bones or osteoporosis, (2) perform necessary tests to diagnose patients, (3) develop a personalized treatment plan, and (4) determine long-term strategies for managing and monitoring bone health.

Evaluation of three novel soil bacterial strains for efficient biodegradation of persistent boscalid fungicide: Kinetics and identification of microbial biodegradation intermediates.

Boscalid, a new fungicide of anilide group, is intended to prevent and treat grey mould (Botrytis cinerea), primarily in vines and other fruit plants. In many regions, its long half-life in soil and water poses a serious environmental threat. Boscalid is reported to be toxic to a variety of aquatic organisms. One of the best ways to lessen the amount of boscalid that gets into surface and ground waters is to reduce its concentration in soil. Soil microbes are crucial for the degradation of organic pollutants including pesticides. The present study reports the assessment of three novel soil bacterial strains isolated from pesticide-contaminated soil of Crop research centre, Pantnagar, Uttarakhand, India, which possess boscalid degradation ability. Two of these bacterial isolates could degrade boscalid up to 85-95% within 36 h of incubation period under shaking conditions in the minimal medium. The growth pattern of degrading bacterial isolates was monitored by recording the optical density (OD) of bacterial suspension using an ultra violet (UV)-visible spectrophotometer, whereas the concentration of primary boscalid was recorded by High-Performance Liquid Chromatography (HPLC-UV). A linear relationship was observed between the bacterial growth and the decrease in the residual concentration of boscalid. The concentration of boscalid during incubation with different bacterial strains could be best predicted by a second-order polynomial relationship with time and OD of the suspension as independent variables. Three degradation intermediates of boscalid namely, N-(1,1'-biphenyl-2-yl)pyridine-3-carboxamide (C18H14N2O, N-{[1,1'-biphenyl]-2-yl}-2-chloropyridine-3-carboxamide (C18H13N2OCl), and N-{[4'-chloro-1,1'-biphenyl]-2-yl}-2-chloropyridine ({C17H11NCl2}OH) were identified by the liquid chromatography-mass spectrometry (LC-MS) analysis of biodegraded samples. The biodegradation of boscalid through bacterial isolates seemed to be an economical and eco-friendly method for degrading a highly persistent boscalid fungicide.

Clinical Relevance of Drug-Drug Interactions With Antibiotics as Listed in a National Medication Formulary: Results From Two Large Population-Based Case-Control Studies in Patients Aged 65-100 Years Using Linked English Primary Care and Hospital Data.

This study evaluated drug-drug interactions (DDIs) between antibiotic and nonantibiotic drugs listed with warnings of severe outcomes in the British National Formulary based on adverse drug reaction (ADR) detectable with routine International Classification of Diseases, Tenth Revision coding. Data sources were Clinical Practice Research Databank GOLD and Aurum anonymized electronic health records from English general practices linked to hospital admission records. In propensity-matched case-control study, outcomes were ADR or emergency admissions. Analyzed were 121,546 ADR-related admission cases matched to 638,238 controls. For most antibiotics, adjusted odds ratios (aORs) for ADR-related hospital admission were large (aOR for trimethoprim 4.13; 95% confidence interval (CI), 3.97-4.30). Of the 51 DDIs evaluated for ADR-related admissions, 38 DDIs (74.5%) had statistically increased aORs of concomitant exposure compared with nonexposure (mean aOR 3.96; range 1.59-11.42); for the 89 DDIs for emergency hospital admission, the results were 75 (84.3%) and mean aOR 2.40; range 1.43-4.17. Changing reference group to single antibiotic exposure reduced aORs for concomitant exposure by 76.5% and 83.0%, respectively. Medicines listed to cause nephrotoxicity substantially increased risks that were related to number of medicines (aOR was 2.55 (95% CI, 2.46-2.64) for current use of 1 and 10.44 (95% CI, 7.36-14.81) for 3 or more medicines). In conclusion, no evidence of substantial risk was found for multiple DDIs with antibiotics despite warnings of severe outcomes in a national formulary and flagging in electronic health record software. It is proposed that the evidence base for inclusion of DDIs in national formularies be strengthened and made publicly accessible and indiscriminate flagging, which compounds alert fatigue, be reduced.

Clinical and health inequality risk factors for non-COVID-related sepsis during the global COVID-19 pandemic: a national case-control and cohort study.

Background: Sepsis, characterised by significant morbidity and mortality, is intricately linked to socioeconomic disparities and pre-admission clinical histories. This study aspires to elucidate the association between non-COVID-19 related sepsis and health inequality risk factors amidst the pandemic in England, with a secondary focus on their association with 30-day sepsis mortality. Methods: With the approval of NHS England, we harnessed the OpenSAFELY platform to execute a cohort study and a 1:6 matched case-control study. A sepsis diagnosis was identified from the incident hospital admissions record using ICD-10 codes. This encompassed 248,767 cases with non-COVID-19 sepsis from a cohort of 22.0 million individuals spanning January 1, 2019, to June 31, 2022. Socioeconomic deprivation was gauged using the Index of Multiple Deprivation score, reflecting indicators like income, employment, and education. Hospitalisation-related sepsis diagnoses were categorised as community-acquired or hospital-acquired. Cases were matched to controls who had no recorded diagnosis of sepsis, based on age (stepwise), sex, and calendar month. The eligibility criteria for controls were established primarily on the absence of a recorded sepsis diagnosis. Associations between potential predictors and odds of developing non-COVID-19 sepsis underwent assessment through conditional logistic regression models, with multivariable regression determining odds ratios (ORs) for 30-day mortality. Findings: The study included 224,361 (10.2%) cases with non-COVID-19 sepsis and 1,346,166 matched controls. The most socioeconomic deprived quintile was associated with higher odds of developing non-COVID-19 sepsis than the least deprived quintile (crude OR 1.80 [95% CI 1.77-1.83]). Other risk factors (after adjusting comorbidities) such as learning disability (adjusted OR 3.53 [3.35-3.73]), chronic liver disease (adjusted OR 3.08 [2.97-3.19]), chronic kidney disease (stage 4: adjusted OR 2.62 [2.55-2.70], stage 5: adjusted OR 6.23 [5.81-6.69]), cancer, neurological disease, immunosuppressive conditions were also associated with developing non-COVID-19 sepsis. The incidence rate of non-COVID-19 sepsis decreased during the COVID-19 pandemic and rebounded to pre-pandemic levels (April 2021) after national lockdowns had been lifted. The 30-day mortality risk in cases with non-COVID-19 sepsis was higher for the most deprived quintile across all periods. Interpretation: Socioeconomic deprivation, comorbidity and learning disabilities were associated with an increased odds of developing non-COVID-19 related sepsis and 30-day mortality in England. This study highlights the need to improve the prevention of sepsis, including more precise targeting of antimicrobials to higher-risk patients. Funding: The UK Health Security Agency, Health Data Research UK, and National Institute for Health Research.

Footwear and insole design parameters to prevent occurrence and recurrence of neuropathic plantar forefoot ulcers in patients with diabetes: a series of N-of-1 trial study protocol.

BACKGROUND: Foot complications occur in conjunction with poorly controlled diabetes. Plantar forefoot ulceration contributes to partial amputation in unstable diabetics, and the risk increases with concomitant neuropathy. Reducing peak plantar forefoot pressure reduces ulcer occurrence and recurrence. Footwear and insoles are used to offload the neuropathic foot, but the success of offloading is dependent on patient adherence. This study aims to determine which design and modification features of footwear and insoles improve forefoot plantar pressure offloading and adherence in people with diabetes and neuropathy. METHODS: This study, involving a series of N-of-1 trials, included 21 participants who had a history of neuropathic plantar forefoot ulcers. Participants were recruited from two public hospitals and one private podiatry clinic in Sydney, New South Wales, Australia. This trial is non-randomised and unblinded. Participants will be recruited from three sites, including two high-risk foot services and a private podiatry clinic in Sydney, Australia. Mobilemat™ and F-Scan® plantar pressure mapping systems by TekScan® (Boston, USA) will be used to measure barefoot and in-shoe plantar pressures. Participants' self-reports will be used to quantify the wearing period over a certain period of between 2 and 4 weeks during the trial. Participant preference toward footwear, insole design and quality-of-life-related information will be collected and analysed. The descriptive and inferential statistical analyses will be performed using IBM SPSS Statistics (version 27). And the software NVivo (version 12) will be utilised for the qualitative data analysis. DISCUSSION: This is the first trial assessing footwear and insole interventions in people with diabetes by using a series of N-of-1 trials. Reporting self-declared wearing periods and participants' preferences on footwear style and aesthetics are the important approaches for this trial. Patient-centric device designs are the key to therapeutic outcomes, and this study is designed with that strategy in mind. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12620000699965p. Registered on June 23, 2020.

Overview of biofertilizers in crop production and stress management for sustainable agriculture.

With the increase in world population, the demography of humans is estimated to be exceeded and it has become a major challenge to provide an adequate amount of food, feed, and agricultural products majorly in developing countries. The use of chemical fertilizers causes the plant to grow efficiently and rapidly to meet the food demand. The drawbacks of using a higher quantity of chemical or synthetic fertilizers are environmental pollution, persistent changes in the soil ecology, physiochemical composition, decreasing agricultural productivity and cause several health hazards. Climatic factors are responsible for enhancing abiotic stress on crops, resulting in reduced agricultural productivity. There are various types of abiotic and biotic stress factors like soil salinity, drought, wind, improper temperature, heavy metals, waterlogging, and different weeds and phytopathogens like bacteria, viruses, fungi, and nematodes which attack plants, reducing crop productivity and quality. There is a shift toward the use of biofertilizers due to all these facts, which provide nutrition through natural processes like zinc, potassium and phosphorus solubilization, nitrogen fixation, production of hormones, siderophore, various hydrolytic enzymes and protect the plant from different plant pathogens and stress conditions. They provide the nutrition in adequate amount that is sufficient for healthy crop development to fulfill the demand of the increasing population worldwide, eco-friendly and economically convenient. This review will focus on biofertilizers and their mechanisms of action, role in crop productivity and in biotic/abiotic stress tolerance.

Nocturnal pollutant uptake contributes significantly to the total stomatal uptake of Mangifera indica.

DO3SE (Deposition of Ozone for Stomatal Exchange), is a dry deposition model, designed to assess tropospheric ozone risk to vegetation, and is based on two alternative algorithms to estimate stomatal conductance: multiplicative and photosynthetic. The multiplicative model has been argued to perform better for leaf-level and regional-level application. In this study, we demonstrate that the photosynthetic model is superior to the multiplicative model even for leaf-level studies using measurements performed on Mangifera indica. We find that the multiplicative model overestimates the daytime stomatal conductance, when compared with measured stomatal conductance and prescribes zero conductance at night while measurements show an average conductance of 100 mmol(H2O)m-2s-1 between 9 p.m. and 4 a.m. The daytime overestimation of the multiplicative model can be significantly reduced when the model is modified to include a response function for ozone-induced stomatal closure. However, nighttime pollutant uptake fluxes can only be accurately assessed with the photosynthetic model which includes the stomatal opening at night during respiration and is capable of reproducing the measured nighttime stomatal conductance. At our site, the nocturnal flux contributes 64%, 39%, 46%, and 88% of the total for NO2 uptake in winter, summer, monsoon, and post-monsoon, respectively. For SO2, nocturnal uptake amounts to 35%, 28%, 28%, and 44% in winter, summer, monsoon, and post-monsoon, respectively while for ozone the nighttime uptake contributes 30%, 17%, 18%, and 29% of the total stomatal uptake in winter, summer, monsoon, and post-monsoon respectively.