Polypharmacy among patients with hypertension attending primary healthcare centres

Introduction: Saudi Arabia has several hypertensive patients who require close attention and specialised care for their medications. Polypharmacy is one of the reasons for the failure of patient compliance with antihypertensive medications. Therefore, this study aims to gain a better perspective on polypharmacy in hypertensive patients attending primary healthcare (PHC) centres in Makkah, Saudi Arabia. Methods: This was an observational, cross-sectional, descriptive study of hypertensive patients followed up at 10 PHC centres in Makkah, Saudi Arabia, from 1 July 2019 to 30 June 2022. Frequencies and percentages were used to present categorical data, and Pearson’s χ2 test was used to measure differences. A P value less than 0.05 was considered statistically significant. Results: A total of 506 patients were included in this study. The mean age of the patients was 60 years, and more than half (69%) were females. Regarding antihypertensive medication use, 64% were on antihypertensive combination therapy, 76% on dual therapy, 21% on triple therapy, and 3% on quadruple therapy. Moreover, 21% of the hypertensive patients were exposed to polypharmacy. There was a significant relationship (P<0.001) between the overall number of chronic medications used per day and the duration of hypertension. Conclusion: More clinical research is needed to identify the impact of polypharmacy on the quality of healthcare in PHC centres in general and hypertensive patients specifically in different regions of Saudi Arabia

Nicotinamide Inhibits Alkylating Agent-Induced Apoptotic Neurodegeneration in the Developing Rat Brain

BACKGROUND: Exposure to the chemotherapeutic alkylating agent thiotepa during brain development leads to neurological complications arising from neurodegeneration and irreversible damage to the developing central nerve system (CNS). Administration of single dose of thiotepa in 7-d postnatal (P7) rat triggers activation of apoptotic cascade and widespread neuronal death. The present study was aimed to elucidate whether nicotinamide may prevent thiotepa-induced neurodegeneration in the developing rat brain. METHODOLOGY/PRINCIPAL FINDINGS: Neuronal cell death induced by thiotepa was associated with the induction of Bax, release of cytochrome-c from mitochondria into the cytosol, activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP-1). Post-treatment of developing rats with nicotinamide suppressed thiotepa-induced upregulation of Bax, reduced cytochrome-c release into the cytosol and reduced expression of activated caspase-3 and cleavage of PARP-1. Cresyl violet staining showed numerous dead cells in the cortex hippocampus and thalamus; post-treatment with nicotinamide reduced the number of dead cells in these brain regions. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) and immunohistochemical analysis of caspase-3 show that thiotepa-induced cell death is apoptotic and that it is inhibited by nicotinamide treatment. CONCLUSION: Nicotinamide (Nic) treatment with thiotepa significantly improved neuronal survival and alleviated neuronal cell death in the developing rat. These data demonstrate that nicotinamide shows promise as a therapeutic and neuroprotective agent for the treatment of neurodegenerative disorders in newborns and infants

Outcomes of obstructed abdominal wall hernia: results from the UK national small bowel obstruction audit

Background: Abdominal wall hernia is a common surgical condition. Patients may present in an emergency with bowel obstruction, incarceration or strangulation. Small bowel obstruction (SBO) is a serious surgical condition associated with significant morbidity. The aim of this study was to describe current management and outcomes of patients with obstructed hernia in the UK as identified in the National Audit of Small Bowel Obstruction (NASBO). Methods: NASBO collated data on adults treated for SBO at 131 UK hospitals between January and March 2017. Those with obstruction due to abdominal wall hernia were included in this study. Demographics, co-morbidity, imaging, operative treatment, and in-hospital outcomes were recorded. Modelling for factors associated with mortality and complications was undertaken using Cox proportional hazards and multivariable regression modelling. Results: NASBO included 2341 patients, of whom 415 (17·7 per cent) had SBO due to hernia. Surgery was performed in 312 (75·2 per cent) of the 415 patients; small bowel resection was required in 198 (63·5 per cent) of these operations. Non-operative management was reported in 35 (54 per cent) of 65 patients with a parastomal hernia and in 34 (32·1 per cent) of 106 patients with an incisional hernia. The in-hospital mortality rate was 9·4 per cent (39 of 415), and was highest in patients with a groin hernia (11·1 per cent, 17 of 153). Complications were common, including lower respiratory tract infection in 16·3 per cent of patients with a groin hernia. Increased age was associated with an increased risk of death (hazard ratio 1·05, 95 per cent c.i. 1·01 to 1·10; P = 0·009) and complications (odds ratio 1·05, 95 per cent c.i. 1·02 to 1·09; P = 0·001). Conclusion: NASBO has highlighted poor outcomes for patients with SBO due to hernia, highlighting the need for quality improvement initiatives in this group

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)

Background: This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic. Methods: CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality. Results: This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121). Conclusion: CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic

National prospective cohort study of the burden of acute small bowel obstruction

Background Small bowel obstruction is a common surgical emergency, and is associated with high levels of morbidity and mortality across the world. The literature provides little information on the conservatively managed group. The aim of this study was to describe the burden of small bowel obstruction in the UK. Methods This prospective cohort study was conducted in 131 acute hospitals in the UK between January and April 2017, delivered by trainee research collaboratives. Adult patients with a diagnosis of mechanical small bowel obstruction were included. The primary outcome was in‐hospital mortality. Secondary outcomes included complications, unplanned intensive care admission and readmission within 30 days of discharge. Practice measures, including use of radiological investigations, water soluble contrast, operative and nutritional interventions, were collected. Results Of 2341 patients identified, 693 (29·6 per cent) underwent immediate surgery (within 24 h of admission), 500 (21·4 per cent) had delayed surgery after initial conservative management, and 1148 (49·0 per cent) were managed non‐operatively. The mortality rate was 6·6 per cent (6·4 per cent for non‐operative management, 6·8 per cent for immediate surgery, 6·8 per cent for delayed surgery; P = 0·911). The major complication rate was 14·4 per cent overall, affecting 19·0 per cent in the immediate surgery, 23·6 per cent in the delayed surgery and 7·7 per cent in the non‐operative management groups (P < 0·001). Cox regression found hernia or malignant aetiology and malnutrition to be associated with higher rates of death. Malignant aetiology, operative intervention, acute kidney injury and malnutrition were associated with increased risk of major complication. Conclusion Small bowel obstruction represents a significant healthcare burden. Patient‐level factors such as timing of surgery, acute kidney injury and nutritional status are factors that might be modified to improve outcomes

Outcomes following small bowel obstruction due to malignancy in the national audit of small bowel obstruction

Introduction Patients with cancer who develop small bowel obstruction are at high risk of malnutrition and morbidity following compromise of gastrointestinal tract continuity. This study aimed to characterise current management and outcomes following malignant small bowel obstruction. Methods A prospective, multicentre cohort study of patients with small bowel obstruction who presented to UK hospitals between 16th January and 13th March 2017. Patients who presented with small bowel obstruction due to primary tumours of the intestine (excluding left-sided colonic tumours) or disseminated intra-abdominal malignancy were included. Outcomes included 30-day mortality and in-hospital complications. Cox-proportional hazards models were used to generate adjusted effects estimates, which are presented as hazard ratios (HR) alongside the corresponding 95% confidence interval (95% CI). The threshold for statistical significance was set at the level of P ≤ 0.05 a-priori. Results 205 patients with malignant small bowel obstruction presented to emergency surgery services during the study period. Of these patients, 50 had obstruction due to right sided colon cancer, 143 due to disseminated intraabdominal malignancy, 10 had primary tumours of the small bowel and 2 patients had gastrointestinal stromal tumours. In total 100 out of 205 patients underwent a surgical intervention for obstruction. 30-day in-hospital mortality rate was 11.3% for those with primary tumours and 19.6% for those with disseminated malignancy. Severe risk of malnutrition was an independent predictor for poor mortality in this cohort (adjusted HR 16.18, 95% CI 1.86 to 140.84, p = 0.012). Patients with right-sided colon cancer had high rates of morbidity. Conclusions Mortality rates were high in patients with disseminated malignancy and in those with right sided colon cancer. Further research should identify optimal management strategy to reduce morbidity for these patient groups

Outcomes of obstructed abdominal wall hernia: results from the UK national small bowel obstruction audit

Background Abdominal wall hernia is a common surgical condition. Patients may present in an emergency with bowel obstruction, incarceration or strangulation. Small bowel obstruction (SBO) is a serious surgical condition associated with significant morbidity. The aim of this study was to describe current management and outcomes of patients with obstructed hernia in the UK as identified in the National Audit of Small Bowel Obstruction (NASBO). Methods NASBO collated data on adults treated for SBO at 131 UK hospitals between January and March 2017. Those with obstruction due to abdominal wall hernia were included in this study. Demographics, co‐morbidity, imaging, operative treatment, and in‐hospital outcomes were recorded. Modelling for factors associated with mortality and complications was undertaken using Cox proportional hazards and multivariable regression modelling. Results NASBO included 2341 patients, of whom 415 (17·7 per cent) had SBO due to hernia. Surgery was performed in 312 (75·2 per cent) of the 415 patients; small bowel resection was required in 198 (63·5 per cent) of these operations. Non‐operative management was reported in 35 (54 per cent) of 65 patients with a parastomal hernia and in 34 (32·1 per cent) of 106 patients with an incisional hernia. The in‐hospital mortality rate was 9·4 per cent (39 of 415), and was highest in patients with a groin hernia (11·1 per cent, 17 of 153). Complications were common, including lower respiratory tract infection in 16·3 per cent of patients with a groin hernia. Increased age was associated with an increased risk of death (hazard ratio 1·05, 95 per cent c.i. 1·01 to 1·10; P = 0·009) and complications (odds ratio 1·05, 95 per cent c.i. 1·02 to 1·09; P = 0·001). Conclusion NASBO has highlighted poor outcomes for patients with SBO due to hernia, highlighting the need for quality improvement initiatives in this group

Study of the immunopathogenesis of Narcolepsy type 1

A Narcolepsie de type 1 (NT1) est une maladie neurologique rare, provoquant une somnolence diurne excessive et une cataplexie. La NT1 se caractérise par une perte des neurones produisant les neuropeptides hypocrétine (HCRT) dans l'hypothalamus latéral. Des facteurs génétiques et environnementaux suggèrent fortement l'implication du système immunitaire dans la perte neuronale. Ainsi, mon projet de thèse avait deux objectifs : (1) Identifier la fréquence, le phénotype et le profil transcriptomique des lymphocytes T CD4+ auto-réactifs. (2) Élucider les mécanismes moléculaires induisant la perte neuronale par l'étude du protéome du liquide céphalo-rachidien (LCR). Pour le premier axe de mon projet, nous avons émis l'hypothèse que les lymphocytes T CD4+ jouent un rôle central dans la pathogenèse de NT1 du fait de la forte association génétique de l'allèle HLA-DQB1*06:02 avec la NT1. Nous avons alors utilisé une approche expérimentale consistant en une expansion in vitro de lymphocytes T mémoire CD4+ spécifiques de l'antigène à partir du sang des patients NT1 ou de témoins. Deux approches pour dépister les lymphocytes T auto-réactifs ont été utilisé : (i) une approche de confirmation utilisant des peptides du HCRT (HCRT54-66 et HCRT-NH54-66) dont il a déjà été démontré qu'ils suscitent des réponses lymphocytaires T auto-réactives chez les patients atteints de NT1 ; (ii) Une approche de découverte utilisant la protéine précurseur pré-pro-HCRT entière. Après 14 jours de culture de lymphocytes T CD4+ mémoires stimulés avec ces autoantigènes, la fréquence des lymphocytes T spécifiques de l'antigène a été analysée en fonction de leur prolifération et de leur fonction (mesure de cytokines dans le surnageant de cultures). Le dépistage de 23 patients NT1 au début de leur maladie et de 16 donneurs sains (HD) appariés pour l'âge, le sexe et le HLA a révélé des fréquences similaires de lymphocytes T CD4+ auto-réactifs spécifiques de HCRT-NH54-66 et pré-pro-HCRT chez les patients NT1 et les HD. Cependant, des fréquences plus élevées de lymphocytes T auto-réactives spécifiques de HCRT54-66 ont été trouvées chez les patients NT1 par rapport aux HD. De plus, des niveaux élevés de GM-CSF ont été détectés dans le surnageant de lymphocytes T CD4+ stimulés par HCRT54-66 provenant de patients NT1. Pour mieux comprendre les mécanismes pathogènes potentiels qui pourraient conduire les cellules T auto-réactives à déclencher la perte de HCRT, nous avons trié les cellules T mémoires CD4+ spécifiques de HCRT54-66 et effectué une analyse transcriptomique. Pour le second axe de mon projet, nous avions pour but de mieux comprendre les altérations moléculaires chez les patients NT1 en étudiant le liquide céphalo-rachidien (LCR), sécrété localement et entourant le système nerveux central (SNC), et représentant donc une fenêtre accessible sur les processus pathologiques du SNC. Nous avons effectué une analyse protéomique du LCR de 21 patients NT1 d'apparition récente et de deux groupes témoins : le groupe 1 présentant des troubles neurologiques non organiques et le groupe 2 composé de patients atteints d'hypersomnie autre que NT1. De cette façon, nous avons pu contrôler tout effet potentiel que les troubles du sommeil pourraient avoir sur la composition du LCR. Les échantillons ont été analysés par spectrométrie de masse/chromatographie liquide à nano-flux (nano-LC-MS/MS). De façon intéressante, l'analyse des voies biologiques enrichis (GSEA) a indiqué que les systèmes du complément et de la coagulation étaient enrichis et activés de manière significative chez les patients NT1 dans les deux cohortes analysées. Des protéines de la voie lectine et alternative du complément ainsi que plusieurs protéines composant le complexe d'attaque membranaire (MAC) sont notamment augmentées de manière congruente chez les patients NT1. Collectivement, nos données visent à affiner notre compréhension des processus immunologiques impliqués dans la pathogenèse de NT1.Narcolepsy type 1 (NT1) is a rare neurological disorder that causes excessive daytime sleepiness and cataplexy. NT1 is characterized by the loss of neurons producing the neuropeptides hypocretin (HCRT) in the lateral hypothalamus. Strong genetic and environmental factors suggest the involvement of the immune system in neuronal loss. Thus, my thesis project had two main objectives : (1) Identify the frequency, phenotype, and transcriptomic profile of CD4+ auto-reactive T lymphocytes. (2) Elucidate the molecular mechanisms leading to neuronal loss by studying the proteome of cerebrospinal fluid (CSF). For the first part of my project, we hypothesized that CD4+ T lymphocytes play a central role in the pathogenesis of NT1 due to the strong genetic association of the HLA-DQB1*06:02 allele with NT1. We used an experimental approach involving in vitro expansion of memory CD4+ T lymphocytes specific to the antigen from the blood of NT1 patients or controls. Two approaches were used to detect auto-reactive T lymphocytes : (i) a confirmation approach using HCRT peptides (HCRT54-66 and HCRT-NH54-66) that had previously been shown to induce auto-reactive T lymphocyte responses in NT1 patients ; (ii) a discovery approach using the entire precursor protein pre-pro-HCRT. After 14 days of culture of memory CD4+ T lymphocytes stimulated with these autoantigens, the frequency of antigen-specific T lymphocytes was analyzed based on their proliferation and function (measurement of cytokines in the culture supernatant). Screening of 23 NT1 patients early in their disease and 16 healthy donors (HD) matched for age, sex, and HLA revealed similar frequencies of CD4+ auto-reactive T lymphocytes specific to HCRT-NH54-66 and pre-pro-HCRT in NT1 patients and HD. However, higher frequencies of auto-reactive T lymphocytes specific to HCRT54-66 were found in NT1 patients compared to HD. Moreover, elevated levels of GM-CSF were detected in the supernatant of CD4+ T lymphocytes stimulated by HCRT54-66 from NT1 patients. To better understand potential pathogenic mechanisms that could lead auto-reactive T cells to trigger HCRT loss, we sorted memory CD4+ T cells specific to HCRT54-66 and performed transcriptomic analysis. For the second part of my project, our aim was to better understand molecular alterations in NT1 patients by studying cerebrospinal fluid (CSF), which is secreted locally and surrounds the central nervous system (CNS), representing an accessible window into CNS pathological processes. We conducted a proteomic analysis of CSF from 21 newly onset NT1 patients and two control groups : Group 1 with non-organic neurological disorders and Group 2 consisting of patients with hypersomnia other than NT1. This allowed us to control for any potential effects of sleep disorders on CSF composition. Samples were analyzed by mass spectrometry/nano-liquid chromatography (nano-LC-MS/MS). Interestingly, the analysis of enriched biological pathways (GSEA) indicated that the complement and coagulation systems were significantly enriched and activated in NT1 patients in both analyzed cohorts. Proteins from the lectin and alternative complement pathways, as well as several proteins composing the membrane attack complex (MAC), were notably increased congruently in NT1 patients. Collectively, our data aim to refine our understanding of the immunological processes involved in the pathogenesis of NT1

Cerebrospinal fluid proteomics in recent-onset Narcolepsy type 1 reveals activation of the complement system

IntroductionNarcolepsy type 1 (NT1) is a rare, chronic and disabling neurological disease causing excessive daytime sleepiness and cataplexy. NT1 is characterized pathologically by an almost complete loss of neurons producing the orexin neuropeptides in the lateral hypothalamus. Genetic and environmental factors strongly suggest the involvement of the immune system in the loss of orexin neurons. The cerebrospinal fluid (CSF), secreted locally and surrounding the central nervous system (CNS), represents an accessible window into CNS pathological processes.MethodsTo gain insight into the biological and molecular changes in NT1 patients, we performed a comparative proteomics analysis of the CSF from 21 recent-onset NT1 patients and from two control groups: group 1 with somatoform disorders, and group 2 patients with hypersomnia other than NT1, to control for any potential effect of sleep disturbances on CSF composition. To achieve an optimal proteomic coverage analysis, the twelve most abundant CSF proteins were depleted, and samples were analyzed by nano-flow liquid chromatography tandem mass spectrometry (nano-LC-MS/MS) using the latest generation of hybrid Orbitrap mass spectrometer.Results and discussionOur study allowed the identification and quantification of up to 1943 proteins, providing a remarkably deep analysis of the CSF proteome. Interestingly, gene set enrichment analysis indicated that the complement and coagulation systems were enriched and significantly activated in NT1 patients in both cohorts analyzed. Notably, the lectin and alternative complement pathway as well as the downstream lytic membrane attack complex were congruently increased in NT1. Our data suggest that the complement dysregulation in NT1 patients can contribute to immunopathology either by directly promoting tissue damage or as part of local inflammatory responses. We therefore reveal an altered composition of the CSF proteome in NT1 patients, which points to an ongoing inflammatory process contributed, at least in part, by the complement system