Outcomes for Children With Vascular Ring Repair Using a Simple Surgical Approach.

INTRODUCTION: Vascular Rings (VRs) are congenital malformations of the aortic arch that can compress the trachea and esophagus producing symptoms. Approximately, 5%-10% of patients experience persistent symptoms postrepair and 9% require reintervention. There are various approaches to repair-simple ligation and division of the ring or more complex procedures. Our objective was to describe outcomes for VR repair using a "simple" surgical approach. METHODS: We identified patients who underwent VR repair from 2012 to 2022 at our institution. Clinical and surgical data, demographics, intraoperative, and postoperative outcomes were extracted from their electronic medical records. Outcomes were analyzed and regression analysis was used to identify risk factors for residual symptoms after repair. RESULTS: Ninety three patients with VR repair were included. Prevalence of symptoms were reduced following surgery (80% preoperative versus 13% postoperative, P 0.03). Tracheomalacia also decreased from 16% to 7% postrepair. No deaths were reported in our cohort and 2% of our patients required reintervention. Multivariable regression analysis showed that preoperative tracheomalacia was associated with having persistent symptoms after VR repair (odds ratio 6.2, 95% CI 1.02-37.6). CONCLUSIONS: Our institutional experience using a simple surgical approach showed a significant decrease in symptoms, a very low reintervention rate and no mortality. Preoperative tracheomalacia can be a risk factor for persistent symptoms postrepair. We believe a simple surgical approach for children with complete VR repair can be effective in relieving symptoms.

Unwarranted variation and the goal of net zero for the NHS in England: exploring the link between efficiency working, patient outcomes and carbon footprint.

In 2020 the NHS in England set a target of reaching net zero carbon emissions by 2040. Progress has already been made towards this goal, with substantial reductions in the use of environmentally harmful anaesthetic gases, such as desflurane, in recent years. Where an effective replacement already exists, changing practice to use low carbon alternatives is relatively easy to achieve, but much greater challenges lie ahead. The Getting It Right First Time (GIRFT) programme is a clinically-led, data-driven clinical improvement initiative with a focus on reducing unwarranted variation in clinical practice and patient outcomes. Reducing unwarranted variation can improve patient care and service efficiency, and can also support the drive to net zero. In this article we set out what the GIRFT programme is doing to support sustainable healthcare in England, why it is uniquely positioned to support this goal and what the future challenges, barriers, enablers and opportunities are likely to be in the drive to net zero.

Safety of day-case paediatric tonsillectomy in England: an analysis of administrative data for the Getting It Right First Time programme.

We used the Hospital Episodes Statistics database to investigate unwarranted variation in the rates Trusts discharged children the same day after scheduled tonsillectomy and associations with adverse postoperative outcomes. We included children aged 2-18 years who underwent tonsillectomy between 1 April 2014 and 31 March 2019. We stratified analyses by category of Trust, non-specialist or specialist, defined as without or with paediatric critical care facilities, respectively. We adjusted analyses for age, sex, year of surgery and aspects of presentation and procedure type. Of 101,180 children who underwent tonsillectomy at non-specialist Trusts, 62,926 (62%) were discharged the same day, compared with 24,138/48,755 (50%) at specialist Trusts. The adjusted proportion of children discharged the same day as tonsillectomy ranged from 5% to 100% at non-specialist Trusts and 9% to 88% at specialist Trusts. Same-day discharge was not independently associated with an increased rate of 30-day emergency re-admission at non-specialist Trusts but was associated with a modest rate increase at specialist Trusts; adjusted probability 8.0% vs 7.7%, odds ratio (95%CI) 1.14 (1.05-1.24). Rates of adverse postoperative outcomes were similar for Trusts that discharged >70% children the same day as tonsillectomy compared with Trusts that discharged <50% children the same day, for both non-specialist and specialist Trust categories. We found no consistent evidence that day-case tonsillectomy is associated with poorer outcomes. All Trusts, but particularly specialist centres, should explore reasons for low day-case rates and should aim for rates >70%.

Volume-outcome relationship for adrenalectomy: analysis of an administrative dataset for the Getting It Right First Time Programme.

BACKGROUND: A minimum volume threshold of at least six procedures per annum per surgeon has been set in UK and European guidelines for adrenal surgery. The aim of this study was to investigate outcomes for adrenal surgery in England relative to annual surgeon and hospital trust volume. METHODS: Data were extracted from the Hospital Episodes Statistics database for England. A 6-year period (January 2013 to December 2018 inclusive) for all adult admissions for unilateral adrenal surgery was used. The primary outcome measure was an emergency readmission within 30 days of discharge following surgery. Procedures were categorized as open or minimally invasive surgery for analysis. Multilevel modelling was used to adjust for hierarchy and potential confounders. RESULTS: Data for 4189 adrenalectomies were identified. Only one third of surgeons (who operated on just over a half of all patients) performed at least six procedures in the year prior to the index procedure. For open surgery, emergency readmission rates fell significantly from 15.2 to 6.4 per cent for surgeons and from 13.2 to 6.1 per cent for trusts between the lowest- and highest-volume categories. Significant, but less dramatic falls were also seen for minimally invasive surgery. CONCLUSION: A volume-outcome effect was identified for adrenal surgery in England. Minimum volume thresholds should be set, although these may need to be more ambitious than the current threshold if outcomes are to be optimized. LAY SUMMARY: Surgery for disease of the adrenal gland can be complex. In many cases the skill and experience of the surgeon and the wider surgical team is thought to be important in determining the success of the procedure. The relative rarity of adrenal surgery means that there is little evidence to support this view. This study looked at outcomes for all 4189 patients who underwent adrenal surgery in England over a 6-year period. There was evidence that outcomes were better for patents when the surgeon and hospital trust had performed a larger number of adrenal surgery procedures in the year prior to the procedure. This was, however, dependent on which patient outcomes were studied and the type of procedure. These findings will inform the ongoing debate as to whether adrenal surgery in England should only be performed in regional centres by experienced teams.

Surgery for disease of the adrenal gland can be complex. In many cases the skill and experience of the surgeon and the wider surgical team is thought to be important in determining the success of the procedure. The relative rarity of adrenal surgery means that there is little evidence to support this view. This study looked at outcomes for all 4189 patients who underwent adrenal surgery in England over a 6-year period. There was evidence that outcomes were better for patents when the surgeon and hospital trust had performed a larger number of adrenal surgery procedures in the year prior to the procedure. This was, however, dependent on which patient outcomes were studied and the type of procedure. These findings will inform the ongoing debate as to whether adrenal surgery in England should only be performed in regional centres by experienced teams.

Uncovering a Role for the Dorsal Hippocampal Commissure in Recognition Memory.

The dorsal hippocampal commissure (DHC) is a white matter tract that provides interhemispheric connections between temporal lobe brain regions. Despite the importance of these regions for learning and memory, there is scant evidence of a role for the DHC in successful memory performance. We used diffusion-weighted magnetic resonance imaging (DW-MRI) and white matter tractography to reconstruct the DHC in both humans (in vivo) and nonhuman primates (ex vivo). Across species, our findings demonstrate a close consistency between the known anatomy and tract reconstructions of the DHC. Anterograde tract-tracer techniques also highlighted the parahippocampal origins of DHC fibers in nonhuman primates. Finally, we derived diffusion tensor MRI metrics from the DHC in a large sample of human subjects to investigate whether interindividual variation in DHC microstructure is predictive of memory performance. The mean diffusivity of the DHC correlated with performance in a standardized recognition memory task, an effect that was not reproduced in a comparison commissure tract-the anterior commissure. These findings highlight a potential role for the DHC in recognition memory, and our tract reconstruction approach has the potential to generate further novel insights into the role of this previously understudied white matter tract in both health and disease.

miR614 Expression Enhances Breast Cancer Cell Motility.

Using a data driven analysis of a high-content screen, we have uncovered new regulators of epithelial-to-mesenchymal transition (EMT) induced cell migration. Our results suggest that increased expression of miR614 can alter cell intrinsic gene expression to enhance single cell and collective migration in multiple contexts. Interestingly, miR614 specifically increased the expression of the EMT transcription factor Slug while not altering existing epithelial character or inducing other canonical EMT regulatory factors. Analysis of two different cell lines identified a set of genes whose expression is altered by the miR614 through direct and indirect mechanisms. Prioritization driven by functional testing of 25 of the miR614 suppressed genes uncovered the mitochondrial small GTPase Miro1 and the transmembrane protein TAPT1 as miR614 suppressed genes that inhibit migration. Notably, the suppression of either Miro1 or TAPT1 was sufficient to increase Slug expression and the rate of cell migration. Importantly, reduced TAPT1 expression correlated with an increased risk of relapse in breast cancer patients. Together, our results reveal how increased miR614 expression and the suppression of TAPT1 and Miro1 modulate the EMT state and migratory properties of breast cancer cells.

Deriving an optimal threshold of waist circumference for detecting cardiometabolic risk in sub-Saharan Africa.

BACKGROUND: Waist circumference (WC) thresholds derived from western populations continue to be used in sub-Saharan Africa (SSA) despite increasing evidence of ethnic variation in the association between adiposity and cardiometabolic disease and availability of data from African populations. We aimed to derive a SSA-specific optimal WC cut-point for identifying individuals at increased cardiometabolic risk. METHODS: We used individual level cross-sectional data on 24 181 participants aged ⩾15 years from 17 studies conducted between 1990 and 2014 in eight countries in SSA. Receiver operating characteristic curves were used to derive optimal WC cut-points for detecting the presence of at least two components of metabolic syndrome (MS), excluding WC. RESULTS: The optimal WC cut-point was 81.2 cm (95% CI 78.5-83.8 cm) and 81.0 cm (95% CI 79.2-82.8 cm) for men and women, respectively, with comparable accuracy in men and women. Sensitivity was higher in women (64%, 95% CI 63-65) than in men (53%, 95% CI 51-55), and increased with the prevalence of obesity. Having WC above the derived cut-point was associated with a twofold probability of having at least two components of MS (age-adjusted odds ratio 2.6, 95% CI 2.4-2.9, for men and 2.2, 95% CI 2.0-2.3, for women). CONCLUSION: The optimal WC cut-point for identifying men at increased cardiometabolic risk is lower (⩾81.2 cm) than current guidelines (⩾94.0 cm) recommend, and similar to that in women in SSA. Prospective studies are needed to confirm these cut-points based on cardiometabolic outcomes.International Journal of Obesity advance online publication, 31 October 2017; doi:10.1038/ijo.2017.240.

Case-fatality and disability in the Tanzanian Stroke Incidence Project cohort.

OBJECTIVES: The burden of stroke on healthcare services in sub-Saharan Africa (SSA) is increasing. However, long-term outcomes from stroke in SSA are not well described. We aimed to investigate case-fatality and health outcomes for stroke survivors at 7- to 10-year follow-up. MATERIALS AND METHODS: The Tanzanian Stroke Incidence Project (TSIP) recruited incidence stroke cases between 2003 and 2006. We followed up cases in 2013, recording date of death in those who had died. RESULTS: Of 130 stroke cases included in this study, case-fatality and date of death data were available for 124 at 7-10 years post-stroke. Of these, 102 (82.3%) had died by 7 years post-stroke. Functional disability, as measured by the Barthel index immediately post-stroke, was a significant predictor of case-fatality at seven-year follow-up with those with severe disability having an almost four-fold increase in the odds of death compared with those with no, mild or moderate disability. CONCLUSIONS: Case-fatality rates are higher than reported in high-income countries, with post-stroke disability a significant predictor of death. Sustainable interventions to reduce post-stroke disability in this setting should be investigated.

The prevalence and burden of behavioural and psychological symptoms of dementia in rural Tanzania.

OBJECTIVES: Behavioural and psychological symptoms (BPS) in dementia are common in high-income countries, but there are few data from sub-Saharan Africa. Our aim was to estimate the prevalence and pattern of BPS and associated caregiver distress in rural Tanzania. METHODS: Prevalent cases of dementia (aged 70 and over) were identified during a community-based door-to-door study in six rural villages in Tanzania. Following cognitive screening, a stratified sample (over-sampled for people with dementia) of cases underwent a detailed clinical assessment including the brief 12 item neuropsychiatric inventory (NPI-Q), which assesses BPS and associated caregiver distress over the preceding 30 days. RESULTS: Of 78 people with dementia, at least one current BPS was reported by 69 (88.4%), with 40 (51.3%) reporting 3 or more symptoms. In 172 people with no cognitive impairment, 110 (64.0%) reported at least one symptom and 48 (27.9%) reported 3 or more. In dementia cases, the most frequent symptoms reported were anxiety (47.4%), agitation/aggression (38.5%), night-time behavioural disturbance (34.6%), irritability (33.3%) and depression (33.3%). CONCLUSION: The frequency of BPS in dementia in this rural Tanzanian population is high and comparable to that reported in prevalence studies from high income countries. Symptoms were also common, although to a lesser degree, amongst cognitively intact subjects. BPS are likely to have a significant impact on quality of life for elderly persons and their carers in low-income settings. Low-cost interventions, such as community-based therapy and education, are needed.

Chronic carbon monoxide treatment attenuates development of obesity and remodels adipocytes in mice fed a high-fat diet.

OBJECTIVE: Induction of heme oxygenase-1 (HO-1) has been demonstrated to result in chronic weight loss in several rodent models of obesity. However, the specific contribution of the HO metabolite, carbon monoxide (CO) to this response remains unknown. In this study, we determined the effect of chronic low level administration of a specific CO donor on the progression of obesity and its effects on metabolism and adipocyte biology in mice fed a high-fat diet. DESIGN: Experiments were performed on C57BL/6J mice fed a high-fat diet (60%) from 4 weeks until 30 weeks of age. Mice were administered either the CO donor, carbon monoxide releasing molecules (CORM)-A1 (5 mg kg(-1), intraperitoneally every other day) or the inactive form of the drug (iCORM-A1). Body weights were measured weekly and fasted blood glucose, insulin as well as body composition were measured every 6 weeks. Food intake, O2 consumption, CO2 production, activity and body heat production were measured at 28 weeks after start of the experimental protocol. RESULTS: Chronic CORM-A1 attenuated the development of high fat induced obesity from 18 weeks until the end of the study. Chronic CORM-A1 treatment in mice fed a high-fat diet resulted in significant decreases in fasted blood glucose, insulin and body fat and increased O2 consumption and heat production as compared with mice treated with iCORM-A1. Chronic CORM-A1 treatment also resulted in a significant decrease in adipocyte size and an increase in adipocyte number and in NRF-1, PGC-1α and UCP1 protein levels in epidydmal fat. CONCLUSION: Our results demonstrate that chronic CO treatment prevents the development of high-fat diet induced obesity via stimulation of metabolism and remodeling of adipocytes.

A comparison of caregiver burden in older persons and persons with Parkinson's disease or dementia in sub-Saharan Africa.

BACKGROUND: Caregiver burden includes the many physical, mental and socio-economic problems arising from caring for individuals with chronic and disabling diseases. Being a carer in sub-Saharan Africa (SSA), where little is known about chronic neurological conditions, may be extremely demanding. Conversely, multigenerational living may allow sharing of care among many caregivers. We wished to determine the relative burden of caring for two chronic neurodegenerative conditions (Parkinson's disease (PD) and dementia) in rural Tanzania. METHODS: All surviving patients from a PD prevalence study, newly identified people with PD from a neurological disorders study and all people with dementia from a dementia prevalence study in Hai, rural Tanzania, were invited to participate. The Zarit Burden Interview (ZBI) was used to determine level of caregiver strain (higher score reflects more strain). RESULTS: Of 25 PD patients ZBI was recorded in 20 (14 male). Five had no identifiable carer as they were largely independent. Three had PD dementia (PDD). Of 75 people with dementia (excluding 3 PDD), 43 (32 female) completed the ZBI. For the other 32, the caregivers felt the care they provided was a normal intergenerational expectation. Median ages were 78.5 and 85 years for PD and dementia, respectively. Median ZBI was 30.5 for PD and 14 for dementia (U = 166.0, z = -3.913, p < 0.001). Disease duration and disease type (PD or dementia) were univariate predictor of ZBI score, although only disease type was predictive by multivariable linear regression. CONCLUSIONS: Caring for an individual with PD may be more burdensome than caring for an individual with dementia in SSA. People with more advanced PD had higher caregiver burden.

Association of day-case rates with post COVID-19 recovery of elective laparoscopic cholecystectomy activity across England.

INTRODUCTION: The aim of this study was to investigate the safety of day-case laparoscopic cholecystectomy, and the association between day-case rates and, post the COVID-19 pandemic, recovery of activity to prepandemic levels for integrated care boards (ICBs) in England. METHODS: This was a retrospective observational study of the Hospital Episodes Statistics (HES) data set. Elective laparoscopic cholecystectomies for the period 1 January 2019 to 31 December 2022 were identified. Activity levels for 2022 were compared with those for the whole of 2019 (baseline). Day-case activity was identified where the length of stay recorded in the HES was zero days. RESULTS: Data were available for 184,252 patients across the 42 ICBs in England, of which 120,408 (65.3%) were day-case procedures. By December 2022, activity levels for the whole of England had returned to 88.2% of prepandemic levels. The South West region stood out as having recovered activity levels to the greatest extent, with activity at 97.3% of prepandemic levels during 2022. The South West also had the highest postpandemic day-case rate at 74.9% of all patients seen as a day-case during 2022; this compares with an England average of 65.3%. At an ICB level, there was a significant correlation between day-case rates and postpandemic activity levels (r = 0.362, p = 0.019). There was no strong or consistent evidence that day-case surgery had poorer patient outcomes than inpatient surgery. CONCLUSIONS: Recovery of elective laparoscopic cholecystectomy activity has been better in South West England than in other regions. Increasing day-case rates may be important if ICBs in other regions are to increase activity levels up to and beyond prepandemic levels.

Factors associated with conversion from day-case to in-patient elective inguinal hernia repair surgery across England: an observational study using administrative data.

PURPOSE: Elective primary inguinal hernia repair surgery is increasingly being conducted as a day-case procedure. However, some patients planned for day-case surgery have to stay in hospital for at least one night. The aim of this study was to identify the factors associated with conversion from day-case to in-patient management for elective inguinal hernia repair surgery. METHODS: This was an exploratory retrospective analysis of observational data from the Hospital Episode Statistics dataset for England. All patients aged ≥ 17 years undergoing a first elective inguinal hernia repair between 1st April 2014 and 31st March 2022 that was planned as day-case surgery were identified. The exposure of interest was discharged on the day of admission (day-case) or requiring overnight stay. The primary outcome of interest was 30-day emergency readmission with an overnight stay. For reporting, providers were aggregated to an Integrated Care Board (ICB) level. RESULTS: A total of 351,528 planned day-case elective primary inguinal hernia repairs were identified over the eight-year study period. Of these, 45,305 (12.9%) stayed in hospital for at least one night and were classed as day-case to in-patient stay conversions. Patients who converted to in-patient stay were older, had more comorbidities, and were more likely to have bilateral surgery and be operated on by a low-annual volume surgeon. Post-procedural complications were strongly associated with conversion. Across the 42 ICBs in England, model-adjusted conversion rates varied from 3.3% to 21.3%. CONCLUSIONS: There was considerable variation in conversion to in-patient stay rates for inguinal hernia repair across ICBs in England. Our findings should help surgical teams to better identify patients suitable for day-case inguinal hernia repair and plan discharge services more effectively. This should help to reduce the variation in conversion rates.

Carbon savings associated with changing surgical trends in total knee arthroplasty in England: a retrospective observational study using administrative data.

BACKGROUND: Best practice pathways for common surgical procedures, including total knee arthroplasty (TKA), have the potential to improve patient outcomes and reduce carbon emissions. We aimed to estimate the reduction in carbon emissions due to changing trends in the care of patients undergoing TKA in England. METHODS: This was a retrospective analysis of Hospital Episode Statistics data from 1 April 2013 to 31 March 2022 on adults undergoing elective primary TKA in England. The carbon footprint for each patient was calculated using carbon factors for multiple steps in the pathway, including ipsilateral knee arthroscopies in the year preceding the TKA, outpatient attendances, the index TKA, revisions of the TKA performed within 180 days of the index procedure, length of hospital stay and emergency readmissions. RESULTS: A total of 648,861 TKA operations were identified. Over the study period, the median length of stay reduced from four to three days, the proportion of patients undergoing ipsilateral knee arthroscopies performed within a year before TKA surgery fell from 5.9% to 0.5% and the number of early revisions and emergency readmissions also fell. The per-patient carbon footprint reduced from 378.8kgCO2e to 295.2kgCO2e over this time. If all the study patients had the same carbon footprint as the average patient in 2021/2022, 32.4kilotons CO2e would have been saved, enough to power 29,509 UK homes for one year. CONCLUSIONS: Practices that were introduced primarily to improve patient outcomes can contribute to a reduction in the carbon footprint.

Surgical pulmonary arterioplasty at bidirectional cavopulmonary anastomosis leads to favorable pulmonary hemodynamics at final stage palliation.

Objective: Pulmonary arterioplasty (PA plasty) at bidirectional cavopulmonary anastomosis (BDCA) is associated with increased morbidity, but outcomes to final stage palliation are unknown. We sought to determine the influence of PA plasty on pulmonary artery growth and hemodyamics at Fontan. Methods: We retrospectively reviewed clinical data and outcomes for BDCA patients from 2006 to 2018. PA plasty was categorized by extent (type 1-4), as previously described. Outcomes included pulmonary artery reintervention and mortality before final palliation. Results: Five hundred eighty-eight patients underwent BDCA. One hundred seventy-nine patients (30.0%) underwent concomitant PA plasty. Five hundred seventy (97%) patients (169 [94%] PA plasty) survived to BDCA discharge. One hundred forty out of 570 survivors (25%) required PA/Glenn reintervention before final stage palliation (59 out of 169 [35%]) PA plasty; 81 out of 401 (20%) non-PA plasty; P < .001). Twelve-, 24-, and 36-month freedom from reintervention after BDCA was 80% (95% CI, 74-86%), 75% (95% CI, 69-82%), and 64% (95% CI, 57-73%) for PA plasty, and 95% (95% CI, 93-97%), 91% (95% CI, 88-94%), and 81% (95% CI, 76-85%) for non-PA plasty (P < .001). Prefinal stage mortality was 37 (6.3%) (14 out of 169 PA plasty; 23 out of 401 non-PA plasty; P = .4). Five hundred four (144 PA plasty and 360 non-PA plasty) patients reached final stage palliation (471 Fontan, 26 1.5-ventricle, and 7 2-ventricular repair). Pre-Fontan PA pressure and pulmonary vascular resistance were 10 mm Hg (range, 9-12 mm Hg) and 1.6 mm Hg (range, 1.3-1.9 mm Hg) in PA plasty and 10 mm Hg (range, 8-12 mm Hg) and 1.5 mm Hg (range, 1.3-1.9 mm Hg) in non-PA plasty patients, respectively (P = .29, .6). Fontan hospital mortality, length of stay, and morbidity were similar. Conclusions: PA plasty at BDCA does not confer additional mortality risk leading to final palliation. Despite increased pulmonary artery reintervention, there was reliable pulmonary artery growth and favorable pulmonary hemodynamics at final stage palliation.

Standardization of the Norwood Procedure Improves Outcomes in a Medium-Sized Volume Center.

The Norwood operation has become common practice to palliate patients with hypoplastic left heart structures. Surgical technique and postoperative care have improved; yet, there remains significant attrition prior to stage II palliation. The objective of this study is to report outcomes before and after standardizing our approach to the Norwood operation. Patients who underwent the Norwood operation at Children's of Alabama were identified, those who underwent hybrid palliation operations were excluded. Pre- (2015-2020) and post- (2020-January 2023) standardization groups were compared and outcomes analyzed. Ninety-one patients were included (pre-standardization 44 (48.3%) and 47 (51.7%) post-standardization). There were no differences in baseline and intraoperative characteristics at Norwood between the pre- and post-standardization groups. Compared with pre-standardization, post-standardization was associated with decreased time to extubation (OR 0.87, 95%CI 0.79-0.96), inotrope duration (OR 0.92, 95%CI 0.86-0.98) and hospital length of stay (OR 0.98, 95%CI 0.96-0.99). There was a trend toward decreased cardiac arrest, reintervention rates, and interstage mortality for the post-standardization group. A standardized approach to complex neonatal cardiac operations such as the Norwood procedure may improve morbidity and decrease hospital resource utilization. We recommend establishing protocols at an institutional level to optimize outcomes in such high-risk patient populations.

Hybrid Thrombectomy and Central Extracorporeal Membrane Oxygenation for Massive Pulmonary Embolism in a Child.

We describe a hybrid thrombectomy and central extracorporeal membrane oxygenation for a child in cardiogenic shock due to a massive pulmonary embolism.

Loss of the mitochondrial citrate carrier, Slc25a1/CIC disrupts embryogenesis via 2-Hydroxyglutarate.

Biallelic germline mutations in the SLC25A1 gene lead to combined D/L-2-hydroxyglutaric aciduria (D/L-2HGA), a fatal systemic disease uniquely characterized by the accumulation of both enantiomers of 2-hydroxyglutaric acid (2HG). How SLC25A1 deficiency contributes to D/L-2HGA and the role played by 2HG is unclear and no therapy exists. Both enantiomers act as oncometabolites, but their activities in normal tissues remain understudied. Here we show that mice lacking both SLC25A1 alleles exhibit developmental abnormalities that mirror human D/L-2HGA. SLC25A1 deficient cells undergo premature senescence, suggesting that loss of proliferative capacity underlies the pathogenesis of D/L-2HGA. Remarkably, D- and L-2HG directly induce senescence and treatment of zebrafish embryos with the combination of D- and L-2HG phenocopies SLC25A1 loss, leading to developmental abnormalities in an additive fashion relative to either enantiomer alone. Metabolic analyses further demonstrate that cells with dysfunctional SLC25A1 undergo mitochondrial respiratory deficit and remodeling of the metabolism and we propose several strategies to correct these defects. These results reveal for the first time pathogenic and growth suppressive activities of 2HG in the context of SLC25A1 deficiency and suggest that targeting the 2HG pathway may be beneficial for the treatment of D/L-2HGA.

The prevalence of neurological disorders in older people in Tanzania.

OBJECTIVES: There are few data on neurological disorders prevalence from low- and middle-income countries, particularly sub-Saharan Africa (SSA) and none specific to the African elderly. We aimed to determined the prevalence of neurological disorders in those aged 70 years and over in a rural African community. MATERIALS AND METHODS: This study was a cross-sectional two-phased community epidemiological survey set in the rural Hai district of Tanzania. Screening was performed with a validated screening questionnaire with high sensitivity and specificity. Positive responders to screening underwent full neurological history and examination to confirm or refute the presence of neurological disorders and to classify the disorder using the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10). RESULTS: Of 2232 participants, there were 384 neurological diagnoses amongst 349 people. The age-adjusted prevalence of people with neurological diagnoses was 154.1 per 1000 (95% CI 139.2-169.1). The age-adjusted prevalence per 1000 of the most common neurological disorders were tremor (48.2), headache (41.8), stroke (23.0), peripheral polyneuropathy (18.6), upper limb mononeuropathy (6.5) and parkinsonism (5.9). CONCLUSIONS: This is the first published community-based neurological disorders prevalence study specifically in the elderly in SSA. It reveals a high prevalence of neurological morbidity and demonstrates the contribution neurological disorders make to the non-communicable disease epidemic. This is likely to increase as the population of low-income countries ages constituting a public health dilemma.

Day-case and in-patient elective inguinal hernia repair surgery across England: an observational study of variation and outcomes.

PURPOSE: Elective primary inguinal hernia repair surgery is increasingly being conducted as a day-case procedure. However, in England there is evidence of wide variation in day-case rates across hospitals. Reducing the extent of this variation has the potential to support more efficient use of resources (e.g., clinician time, hospital beds) and help the recovery of elective surgical activity following the COVID-19 pandemic. The aims of this study were to explore the extent of variation in day-case rates across healthcare providers in England and to evaluate the safety of day-case elective primary inguinal hernia repair surgery. METHODS: This was an exploratory, retrospective analysis of observational data from the Hospital Episode Statistics data set for England. All patients aged ≥ 17 years undergoing a first elective inguinal hernia repair between 1st April 2014 and 31st March 2022 were identified. The exposure of interest was day-case or in-patient stay, and the primary outcome of interest was 30-day emergency readmission with an overnight stay. For reporting, providers were aggregated to an Integrated Care Board (ICB) level. RESULTS: A total of 413,059 elective primary inguinal hernia repairs were identified over the 8-year study period. Of these, 326,833 (79.1%) were day-case procedures. During the most recent financial year (2021-22), the highest day-case rate for an ICB was 93.8% and the lowest 66.1%. After adjusting for covariates, day-case surgery was associated with significantly lower rates of 30-day emergency readmission (odds ratio (OR) 0.61, 95% confidence interval (CI) 0.58-0.64, p < 0.001) and for the secondary outcomes 180-day mortality and haemorrhage, infection and pain at 30-day post-discharge. Rates of 30-day emergency readmission were significantly lower in ICBs with high rates of day-case surgery (OR 0.84, 95% CI 0.74-0.96, p < 0.001) than in ICBs with low rates of day-case surgery, although rates of post-procedural haemorrhage within 30 days of discharge were significantly higher in trusts with high day-case rates (OR 1.20, 95% CI 1.04-1.40, p = 0.015). CONCLUSIONS: For the outcomes studied, we found no consistent evidence that day-case elective inguinal hernia repair was unsafe for selected patients. Currently, there is substantial variation between ICBs in terms of delivering day-case surgery. Reducing this variability may help address the current pressures on the NHS in elective surgery.