Glutamate neurotransmission from leptin receptor cells is required for typical puberty and reproductive function in female mice.

The hypothalamic ventral premammillary nucleus (PMv) is a glutamatergic nucleus essential for the metabolic control of reproduction. However, conditional deletion of leptin receptor (LepRb) in vesicular glutamate transporter 2 (Vglut2) expressing neurons results in virtually no reproductive deficits. In this study, we determine the role of glutamatergic signaling from leptin responsive PMv neurons on puberty and fertility. We first assessed if stimulation of PMv neurons induces LH release in fed adult females. We used the stimulatory form of designer receptor exclusively activated by designer drugs (DREADDs) in LepRb-Cre mice. We collected blood sequentially before and for 1h after iv. clozapine-N-oxide injection. LH level increased in animals correctly targeted to the PMv, and LH level was correlated to the number of cFos immunoreactive neurons in the PMv. Next, females with deletion of Vglut2 in LepRb neurons (LepR∆VGlut2) showed delayed age of puberty, disrupted estrous cycles, increased GnRH concentration in the axon terminals and disrupted LH responses, suggesting impaired GnRH release. To assess if glutamate is required for PMv actions in pubertal development, we generated a Cre-induced reexpression of endogenous LepRb (LepRloxTB) with concomitant deletion of Vglut2 (Vglut2-floxed) mice. Rescue of Lepr and deletion of Vglut2 in the PMv was obtained by stereotaxic injection of an adeno-associated virus vector expressing Cre recombinase. Control LepRloxTB mice with PMv LepRb rescue showed vaginal opening, follicle maturation and became pregnant, while LepRloxTB;Vglut2flox mice showed no pubertal development. Our results indicate that glutamatergic signaling from leptin sensitive neurons regulates the reproductive axis, and that leptin action on pubertal development via PMv neurons requires Vglut2.

Multiple NTS neuron populations cumulatively suppress food intake.

Several discrete groups of feeding-regulated neurons in the nucleus of the solitary tract (nucleus tractus solitarius; NTS) suppress food intake, including avoidance-promoting neurons that express Cck (NTSCck cells) and distinct Lepr- and Calcr-expressing neurons (NTSLepr and NTSCalcr cells, respectively) that suppress food intake without promoting avoidance. To test potential synergies among these cell groups, we manipulated multiple NTS cell populations simultaneously. We found that activating multiple sets of NTS neurons (e.g. NTSLepr plus NTSCalcr [NTSLC], or NTSLC plus NTSCck [NTSLCK]) suppressed feeding more robustly than activating single populations. While activating groups of cells that include NTSCck neurons promoted conditioned taste avoidance (CTA), NTSLC activation produced no CTA despite abrogating feeding. Thus, the ability to promote CTA formation represents a dominant effect but activating multiple non-aversive populations augments the suppression of food intake without provoking avoidance. Furthermore, silencing multiple NTS neuron groups augmented food intake and body weight to a greater extent than silencing single populations, consistent with the notion that each of these NTS neuron populations plays crucial and cumulative roles in the control of energy balance. We found that silencing NTSLCK neurons failed to blunt the weight-loss response to vertical sleeve gastrectomy (VSG) and that feeding activated many non-NTSLCK neurons, however, suggesting that as-yet undefined NTS cell types must make additional contributions to the restraint of feeding.

Report From the 2022 Mary Tyler Moore Vision Initiative Diabetic Retinal Disease Clinical Endpoints Workshop.

The Mary Tyler Moore Vision Initiative Diabetic Retinal Disease (DRD) Clinical Endpoints Workshop was held on October 22, 2022 to accelerate progress toward establishment of useful clinical and research endpoints and development of new therapeutics that have important relevance across the full spectrum of DRD pathology. More than 90 patient representatives, clinicians, scientists, funding and regulatory agencies, diagnostic, therapeutic and biotech industry representatives discussed the needs for new diagnostic and therapeutic approaches to prevent and restore retinal neurovascular unit integrity. Phase I of the MTM Vision Initiative plans, notably updating the DRD staging system and severity scale, establishing a human ocular biorepository and resource, and clinical endpoints and biomarker development and validation, was emphasized.

Suppression of food intake by Glp1r/Lepr-coexpressing neurons prevents obesity in mouse models.

The adipose-derived hormone leptin acts via its receptor (LepRb) in the brain to control energy balance. A potentially unidentified population of GABAergic hypothalamic LepRb neurons plays key roles in the restraint of food intake and body weight by leptin. To identify markers for candidate populations of LepRb neurons in an unbiased manner, we performed single-nucleus RNA-Seq of enriched mouse hypothalamic LepRb cells, identifying several previously unrecognized populations of hypothalamic LepRb neurons. Many of these populations displayed strong conservation across species, including GABAergic Glp1r-expressing LepRb (LepRbGlp1r) neurons, which expressed more Lepr than other LepRb cell populations. Ablating Lepr from LepRbGlp1r cells provoked hyperphagic obesity without impairing energy expenditure. Similarly, improvements in energy balance caused by Lepr reactivation in GABA neurons of otherwise Lepr-null mice required Lepr expression in GABAergic Glp1r-expressing neurons. Furthermore, restoration of Glp1r expression in LepRbGlp1r neurons in otherwise Glp1r-null mice enabled food intake suppression by the GLP1R agonist, liraglutide. Thus, the conserved GABAergic LepRbGlp1r neuron population plays crucial roles in the suppression of food intake by leptin and GLP1R agonists.

Eleven key measures for monitoring general practice clinical activity during COVID-19: A retrospective cohort study using 48 million adults' primary care records in England through OpenSAFELY.

Background: The COVID-19 pandemic has had a significant impact on delivery of NHS care. We have developed the OpenSAFELY Service Restoration Observatory (SRO) to develop key measures of primary care activity and describe the trends in these measures throughout the COVID-19 pandemic. Methods: With the approval of NHS England, we developed an open source software framework for data management and analysis to describe trends and variation in clinical activity across primary care electronic health record (EHR) data on 48 million adults.We developed SNOMED-CT codelists for key measures of primary care clinical activity such as blood pressure monitoring and asthma reviews, selected by an expert clinical advisory group and conducted a population cohort-based study to describe trends and variation in these measures January 2019-December 2021, and pragmatically classified their level of recovery one year into the pandemic using the percentage change in the median practice level rate. Results: We produced 11 measures reflective of clinical activity in general practice. A substantial drop in activity was observed in all measures at the outset of the COVID-19 pandemic. By April 2021, the median rate had recovered to within 15% of the median rate in April 2019 in six measures. The remaining measures showed a sustained drop, ranging from a 18.5% reduction in medication reviews to a 42.0% reduction in blood pressure monitoring. Three measures continued to show a sustained drop by December 2021. Conclusions: The COVID-19 pandemic was associated with a substantial change in primary care activity across the measures we developed, with recovery in most measures. We delivered an open source software framework to describe trends and variation in clinical activity across an unprecedented scale of primary care data. We will continue to expand the set of key measures to be routinely monitored using our publicly available NHS OpenSAFELY SRO dashboards with near real-time data. Funding: This research used data assets made available as part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref MC_PC_20058).The OpenSAFELY Platform is supported by grants from the Wellcome Trust (222097/Z/20/Z); MRC (MR/V015757/1, MC_PC-20059, MR/W016729/1); NIHR (NIHR135559, COV-LT2-0073), and Health Data Research UK (HDRUK2021.000, 2021.0157).

Beginning to address vaccine reluctance and refusal.

Those who refuse immunizations are risks to the public health. Others who are vaccine reluctant are also problematic because they may reinforce the uncertainties of others and refuse vaccines in the future. Common to the multiple, complex causes of vaccine reluctance and refusal is the fact that many have little knowledge about microbiology, infectious diseases, or public health. Consequently, it is not surprising that many have questions about vaccines, find making vaccine decisions difficult, and are vulnerable to vaccine misinformation. Therefore, improving the knowledge of consumers about these biologic sciences would seem to be essential to begin addressing vaccine reluctance and refusal. This would be most effective if it were accomplished before they need to begin to make vaccine decisions.

European Society of Hypertension recommendations for the validation of cuffless blood pressure measuring devices: European Society of Hypertension Working Group on Blood Pressure Monitoring and Cardiovascular Variability.

BACKGROUND: There is intense effort to develop cuffless blood pressure (BP) measuring devices, and several are already on the market claiming that they provide accurate measurements. These devices are heterogeneous in measurement principle, intended use, functions, and calibration, and have special accuracy issues requiring different validation than classic cuff BP monitors. To date, there are no generally accepted protocols for their validation to ensure adequate accuracy for clinical use. OBJECTIVE: This statement by the European Society of Hypertension (ESH) Working Group on BP Monitoring and Cardiovascular Variability recommends procedures for validating intermittent cuffless BP devices (providing measurements every >30 sec and usually 30-60 min, or upon user initiation), which are most common. VALIDATION PROCEDURES: Six validation tests are defined for evaluating different aspects of intermittent cuffless devices: static test (absolute BP accuracy); device position test (hydrostatic pressure effect robustness); treatment test (BP decrease accuracy); awake/asleep test (BP change accuracy); exercise test (BP increase accuracy); and recalibration test (cuff calibration stability over time). Not all these tests are required for a given device. The necessary tests depend on whether the device requires individual user calibration, measures automatically or manually, and takes measurements in more than one position. CONCLUSION: The validation of cuffless BP devices is complex and needs to be tailored according to their functions and calibration. These ESH recommendations present specific, clinically meaningful, and pragmatic validation procedures for different types of intermittent cuffless devices to ensure that only accurate devices will be used in the evaluation and management of hypertension.

National recommendations to standardise acute kidney injury detection and alerting.

BACKGROUND: National Health Service England issued a Patient Safety Alert in 2014 mandating all acute Trusts in England to implement Acute Kidney Injury (AKI) warning stage results and to do so using a standardised algorithm. In 2021, the Renal and Pathology Getting It Right First Time (GIRFT) teams found significant variation in AKI reporting across the UK. A survey was designed to capture information on the entire AKI detection and alerting process to investigate the potential sources of this unwarranted variation. METHODS: In August 2021, an online survey consisting of 54 questions was made available to all UK laboratories. The questions covered creatinine assays, laboratory information management systems (LIMS), the AKI algorithm and AKI reporting. RESULTS: We received 101 responses from laboratories. Data were reviewed for England only - 91 laboratories. Findings included that 72% used enzymatic creatinine. In addition, 7 manufacturer-analytical platforms, 15 different LIMS and a wide range of creatinine reference ranges were in use. In 68% of laboratories, the AKI algorithm was installed by the LIMS provider. Marked variation was found in the minimum age of AKI reporting with only 18% starting at the recommended 1 month/28-days. Some 89% phoned all new AKI2s and AKI3s, as per AKI guidance while 76% provided comments/hyperlinks in reports. CONCLUSIONS: The national survey has identified laboratory practices that potentially contribute to unwarranted variation in the reporting of AKI in the England. This has formed the basis for improvement work to remedy the situation, including national recommendations, included within this article.

OpenSAFELY NHS Service Restoration Observatory 2: changes in primary care clinical activity in England during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has disrupted healthcare activity across a broad range of clinical services. The NHS stopped non-urgent work in March 2020, later recommending services be restored to near-normal levels before winter where possible. AIM: To describe changes in the volume and variation of coded clinical activity in general practice across six clinical areas: cardiovascular disease, diabetes, mental health, female and reproductive health, screening and related procedures, and processes related to medication. DESIGN AND SETTING: With the approval of NHS England, a cohort study was conducted of 23.8 million patient records in general practice, in situ using OpenSAFELY. METHOD: Common primary care activities were analysed using Clinical Terms Version 3 codes and keyword searches from January 2019 to December 2020, presenting median and deciles of code usage across practices per month. RESULTS: Substantial and widespread changes in clinical activity in primary care were identified since the onset of the COVID-19 pandemic, with generally good recovery by December 2020. A few exceptions showed poor recovery and warrant further investigation, such as mental health (for example, for 'Depression interim review' the median occurrences across practices in December 2020 was down by 41.6% compared with December 2019). CONCLUSION: Granular NHS general practice data at population-scale can be used to monitor disruptions to healthcare services and guide the development of mitigation strategies. The authors are now developing real-time monitoring dashboards for the key measures identified in this study, as well as further studies using primary care data to monitor and mitigate the indirect health impacts of COVID-19 on the NHS.

Neither GLP-1 receptors nor GFRAL neurons are required for aversive or anorectic response to DON (vomitoxin).

Deoxynivalenol (DON), a type B trichothecene mycotoxin contaminating grains, promotes nausea, emesis and anorexia. With DON exposure, circulating levels of intestinally derived satiation hormones, including glucagon-like peptide 1 (GLP-1) are elevated. To directly test whether GLP-1 signaling mediates the effects of DON, we examined the response of GLP-1 or GLP-1R-deficient mice to DON injection. We found comparable anorectic and conditioned taste avoidance learning responses in GLP-1/GLP-1R deficient mice compared to control littermates, suggesting that GLP-1 is not necessary for the effects of DON on food intake and visceral illness. We then used our previously published data from translating ribosome affinity purification with RNA sequencing (TRAP-seq) analysis of area postrema neurons that express the receptor for the circulating cytokine growth differentiation factor (GDF15), growth differentiation factor a-like (GFRAL). Interestingly, this analysis showed that a cell surface receptor for DON, calcium sensing receptor (CaSR), is heavily enriched in GFRAL neurons. Given that GDF15 potently reduces food intake and can cause visceral illness by signaling through GFRAL neurons, we hypothesized that DON may also signal by activating CaSR on GFRAL neurons. Indeed, circulating GDF15 levels are elevated after DON administration but both GFRAL knockout and GFRAL neuron-ablated mice exhibited similar anorectic and conditioned taste avoidance responses compared to WT littermates. Thus, GLP-1 signaling and GFRAL signaling and neurons are not required for DON-induced visceral illness or anorexia.

Role of the Beta and Gamma Isoforms of the Adapter Protein SH2B1 in Regulating Energy Balance.

Human variants of the adapter protein SH2B1 are associated with severe childhood obesity, hyperphagia, and insulin resistance-phenotypes mimicked by mice lacking Sh2b1. SH2B1ß and γ isoforms are expressed ubiquitously, whereas SH2B1α and δ isoforms are expressed primarily in the brain. Restoring SH2B1ß driven by the neuron-specific enolase promoter largely reverses the metabolic phenotype of Sh2b1-null mice, suggesting crucial roles for neuronal SH2B1ß in energy balance control. Here we test this hypothesis by using CRISPR/Cas9 gene editing to delete the ß and γ isoforms from the neurons of mice (SH2B1ßγ neuron-specific knockout [NKO] mice) or throughout the body (SH2B1ßγ knockout [KO] mice). While parameters of energy balance were normal in both male and female SH2B1ßγ NKO mice, food intake, body weight, and adiposity were increased in male (but not female) SH2B1ßγ KO mice. Analysis of long-read single-cell RNA seq data from wild-type mouse brain revealed that neurons express almost exclusively the α and δ isoforms, whereas neuroglial cells express almost exclusively the ß and γ isoforms. Our work suggests that neuronal SH2B1ß and γ are not primary regulators of energy balance. Rather, non-neuronal SH2B1ß and γ in combination with neuronal SH2B1α and δ suffice for body weight maintenance. While SH2B1ß/γ and SH2B1α/δ share some functionality, SH2B1ß/γ appears to play a larger role in promoting leanness.

Deletion of Androgen Receptor in LepRb Cells Improves Estrous Cycles in Prenatally Androgenized Mice.

Androgens are steroid hormones crucial for sexual differentiation of the brain and reproductive function. In excess, however, androgens may decrease fertility as observed in polycystic ovary syndrome, a common endocrine disorder characterized by oligo/anovulation and/or polycystic ovaries. Hyperandrogenism may also disrupt energy homeostasis, inducing higher central adiposity, insulin resistance, and glucose intolerance, which may exacerbate reproductive dysfunction. Androgens bind to androgen receptors (ARs), which are expressed in many reproductive and metabolic tissues, including brain sites that regulate the hypothalamo-pituitary-gonadal axis and energy homeostasis. The neuronal populations affected by androgen excess, however, have not been defined. We and others have shown that, in mice, AR is highly expressed in leptin receptor (LepRb) neurons, particularly in the arcuate (ARH) and the ventral premammillary nuclei (PMv). Here, we assessed if LepRb neurons, which are critical in the central regulation of energy homeostasis and exert permissive actions on puberty and fertility, have a role in the pathogenesis of female hyperandrogenism. Prenatally androgenized (PNA) mice lacking AR in LepRb cells (LepRbΔAR) show no changes in body mass, body composition, glucose homeostasis, or sexual maturation. They do show, however, a remarkable improvement of estrous cycles combined with normalization of ovary morphology compared to PNA controls. Our findings indicate that the prenatal androgenization effects on adult reproductive physiology (ie, anestrus and anovulation) are mediated by a subpopulation of LepRb neurons directly sensitive to androgens. They also suggest that the effects of hyperandrogenism on sexual maturation and reproductive function in adult females are controlled by distinct neural circuits.

LepRb+ cell-specific deletion of Slug mitigates obesity and nonalcoholic fatty liver disease in mice.

Leptin exerts its biological actions by activating the long-form leptin receptor (LepRb). LepRb signaling impairment and leptin resistance are believed to cause obesity. The transcription factor Slug - also known as Snai2 - recruits epigenetic modifiers and regulates gene expression by an epigenetic mechanism; however, its epigenetic action has not been explored in leptin resistance. Here, we uncover a proobesity function of neuronal Slug. Hypothalamic Slug was upregulated in obese mice. LepRb+ cell-specific Slug-knockout (SlugΔLepRb) mice were resistant to diet-induced obesity, type 2 diabetes, and liver steatosis and experienced decreased food intake and increased fat thermogenesis. Leptin stimulated hypothalamic Stat3 phosphorylation and weight loss to a markedly higher level in SlugΔLepRb than in Slugfl/fl mice, even before their body weight divergence. Conversely, hypothalamic LepRb+ neuron-specific overexpression of Slug, mediated by AAV-hSyn-DIO-Slug transduction, induced leptin resistance, obesity, and metabolic disorders in mice on a chow diet. At the genomic level, Slug bound to and repressed the LepRb promoter, thereby inhibiting LepRb transcription. Consistently, Slug deficiency decreased methylation of LepRb promoter H3K27, a repressive epigenetic mark, and increased LepRb mRNA levels in the hypothalamus. Collectively, these results unravel what we believe to be a previously unrecognized hypothalamic neuronal Slug/epigenetic reprogramming/leptin resistance axis that promotes energy imbalance, obesity, and metabolic disease.

TBK1-mTOR Signaling Attenuates Obesity-Linked Hyperglycemia and Insulin Resistance.

The innate immune kinase TBK1 (TANK-binding kinase 1) responds to microbial-derived signals to initiate responses against viral and bacterial pathogens. More recent work implicates TBK1 in metabolism and tumorigenesis. The kinase mTOR (mechanistic target of rapamycin) integrates diverse environmental cues to control fundamental cellular processes. Our prior work demonstrated in cells that TBK1 phosphorylates mTOR (on S2159) to increase mTORC1 and mTORC2 catalytic activity and signaling. Here we investigate a role for TBK1-mTOR signaling in control of glucose metabolism in vivo. We find that mice with diet-induced obesity (DIO) but not lean mice bearing a whole-body "TBK1-resistant" Mtor S2159A knock-in allele (MtorA/A) display exacerbated hyperglycemia and systemic insulin resistance with no change in energy balance. Mechanistically, Mtor S2159A knock-in in DIO mice reduces mTORC1 and mTORC2 signaling in response to insulin and innate immune agonists, reduces anti-inflammatory gene expression in adipose tissue, and blunts anti-inflammatory macrophage M2 polarization, phenotypes shared by mice with tissue-specific inactivation of TBK1 or mTOR complexes. Tissues from DIO mice display elevated TBK1 activity and mTOR S2159 phosphorylation relative to lean mice. We propose a model whereby obesity-associated signals increase TBK1 activity and mTOR phosphorylation, which boost mTORC1 and mTORC2 signaling in parallel to the insulin pathway, thereby attenuating insulin resistance to improve glycemic control during diet-induced obesity.

Hindbrain circuits in the control of eating behaviour and energy balance.

Body weight and adiposity represent biologically controlled parameters that are influenced by a combination of genetic, developmental and environmental variables. Although the hypothalamus plays a crucial role in matching caloric intake with energy expenditure to achieve a stable body weight, it is now recognized that neuronal circuits in the hindbrain not only serve to produce nausea and to terminate feeding in response to food consumption or during pathological states, but also contribute to the long-term control of body weight. Additionally, recent work has identified hindbrain neurons that are capable of suppressing food intake without producing aversive responses like those associated with nausea. Here we review recent advances in our understanding of the hindbrain neurons that control feeding, particularly those located in the area postrema and the nucleus tractus solitarius. We frame this information in the context of new atlases of hindbrain neuronal populations and develop a model of the hindbrain circuits that control food intake and energy balance, suggesting important areas for additional research.

Cuffless blood pressure measuring devices: review and statement by the European Society of Hypertension Working Group on Blood Pressure Monitoring and Cardiovascular Variability.

BACKGROUND: Many cuffless blood pressure (BP) measuring devices are currently on the market claiming that they provide accurate BP measurements. These technologies have considerable potential to improve the awareness, treatment, and management of hypertension. However, recent guidelines by the European Society of Hypertension do not recommend cuffless devices for the diagnosis and management of hypertension. OBJECTIVE: This statement by the European Society of Hypertension Working Group on BP Monitoring and Cardiovascular Variability presents the types of cuffless BP technologies, issues in their validation, and recommendations for clinical practice. STATEMENTS: Cuffless BP monitors constitute a wide and heterogeneous group of novel technologies and devices with different intended uses. Cuffless BP devices have specific accuracy issues, which render the established validation protocols for cuff BP devices inadequate for their validation. In 2014, the Institute of Electrical and Electronics Engineers published a standard for the validation of cuffless BP devices, and the International Organization for Standardization is currently developing another standard. The validation of cuffless devices should address issues related to the need of individual cuff calibration, the stability of measurements post calibration, the ability to track BP changes, and the implementation of machine learning technology. Clinical field investigations may also be considered and issues regarding the clinical implementation of cuffless BP readings should be investigated. CONCLUSION: Cuffless BP devices have considerable potential for changing the diagnosis and management of hypertension. However, fundamental questions regarding their accuracy, performance, and implementation need to be carefully addressed before they can be recommended for clinical use.

Remote digital urinalysis with smartphone technology as part of remote management of glomerular disease during the SARS-CoV-2 virus pandemic: single-centre experience in 25 patients.

Background: The COVID-19 pandemic has necessitated the provision of healthcare through remote and increasingly digitalized means. The management of glomerular pathology, for which urinalysis is crucial, has been notably affected. Here we describe our single-centre experience of using remote digital urinalysis in the management of patients with glomerular disease during the COVID-19 pandemic. Method: All patients with native kidney glomerular disease who consented to participate in digital smartphone urinalysis monitoring between March 2020 and July 2021 were included. Electronic health records were contemporaneously reviewed for outcome data. Patient feedback was obtained through the testing portal. Results: Twenty-five patients utilized the digital urinalysis application. A total of 105 digital urinalysis tests were performed for a wide variety of indications. Four patients experienced a relapse (detected remotely) and two patients underwent three successful pregnancies. The majority of patients were managed virtually (60%) or virtually and face to face (F2F) combined (32%). The average number of clinic reviews and urine tests performed during the pandemic either virtually and/or F2F was comparable to levels pre-pandemic and the ratio of reviews to urinalysis (R:U) was stable (pre-pandemic 1:0.9 versus during the pandemic 1:0.8). Patients seen exclusively F2F with supplementary home monitoring had the highest R:U ratio at 1:2.1. A total of 95% of users provided feedback, all positive. Conclusion: Remote urinalysis proved a safe and convenient tool to facilitate decision-making where traditional urinalysis was difficult, impractical or impossible. Our approach allowed us to continue care in this vulnerable group of patients despite a lack of access to traditional urinalysis.

Amantadine as a Potential Treatment for Marchiafava-Bignami Disease: Case Reports and a Possible Mechanism.

Introduction: Several reports have described the use of amantadine for managing symptoms in Marchiafava-Bignami disease (MBD); however, amantadine's role for the treatment of MBD symptoms is unclear. Here, we describe 2 patients with MBD who were treated with amantadine and hypothesize a potential mechanism responsible for clinical benefit. Case 1. A 38-year-old woman with excessive wine drinking presented with agitation, impaired speech, and a minimally conscious state. MRI revealed lesions in the splenium and genu. After being diagnosed with MBD, she was treated with intravenous thiamine, multivitamins, and 100 mg of amantadine twice a day for 2 weeks. She recovered to near baseline after 3 weeks. Case 2. A 54-year-old woman with years of heavy alcohol use presented with sudden bradyphrenia, acalculia, disinhibited behavior, weakness, and urinary incontinence. MRI revealed a large anterior callosal lesion. Two years after initial recovery from MBD, she noted that consuming "energy drinks" resulted in a transient, near-complete resolution of her residual behavioral, fatigue, and language symptoms. 100 mg of amantadine twice a day was trialled. After noted improvement, a further escalation to 200 mgs 3 times a day resulted in significant improvement in language and behavioral symptoms. Conclusion: Amantadine in addition to vitamins may be beneficial in the treatment of MBD. It is possible that the dopaminergic effect of amantadine leads to improved recovery and function in dopamine-mediated pathways, including mesocortical and mesolimbic pathways during initial recovery, as well as improved speech, behavior, and fatigue in the following months. The role of amantadine in the treatment of MBD warrants further study.

A cohort study of duplicate faecal immunochemical testing in patients at risk of colorectal cancer from North-West England.

OBJECTIVES: We sought to investigate if duplicate faecal immunochemical testing (FIT) sampling improves the negative and positive predictive value of patients thought to be at risk of colorectal cancer (CRC). Specifically, we aimed to investigate whether the proportion of FIT-negative CRC missed by a single FIT test in symptomatic patients could be reduced by duplicate FIT testing. DESIGN: A retrospective service evaluation cohort study of the diagnostic accuracy of duplicate FIT testing. SETTING: Patients referred from primary care with suspected CRC to four secondary care trusts in North-West England. PARTICIPANTS: 28 622 patients over 18-years-old with lower gastrointestinal symptoms suggestive of CRC who completed two FIT samples. PRIMARY AND SECONDARY OUTCOME MEASURES: The performance of duplicate FIT for detecting CRC at a threshold of 10 µgHb/g. RESULTS: The sensitivity if either test was >10 µgHb/g was 0.978 (0.955-0.989), specificity was 0.662 (0.657-0.668), positive predictive value 0.031 (0.028-0.035) and negative predictive value 1.00 (0.999-1.00). Despite two-thirds of patients (18952) being negative following two tests, at this threshold only seven CRC were missed over a 26-month period. All seven patients had other high-risk features which should have prompted investigation. CONCLUSIONS: This study suggests that in routine NHS practice, a duplicate FIT sample strategy together with clinical evaluation for evidence of anaemia and weight loss is superior to a single FIT sample alone and would allow symptomatic patients to be managed in primary care without the need for urgent referral to secondary care for urgent colonic imaging.

Clinical Trial Design Principles and Outcomes Definitions for Device-Based Therapies for Hypertension: A Consensus Document From the Hypertension Academic Research Consortium.

The clinical implications of hypertension in addition to a high prevalence of both uncontrolled blood pressure and medication nonadherence promote interest in developing device-based approaches to hypertension treatment. The expansion of device-based therapies and ongoing clinical trials underscores the need for consistency in trial design, conduct, and definitions of clinical study elements to permit trial comparability and data poolability. Standardizing methods of blood pressure assessment, effectiveness measures beyond blood pressure alone, and safety outcomes are paramount. The Hypertension Academic Research Consortium (HARC) document represents an integration of evolving evidence and consensus opinion among leading experts in cardiovascular medicine and hypertension research with regulatory perspectives on clinical trial design and methodology. The HARC document integrates the collective information among device-based therapies for hypertension to better address existing challenges and identify unmet needs for technologies proposed to treat the world's leading cause of death and disability. Consistent with the Academic Research Consortium charter, this document proposes pragmatic consensus clinical design principles and outcomes definitions for studies aimed at evaluating device-based hypertension therapies.