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The hippocampus is heterogeneous in its architecture. It contributes to cognitive processes such as memory and spatial navigation and is susceptible to neurodegenerative disease. Cytoarchitectural features such as neuron size and neuronal collinearity have been used to parcellate the hippocampal subregions. Moreover, pyramidal neuron orientation (orientation of one individual neuron) and collinearity (how neurons align) have been investigated as a measure of disease in schizophrenia. However, a comprehensive quantitative study of pyramidal neuron orientation and collinearity within the hippocampal subregions has not yet been conducted. In this study, we present a high-throughput deep learning approach for the automated extraction of pyramidal neuron orientation in the hippocampal subregions. Based on the pretrained Cellpose algorithm for cellular segmentation, we measured 479 873 pyramidal neurons in 168 hippocampal partitions. We corrected the neuron orientation estimates to account for the curvature of the hippocampus and generated collinearity measures suitable for inter- and intra-individual comparisons. Our deep learning results were validated with manual orientation assessment. This study presents a quantitative metric of pyramidal neuron collinearity within the hippocampus. It reveals significant differences among the individual hippocampal subregions ( P   < 0.001), with cornu ammonis 3 being the most collinear, followed by cornu ammonis 2, cornu ammonis 1, the medial/uncal subregions and subiculum. Our data establishes pyramidal neuron collinearity as a quantitative parameter for hippocampal subregion segmentation, including the differentiation of cornu ammonis 2 and cornu ammonis 3. This novel deep learning approach could facilitate large-scale multicentric analyses in subregion parcellation and lays groundwork for the investigation of mental illnesses at the cellular level., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Neuroimaging studies have routinely used hippocampal volume as a measure of Alzheimer's disease severity, but hippocampal changes occur too late in the disease process for potential therapies to be effective. The entorhinal cortex is one of the first cortical areas affected by Alzheimer's disease; its neurons are especially vulnerable to neurofibrillary tangles. Entorhinal atrophy also relates to the conversion from non-clinical to clinical Alzheimer's disease. In neuroimaging, the human entorhinal cortex has so far mostly been considered in its entirety or divided into a medial and a lateral region. Cytoarchitectonic differences provide the opportunity for subfield parcellation. We investigated the entorhinal cortex on a subfield-specific level-at a critical time point of Alzheimer's disease progression. While MRI allows multidimensional quantitative measurements, only histology provides enough accuracy to determine subfield boundaries-the pre-requisite for quantitative measurements within the entorhinal cortex. This study used histological data to validate ultra-high-resolution 7 Tesla ex vivo MRI and create entorhinal subfield parcellations in a total of 10 pre-clinical Alzheimer's disease and normal control cases. Using ex vivo MRI, eight entorhinal subfields (olfactory, rostral, medial intermediate, intermediate, lateral rostral, lateral caudal, caudal, and caudal limiting) were characterized for cortical thickness , volume , and pial surface area . Our data indicated no influence of sex, or Braak and Braak staging on volume , cortical thickness , or pial surface area . The volume and pial surface area for mean whole entorhinal cortex were 1131 ± 55.72 mm 3 and 429 ± 22.6 mm 2 (mean ± SEM), respectively. The subfield volume percentages relative to the entire entorhinal cortex were olfactory: 18.73 ± 1.82%, rostral: 14.06 ± 0.63%, lateral rostral: 14.81 ± 1.22%, medial intermediate: 6.72 ± 0.72%, intermediate: 23.36 ± 1.85%, lateral caudal: 5.42 ± 0.33%, caudal: 10.99 ± 1.02%, and caudal limiting: 5.91 ± 0.40% (all mean ± SEM). Olfactory and intermediate subfield revealed the most extensive intra-individual variability (cross-subject variance) in volume and pial surface area. This study provides validated measures. It maps individuality and demonstrates human variability in the entorhinal cortex, providing a baseline for approaches in individualized medicine. Taken together, this study serves as a ground-truth validation study for future in vivo comparisons and treatments., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Organisms adapted to life in extreme habitats (extremophiles) can further our understanding of the mechanisms of genetic stability, particularly replication and repair. Despite the harsh environmental conditions they endure, these extremophiles represent a great deal of the Earth's biodiversity. Here, for the first time in a member of the archaeal domain, we report a genome-wide assay of spontaneous mutations in the halophilic species Haloferax volcanii using a direct and unbiased method: mutation accumulation experiments combined with deep whole-genome sequencing. H. volcanii is a key model organism not only for the study of halophilicity, but also for archaeal biology in general. Our methods measure the genome-wide rate, spectrum, and spatial distribution of spontaneous mutations. The estimated base substitution rate of 3.15 × 10 -10 per site per generation, or 0.0012 per genome per generation, is similar to the value found in mesophilic prokaryotes (optimal growth at ∼20-45°). This study contributes to a comprehensive phylogenetic view of how evolutionary forces and molecular mechanisms shape the rate and molecular spectrum of mutations across the tree of life., (Copyright © 2020 by the Genetics Society of America.)

Engineering of enzymes to more efficiently activate genotoxic prodrugs holds great potential for improving anticancer gene or antibody therapies. We report the development of a new, GFP-based, high-throughput screening platform to enable engineering of prodrug-activating enzymes by directed evolution. By fusing an inducible SOS promoter to an engineered GFP reporter gene, we were able to measure levels of DNA damage in intact Escherichia coli and separate cell populations by fluorescence activating cell sorting (FACS). In two FACS iterations, we were able to achieve a 90,000-fold enrichment of a functional prodrug-activating nitroreductase from a null library background., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Anecdotal accounts indicate that Basic Combat Training (BCT) is associated with significant sleep impairment, which conceivably could impact health, attrition, and training. However, there has been little empirical investigation of sleep during BCT. The aim of this study was to obtain a qualitative assessment of soldiers' perceptions about their sleep and consequences of sleep disruption during BCT. During November/December of 2010, focus group discussions were conducted with soldiers, ages > or = 18 years, who had completed at least 4 weeks of BCT at Fort Jackson, SC. The soldiers were assessed in 45 to 60 min sessions involving three groups of female soldiers (total n = 28) and three groups of male soldiers (total n = 38). Soldiers reported reductions in their sleep duration and quality, which were attributed to many factors, particularly noise, nighttime work detail, stress, and hunger. These sleep changes had many perceived negative effects on performance, mood, and other components of BCT. These effects were more evident in soldiers of lower physical fitness. This study suggests associations between sleep and BCT outcomes. Whether these associations warrant changes in the sleep environment of BCT will require much further investigation.

The Soldier Health Promotion to Examine and Reduce Health Disparities (SHPERHD) Project was designed to be a partnership between the Institute for Partnerships to Eliminate Health Disparities at the University of South Carolina and the Fort Jackson United States Army Base located in Columbia, South Carolina. SHPERHD Project researchers are studying problems related to obesity and weight management, musculoskeletal injuries and infection, and mental health issues during recruitment, basic training, and post-deployment. In order to successfully develop targeted interventions to prevent and lower the incidence of injury, promote healthy nutrition, and decrease mental health issues, at the same time also reducing disparity gaps, the SHPERHD Project comprises a professional, technical, and administrative staff with specific competence in the operation of a Coordinating Center to handle the wide variety of areas related to military studies. This article discusses the procedures and processes that were implemented in the development of the SHPERHD Project Coordinating Center.

Objectives: Comorbid conditions in colorectal cancer patients can influence both clinical eligibility for treatment and survival. We aimed to evaluate the effect of comorbidity on 1 year survival from colorectal cancer, and to assess whether this effect varied with the timing of the comorbidity in relation to the cancer diagnosis., Study Design and Setting: A population based cohort of 29,563 colorectal cancer patients diagnosed between 1997 and 2004 in the North West of England was evaluated. The excess hazard of death up to 1 year after diagnosis was estimated using deprivation and region specific life tables to adjust for background mortality. Results were adjusted for age and stage at diagnosis., Results: Comorbid conditions diagnosed during the period 18 to 6 months before the diagnosis of colorectal cancer were strongly associated with lower survival at 1 year. Stage and age remained the strongest predictors of cancer related mortality even after adjustment for comorbidity., Conclusions: Administrative data provide a good estimate of the prevalence of most comorbid conditions but may be biased for some comorbid conditions that can be contra-indicators for cancer treatment. The time window in which a comorbid condition occurs in relation to the cancer diagnosis should be taken into account. Adjustment should be carried out, where possible, to provide more robust and clinically appropriate comparisons of population based cancer patient survival.

Broken configuration errors on the WAIS-R Block Design subtest have been associated with right hemisphere brain damage. This study examined whether pre-surgical epilepsy patients with seizure foci restricted to the right hemisphere would break configuration more frequently than those with left hemisphere foci. Subjects included 38 patients with unilateral right or left hemisphere epilepsy of frontal or temporal lobe origin. The left and right hemisphere groups did not differ significantly in demographic or disease variables, IQ, or Block Design standard scores. Right hemisphere patients made more broken configurations than did those with left hemisphere foci. In the right hemisphere group, more broken configurations were associated with a lower Block Design Scaled Score and Full Scale IQ. These results suggest that the observation of broken configurations in the Block Design can assist in corroborating the seizure focus and highlight the importance of qualitative Block Design analysis.

Background: In cancer registration, data cleaning (i.e. amendments made by data users to datasets released by registries) is potentially informative for quality assurance, but generally underreported., Aim: To assess the scope for learning lessons about cancer registration quality assurance from a data user (using skin cancer as the example)., Methods: The main design features were: (i) A descriptive study identifying, qualitatively and quantitatively, the breadth, depth, and impact of quality assurance issues raised by a user cleaning Merseyside and Cheshire Cancer Registry skin cancer data. Errors were rectified and pitfalls for interpretation were identified. (ii) A nested validation of morphology and site coding on random samples of cutaneous malignant melanomas, basal cell carcinomas (BCC), and squamous cell carcinomas. The 33132-record dataset comprised: all registered skin lesions, except metastases; most recorded variables (about patient, lesion, treatment, outcome); for Merseyside and Cheshire residents diagnosed 1970-1991., Results: (i) Ineligible cases represented 0.3% (97/33132), and were detected best by morphology checks. Most quality assurance issues identified related to local custom and practice, staff training, and computerization, being particularly illustrated by problematic BCC registration practice (e.g. records written over unchallenged by range checks; and idiosyncratic use of variables). (ii) Post-cleaning, morphology coding errors were minimal in the random samples., Conclusion: There is great scope for data users to contribute to cancer registration quality assurance. Ultimately, the study dataset appeared fit for epidemiological analysis and important quality assurance messages emerged. Shared explicit standard guidelines for data preparation and validation are needed by users, whose insights could and should be better recognized by cancer registries.

Background: This review aims to document and analyse aspects of death certification that are relevant to public health., Methods: A literature review on death certification primarily used the computerized Index Medicus (1981 to mid-1995), and concentrated on completing death certificates, accuracy, standards, education and procedural requirements. Further sentinel publications pre-dating this were identified from the main literature base., Results: The uses of mortality data, historical and procedural context for recording death, the philosophy of Underlying Cause of Death and its relationship to the truth, the extent and impact of "inaccuracy', the certificate and the certifier, and possible ways forward are discussed. It is argued that the question "How inaccurate are cause of death data?' is harder to answer than the literature suggests. Deriving a useful estimate is difficult because of inter-study differences in (1) definition, measurement (how and by whom?) and practical importance of error, and standards used; (2) focus (e.g. death certificate or mortality data), observing everyday practice or simulation exercises, diagnostic and/or semantic issues., Conclusion: The traditional perspective on improving the quality of death certification has not worked. There is a need for reorientated thinking rather than just urging more education. Evidence-based educational interventions are needed. The flaws in the theoretical framework of cause of death and the routine nature of death certification are unavoidable, but require consideration. Certifiers need practical feedback mechanisms, integral to continuing quality assurance at all levels and fostering an understanding of the construction of mortality data. Continued development should be a core public health medicine role.

Background: We examined the circumstances surrounding death from asthma in Mersey Region and the feasibility of conducting a regional confidential enquiry, as suggested by the British Thoracic Society in response to the proposal in the Green Paper the health of the nation that asthma should be a key area for action., Method: Sixty-three Mersey residents, aged 16-65 years, died in Mersey Region in 1989 and 1990 with ICD code 493. Diagnostic criteria for asthma were applied to each case. Anonymized case-note summaries were assessed by a chest physician (M.P.) for (1) severity of symptoms/disease, (2) risk of a respiratory death and (3)avoidable factors in the circumstances surrounding death., Results: Some written information was available on every patients. In 43/63 (68 percent) cases asthma was the true cause of death; 41/43 had had asthma diagnosed in life. Mean age (47 years) and median age of onset of asthma (10 years) were similar to those found in previous studies, but the proportion of men (58 percent) was higher. Only 6 (14 percent) deaths occurred after more than a few hours in hospital; for the rest, hospital contact was either too late (19 percent) or did not occur (67 percent). Of 22/43 (51 percent) patients considered at high risk of a respiratory death, 15 had poorly controlled symptoms for at least a year before their deaths. Avoidable factors were present in 29/43 (67 percent) cases; most commonly lack of assessment, inadequate doses of steroids and over-reliance on bronchodilators., Conclusion: These findings resemble those of previous studies, showing that little has changed. Asthma deaths occur mostly outside hospital; thus to replace deaths, resources should be directed at the community to improve the recognition of asthma by patients, their families and the primary care team. A regional confidential enquiry is feasible and could be an effective mechanism for proving management.

The objective of this study was to assess the knowledge, attitudes and behaviour of House Officers and General Practitioners (GPs) in relation to death certification, to determine the scope for future intervention. A postal questionnaire was used to survey all House Officers (174) and a 10 per cent random sample of GPs (131) in Mersey Region. The main outcome measures were: death certification experience; knowledge, attitudes and behaviour in relation to data uses and coding; and acceptability of Cause of Death statements. Response rates were comparable-119/174 House Officers (68.4 per cent) and 95/131 GPs (72.5 per cent). Most House Officers (78.8 per cent) and GPs (85.3 per cent) reported that they made the best possible Cause of Death statement but, respectively, 62.4 per cent and 59.3 per cent of these might modify a statement in some circumstances. Significantly more House Officers (70.3 per cent) than GPs (44.2 per cent) acknowledge room for improvement and were amenable to more training (86.6 per cent versus 52.5 per cent), but significantly fewer felt sufficiently instructed (23.7 per cent versus 52.6 per cent). Most respondents (> 90 per cent) considered accurate death certification important, but 46.2 per cent of House Officers had not read the death certificate book instructions. Knowledge was variable, especially concerning Underlying Cause of Death. Written Cause of Death statements were broadly similar in style and standard between groups. Experience did not appear to improve death certification practice. Better and co-ordinated undergraduate and early post-graduate education (which should be continuing and audited), and practical accessible guidance on death certificate completion, might improve standards of practice and performance within the existing framework. Alternative methods of presenting guidance on death certificate completion should be explored.

The uptake of breast cancer screening in women aged 45-64 years, living in Aylesbury Vale district, was determined between 1984 and 1988. During this period, self-referral gave way to invitation as the method of gaining access to the service. In the initial period of open access the estimated uptake was 27.9 per cent. A pilot study of response to invitation (and reminder) in two general practices resulted in a compliance of 80.6 per cent. Extended to 20 general practices in Aylesbury Vale, overall compliance with invitation was 73.7 per cent. The response amongst previously screened volunteers was higher (91.5 per cent) than amongst unscreened women (67.6 per cent). There was no significant trend in compliance with age although the oldest women had the lowest uptake. Second round compliance in the two pilot practices reduced to 77 per cent, with 86.1 per cent of a cohort of screened women responding to a second offer of screening. The implications of these results for the national breast cancer screening programme are discussed together with the difficulties associated with the routine derivation of uptake. It is concluded that not only must the accuracy of population registers be improved, but also standard definitions of uptake measurements should be agreed and adopted.

Previous studies of widely different concentrations of propafenone in various species have reported that in addition to having class 1 antiarrhythmic action, the drug was a beta adrenoceptor blocker and a calcium antagonist. High concentration shortened action potential duration in animal experiments, but Q-T interval was reported as being lengthened in man. It was thought desirable to study the effects of propafenone over a range of concentrations equivalent to those used clinically in various cardiac tissues of a single species, the rabbit. It was concluded that although the primary action of propafenone was on fast inward current, the drug being categorised as of group 1c, its potency as a beta blocker was sufficient for the effect to be of clinical significance. Its potency as a calcium antagonist was relatively weak. Action potential duration and effective refractory period were lengthened in both atrium and ventricle, the effects being long-lasting and persisting on wash-out of the drug when other measurements had returned to control values.

Depolarization of cardiac muscle is achieved by 'fast inward current' through channels which are inactivated within about 1 ms. When the cells are repolarized the process of inactivation of fast channels is rapidly reversed. The class 1 anti-arrhythmic drugs delay the disappearance of inactivation until long after repolarization is complete. In theory, it should be possible to produce a similar extension of refractory period by delaying the repolarization itself. Quinidine and disopyramide caused minor delays of repolarization, but both were primarily class 1 agents, and in addition had undesirable anticholinergic activity. Amiodarone, already in use for many years as an antianginal drug, prolonged action potential duration (APD) and was shown to have an anti-arrhythmic action in rabbits, dogs and man. Although prolongation of APD lengthens QT, a long QT may be caused by phenomena other than prolonged APD, such as heterogeneity of sympathetic drive. Association of long QT with arrhythmia does not, therefore, invalidate the principle that homogeneously prolonged APD should be anti-arrhythmic. In practice, amiodarone, bretylium, sotalol, thyroidectomy, and long-term beta-blockade prolong APD, and are associated with low incidence of arrhythmia. Many mechanisms controlling cardiac repolarization have been proposed, but how repolarization is delayed by individual agents is not fully elucidated.