Longitudinal Impacts of Precision Greenness on Alzheimer's Disease.

BACKGROUND: The potential for greenness as a novel protective factor for Alzheimer's disease (AD) requires further exploration. OBJECTIVES: This study assesses prospectively and longitudinally the association between precision greenness - greenness measured at the micro-environmental level, defined as the Census block - and AD incidence. DESIGN: Older adults living in consistently high greenness Census blocks across 2011 and 2016 were compared to those living in consistently low greenness blocks on AD incidence during 2012-2016. SETTING: Miami-Dade County, Florida, USA. PARTICIPANTS: 230,738 U.S. Medicare beneficiaries. MEASUREMENTS: U.S. Centers for Medicare and Medicaid Services Chronic Condition Algorithm for AD based on ICD-9 codes, Normalized Difference Vegetation Index, age, sex, race/ethnicity, neighborhood income, and walkability. RESULTS: Older adults living in the consistently high greenness tertile, compared to those in the consistently low greenness tertile, had 16% lower odds of AD incidence (OR=0.84, 95% CI: 0.76-0.94, p=0.0014), adjusting for age, sex, race/ethnicity, and neighborhood income. Age, neighborhood income and walkability moderated greenness' relationship to odds of AD incidence, such that younger ages (65-74), lower-income, and non-car dependent neighborhoods may benefit most from high greenness. CONCLUSIONS: High greenness, compared to low greenness, is associated with lower 5-year AD incidence. Residents who are younger and/or who reside in lower-income, walkable neighborhoods may benefit the most from high greenness. These findings suggest that consistently high greenness at the Census block-level, may be associated with reduced odds of AD incidence at a population level.

Multisystem inflammatory syndrome in children during the first two years of the COVID-19 pandemic in Luxembourg.

Objective: Estimate the incidence of multisystem inflammatory syndrome (MIS-C) in children (0-15 years), the role of SARS-CoV-2 variants during the first two years of COVID-19 pandemic in Luxembourg; and describe the demographic, biological and clinical characteristics of the patients. Method: Observational retrospective cohort study. Cases between March 2020 and February 2022 were ascertained from the national registry of MIS-C cases by a retrospective review of medical records. Reported SARS-CoV-2 infections were obtained from the national COVID-19 surveillance system. We calculated monthly MIS-C incidence, the ratio between MIS-C and SARS-CoV-2 infections and associated rate ratios by the periods corresponding to the circulation of different variants. Results: 18 children were diagnosed with MIS-C among 35,200 reported infections. The incidence rate of MIS-C was 7.2 [95% confidence interval (CI) 4.5-11.4] per 1,000,000 person-months. A higher incidence of MIS-C was observed between September and December 2021, corresponding to the circulation of the Delta variant than during the first year of the pandemic (RR 3.6, 95% CI, 1.1-12.3). The lowest rate of MIS-C per infection was observed during the Omicron (RR 0.17, 95% CI, 0.03-0.82). Median age at diagnosis was 6.5 years. Previously healthy children made up 88% of MIS-C cases, none were vaccinated against SARS-CoV-2. 33% required intensive care. All patients recovered fully. Conclusions: MIS-C incidence and MIS-C risk per infection changed significantly over time during the first two years of COVID-19 pandemic. Monitoring of MIS-C incidence in future SARS-CoV-2 waves will be essential to guide public health interventions and vaccination policies for children.

Reasonable requests: echocardiography referral forms as a measure of coherent clinical communication.

BACKGROUND: Well performed clinical communication is a cornerstone of collaborative care in medicine but may be confounded by inconsistent intentions of the messenger and biased interpretation by the recipient. A comparison of the findings of electronic echocardiography reports with clinician-completed standardised request forms provided an opportunity to assess communication quality. AIM: The study aimed to determine clinician aptitude to complete written echocardiography referral forms by assessing the completeness, appropriateness, accuracy, and coherency of the reported clinical findings, conclusions and requests made on the referral forms. The study explored factors that may influence the quality of communication through this referral medium. METHODS: A retrospective cohort study was conducted on patients who underwent trans-thoracic echocardiography imaging at Cecilia Makiwane Hospital in East London over 26 months. Paper echocardiography request forms that recorded the requesting clinician's findings on examination, the provisional clinical diagnosis, and the specific echocardiographic information sought, were compared with the actual findings on echocardiography. RESULTS: Of 613 request forms reviewed, 97 cases were excluded due to illegibility or because they lacked analysable information or requester details, leaving 516 forms suitable for study. No pathology was found on echocardiography in 31%. Of the murmurs expected from the echocardiography findings, only half were recorded on the request form (sensitivity and positive predictive value both 52%.). Only 35% of request forms that mentioned a mitral systolic murmur gave a working diagnosis of mitral regurgitation and only 38% of request forms that mentioned an aortic systolic murmur considered aortic stenosis. Clinically suspected cardiomyopathy (CMO) had a PPV of 43% and echocardiographic CMO was missed clinically in 41%. Apex beat displacement reported clinically was not associated with echocardiographic LV dilatation in 65% of cases. One-third (34%) of forms reporting murmurs did not request valve function assessment and 17% considering cardiomyopathy did not request left ventricular function assessment. CONCLUSION: Echocardiography request forms highlight vulnerabilities in clinical communication. Specifically, important clinical features were missing and more concerningly, included when unlikely to be present. There was a lack of concordance between recorded clinical findings and postulated diagnoses. Clinicians sometimes appeared unclear about the value or appropriateness of the requested assistance. Greater emphasis on teaching examination and communication skills may foster safer and more efficient use of scarce resources.

Meta-analytic magic, ivermectin, and socially responsible reporting.

Some clinicians prescribe ivermectin for COVID-19 despite a lack of support from any credible South African professional body. They argue that when faced by clinical urgency, weak signals of efficacy should trigger action if harm is unlikely. Several recent reviews found an apparent mortality benefit by including studies at high risk of bias and with active rather than placebo controls. If these studies are discounted, the pooled mortality effect is no longer statistically significant, and evidence of benefit is very weak. Relying on this evidence could cause clinical harm if used to justify vaccine hesitancy. Clinicians remain responsible for ensuring that guidance they follow is both legitimate and reliable. In the ivermectin debate, evidence-based medicine (EBM) principles have largely been ignored under the guise thatin a pandemic the 'rules are different', probably to the detriment of vulnerable patients and certainly to the detriment of the profession's image. Medical schools and professional interest groups are responsible for transforming EBM from a taught but seldom-used tool into a process of lifelong learning, promoting a consistent call for evidence-based and unconflicted debate integral to clinical practice.

But is it publishable? Mastering the MMed message.

The research requirement for South African specialist registration offers opportunities and challenges. For some clinicians it may spark a lifelong interest in clinical investigation, while for many others it may provide a potential publication opportunity. Integrating the specific requirements of an MMed mini-dissertation with those of standard medical publications can be difficult for first-time authors and their supervisors; published guidance caters to full-length laboratory Master's or doctoral research. We suggest that research is more likely to be publishable if it is locally relevant, has a clear clinical message and is coherently presented.

Mind the message: Referral letter quality at a South African medical outpatient department.

BACKGROUND: Some patients need referral within the health system to achieve optimal care, and referral letters are an important part of this process. Healthcare practitioners often complain that referral letters lack information, are inaccurate, or direct patients to the wrong place. Poor communication affects patient experience and outcomes, has budgetary and service planning implications, and impacts on staff relationships and morale. OBJECTIVES: To investigate the quality and appropriateness of referral letters received by the medical outpatient department of a regional hospital in Eastern Cape Province, South Africa. METHODS: Letters were collected by departmental staff as patients arrived at the clinic. Each letter was independently analysed by two healthcare workers for content and appropriateness, using defined criteria. RESULTS: Of 100 letters collected between March and May 2017, 85 were suitable for analysis. Patient and clinician identifiers were present in >85%, but key clinical information was missing in 87%, and 48% did not state a reason for referral. It was possible to make triage decisions based on the letter in only 35% of cases. Nineteen percent of referrals were classified as inappropriate. CONCLUSIONS: Most letters lacked important clinical information, probably because of a combination of factors: gaps in clinical knowledge of referring clinicians who service a population with a high burden of disease and complex pathology; under-resourced peripheral healthcare clinics; inadequate staff-to-patient ratios; and time constraints. A suggested focus for improvement is education at undergraduate and postgraduate level, which should emphasise preparation for community service, specifically highlighting techniques for preparing good-quality referrals.

Adjuvant trastuzumab in early HER2-positive breast cancer: Journeying towards the optimal duration of therapy in South Africa.

Trastuzumab was added to the South African Essential Medicines List (EML) in 2017 for the adjuvant management of human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. However, access has remained inconsistent, as some provinces continue to regard trastuzumab as unaffordable within the contexts of their respective oncology budgets. The intention of providing access to trastuzumab through its inclusion on the EML, therefore, has not been met. The National EML Committee (NEMLC) recently reviewed newly published peer-reviewed information investigating the impact of a shorter trastuzumab treatment period on both clinical efficacy and safety. On account of this review, and with a view to improving access while reducing cost and toxicity, the NEMLC has revised the duration of trastuzumab therapy, i.e. from 12 months to 6 months in the adjuvant management of early HER2-positive breast cancer. This article explores and reports on the data used to make this policy amendment.

Essential medicine selection during the COVID-19 pandemic: Enabling access in uncharted territory.

The COVID-19 pandemic requires urgent decisions regarding treatment policy in the face of rapidly evolving evidence. In response, the South African Essential Medicines List Committee established a subcommittee to systematically review and appraise emerging evidence, within very short timelines, in order to inform the National Department of Health COVID-19 treatment guidelines. To date, the subcommittee has reviewed 14 potential treatments, and made recommendations based on local context, feasibility, resource requirements and equity. Here we describe the rapid review and evidence-to-decision process, using remdesivir and dexamethasone as examples. Our experience is that conducting rapid reviews is a practical and efficient way to address medicine policy questions under pandemic conditions.

Objectively measured sedentary behaviour and health and development in children and adolescents: systematic review and meta-analysis.

Sedentary behaviour has emerged as a unique determinant of health in adults. Studies in children and adolescents have been less consistent. We reviewed the evidence to determine if the total volume and patterns (i.e. breaks and bouts) of objectively measured sedentary behaviour were associated with adverse health outcomes in young people, independent of moderate-intensity to vigorous-intensity physical activity. Four electronic databases (EMBASE MEDLINE, Ovid EMBASE, PubMed and Scopus) were searched (up to 12 November 2015) to retrieve studies among 2- to 18-year-olds, which used cross-sectional, longitudinal or experimental designs, and examined associations with health outcomes (adiposity, cardio-metabolic, fitness, respiratory, bone/musculoskeletal, psychosocial, cognition/academic achievement, gross motor development and other outcomes). Based on 88 eligible observational studies, level of evidence grading and quantitative meta-analyses indicated that there is limited available evidence that the total volume or patterns of sedentary behaviour are associated with health in children and adolescents when accounting for moderate-intensity to vigorous-intensity physical activity or focusing on studies with low risk of bias. Quality evidence from studies with robust designs and methods, objective measures of sitting, examining associations for various health outcomes, is needed to better understand if the overall volume or patterns of sedentary behaviour are independent determinants of health in children and adolescents.

Validation of a dosing regimen for fixed-dose, weight-adjusted, subcutaneous unfractionated heparin for the acute treatment of venous thrombo-embolism in a population from a resource-constrained environment.

A study in Canada and New Zealand (Kearon et al.) suggested that fixed-dose unmonitored subcutaneous (SC) unfractionated heparin (UFH) is as effective and safe as low-molecular-weight heparin (LMWH) for the acute treatment of venous thrombo-embolism. While this trial has limitations, it provides evidence to support the use of SC UFH in a resource-constrained environment. However, because public sector patients with VTE in South Africa often have multiple co-morbidities and are thinner and younger than those in that study, the local validity of the published dosing regimen is unclear.

A review of internal medicine re-admissions in a peri-urban South African hospital.

OBJECTIVE: To measure the re-admission rate and the number of preventable re-admissions in a secondary-level South African hospital, and to identify factors predictive of re-admission. METHOD: The admission register for the medical wards at Cecilia Makiwane Hospital (CMH) was used to identify re-admitted patients, whose folders were then reviewed. A comparison group of patients who were not re-admitted was randomly generated from the same register. RESULTS: The re-admission rate for the 7 months ending October 2006 was 8.5% (262/3 083). Patients who were more likely to be re-admitted had chronic respiratory disease (odds ratio (OR) 4.2, 95% confidence interval (CI) 1.2 - 14.6), HIV infection (OR 5.0, CI 2.1 - 12.0), were older than 50 years (OR 5.2, CI 2.5 - 10.9), had a first admission of more than 8 days (OR 3.2, CI 1.5 - 6.6) or a booked medical outpatients followup (OR 5.1, CI 2.6 - 10.3). Age distribution of re-admissions was bimodal, with HIV-positive individuals (27.4% overall) accounting for 50% of all admissions younger than 50 years, but only 9.1% of those 50 years or older. In individuals older than 50 years, 42.1% of admissions were due to chronic cardiorespiratory illnesses. Half of re-admissions were judged to be potentially preventable, mainly through improved patient education. CONCLUSION: One in 12 general medical patients was readmitted. Chronic diseases and inadequate patient education and discharge planning accounted for the largest group of re-admissions in older patients. Re-admission of HIV/AIDS patients has generated a second peak in younger individuals, and the impact of the antiretroviral roll-out on admission rates warrants further scrutiny.

Activation of estrogen signaling pathways collaborates with loss of Brca1 to promote development of ERalpha-negative and ERalpha-positive mammary preneoplasia and cancer.

BRCA1 can regulate estrogen receptor-alpha (ERalpha) activity. This study tested the hypotheses that Brca1 loss in mammary epithelium alters the estrogenic growth response and that exposure to increased estrogen or ERalpha collaborates with Brca1 deficiency to accelerate preneoplasia and cancer development. Longer ductal extension was found in mammary glands of Brca1(f/f;MMTV-Cre) mice during puberty as compared to wild-type mice. Terminal end bud differentiation was impaired in Brca1 mutant mice with preservation of prolactin-induced alveolar differentiation. Exogenous estrogen stimulated an abnormal sustained increase in mammary epithelial cell proliferation and the appearance of ERalpha-negative preneoplasia in postpubertal Brca1 mutant mice. Carcinogenesis was investigated using Brca1(f/f;MMTV-Cre) mice hemizygous for p53. Exogenous estrogen increased the percentage of mice with multiple hyperplastic alveolar nodules. Targeted conditional ERalpha overexpression in mammary epithelial cells of mice that were Brca1 mutant and hemizygous for p53 increased the percentage of mice exhibiting multiple hyperplastic nodules, invasive mammary cancers and cancer multiplicity. Significantly more than half of the preneoplasia and cancers were ERalpha negative even as their initiation was promoted by ERalpha overexpression.

Mortality in Patients Treated for Tuberculous Pericarditis in Sub-Saharan Africa

Objective: To determine the mortality rate and its predictors in patients with a presumptive diagnosis of tuberculous pericarditis in sub-Saharan Africa. Design: Between 1 March 2004 and 31 October 2004; we enrolled 185 consecutive patients with presumed tuberculous pericarditis from 15 referral hospitals in Cameroon; Nigeria; and South Africa; and observed them during the 6-month course of antituberculosis treatment for the major outcome of mortality. This was an observational study; with the diagnosis and management of each patient left at the discretion of the attending physician. Using Cox regression; we have assessed the effect of clinical and therapeutic characteristics (recorded at baseline) on mortality during follow-up. Results: We obtained the vital status of 174 (94) patients (median age 33; range 14-87 years). The overall mortality rate was 26. Mortality was higher in patients who had clinical features of HIV infection than in those who did not (40versus 17; P=0.001). Independent predictors of death during follow-up were: (1) a proven non-tuberculosis final diagnosis (hazard ratio [HR] 5.35; 95confidence interval 1.76 to 16.25); (2) the presence of clinical signs of HIV infection (HR 2.28; 1.14-4.56); (3) co-existent pulmonary tuberculosis (HR 2.33; 1.20-4.54); and (4) older age (HR 1.02; 1.01-1.05). There was also a trend towards an increase in death rate in patients with haemodynamic instability (HR 1.80; 0.90-3.58) and a decrease in those who underwent pericardiocentesis (HR 0.34; 0.10-1.19). Conclusion : A presumptive diagnosis of tuberculous pericarditis is associated with a high mortality in sub-Saharan Africans. Attention to rapid aetiological diagnosis of pericardial effusion and treatment of concomitant HIV infection may reduce the high mortality associated with the disease

Increased susceptibility of aging kidney to ischemic injury: identification of candidate genes changed during aging, but corrected by caloric restriction.

Aging is associated with an increased incidence and severity of acute renal failure. However, the molecular mechanism underlying the increased susceptibility to injury remains undefined. These experiments were designed to investigate the influence of age on the response of the kidney to ischemic injury and to identify candidate genes that may mediate this response. Renal slices prepared from young (5 mo), aged ad libitum (aged-AL; 24 mo), and aged caloric-restricted (aged-CR; 24 mo) male Fischer 344 rats were subjected to ischemic stress (100% N(2)) for 0-60 min. As assessed by biochemical and histological evaluation, slices from aged-AL rats were more susceptible to injury than young counterparts. Importantly, caloric restriction attenuated the increased susceptibility to injury. In an attempt to identify the molecular pathway(s) underlying this response, microarray analysis was performed on tissue harvested from the same animals used for the viability experiments. RNA was isolated and the corresponding cDNA was hybridized to CodeLink Rat Whole Genome Bioarray slides. Subsequent gene expression analysis was performed using GeneSpring software. Using two-sample t-tests and a twofold cut-off, the expression of 92 genes was changed during aging and attenuated by caloric restriction, including claudin-7, kidney injury molecule-1 (Kim-1), and matrix metalloproteinase-7 (MMP-7). Claudin-7 gene expression peaked at 18 mo; however, increased protein expression in certain tubular epithelial cells was seen at 24 mo. Kim-1 gene expression was not elevated at 8 or 12 mo but was at 18 and 24 mo. However, changes in Kim-1 protein expression were only seen at 24 mo and corresponded to increased urinary levels. Importantly, these changes were attenuated by caloric restriction. MMP-7 gene expression was decreased at 8 mo, but an age-dependent increase was seen at 24 mo. Increased MMP-7 protein expression in tubular epithelial cells at 24 mo was correlated with the gene expression pattern. In summary, we identified genes changed by aging and changes attenuated by caloric restriction. This will facilitate investigation into the molecular mechanism mediating the age-related increase in susceptibility to injury.