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Amyloid precursor protein (APP) is endoproteolytically processed by BACE1 and gamma-secretase to release amyloid peptides (Abeta40 and 42) that aggregate to form senile plaques in the brains of patients with Alzheimer's disease (AD). The C-terminus of Abeta40/42 is generated by gamma-secretase, whose activity is dependent upon presenilin (PS 1 or 2). Missense mutations in PS1 (and PS2) occur in patients with early-onset familial AD (FAD), and previous studies in transgenic mice and cultured cell models demonstrated that FAD-PS1 variants shift the ratio of Abeta40 : 42 to favor Abeta42. One hypothesis to explain this outcome is that mutant PS alters the specificity of gamma-secretase to favor production of Abeta42 at the expense of Abeta40. To test this hypothesis in vivo, we studied Abeta40 and 42 levels in a series of transgenic mice that co-express the Swedish mutation of APP (APPswe) with two FAD-PS1 variants that differentially accelerate amyloid pathology in the brain. We demonstrate a direct correlation between the concentration of Abeta42 and the rate of amyloid deposition. We further show that the shift in Abeta42 : 40 ratios associated with the expression of FAD-PS1 variants is due to a specific elevation in the steady-state levels of Abeta42, while maintaining a constant level of Abeta40. These data suggest that PS1 variants do not simply alter the preferred cleavage site for gamma-secretase, but rather that they have more complex effects on the regulation of gamma-secretase and its access to substrates.

Physician burnout is a universal dilemma that is seen in healthcare professionals, particularly physicians, and is characterized by emotional exhaustion, depersonalization, and a feeling of low personal accomplishment. In this review, we discuss the contributing factors leading to physician burnout and its consequences for the physician's health, patient outcomes, and the healthcare system. Physicians face daily challenges in providing care to their patients, and burnout may be from increased stress levels in overworked physicians. Additionally, the healthcare system mandates physicians to keep a meticulous record of their physician-patient encounters along with clerical responsibilities. Physicians are not well-trained in managing clerical duties, and this might shift their focus from solely caring for their patients. This can be addressed by the systematic application of evidence-based interventions, including but not limited to group interventions, mindfulness training, assertiveness training, facilitated discussion groups, and promoting a healthy work environment.

BACKGROUND: Appropriate representation of specific groups of patients in randomized controlled trials (RCTs) and generalizability of evidence obtained have been questioned. We sought to compare the characteristics of patients in heart failure (HF) RCTs with those of patients with HF in the community, and to document these trends over time. METHODS: MEDLINE was searched from 1985 through December 1999 for all HF RCTs. Additional trials were obtained through bibliographies of the reviewed articles, previous meta-analyses, and overviews of the HF trials. Original reports of RCTs of interventions for chronic HF were selected if they were published in the English language and included 50 or more participants. Publication year, sources of support, location of principal investigator, sample size, type of intervention, inclusion and exclusion criteria, characteristics of participants, and the use of invasive diagnostic tests were extracted. RESULTS: Participants in the 59 HF RCTs we reviewed were markedly different from the patients with HF in the community. Patients in RCTs were younger, more often male, more likely to have subnormal systolic ejection fraction, and were most commonly white. We did not find a significant improvement in the representation of the trials, with respect to these characteristics, among those published recently compared with those from the late 1980s and early 1990s. CONCLUSIONS: Clinical trials are focusing on a relatively small segment of the HF population. The consequences of underrepresenting minorities, women, and elderly are unknown but may be particularly important for HF. Future clinical trials should adequately include populations that carry the burden of the disease.

OBJECTIVE: To compare the neuropathy associated with impaired glucose tolerance (IGT) and diabetes mellitus (DM) determined by oral glucose tolerance testing (OGTT). METHODS: Patients with peripheral neuropathy of unknown cause were prescribed OGTT. Duration of neuropathic symptoms, neuropathic pain, neuropathy classification, nerve conduction test results, and intraepidermal nerve fiber densities (IENFD) were compared between IGT and DM groups. RESULTS: Seventy-three patients completed OGTT; 41 (56%) had abnormal results. Of these 41 patients, 26 had IGT and 15 had DM. Patients with IGT had less severe neuropathy than patients with diabetes, as measured by sural nerve amplitudes (p = 0.056), sural nerve conduction velocities (p = 0.03), and distal leg IENFD (p = 0.01). Patients with IGT had predominantly small fiber neuropathy, compared to patients with DM (p = 0.05), who had more involvement of large nerve fibers. CONCLUSIONS: The neuropathy associated with IGT is milder than the neuropathy associated with DM. Small nerve fibers are prominently affected and may be the earliest detectable sign of neuropathy in glucose dysmetabolism. OGTT is appropriate in patients with idiopathic neuropathy.

In the past decade, outbreaks of human illness associated with the consumption of raw vegetables and fruits (or unpasteurized products produced from them) have increased in the United States. Changes in agronomic, harvesting, distribution, processing, and consumption patterns and practices have undoubtedly contributed to this increase. Pathogens such as Listeria monocytogenes, Clostridium botulinum, and Bacillus cereus are naturally present in some soil, and their presence on fresh produce is not rare. Salmonella, Escherichia coli O157:H7, Campylobacter jejuni, Vibrio cholerae, parasites, and viruses are more likely to contaminate fresh produce through vehicles such as raw or improperly composted manure, irrigation water containing untreated sewage, or contaminated wash water. Contact with mammals, reptiles, fowl, insects, and unpasteurized products of animal origin offers another avenue through which pathogens can access produce. Surfaces, including human hands, which come in contact with whole or cut produce represent potential points of contamination throughout the total system of growing, harvesting, packing, processing, shipping, and preparing produce for consumption. Treatment of produce with chlorinated water reduces populations of pathogenic and other microorganisms on fresh produce but cannot eliminate them. Reduction of risk for human illness associated with raw produce can be better achieved through controlling points of potential contamination in the field; during harvesting; during processing or distribution; or in retail markets, food-service facilities, or the home.

The 2019 novel coronavirus (COVID-19) has gained global attention after it originated from China at the end of 2019, and later turned into pandemic as it affected about 118,000 in 114 countries by March 11, 2020. By March 13, 2020, it was declared a national emergency in the United States as the number of COVID-19 cases, and the death toll rose exponentially. To contain the spread of the disease, the world scientist community came together. However, the unpreparedness of the nations, even with the advanced medical sciences and resources, has failed to address the mental health aspect amongst the public, as all efforts are focused on understanding the epidemiology, clinical features, transmission patterns, and management of COVID-19 pneumonia. Our efforts in this review are to evaluate and study similar outbreaks from the past to understand its adverse impact on mental health, implement adequate steps to tackle and provide a background to physicians and healthcare workers at the time of such outbreaks to apply psychological first aid.

Cocoa contains more phenolic antioxidants than most foods. Flavonoids, including catechin, epicatechin, and procyanidins predominate in antioxidant activity. The tricyclic structure of the flavonoids determines antioxidant effects that scavenge reactive oxygen species, chelate Fe2+ and Cu+, inhibit enzymes, and upregulate antioxidant defenses. The epicatechin content of cocoa is primarily responsible for its favorable impact on vascular endothelium via its effect on both acute and chronic upregulation of nitric oxide production. Other cardiovascular effects are mediated through anti-inflammatory effects of cocoa polyphenols, and modulated through the activity of NF-κB. Antioxidant effects of cocoa may directly influence insulin resistance and, in turn, reduce risk for diabetes. Further, cocoa consumption may stimulate changes in redox-sensitive signaling pathways involved in gene expression and the immune response. Cocoa can protect nerves from injury and inflammation, protect the skin from oxidative damage from UV radiation in topical preparations, and have beneficial effects on satiety, cognitive function, and mood. As cocoa is predominantly consumed as energy-dense chocolate, potential detrimental effects of overconsumption exist, including increased risk of weight gain. Overall, research to date suggests that the benefits of moderate cocoa or dark chocolate consumption likely outweigh the risks.

This is the first scientific statement from the American Heart Association on maternal resuscitation. This document will provide readers with up-to-date and comprehensive information, guidelines, and recommendations for all aspects of maternal resuscitation. Maternal resuscitation is an acute event that involves many subspecialties and allied health providers; this document will be relevant to all healthcare providers who are involved in resuscitation and specifically maternal resuscitation.

Abstract Using a novel database of firm patents and board characteristics across 45 countries, we examine both within- and cross-country determinants of board gender diversity and its relation to corporate innovation. Boards are more likely to include women in countries with narrower gender gaps, higher female labor market participation, and less masculine cultures. Firms with gender diverse boards have more patents and novel patents, and a higher innovative efficiency. Further analyses suggest that gender diverse boards are associated with more failure-tolerant and long-term chief executive officer (CEO) incentives, more innovative corporate cultures, and more diverse inventors, characteristics that are conducive to an improved innovative performance.

Diet is established among the most important influences on health in modern societies. Injudicious diet figures among the leading causes of premature death and chronic disease. Optimal eating is associated with increased life expectancy, dramatic reduction in lifetime risk of all chronic disease, and amelioration of gene expression. In this context, claims abound for the competitive merits of various diets relative to one another. Whereas such claims, particularly when attached to commercial interests, emphasize distinctions, the fundamentals of virtually all eating patterns associated with meaningful evidence of health benefit overlap substantially. There have been no rigorous, long-term studies comparing contenders for best diet laurels using methodology that precludes bias and confounding, and for many reasons such studies are unlikely. In the absence of such direct comparisons, claims for the established superiority of any one specific diet over others are exaggerated. The weight of evidence strongly supports a theme of healthful eating while allowing for variations on that theme. A diet of minimally processed foods close to nature, predominantly plants, is decisively associated with health promotion and disease prevention and is consistent with the salient components of seemingly distinct dietary approaches. Efforts to improve public health through diet are forestalled not for want of knowledge about the optimal feeding of Homo sapiens but for distractions associated with exaggerated claims, and our failure to convert what we reliably know into what we routinely do. Knowledge in this case is not, as of yet, power; would that it were so.

To determine whether clinical manifestations are associated with genotypes or subtypes of Cryptosporidium spp., we studied a 4-year longitudinal birth cohort of 533 children in Peru. A total of 156 infection episodes were found in 109 children. Data from first infections showed that C. hominis was associated with diarrhea, nausea, vomiting, general malaise, and increased oocyst shedding intensity and duration. In contrast, C. parvum, C. meleagridis, C. canis, and C. felis were associated with diarrhea only. C. hominis subtype families were identified (Ia, Ib, Id, and Ie); all were associated with diarrhea. Ib was also associated with nausea, vomiting, and general malaise. All C. parvum specimens belonged to subtype family IIc. Analysis of risk factors did not show associations with specific Cryptosporidium spp. genotypes or subtypes. These findings strongly suggest that Cryptosporidium spp. and subtypes are linked to different clinical manifestations in children.

In a complex system of interrelated reactions, the heart converts chemical energy to mechanical energy. Energy transfer is achieved through coordinated activation of enzymes, ion channels, and contractile elements, as well as structural and membrane proteins. The heart's needs for energy are difficult to overestimate. At a time when the cardiovascular research community is discovering a plethora of new molecular methods to assess cardiac metabolism, the methods remain scattered in the literature. The present statement on "Assessing Cardiac Metabolism" seeks to provide a collective and curated resource on methods and models used to investigate established and emerging aspects of cardiac metabolism. Some of those methods are refinements of classic biochemical tools, whereas most others are recent additions from the powerful tools of molecular biology. The aim of this statement is to be useful to many and to do justice to a dynamic field of great complexity.

In experimental animals, as in humans, techniques for measuring blood pressure (BP) have improved considerably over the past decade. In this document, we present recommendations for measuring BP in experimental animals with the goal of helping investigators select optimal methods for BP monitoring in the research laboratory. The advantages and disadvantages of various BP measurement methods are discussed and specific recommendations are provided for selecting the optimal technique depending on the study objective. Although indirect techniques that permit only sporadic measurements of BP may be suitable for some purposes, methods for directly measuring BP are generally preferred because of their ability to monitor the highly dynamic nature of BP in a comprehensive fashion. Selection of the methods to be used should ultimately be guided by the study objectives to insure that the techniques chosen are appropriate for the experimental questions being explored.

RATIONALE, AIMS AND OBJECTIVES: Utilizing information technology, such as Internet and cellphones, holds great promise in enhancing diabetic care. Yet few studies have examined the impact of cellphone technology on type 2 diabetics' self-care. The primary aim of the study is to examine the feasibility of utilizing this technology to assist with diabetes self-care in a clinic population as well as its impact on clinical outcomes. METHODS: Thirty patients with a diagnosis of type 2 diabetes at two Community Health Centers were randomized to intervention or control. Intervention patients participated in a brief intervention and received tailored daily messages via cellphone prompting them to enhance their diabetic self-care behaviour. Patients at the control site continued with their standard diabetes self-management. RESULTS: A mean improvement in HbA1c levels was apparent (-0.1, SD = 0.3%; P = 0.1534) in the intervention group, compared with a mean deterioration in the control (0.3, SD = 1.0%; P = 0.3813), yet without statistical significance. Self-efficacy scores improved significantly in the intervention group (-0.5, SD = 0.6; P = 0.0080) compared with no improvement in the control (0.0, SD = 1.0; P = 0.9060). Participants encountered numerous technological barriers when attempting to adhere to the intervention protocol. CONCLUSION: The results indicate the intervention had a positive impact on some clinical outcome and self-efficacy. Although the technology appears feasible in a clinical setting technology must be made more user-friendly before a larger phase II trial is conducted.

OBJECTIVE: Although the association between depression and the incidence of coronary heart disease has been established in many studies, the impact of depression on the incidence of heart failure has not been previously investigated. METHODS: We examined the effect of depression (assessed by means of the Center for Epidemiological Studies Depression Scale (CES-D) with a cutoff point of > or =21) on the incidence of heart failure in a community sample of persons aged > or =65 years who were participants in the New Haven cohort of the Established Populations for Epidemiological Studies in the Elderly. RESULTS: At baseline 2501 individuals were free of heart failure. Of these, 188 (132 women and 56 men) scored as depressed. Depressed participants were significantly more likely to have hypertension, diabetes, and mobility-related functional limitations and were less likely to be male or married. During the 14-year follow-up period, 313 participants (146 men and 167 women) developed heart failure, defined as hospital admission for heart failure or mortality with heart failure as the underlying cause of death. After adjusting for baseline differences in demographic and comorbidity factors and functional status using Cox regression, depression tended to be associated with a greater risk of heart failure (hazard ratio (HR) = 1.52, 95% confidence interval (CI) = 0.94-2.43, p =.09). This effect was significant in women (HR = 1.96, 95% CI = 1.11-3.46, p =.02) but not in men (HR = 0.62, 95% CI = 0.23-1.71, p =.05 for the interaction term between sex and depression). CONCLUSIONS: Depression is an independent risk factor for heart failure among elderly women but not elderly men.

A PCR-based test was developed to differentiate Escherichia coli from other Gram-negative bacteria. The assay employed primers derived from the nucleotide sequences flanking the gene encoding the universal stress protein (uspA) and was found to be highly specific for E. coli. An 884 base pair (bp) specific product was amplified from all of the E. coli tested (n = 45), whereas no amplification was associated with non-E. coli Gram-negative bacteria (n = 11).

BACKGROUND AND PURPOSE: Many ischemic strokes or transient ischemic attacks are labeled cryptogenic but may have undetected atrial fibrillation (AF). We sought to identify those most likely to have subclinical AF. METHODS: We prospectively studied patients with cryptogenic stroke or transient ischemic attack aged ≥55 years in sinus rhythm, without known AF, enrolled in the intervention arm of the 30 Day Event Monitoring Belt for Recording Atrial Fibrillation After a Cerebral Ischemic Event (EMBRACE) trial. Participants underwent baseline 24-hour Holter ECG poststroke; if AF was not detected, they were randomly assigned to 30-day ECG monitoring with an AF auto-detect external loop recorder. Multivariable logistic regression assessed the association between baseline variables (Holter-detected atrial premature beats [APBs], runs of atrial tachycardia, age, and left atrial enlargement) and subsequent AF detection. RESULTS: Among 237 participants, the median baseline Holter APB count/24 h was 629 (interquartile range, 142-1973) among those who subsequently had AF detected versus 45 (interquartile range, 14-250) in those without AF (P<0.001). APB count was the only significant predictor of AF detection by 30-day ECG (P<0.0001), and at 90 days (P=0.0017) and 2 years (P=0.0027). Compared with the 16% overall 90-day AF detection rate, the probability of AF increased from <9% among patients with <100 APBs/24 h to 9% to 24% in those with 100 to 499 APBs/24 h, 25% to 37% with 500 to 999 APBs/24 h, 37% to 40% with 1000 to 1499 APBs/24 h, and 40% beyond 1500 APBs/24 h. CONCLUSIONS: Among older cryptogenic stroke or transient ischemic attack patients, the number of APBs on a routine 24-hour Holter ECG was a strong dose-dependent independent predictor of prevalent subclinical AF. Those with frequent APBs have a high probability of AF and represent ideal candidates for prolonged ECG monitoring for AF detection. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00846924.

OBJECTIVE: We evaluated the role of a single measurement of HbA(1c) in a diabetes case finding in hospitalized patients with random hyperglycemia at admission. RESEARCH DESIGN AND METHODS: From 20 March to 31 July 2000, 508 patients admitted through the emergency department of one hospital were tested for random hyperglycemia (plasma glucose [PG] >125 mg/dl). Consenting patients with hyperglycemia (without preexisting diabetes or on corticosteroids) underwent testing for HbA(1c) levels, two fasting PG levels, and an outpatient oral glucose tolerance test (OGTT) if necessary. RESULTS: Of the patients, 50 (9.8%) met the inclusion criteria. Of these, 70% (n = 35) completed the study, and 60% (n = 21) were diagnosed with diabetes. Patients with diabetes had higher HbA(1c) levels than subjects without diabetes (6.8 +/- 0.4 vs. 5.3 +/- 0.1%, P = 0.002). An HbA(1c) level >6.0% was 100% specific (14/14) and 57% sensitive (12/21) for the diagnosis of diabetes. When a lower cutoff value of HbA(1c) at 5.2% was used, specificity was 50% (10/21) and sensitivity was 100% (7/14). CONCLUSIONS: In acutely ill patients with random hyperglycemia at hospital admission, an HbA(1c) >6.0% reliably diagnoses diabetes, and an HbA(1c) level <5.2% reliably excludes it (paralleling the operating characteristics of the standard fasting glucose measurements); however, the rapidity of the HbA(1c) level can be useful for diabetes case finding and treatment initiation early in the hospital course.

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The effects of academic final examinations on serum cholesterol levels were studied on 2 groups of medical students. A significant increase in the mean total serum cholesterol levels were observed during examination periods as compared to control periods of relaxation. These findings support previous reports of the effects of mental tension on serum cholesterol levels.