Mosaic Muir Torre Syndrome: Keratoacanthoma as a Piece of the Puzzle.

ABSTRACT: Lynch syndrome is an inherited condition, which increases the risk of numerous visceral malignancies and cutaneous tumors such as keratoacanthomas and sebaceous tumors. It is typically identified by immunohistochemistry of tissue taken from tumors or through genetic testing with next-generation sequencing. Diagnosing Lynch syndrome becomes more complex when the individual is mosaic for the relevant pathogenic variant. There are very few cases of this reported in the medical literature. It is even more unusual for the diagnosis to be made based on testing of a keratoacanthoma lesion. We report a case where immunohistochemistry of a keratoacanthoma helped make a diagnosis of mosaic Lynch syndrome. We will explore how mosaicism should be considered when a phenotype is strong, even if next-generation sequencing reports no pathogenic or likely pathogenic variant and how lesions such as keratoacanthomas can have a role in the early detection and treatment of future malignancies.

The process of harmonizing competency-based curricula for medicine and nursing degree programmes: A Multi-institutional and multi-professional experience from Tanzania.

In many low- and middle-income countries, there seems to be a mismatch between graduate skills and healthcare industry requirements due to variability in curricula. With the current increased global demand for competent health profession graduates, harmonizing competency-based curricula (CBC) is necessary to address this mismatch. This paper describes how three health professions training universities in Tanzania and their two long-standing United States partners embarked on developing harmonized CBC for undergraduate medicine and nursing degrees. The main goal of the activity was to develop templates to harmonize curricula that would support graduates to acquire mandatory national Graduate Minimum Essential Competencies (GMEC) irrespective of the institution of their training. The paper describes the processes of engaging multiple institutions, the professions of medicine and nursing and various stakeholders to develop mandatory curricula generic competencies, creating milestones for assessing competencies, training faculty at each of the three partnering institutions in curriculum delivery and assessments, resulting in the adoption of the curricula by the University leadership at each institution. Ultimately the Tanzania Commission for Universities (TCU) a regulatory body required all schools of medicine and nursing in the country to adopt the curricula, thus creating a harmonized national standard for teaching medicine and nursing beginning October 2022.

Metastasising Fibroblasts Show an HDAC6-Dependent Increase in Migration Speed and Loss of Directionality Linked to Major Changes in the Vimentin Interactome.

Metastasising cells express the intermediate filament protein vimentin, which is used to diagnose invasive tumours in the clinic. We aimed to clarify how vimentin regulates the motility of metastasising fibroblasts. STED super-resolution microscopy, live-cell imaging and quantitative proteomics revealed that oncogene-expressing and metastasising fibroblasts show a less-elongated cell shape, reduced cell spreading, increased cell migration speed, reduced directionality, and stronger coupling between these migration parameters compared to normal control cells. In total, we identified and compared 555 proteins in the vimentin interactome. In metastasising cells, the levels of keratin 18 and Rab5C were increased, while those of actin and collagen were decreased. Inhibition of HDAC6 reversed the shape, spreading and migration phenotypes of metastasising cells back to normal. Inhibition of HDAC6 also decreased the levels of talin 1, tropomyosin, Rab GDI ß, collagen and emilin 1 in the vimentin interactome, and partially reversed the nanoscale vimentin organisation in oncogene-expressing cells. These findings describe the changes in the vimentin interactome and nanoscale distribution that accompany the defective cell shape, spreading and migration of metastasising cells. These results support the hypothesis that oncogenes can act through HDAC6 to regulate the vimentin binding of the cytoskeletal and cell-extracellular matrix adhesion components that contribute to the defective motility of metastasising cells.

Breast Cancer knowledge, perceptions and practices in a rural Community in Coastal Kenya.

BACKGROUND: Data on breast healthcare knowledge, perceptions and practice among women in rural Kenya is limited. Furthermore, the role of the male head of household in influencing a woman's breast health seeking behavior is also not known. The aim of this study was to assess the knowledge, perceptions and practice of breast cancer among women, male heads of households, opinion leaders and healthcare providers within a rural community in Kenya. Our secondary objective was to explore the role of male heads of households in influencing a woman's breast health seeking behavior. METHODS: This was a mixed method cross-sectional study, conducted between Sept 1st 2015 Sept 30th 2016. We administered surveys to women and male heads of households. Outcomes of interest were analysed in Stata ver 13 and tabulated against gender. We conducted six focus group discussions (FGDs) and 22 key informant interviews (KIIs) with opinion leaders and health care providers, respectively. Elements of the Rapid Assessment Process (RAP) were used to guide analysis of the FGDs and the KIIs. RESULTS: A total of 442 women and 237 male heads of households participated in the survey. Although more than 80% of respondents had heard of breast cancer, fewer than 10% of women and male heads of households had knowledge of 2 or more of its risk factors. More than 85% of both men and women perceived breast cancer as a very serious illness. Over 90% of respondents would visit a health facility for a breast lump. Variable recognition of signs of breast cancer, limited decision- autonomy for women, a preference for traditional healers, lack of trust in the health care system, inadequate access to services, limited early-detection services were the six themes that emerged from the FGDs and the KIIs. There were discrepancies between the qualitative and quantitative data for the perceived role of the male head of household as a barrier to seeking breast health care. CONCLUSIONS: Determining level of breast cancer knowledge, the characteristics of breast health seeking behavior and the perceived barriers to accessing breast health are the first steps in establishing locally relevant intervention programs.

Image training, using random images of melanoma, performs as well as the ABC(D) criteria in enabling novices to distinguish between melanoma and mimics of melanoma.

Robust experimental evidence supporting many attempts to facilitate early melanoma diagnosis is lacking. In an experimental study using a browser interface we have examined diagnostic accuracy, sensitivity and specificity of novices in distinguishing between melanomas and mimics of melanoma. We show that rule-based ABC methods and image training, based on random images of melanoma, improve specificity to similar degrees, with-out effects on sensitivity, leading to small improvements in overall accuracy. There was a significant effect of age with older subjects performing better. Although both the ABC method and image training groups showed improved performance over the control group, overall performance was poor. For instance, for a task in which 1 in 4 test images was a melanoma, and 3 out of 4 benign, both interventions (ABC or image training) increased accuracy from the control value of 53% to around 61%. For reference, dermatology trainees performed at a much higher level of accuracy. Our study provides little support for the use of such methods in public education, but suggests ways in which performance might be improved.

Preparing Institutions to Implement Harmonized Medicine and Nursing Curricula Through the Use of Cross-Institutional Faculty Developers.

Background: Effective implementation of new curricula requires faculty to be knowledgeable about curriculum goals and have the appropriate pedagogical skills to implement the curriculum, even more so if the new curriculum is being deployed at multiple institutions. In this paper, we describe the process of creating a common faculty development program to train cross-institutional faculty developers to support the implementation of national harmonized medicine and nursing curricula. Methods: A five-step approach was used, including a cross-institutional needs assessment survey for faculty development needs, the development of a generic faculty development program, the identification and training of cross-institutional faculty educators, and the implementation of cross-institutional faculty capacity-building workshops. Results: A list of common cross-cutting faculty development needs for teaching and learning was identified from the needs assessment survey and used to develop an accredited, cross-institutional faculty development program for competency-based learning and assessment. A total of 24 cross-institutional faculty developers were identified and trained in 8 core learning and assessment workshops. A total of 18 cross-institutional and 71 institutional workshops were conducted, of which 1292 faculty members and 412 residents were trained, and three cross-institutional educational research projects were implemented. Conclusion: The success attained in this study shows that the use of cross-institutional faculty developers is a viable model and sustainable resource that can be used to support the implementation of harmonized national curricula.

Human resource and funding constraints for essential surgery in district hospitals in Africa: a retrospective cross-sectional survey.

BACKGROUND: There is a growing recognition that the provision of surgical services in low-income countries is inadequate to the need. While constrained health budgets and health worker shortages have been blamed for the low rates of surgery, there has been little empirical data on the providers of surgery and cost of surgical services in Africa. This study described the range of providers of surgical care and anesthesia and estimated the resources dedicated to surgery at district hospitals in three African countries. METHODS AND FINDINGS: We conducted a retrospective cross-sectional survey of data from eight district hospitals in Mozambique, Tanzania, and Uganda. There were no specialist surgeons or anesthetists in any of the hospitals. Most of the health workers were nurses (77.5%), followed by mid-level providers (MLPs) not trained to provide surgical care (7.8%), and MLPs trained to perform surgical procedures (3.8%). There were one to six medical doctors per hospital (4.2% of clinical staff). Most major surgical procedures were performed by doctors (54.6%), however over one-third (35.9%) were done by MLPs. Anesthesia was mainly provided by nurses (39.4%). Most of the hospital expenditure was related to staffing. Of the total operating costs, only 7% to 14% was allocated to surgical care, the majority of which was for obstetric surgery. These costs represent a per capita expenditure on surgery ranging from US$0.05 to US$0.14 between the eight hospitals. CONCLUSION: African countries have adopted different policies to ensure the provision of surgical care in their respective district hospitals. Overall, the surgical output per capita was very low, reflecting low staffing ratios and limited expenditures for surgery. We found that most surgical and anesthesia services in the three countries in the study were provided by generalist doctors, MLPs, and nurses. Although more information is needed to estimate unmet need for surgery, increasing the funds allocated to surgery, and, in the absence of trained doctors and surgeons, formalizing the training of MLPs appears to be a pragmatic and cost-effective way to make basic surgical services available in underserved areas. Please see later in the article for the Editors' Summary.

Essential surgery at the district hospital: a retrospective descriptive analysis in three African countries.

BACKGROUND: Surgical conditions contribute significantly to the disease burden in sub-Saharan Africa. Yet there is an apparent neglect of surgical care as a public health intervention to counter this burden. There is increasing enthusiasm to reverse this trend, by promoting essential surgical services at the district hospital, the first point of contact for critical conditions for rural populations. This study investigated the scope of surgery conducted at district hospitals in three sub-Saharan African countries. METHODS AND FINDINGS: In a retrospective descriptive study, field data were collected from eight district hospitals in Uganda, Tanzania, and Mozambique using a standardized form and interviews with key informants. Overall, the scope of surgical procedures performed was narrow and included mainly essential and life-saving emergency procedures. Surgical output varied across hospitals from five to 45 major procedures/10,000 people. Obstetric operations were most common and included cesarean sections and uterine evacuations. Hernia repair and wound care accounted for 65% of general surgical procedures. The number of beds in the studied hospitals ranged from 0.2 to 1.0 per 1,000 population. CONCLUSION: The findings of this study clearly indicate low levels of surgical care provision at the district level for the hospitals studied. The extent to which this translates into unmet need remains unknown although the very low proportions of live births in the catchment areas of these eight hospitals that are born by cesarean section suggest that there is a substantial unmet need for surgical services. The district hospital in the current health system in sub-Saharan Africa lends itself to feasible integration of essential surgery into the spectrum of comprehensive primary care services. It is therefore critical that the surgical capacity of the district hospital is significantly expanded; this will result in sustainable preventable morbidity and mortality. Please see later in the article for the Editors' Summary.

Oral administration of curcumin emulsified in carboxymethyl cellulose has a potent anti-inflammatory effect in the IL-10 gene-deficient mouse model of IBD.

Curcumin is a tumeric-derived, water-insoluble polyphenol with potential beneficial health effects for humans. It has been shown to have preventive as well as therapeutic effects in chemically induced murine models of colitis. To investigate whether curcumin exerts a similar effect on the spontaneous colitis in interleukin (IL)-10 gene-deficient mice, we gavaged these mice daily for 2 weeks with 200 mg/kg per day curcumin emulsified in carboxymethyl cellulose, a food additive generally used as a viscosity modifier. Mice fed the curcumin/carboxymethyl cellulose mixture and those receiving carboxymethyl cellulose alone demonstrated similar reductions in histological injury score and colon weight/length ratio compared to water-fed controls. However, significant reductions in pro-inflammatory cytokine release in intestinal explant cultures were only seen in mice treated with the curcumin mixture. Our data demonstrate that in IL-10 gene-deficient mice, both oral curcumin and carboxymethyl cellulose, appear to have modifying effects on colitis. However, curcumin has additional anti-inflammatory effects mediated through a reduced production of potent pro-inflammatory mucosal cytokines.

Distinct Biomarker Profiles Distinguish Malawian Children with Malarial and Non-malarial Sepsis.

Presently, it is difficult to accurately diagnose sepsis, a common cause of childhood death in sub-Saharan Africa, in malaria-endemic areas, given the clinical and pathophysiological overlap between malarial and non-malarial sepsis. Host biomarkers can distinguish sepsis from uncomplicated fever, but are often abnormal in malaria in the absence of sepsis. To identify biomarkers that predict sepsis in a malaria-endemic setting, we retrospectively analyzed data and sera from a case-control study of febrile Malawian children (aged 6-60 months) with and without malaria who presented to a community health center in Blantyre (January-August 2016). We characterized biomarkers for 29 children with uncomplicated malaria without sepsis, 25 without malaria or sepsis, 17 with malaria and sepsis, and 16 without malaria but with sepsis. Sepsis was defined using systemic inflammatory response criteria; biomarkers (interleukin-6 [IL-6], tumor necrosis factor receptor-1, interleukin-1 ß [IL-1ß], interleukin-10 [IL-10], von Willebrand factor antigen-2, intercellular adhesion molecule-1, and angiopoietin-2 [Ang-2]) were measured with multiplex magnetic bead assays. IL-6, IL-1ß, and IL-10 were elevated, and Ang-2 was decreased in children with malaria compared with non-malarial fever. Children with non-malarial sepsis had greatly increased IL-1ß compared with the other subgroups. IL-1ß best predicted sepsis, with an area under the receiver operating characteristic (AUROC) of 0.71 (95% CI: 0.57-0.85); a combined biomarker-clinical characteristics model improved prediction (AUROC of 0.77, 95% CI: 0.67-0.85). We identified a distinct biomarker profile for non-malarial sepsis and developed a sepsis prediction model. Additional clinical and biological data are necessary to further explore sepsis pathophysiology in malaria-endemic regions.

The way forward.

Good public-health decisionmaking is dependent on reliable and timely statistics on births and deaths (including the medical causes of death). All high-income countries, without exception, have national civil registration systems that record these events and generate regular, frequent, and timely vital statistics. By contrast, these statistics are not available in many low-income and lower-middle-income countries, even though it is in such settings that premature mortality is most severe and the need for robust evidence to back decisionmaking most critical. Civil registration also has a range of benefits for individuals in terms of legal status, and the protection of economic, social, and human rights. However, over the past 30 years, the global health and development community has failed to provide the needed technical and financial support to countries to develop civil registration systems. There is no single blueprint for establishing and maintaining such systems and ensuring the availability of sound vital statistics. Each country faces a different set of challenges, and strategies must be tailored accordingly. There are steps that can be taken, however, and we propose an approach that couples the application of methods to generate better vital statistics in the short term with capacity-building for comprehensive civil registration systems in the long run.

Urinary metabolic profiles of inflammatory bowel disease in interleukin-10 gene-deficient mice.

Inflammatory bowel disease (IBD) is a chronic debilitating disorder that is thought to have both genetic and environmental contributors. Commensal microflora have been shown to play a key part in the disease process. Metabolomics, the study of large numbers of small molecule metabolites, has demonstrated that disease and/or changes in gut microbial composition modulate mammalian urine metabolite fingerprints. The aim of this project was to associate the development of IBD with specific changes in a mouse urinary metabolic fingerprint. Interleukin-10 (IL-10) gene-deficient mice were raised alongside age-matched 129/SvEv controls in conventional housing. Urine samples (22 h) were collected at ages 4, 6, 8, 12, 16, and 20 weeks. Metabolite concentrations were derived from analysis of nuclear magnetic resonance spectra, and both multivariate and two-way analysis of variance (ANOVA) statistical techniques were applied to the resulting data. Principal component analysis and partial least-squares-discriminant analysis of urine derived from the control and IL-10 gene-deficient mice revealed that while both groups initially had similar metabolic profiles, they diverged substantially with the onset of IBD as assessed through external phenotypic changes. Several metabolites, including trimethylamine (TMA) and fucose, changed dramatically in the IL-10 gene-deficient mice following 8 weeks of age, concomitant with the known timeline for development of severe histological injury. This study illustrates that metabolomics is effective at distinguishing IBD using urinary metabolite profiles.

Think globally, act locally, and collaborate internationally: global health sciences at the University of California, San Francisco.

The University of California, San Francisco (UCSF) established Global Health Sciences (GHS) as a campus-wide initiative in 2003. The mission of GHS is to facilitate UCSF's engagement in global health across its four schools by (1) creating a supportive environment that promotes UCSF's leadership role in global health, (2) providing education and training in global health, (3) convening and coordinating global health research activities, (4) establishing global health outreach programs locally in San Francisco and California, (5) partnering with academic centers, especially less-well-resourced institutions in low- and middle-income countries, and (6) developing and collaborating in international initiatives that address neglected global health issues.GHS education programs include a master of science (MS) program expected to start in September 2008, an introduction to global health for UCSF residents, and a year of training at UCSF for MS and PhD students from low- and middle-income countries that is "sandwiched" between years in their own education program and results in a UCSF Sandwich Certificate. GHS's work with partner institutions in California has a preliminary focus on migration and health, and its work with academic centers in low- and middle-income countries focuses primarily on academic partnerships to train human resources for health. Recognizing that the existing academic structure at UCSF may be inadequate to address the complexity of global health threats in the 21st century, GHS is working with the nine other campuses of the University of California to develop a university-wide transdisciplinary initiative in global health.

In the name of global health: trends in academic institutions.

This paper describes accelerating development of programs in global health, particularly in North American academic institutions, and sets this phenomenon in the context of earlier programs in tropical medicine and international health that originated predominantly in Europe. Like these earlier programs, the major focus of the new global health programs is on the health needs of developing countries, and perhaps for this reason, few similar programs have emerged in academic institutions in the developing countries themselves. If global health is about the improvement of health worldwide, the reduction of disparities, and protection of societies against global threats that disregard national borders, it is essential that academic institutions reach across geographic, cultural, economic, gender, and linguistic boundaries to develop mutual understanding of the scope of global health and to create collaborative education and research programs. One indication of success would be emergence of a new generation of truly global leaders working on a shared and well-defined agenda--and doing so on equal footing.

Epithelial barrier disruption allows nondisease-causing bacteria to initiate and sustain IBD in the IL-10 gene-deficient mouse.

BACKGROUND: In the IL-10 gene-deficient mouse model, development of intestinal inflammation is associated with a defect in epithelial barrier integrity that is thought to allow sufficient passage of bacteria or bacterial antigens to initiate a mucosal immune response. Microbial monoassociation experiments into axenic animals have shown that some, but not all, endogenous bacteria will initiate an intestinal inflammatory response. For instance, Bacteroides vulgatus does not initiate intestinal inflammation in axenic IL-10 gene-deficient mice. We investigated whether B. vulgatus requires concomitant disruption of the intestinal epithelial barrier integrity in order to initiate an inflammatory response. METHODS: We first identified a dose of the indomethacin that would cause a primary disruption of the epithelial barrier without causing intestinal inflammation. IL-10 axenic mice were then administered this dose of indomethacin in their drinking water for 7 days and concomitantly monoassociated, by oral gavage, with B. vulgatus. RESULTS: Indomethacin treatment (2 microg/g/d) for 7 days resulted in disruption of epithelial barrier integrity, but it caused neither a systemic inflammatory response nor a mucosal inflammatory response in the colon or cecum. Monoassociation with B. vulgatus alone did not lead to a mucosal inflammatory response, despite a measurable systemic response. In contrast, administration of indomethacin plus B. vulgatus-monoassociation resulted in a marked intestinal inflammatory response in colon and cecum. CONCLUSIONS: Our data show that, in a genetically predisposed animal model, the nondisease-causing endogenous bacteria, B. vulgatus, is able to cause an intestinal inflammatory response provided that disruption of the intestinal epithelial barrier has occurred.

Population Health Science: A Core Element of Health Science Education in Sub-Saharan Africa.

Sub-Saharan Africa suffers an inordinate burden of disease and does not have the numbers of suitably trained health care workers to address this challenge. New concepts in health sciences education are needed to offer alternatives to current training approaches.A perspective of integrated training in population health for undergraduate medical and nursing education is advanced, rather than continuing to take separate approaches for clinical and public health education. Population health science educates students in the social and environmental origins of disease, thus complementing disease-specific training and providing opportunities for learners to take the perspective of the community as a critical part of their education.Many of the recent initiatives in health science education in sub-Saharan Africa are reviewed, and two case studies of innovative change in undergraduate medical education are presented that begin to incorporate such population health thinking. The focus is on East Africa, one of the most rapidly growing economies in sub-Saharan Africa where opportunities for change in health science education are opening. The authors conclude that a focus on population health is a timely and effective way for enhancing training of health care professionals to reduce the burden of disease in sub-Saharan Africa.

Utilization of health services in a resource-limited rural area in Kenya: Prevalence and associated household-level factors.

BACKGROUND AND METHODS: Knowledge of utilization of health services and associated factors is important in planning and delivery of interventions to improve health services coverage. We determined the prevalence and factors associated with health services utilization in a rural area of Kenya. Our findings inform the local health management in development of appropriately targeted interventions. We used a cluster sample survey design and interviewed household key informants on history of illness for household members and health services utilization in the preceding month. We estimated prevalence and performed random effects logistic regression to determine the influence of individual and household level factors on decisions to utilize health services. RESULTS AND CONCLUSIONS: 1230/6,440 (19.1%, 95% CI: 18.3%-20.2%) household members reported an illness. Of these, 76.7% (95% CI: 74.2%-79.0%) sought healthcare in a health facility. The majority (94%) of the respondents visited dispensary-level facilities and only 60.1% attended facilities within the study sub-counties. Of those that did not seek health services, 43% self-medicated by buying non-prescription drugs, 20% thought health services were too costly, and 10% indicated that the sickness was not serious enough to necessitate visiting a health facility. In the multivariate analyses, relationship to head of household was associated with utilization of health services. Relatives other than the nuclear family of the head of household were five times less likely to seek medical help (Odds Ratio 0.21 (95% CI: 0.05-0.87)). Dispensary level health facilities are the most commonly used by members of this community, and relations at the level of the household influence utilization of health services during an illness. These data enrich the perspective of the local health management to better plan the allocation of healthcare resources according to need and demand. The findings will also contribute in the development of community-level health coverage interventions that target the disadvantaged household groups.

Where teachers are few: documenting available faculty in five Tanzanian medical schools.

BACKGROUND: Faced with one of the lowest physician-to-population ratios in the world, the Government of Tanzania is urging its medical schools to train more physicians. The annual number of medical students admitted across the country rose from 55 in the 1990s to 1,680 approved places for the 2015/16 academic year. These escalating numbers strain existing faculty. OBJECTIVE: To describe the availability of faculty in medical schools in Tanzania. DESIGN: We identified faculty lists published on the Internet by five Tanzanian medical schools for the 2011/12 academic year and analyzed the appointment status, rank, discipline, and qualifications of faculty members. RESULTS: The five schools reported 366 appointed faculty members (excluding visiting, part-time, or honorary appointments) for an estimated total enrolled student capacity of 3,275. Thirty-eight percent of these faculty were senior lecturers or higher. Twenty-seven percent of the appointments were in basic science, 51% in clinical science, and 21% in public health departments. The most populated disciplines (more than 20 faculty members across the five institutions) were biochemistry and molecular biology, medicine, obstetrics and gynecology, pediatrics, and surgery; the least populated disciplines (less than 10 faculty members) were anesthesiology, behavioral sciences, dermatology, dental surgery, emergency medicine, hematology, ophthalmology, orthopedics, otorhinolaryngology, oncology and radiology, psychiatry. These figures are only indicative of faculty numbers because of differences in the way the schools published their faculty lists. CONCLUSIONS: Universities are not recruiting faculty at the same rate that they are admitting students, and there is an imbalance in the distribution of faculty across disciplines. Although there are differences among the universities, all are struggling to recruit and retain staff. If Tanzanian universities, the government, donors, and international partners commit resources to develop, recruit, and retain new faculty, Tanzania could build faculty numbers to permit a quality educational experience for its doctors of tomorrow.