Whole-body and adipose tissue-specific mechanisms underlying the metabolic effects of fibroblast growth factor 21 in the Siberian hamster.

OBJECTIVE: Fibroblast growth factor 21 (FGF21) has been shown to rapidly lower body weight in the Siberian hamster, a preclinical model of adiposity. This induced negative energy balance mediated by FGF21 is associated with both lowered caloric intake and increased energy expenditure. Previous research demonstrated that adipose tissue (AT) is one of the primary sites of FGF21 action and may be responsible for its ability to increase the whole-body metabolic rate. The present study sought to determine the relative importance of white (subcutaneous AT [sWAT] and visceral AT [vWAT]), and brown (interscapular brown AT [iBAT]) in governing FGF21-mediated metabolic improvements using the tissue-specific uptake of glucose and lipids as a proxy for metabolic activity. METHODS: We used positron emission tomography-computed tomography (PET-CT) imaging in combination with both glucose (18F-fluorodeoxyglucose) and lipid (18F-4-thiapalmitate) tracers to assess the effect of FGF21 on the tissue-specific uptake of these metabolites and compared responses to a control group pair-fed to match the food intake of the FGF21-treated group. In vivo imaging was combined with ex vivo tissue-specific functional, biochemical, and molecular analyses of the nutrient uptake and signaling pathways. RESULTS: Consistent with previous findings, FGF21 reduced body weight via reduced caloric intake and increased energy expenditure in the Siberian hamster. PET-CT studies demonstrated that FGF21 increased the uptake of glucose in BAT and WAT independently of reduced food intake and body weight as demonstrated by imaging of the pair-fed group. Furthermore, FGF21 increased glucose uptake in the primary adipocytes, confirming that these in vivo effects may be due to a direct action of FGF21 at the level of the adipocytes. Mechanistically, the effects of FGF21 are associated with activation of the ERK signaling pathway and upregulation of GLUT4 protein content in all fat depots. In response to treatment with FGF21, we observed an increase in the markers of lipolysis and lipogenesis in both the subcutaneous and visceral WAT depots. In contrast, FGF21 was only able to directly increase the uptake of lipid into BAT. CONCLUSIONS: These data identify brown and white fat depots as primary peripheral sites of action of FGF21 in promoting glucose uptake and also indicate that FGF21 selectively stimulates lipid uptake in brown fat, which may fuel thermogenesis

Performance of Two-Stage Cervical Cancer Screening With Primary High-Risk Human Papillomavirus Testing in Women Living With Human Immunodeficiency Virus

OBJECTIVE: To evaluate the performance of cervical cancer screening algorithms for women living with human immunodeficiency virus (HIV), using primary high-risk human papillomavirus (HPV) testing followed by cytology, visual inspection with acetic acid, or colposcopy. METHODS: We conducted a prospective cohort study of women living with HIV in Botswana. All participants underwent high-risk HPV testing. Participants with positive high-risk HPV test results underwent cytology, visual inspection with acetic acid, colposcopy, and biopsy. Participants with negative high-risk HPV test results also underwent cytology. Histopathology was the reference standard for determination of preinvasive cervical disease and cervical cancer. Sensitivity, specificity, positive predictive value (PPV), negative predictive value, and likelihood ratios (LR) of high-risk HPV-based two-stage screening algorithms were calculated. RESULTS: Among 300 women screened, 88 (29%) had a positive high-risk HPV test result, and 29 of the 88 (35%) women who tested positive for high-risk HPV had CIN 2 or higher on histopathology. High-risk HPV followed by colposcopy resulted in a sensitivity of 83%, specificity of 49%, PPV of 47%, LR+ of +1.6, and LR− of −0.4. High-risk HPV followed by visual inspection with acetic acid resulted in a reduced sensitivity of 59%, specificity of 49%, PPV of 39%, LR+ of +1.2, and LR− of −0.8. High-risk HPV testing followed by cytology also resulted in a reduced sensitivity of 62%, specificity of 77%, PPV of 60%, LR+ of +2.7, and LR− of −0.5. Stratification by HPV 16/18/45 did not improve performance of the algorithms. CONCLUSION: In a high-risk population with HIV, high-risk HPV testing followed by colposcopy demonstrated the highest sensitivity and PPV in detecting high-grade cervical dysplasia. Allocating resources to colposcopy in resource-limited settings may be more effective than other screening strategies

Maternal weight and birth outcomes among women on antiretroviral treatment from conception in a birth surveillance study in Botswana.

Antiretrovirals such as dolutegravir (DTG) and tenofovir alafenamide (TAF) have been associated with excessive weight gain. The objective of this study was to understand the potential impact of ART-associated weight gain on pregnancy outcomes among women living with HIV. Using data from the Tsepamo birth outcomes surveillance study in Botswana, we evaluated the relationship between maternal weight (and weight gain) and severe birth outcomes (very preterm delivery  4000 g) and maternal hypertension. We estimated the relative risk of each outcome by baseline weight (first weight in pregnancy 90 kg) was associated with increased risk of macrosomia (aRR 3.24, 95% CI 2.36, 4.44) and maternal hypertension (aRR 1.79, 95% CI 1.62, 1.97). Baseline weight was not associated with stillbirth or early neonatal death. For all outcomes, second trimester weight gain showed weaker associations than did baseline weight. Duration of pre-pregnancy ART (years) was associated with higher baseline weight for DTG but not for EFV, and the risk of maternal hypertension by baseline weight category was higher for DTG than EFV for all strata. ART regimens associated with weight gain may reduce the number of women at risk for certain severe adverse pregnancy outcomes associated with low weight but increase the number at risk of macrosomia and maternal hypertension. Further research could determine whether weight-based ART treatment strategies improve maternal and child health. [Abstract copyright: © 2021 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.

Building Health System Capacity through Medical Education: A Targeted Needs Assessment to Guide Development of a Structured Internal Medicine Curriculum for Medical Interns in Botswana

Background: Medical internship is the final year of training before independent practice for most doctors in Botswana. Internship training in Botswana faces challenges including variability in participants’ level of knowledge and skill related to their completion of medical school in a variety of settings (both foreign and domestic), lack of planned curricular content, and limited time for structured educational activities. Data on trainees’ opinions regarding the content and delivery of graduate medical education in settings like Botswana are limited, which makes it difficult to revise programs in a learner-centered way. Objective: To understand the perceptions and experiences of a group of medical interns in Botswana, in order to inform a large curriculum initiative. Methods: We conducted a targeted needs assessment using structured interviews at one district hospital. The interview script included demographic, quantitative, and free- response questions. Fourteen interns were asked their opinions about the content and format of structured educational activities, and provided feedback on the preferred characteristics of a new curriculum. Descriptive statistics were calculated. Findings: In the current curriculum, training workshops were the highest-scored teaching format, although most interns preferred lectures overall. Specialists were rated as the most useful teachers, and other interns and medical officers were rated as average. Interns felt they had adequate exposure to content such as HIV and tuberculosis, but inadequate exposure to areas including medical emergencies, non-communicable diseases, pain management, procedural skills, X-ray and EKG interpretation, disclosing medical information, and identifying career goals. For the new curriculum, interns preferred a structured case discussion format, and a focus on clinical reasoning and procedural skills. Conclusions: This needs assessment identified several foci for development, including a shift toward interactive sessions focused on skill development, the need to empower interns and medical officers to improve teaching skills, and the value of shifting curricular content to mirror the epidemiologic transition occurring in Botswana. Interns’ input is being used to initiate a large curriculum intervention that will be piloted and scaled nationally over the next several years. Our results underscore the value of seeking the opinion of trainees, both to aid educators in building programs that serve them and in empowering them to direct their education toward their needs and goals

Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis

The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and diseaserelated end points. Here we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy

Integration of oncology and palliative care : a Lancet Oncology Commission

Full integration of oncology and palliative care relies on the specific knowledge and skills of two modes of care: the tumour-directed approach, the main focus of which is on treating the disease; and the host-directed approach, which focuses on the patient with the disease. This Commission addresses how to combine these two paradigms to achieve the best outcome of patient care. Randomised clinical trials on integration of oncology and palliative care point to health gains: improved survival and symptom control, less anxiety and depression, reduced use of futile chemotherapy at the end of life, improved family satisfaction and quality of life, and improved use of health-care resources. Early delivery of patient-directed care by specialist palliative care teams alongside tumour-directed treatment promotes patient-centred care. Systematic assessment and use of patient-reported outcomes and active patient involvement in the decisions about cancer care result in better symptom control, improved physical and mental health, and better use of health-care resources. The absence of international agreements on the content and standards of the organisation, education, and research of palliative care in oncology are major barriers to successful integration. Other barriers include the common misconception that palliative care is end-of-life care only, stigmatisation of death and dying, and insufficient infrastructure and funding. The absence of established priorities might also hinder integration more widely. This Commission proposes the use of standardised care pathways and multidisciplinary teams to promote integration of oncology and palliative care, and calls for changes at the system level to coordinate the activities of professionals, and for the development and implementation of new and improved education programmes, with the overall goal of improving patient care. Integration raises new research questions, all of which contribute to improved clinical care. When and how should palliative care be delivered? What is the optimal model for integrated care? What is the biological and clinical effect of living with advanced cancer for years after diagnosis? Successful integration must challenge the dualistic perspective of either the tumour or the host, and instead focus on a merged approach that places the patient's perspective at the centre. To succeed, integration must be anchored by management and policy makers at all levels of health care, followed by adequate resource allocation, a willingness to prioritise goals and needs, and sustained enthusiasm to help generate support for better integration. This integrated model must be reflected in international and national cancer plans, and be followed by developments of new care models, education and research programmes, all of which should be adapted to the specific cultural contexts within which they are situated. Patient-centred care should be an integrated part of oncology care independent of patient prognosis and treatment intention. To achieve this goal it must be based on changes in professional cultures and priorities in health care

Impact of cervicitis on performance of cervical cancer screening using HRHPV testing and visual evaluation in women living with HIV in Botswana

Cervicitis may affect the accuracy of cervical cancer screening in women living with HIV, even when testing for high‐risk HPV is used

Results of an inner-city school-based asthma and allergy screening pilot study: a combined approach using written questionnaires and step testing.

BACKGROUND: A questionnaire alone may not be an adequate screening tool for asthma. OBJECTIVE: To determine whether an asthma questionnaire used in combination with an exercise step test is better than a questionnaire alone in screening for asthma in children and to evaluate the validity of a rhinitis questionnaire in determining atopy. METHODS: The International Study of Asthma and Allergies in Childhood (ISAAC) asthma core questionnaire was used to screen for asthma in 307 inner-city first through third graders. All children who had scores consistent with a diagnosis of asthma underwent step testing, as did a subset of children who had negative overall scores. All children who had inconsistent asthma scores and step test results underwent methacholine challenge testing. The same 307 children underwent rhinitis screening and children who had one or more positive responses on the ISAAC rhinitis questionnaire underwent skin testing as did a subset of children who had all negative responses. RESULTS: Three hundred of 307 asthma and rhinitis questionnaires were returned. Twenty-eight children (9%) had global asthma scores that were considered to be positive (5 or above). Twenty-four of these children underwent step testing as did 34 randomly selected children who had negative global asthma scores. Thirty-one (91%) of the 34 children who had negative global asthma scores had negative step tests. Similarly, 20 of 24 children (83%) of the children who had positive global asthma scores had negative step tests. Only 4 children who had positive global asthma scores were step test-positive or had reversible airway obstruction at baseline. Using a positive methacholine challenge as the gold standard for establishing bronchial hyperresponsiveness, the global asthma score derived from the eight-item ISAAC asthma questionnaire yielded a sensitivity of 64%, a specificity of 11%, a positive predictive value of 47%, and a negative predictive value of 20%. Comparing the six-item ISAAC rhinitis questionnaire results to the gold standard, skin test reactivity, the questionnaire yielded a sensitivity of 76%, a specificity of 21%, a positive predictive value of 56%, and a negative predictive value of 40%. CONCLUSIONS: Step testing was not useful as a screening tool for asthma. In addition, the ISAAC asthma questionnaire may not be a good asthma screening tool for inner-city pediatric populations, especially if the form is self-administered. Investigators should first validate both the ISAAC asthma and rhinitis screening questionnaires in the particular population to be studied before widespread asthma and allergy screening efforts are initiated using these tools

Knowledge and Attitudes of Allied Health Professionals Towards End-Of-Life and Advance Care Planning Discussions With People With COPD: A Cross-Sectional Survey Study

Chronic obstructive pulmonary disease (COPD) is a progressive, life-limiting condition. End-of-life (EOL) and Advance Care Planning (ACP) discussions are essential, yet access and support remain inadequate. Allied health professionals (AHPs) commonly have ongoing relationships with patients and opportunities to discuss care outside acute crises as is considered best practice. Australian and New Zealand AHPs were invited to complete an anonymous, online, cross-sectional survey that aimed to explore knowledge, attitudes and practices, and associated perceived triggers and barriers to EOL and ACP discussions with patients with COPD. Closed survey responses were summarized descriptively and free-text thematically analysed. One hundred and one AHPs (physiotherapists, social workers and occupational therapists) participated. Many held positive attitudes towards ACP but lacked procedural knowledge. Half (50%) of participants routinely discussed EOL care with patients when perceiving this to be appropriate but only 21% actually discussed ACP with the majority of their patients. Many cited lack of training to engage in sensitive EOL discussions, with barriers including: 1) clinician lack of confidence/fear of distressing patients (75%); 2) perceived patient and family reluctance (51%); 3) organizational challenges (28%); and 4) lack of role clarity (39%). AHPs commonly have ongoing relationships with patients with chronic conditions but lack the confidence and role clarity to utilise this position to engage ongoing EOL and ACP discussions. While AHPs may not traditionally consider EOL and ACP discussions as part of their role, it is crucial that they feel prepared to respond if patients broach the topic