Patients', physiotherapists' and other stakeholders' experiences and perceptions about supported home physiotherapy for people with musculoskeletal conditions: a qualitative study.

OBJECTIVES: Exercise, support and advice are the key treatment strategies of musculoskeletal problems. The aims of this study were to determine patients', physiotherapists', and other stakeholders' perspectives about supported home physiotherapy for the management of musculoskeletal problems and to identify the barriers and facilitators to rolling out this model of physiotherapy service delivery. METHODS: This study was conducted as part of a process evaluation run alongside a large trial designed to determine whether supported home physiotherapy is as good or better than a course of in-person physiotherapy. Forty interviews were conducted with 20 trial participants, 15 physiotherapists, and 5 other stakeholders. The interviews were semi-structured and based on interview guides. Each interview was transcribed and a three-tiered coding tree was developed. RESULTS: Six key themes were identified. Supported home physiotherapy (i) is convenient for some patients, (ii) does not always align with patients' and therapists' expectations about treatment (iii) is suitable for some but not all, (iv) can reduce personal connection and accountability, (v) has implications for physiotherapists' workloads, and (vi) has barriers and facilitators to future implementation. CONCLUSIONS: Findings suggest that patients are far more accepting of supported home physiotherapy than physiotherapists assume. This model of service delivery could be rolled out to improve access to physiotherapy and to provide a convenient and effective way of delivering physiotherapy to some patients with musculoskeletal conditions if our trial results indicate that supported home physiotherapy is as good or better than in-person physiotherapy. CLINICAL TRIAL REGISTRY NUMBER: ACTRN12619000065190 CONTRIBUTIONS OF THIS PAPER.

Remotely delivered physiotherapy is as effective as face-to-face physiotherapy for musculoskeletal conditions (REFORM): a randomised trial.

QUESTION: Is remotely delivered physiotherapy as good or better than face-to-face physiotherapy for the management of musculoskeletal conditions? DESIGN: Randomised controlled, non-inferiority trial with concealed allocation, blinded assessors and intention-to-treat analysis. PARTICIPANTS: A total of 210 adult participants with a musculoskeletal condition who presented for outpatient physiotherapy at five public hospitals in Sydney. INTERVENTION: One group received a remotely delivered physiotherapy program for 6 weeks that consisted of one face-to-face physiotherapy session in conjunction with weekly text messages, phone calls at 2 and 4 weeks, and an individualised home exercise program delivered through an app. The other group received usual face-to-face physiotherapy care in an outpatient setting. OUTCOME MEASURES: The primary outcome was the Patient Specific Functional Scale at 6 weeks with a pre-specified non-inferiority margin of -15 out of 100 points. Secondary outcomes included: the Patient Specific Functional Scale at 26 weeks; kinesiophobia, pain, function/disability, global impression of change and quality of life at 6 and 26 weeks; and satisfaction with service delivery at 6 weeks. RESULTS: The mean between-group difference (95% CI) for the Patient Specific Functional Scale at 6 weeks was 2.7 out of 100 points (-3.5 to 8.8), where a positive score favoured remotely delivered physiotherapy. The lower end of the 95% CI was greater than the non-inferiority margin. Whilst non-inferiority margins were not set for the secondary outcomes, the 95% CI of the mean between-group difference ruled out clinically meaningful differences. CONCLUSION: Remotely delivered physiotherapy with support via phone, text and an app is as good as face-to-face physiotherapy for the management of musculoskeletal conditions. TRIAL REGISTRATION: ACTRN12619000065190.

Endometrial Assembloids to Model Human Embryo Implantation In Vitro.

Understanding the process of human embryo implantation is impeded by the inability to study this phenomenon in vivo, thus limiting opportunities to gain knowledge to in vitro modeling. Previous models have relied on monolayer co-cultures, which do not replicate the complexity of endometrial tissue. Here, we detail the establishment of three-dimensional endometrial assembloids, comprising gland-like epithelial organoids in a stromal matrix. Endometrial assembloids mimic endometrial tissue structure more faithfully and can be used to study human embryo-endometrial interactions. Co-cultures of human embryos and endometrial assembloids will enhance our fundamental understanding of these processes as well as allowing us to study the mechanisms of persistent reproductive failure.

A Shoulder/Elbow Triage and Assessment model of care reduced a public orthopaedic shoulder/elbow clinic waitlist with high patient satisfaction.

BACKGROUND: Patients referred to public orthopaedic clinics can experience long waiting times before assessment. This study aims to evaluate the effectiveness of a collaborative Shoulder/Elbow Triage and Assessment (SHELTA) model of care involving orthopaedic surgeons and physiotherapists to reduce the waitlist and improve service and clinical outcomes for patients on an orthopaedic shoulder/elbow clinic waitlist. METHODS: Patients on the waitlist were triaged by surgeons and physiotherapists and invited to an assessment by experienced physiotherapists. Patients were treated nonoperatively or transferred to orthopaedic management based on clinical discussion. The primary outcome was the number of patients on the waitlist. Secondary outcomes included adverse events, patient satisfaction, re-referral and conversion to surgery rates. Pain, function and patient global impression of change were recorded for participants managed nonoperatively. RESULTS: From July 2019 to December 2019, the waitlist reduced from 451 to 298 patients with no adverse events. Seventy-nine patients could not be contacted and 25 no longer required assessment, and were removed from the waitlist. Nonoperatively managed participants reported satisfaction with the service, a median score of 6 on a 7-point Patient Global Impression of Change scale, change in pain of -2.5/10 (95% CI -3.3, -1.7; P < 0.001) on a numerical pain rating scale, and change in function of -17.4/100 (95% CI: -24.1, -10.8; P < 0.001) on the QuickDASH, indicating improvement. CONCLUSIONS: The SHELTA model of care effectively reduced the number of patients on an orthopaedic shoulder/elbow clinic waitlist with good service and clinical outcomes.

The first mitotic division of human embryos is highly error prone.

Human beings are made of ~50 trillion cells which arise from serial mitotic divisions of a single cell - the fertilised egg. Remarkably, the early human embryo is often chromosomally abnormal, and many are mosaic, with the karyotype differing from one cell to another. Mosaicism presumably arises from chromosome segregation errors during the early mitotic divisions, although these events have never been visualised in living human embryos. Here, we establish live cell imaging of chromosome segregation using normally fertilised embryos from an egg-share-to-research programme, as well as embryos deselected during fertility treatment. We reveal that the first mitotic division has an extended prometaphase/metaphase and exhibits phenotypes that can cause nondisjunction. These included multipolar chromosome segregations and lagging chromosomes that lead to formation of micronuclei. Analysis of nuclear number and size provides evidence of equivalent phenotypes in 2-cell human embryos that gave rise to live births. Together this shows that errors in the first mitotic division can be tolerated in human embryos and uncovers cell biological events that contribute to preimplantation mosaicism.

Protocol for a process evaluation: face-to-face physiotherapy compared with a supported home exercise programme for the management of musculoskeletal conditions: the REFORM trial.

INTRODUCTION: The REFORM (REhabilitation FOR Musculoskeletal conditions) trial is a non-inferiority randomised controlled trial (n=210) designed to determine whether a supported home exercise programme is as good or better than a course of face-to-face physiotherapy for the management of some musculoskeletal conditions. The trial is currently being conducted across Sydney government hospitals in Australia. This process evaluation will run alongside the REFORM trial. It combines qualitative and quantitative data to help explain the trial results and determine the feasibility of rolling out supported home exercise programmes in settings similar to the REFORM trial. METHODS AND ANALYSIS: Two theoretical frameworks underpin our process evaluation methodology: the Realist framework (context, mechanism, outcomes) considers the causal assumptions as to why a supported home exercise programme may be as good or better than face-to-face physiotherapy in terms of the context, mechanisms and outcomes of the trial. The RE-AIM framework describes the Reach, Effectiveness, Adoption, Implementation and Maintenance of the intervention. These two frameworks will be broadly used to guide this process evaluation using a mixed-methods approach. For example, qualitative data will be derived from interviews with patients, healthcare professionals and stakeholders, and quantitative data will be collected to determine the cost and feasibility of providing supported home exercise programmes. These data will be analysed iteratively before the analysis of the trial results and will be triangulated with the results of the primary and secondary outcomes. ETHICS AND DISSEMINATION: This trial will be conducted in accordance with the National Health and Medical Research Council National Statement on Ethical Conduct in Human Research (2018) and the Note for Good Clinical Practice (CPMP/ICH-135/95). Ethical approval was obtained on 17 March 2017 from the Northern Sydney Local Health District Human Research Ethics Committee (trial number: HREC/16HAWKE/431-RESP/16/287) with an amendment for the process evaluation approved on 4 February 2020. The results of the process evaluation will be disseminated through publications in peer-reviewed journals and presentations at scientific conferences. TRIAL REGISTRATION NUMBER: ACTRN12619000065190.

Evaluating Surgical Complexity of Endoscopic Hysterectomy: An Inter-rater and Intra-rater Agreement Study of Novel Scoring Tool.

STUDY OBJECTIVE: Evaluate inter-rater and intrarater reliability of a novel scoring tool for surgical complexity assessment of endoscopic hysterectomy. DESIGN: Validation study. SETTING: Academic medical center. PARTICIPANTS: Total of 11 academic obstetrician-gynecologists with varying years of postresidency training, clinical practice, and surgical volumes. INTERVENTIONS: Application of a novel scoring tool to evaluate surgical complexity of 150 sets of images taken in a standardized fashion before surgical intervention (global pelvis, anterior cul-de-sac, posterior cul-de-sac, right adnexa, left adnexa). Using only these images, raters were asked to assess uterine size, number, and location of myomas, adnexal and uterine mobility, need for ureterolysis, and presence of endometriosis or adhesions in relevant locations. Surgical complexity was staged on a scale of 1 to 4 (low to high complexity). MEASUREMENTS AND MAIN RESULTS: Number of postresidency years in practice for participating surgeons ranged from 2 to 15, with an average of 8 years. A total of 8 obstetrician-gynecologists (72.7%) had completed a fellowship in minimally invasive gynecologic surgery. Six (54.6%) reported an annual volume of >50 hysterectomies. Raters reported that 95.4% of the images were satisfactory for assessment. Of the 150 sets of images, most were found to be stage 1 to 2 complexity (stage 1: 23.8%, stage 2: 41.6%, stage 3: 32.8%, stage 4: 1.8%). The level of inter-rater agreement regarding stage 1 to 2 vs 3 to 4 complexity was moderate (κ = 0.49; 95% confidence interval [CI], 0.42-0.56). Moderate inter-rater agreement was also found between surgeon raters with an annual hysterectomy volume >50 (κ = 0.49; 95% CI, 0.40-0.57) as well as between surgeon raters with fellowship experience (κ = 0.50; 95% CI, 0.42-0.58). Intrarater agreement averaged 80.2% among all raters and also achieved moderate agreement (mean weighted κ = 0.53; range, 0.38-0.72). CONCLUSION: This novel scoring tool uses clinical assessment of preintervention anatomic images to stratify the surgical complexity of endoscopic hysterectomy. It has rich and comprehensive evaluation capabilities and achieved moderate inter-rater and intrarater agreement. The tool can be used in conjunction with or instead of traditional markers of surgical complexity such as uterine weight, estimated blood loss, and operative time.

Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids.

Decidual remodelling of midluteal endometrium leads to a short implantation window after which the uterine mucosa either breaks down or is transformed into a robust matrix that accommodates the placenta throughout pregnancy. To gain insights into the underlying mechanisms, we established and characterized endometrial assembloids, consisting of gland-like organoids and primary stromal cells. Single-cell transcriptomics revealed that decidualized assembloids closely resemble midluteal endometrium, harbouring differentiated and senescent subpopulations in both glands and stroma. We show that acute senescence in glandular epithelium drives secretion of multiple canonical implantation factors, whereas in the stroma it calibrates the emergence of anti-inflammatory decidual cells and pro-inflammatory senescent decidual cells. Pharmacological inhibition of stress responses in pre-decidual cells accelerated decidualization by eliminating the emergence of senescent decidual cells. In co-culture experiments, accelerated decidualization resulted in entrapment of collapsed human blastocysts in a robust, static decidual matrix. By contrast, the presence of senescent decidual cells created a dynamic implantation environment, enabling embryo expansion and attachment, although their persistence led to gradual disintegration of assembloids. Our findings suggest that decidual senescence controls endometrial fate decisions at implantation and highlight how endometrial assembloids may accelerate the discovery of new treatments to prevent reproductive failure.

At the beginning of a human pregnancy, the embryo implants into the uterus lining, known as the endometrium. At this point, the endometrium transforms into a new tissue that helps the placenta to form. Problems in this transformation process are linked to pregnancy disorders, many of which can lead to implantation failure (the embryo fails to invade the endometrium altogether) or recurrent miscarriages (the embryo implants successfully, but the interface between the placenta and the endometrium subsequently breaks down). Studying the implantation of human embryos directly is difficult due to ethical and technical barriers, and animals do not perfectly mimic the human process, making it challenging to determine the causes of pregnancy disorders. However, it is likely that a form of cellular arrest called senescence, in which cells stop dividing but remain metabolically active, plays a role. Indeed, excessive senescence in the cells that make up the endometrium is associated with recurrent miscarriage, while a lack of senescence is associated with implantation failure. To study this process, Rawlings et al. developed a new laboratory model of the human endometrium by assembling two of the main cell types found in the tissue into a three-dimensional structure. When treated with hormones, these 'assembloids' successfully mimic the activity of genes in the cells of the endometrium during implantation. Rawlings et al. then exposed the assembloids to the drug dasatinib, which targets and eliminates senescent cells. This experiment showed that assembloids become very robust and static when devoid of senescent cells. Rawlings et al. then studied the interaction between embryos and assembloids using time-lapse imaging. In the absence of dasatinib treatment, cells in the assembloid migrated towards the embryo as it expanded, a process required for implantation. However, when senescent cells were eliminated using dasatinib, this movement of cells towards the embryo stopped, and the embryo failed to expand, in a situation that mimicks implantation failure. The assembloid model of the endometrium may help scientists to study endometrial defects in the lab and test potential treatments. Further work will include other endometrial cell types in the assembloids, and could help increase the reliability of the model. However, any drug treatments identified using this model will need further research into their safety and effectiveness before they can be offered to patients.

TEXT4myBACK - The Development Process of a Self-Management Intervention Delivered Via Text Message for Low Back Pain.

OBJECTIVE: To develop a bank of text messages for a lifestyle-based self-management intervention for people with low back pain (LBP). DESIGN: Iterative development process. SETTING: Community and primary care. PARTICIPANTS: Fifteen researchers, clinicians, and consumer representatives participated in the concept and initial content development phase. Twelve experts (researchers and clinicians) and 12 consumers participated in the experts and consumers review phase. Full study sample of participants was N=39. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We first conducted two 2-hour workshops to identify important domains for people with LBP, sources of content, appropriate volume, and timing of the messages. The messages were then drafted by a team of writers. Second, we invited expert researchers and clinicians to review and score the messages using a 5-item psychometric scale according to (1) the appropriateness of the content and (2) the likelihood of clinical effectiveness and to provide written feedback. Messages scoring ≤8 out of 10 points would be modified accordingly. Consumers were invited to review the messages and score them using a 5-item psychometric scale according to the utility of the content, the understanding of the content, and language acceptability and to provide feedback. Messages scoring ≤12 out of 15 points would be improved. RESULTS: Exercise, education, mood, sleep, use of care, and medication domains were identified and 82 domain-specific evidence-based messages were written. Messages received a mean score of 8.3 out of 10 points by experts. Twenty-nine messages were modified accordingly. The mean score of the messages based on consumers feedback was of 12.5 out of 15 points. Thirty-six messages were improved. CONCLUSIONS: We developed a bank of text messages for an evidence-based self-management intervention using a theory-based, iterative, codesign process with researchers, consumers, and clinicians. This article provides scientific support for future development of text message interventions within the pain field.

Face-to-face physiotherapy compared with a supported home exercise programme for the management of musculoskeletal conditions: protocol of a multicentre, randomised controlled trial-the REFORM trial.

INTRODUCTION: Exercise, support and advice are considered core components of management for most musculoskeletal conditions and are typically provided by physiotherapists through regular face-to-face treatments. However, exercise can be provided remotely as part of a home exercise programme, while support and advice can be provided over the telephone. There is initial evidence from trials and systematic reviews to suggest that remotely provided physiotherapy can be used to manage a variety of musculoskeletal conditions safely and effectively. METHODS AND ANALYSIS: The aim of this single-blind randomised controlled non-inferiority trial is to determine whether a supported home exercise programme is as good as or better than face-to-face physiotherapy for the treatment of musculoskeletal conditions. Two hundred and ten participants will be recruited from five public hospitals in Sydney, Australia. Participants will be randomised to either the supported home exercise group or the face-to-face physiotherapy group. Participants allocated to the supported home exercise group will initially receive one face-to-face session with the trial physiotherapist and will then be managed remotely for the next 6 weeks. Participants allocated to the face-to-face physiotherapy group will receive a course of physiotherapy as typically provided in Sydney government hospitals. The primary outcome is function measured by the Patient Specific Functional Scale at 6 weeks. There will be nine secondary outcomes measured at 6 and 26 weeks. Separate analyses will be conducted on each outcome, and all analyses will be conducted on an intention-to-treat basis. A health economic evaluation will be conducted from a health funder plus patient perspective. ETHICS AND DISSEMINATION: Ethical approval was obtained on the 17 March 2017 from the Northern Sydney Local Health District HREC, trial number HREC/16HAWKE/431-RESP/16/287. The results of this study will be submitted for publication to peer-reviewed journals and be presented at national and international conferences. Recruitment commenced in March 2019, and it is anticipated that the trial will be completed by December 2021. This trial will investigate two different models of physiotherapy care for people with musculoskeletal conditions. TRIAL REGISTRATION NUMBER: CPMP/ICH-135/95. PROTOCOL VERSION: The most recent version of the protocol is V.1.2 dated November 2019.

Assessing spirometry competence through certification in community-based healthcare settings in Australia and New Zealand: A position paper of the Australian and New Zealand Society of Respiratory Science.

Spirometry has been established as an essential test for diagnosing and monitoring respiratory disease, particularly asthma and COPD, as well as in occupational health surveillance. In Australia and New Zealand, there is currently no pathway for spirometry operators in community-based healthcare settings to demonstrate spirometry competence. The Australia and New Zealand Society of Respiratory Science (ANZSRS) has identified a need for developing a pathway for operators working in community-based practices in Australia and New Zealand to demonstrate spirometry competence and certification. Spirometry certification provides evidence to patients, clients, employers and organizations that an individual has participated in an assessment process that qualifies them to perform spirometry to current international spirometry standards set out by the American Thoracic Society and the European Respiratory Society (ATS/ERS). This document describes a competence assessment pathway that incorporates a portfolio and practical assessment. The completion of this pathway and the award of certification confer an individual is competent to perform spirometry for 3 years, after which re-certification is required. The adoption of this competency assessment and certification process by specialist organizations, and the commitment of operators performing spirometry to undergo this process, will enhance spirometry quality and practice in community-based healthcare settings.

Chromosome errors in human eggs shape natural fertility over reproductive life span.

Chromosome errors, or aneuploidy, affect an exceptionally high number of human conceptions, causing pregnancy loss and congenital disorders. Here, we have followed chromosome segregation in human oocytes from females aged 9 to 43 years and report that aneuploidy follows a U-curve. Specific segregation error types show different age dependencies, providing a quantitative explanation for the U-curve. Whole-chromosome nondisjunction events are preferentially associated with increased aneuploidy in young girls, whereas centromeric and more extensive cohesion loss limit fertility as women age. Our findings suggest that chromosomal errors originating in oocytes determine the curve of natural fertility in humans.

A Pilot Study to Address Tolerance of Uncertainty Among Family Medicine Residents.

BACKGROUND AND OBJECTIVES: Because patients often present to their family physicians with undifferentiated medical problems, uncertainty is common. Family medicine residents must manage both the ambiguity inherent in the field as well as the very real uncertainty of learning to become a skilled physician with little experience to serve as a guide. The purpose of this analysis was to assess the impact of a new curriculum on family medicine residents' tolerance of ambiguity. METHODS: We conducted an exploratory quasi-experimental study to assess the impact of a novel curriculum designed to improve family medicine residents' tolerance of ambiguity. Four different surveys were administered to 25 family medicine residents at different stages in their training prior to and immediately and 6 months after the new curriculum. RESULTS: Although many constructs remained unchanged with the intervention, one important construct, namely perceived threats of ambiguity, showed significant and sustained improvement relative to before undertaking this curriculum (score of 26.2 prior to the intervention, 22.1 immediately after, and 22.0 6 months after the intervention). CONCLUSIONS: A new curriculum designed to improve tolerance to ambiguity appears to reduce the perceived threats of ambiguity in this small exploratory study.

Interventions to increase access to or uptake of physical health screening in people with severe mental illness: a realist review.

OBJECTIVES: To identify and evaluate interventions aimed at increasing uptake of, or access to, physical health screening by adults with severe mental illness; to examine why interventions might work. DESIGN: Realist review. SETTING: Primary, secondary and tertiary care. RESULTS: A systematic search identified 1448 studies, of which 22 met the inclusion criteria. Studies were from Australia (n=3), Canada (n=1), Hong Kong (n=1), UK (n=11) and USA (n=6). The studies focused on breast cancer screening, infection preventive services and metabolic syndrome (MS) screening by targeting MS-related risk factors. The interventions could be divided into those focusing on (1) health service delivery changes (12 studies), using quality improvement, randomised controlled trial, cluster randomised feasibility trial, retrospective audit, cross-sectional study and satisfaction survey designs and (2) tests of tools designed to facilitate screening (10 studies) using consecutive case series, quality improvement, retrospective evaluation and pre-post audit study designs. All studies reported improved uptake of screening, or that patients had received screening they would not have had without the intervention. No estimation of overall effect size was possible due to heterogeneity in study design and quality. The following factors may contribute to intervention success: staff and stakeholder involvement in screening, staff flexibility when taking physical measurements (eg, using adapted equipment), strong links with primary care and having a pharmacist on the ward. CONCLUSIONS: A range of interventions may be effective, but better quality research is needed to determine any effect size. Researchers should consider how interventions may work when designing and testing them in order to target better the specific needs of this population in the most appropriate setting. Behaviour-change interventions to reduce identified barriers of patient and health professional resistance to screening this population are required. Resource constraints, clarity over professional roles and better coordination with primary care need to be addressed.

Clinical and experimental studies of a novel P525R FUS mutation in amyotrophic lateral sclerosis.

OBJECTIVE: To describe the clinical features of a novel fused in sarcoma (FUS) mutation in a young adult female amyotrophic lateral sclerosis (ALS) patient with rapid progression of weakness and to experimentally validate the consequences of the P525R mutation in cellular neuronal models. METHODS: We conducted sequencing of genomic DNA from the index patient and her family members. Immunocytochemistry was performed in various cellular models to determine whether the newly identified P525R mutant FUS protein accumulated in cytoplasmic inclusions. Clinical features of the index patient were compared with 19 other patients with ALS carrying the P525L mutation in the same amino acid position. RESULTS: A novel mutation c.1574C>G (p.525P>R) in the FUS gene was identified in the index patient. The clinical symptoms are similar to those in familial ALS patients with the P525L mutation at the same position. The P525R mutant FUS protein showed cytoplasmic localization and formed large stress granule-like cytoplasmic inclusions in multiple cellular models. CONCLUSIONS: The clinical features of the patient and the cytoplasmic inclusions of the P525R mutant FUS protein strengthen the notion that mutations at position 525 of the FUS protein result in a coherent phenotype characterized by juvenile or young adult onset, rapid progression, variable positive family history, and female preponderance.

Using Reflections to Evaluate the STFM Behavioral Science/Family Systems Educator Fellowship.

BACKGROUND AND OBJECTIVES: A group of family medicine educators identified a need and developed a 1-year fellowship for early career behavioral science educators. This occurred in response to a reduction in previous opportunities and resources. The program was designed to shape and mentor new behavioral science faculty teaching in family medicine departments and programs. Quantitative data analysis from pre- and post-fellowship survey data from years 1-4 confirmed fellowship objectives were met. METHODS: The 1-year fellowship, developed by senior faculty in STFM features a blend of classroom style learning, mentored small-group interactions, reflective writing and a scholarly project requirement. As one aspect of program evaluation, reflective writings submitted by fellows and faculty were analyzed using qualitative methodology for themes related to curricular objectives. RESULTS: From 2010-2013, 44 fellows completed the program. Authors analyzed reflective writings from 15 fellows and 6 small-group mentors. Four overarching themes emerged: emerging professional competence, evolving professional identity, connectedness, and generativity. An unexpected finding was that the fellowship mentors benefited in ways parallel to that of the fellows. CONCLUSIONS: A qualitative analytical approach to examining the reflective writings of fellowship participants yielded confirmation that program goals were achieved. In addition, a commitment to "paying it forward" as ongoing and future leaders in family medicine education resulted for both fellows and faculty mentors.

HCV-Mediated Apoptosis of Hepatocytes in Culture and Viral Pathogenesis.

Chronic Hepatitis C Virus (HCV) infection is associated with progressive liver injury and subsequent development of fibrosis and cirrhosis. The death of hepatocytes results in the release of cytokines that induce inflammatory and fibrotic responses. The mechanism of liver damage is still under investigation but both apoptosis and immune-mediated processes may play roles. By observing the changes in gene expression patterns in HCV-infected cells, both markers and the causes of HCV-associated liver injury may be elucidated. HCV genotype 1b virus from persistently infected VeroE6 cells induced a strong cytopathic effect when used to infect Huh7.5 hepatoma cells. To determine if this cytopathic effect was a result of apoptosis, ultrastructural changes were observed by electron microscopy and markers of programmed cell death were surveyed. Screening of a human PCR array demonstrated a gene expression profile that contained upregulated markers of apoptosis, including tumor necrosis factor, caspases and caspase activators, Fas, Bcl2-interacting killer (BIK) and tumor suppressor protein, p53, as a result of HCV genotype 1b infection. The genes identified in this study should provide new insights into understanding viral pathogenesis in liver cells and may possibly help to identify novel antiviral and antifibrotic targets.

The Food and Drug Administration Office of Women's Health: Impact of Science on Regulatory Policy: An Update.

The U.S. Food and Drug Administration Office of Women's Health (FDA OWH) has supported women's health research for ∼20 years, funding more than 300 studies on women's health issues, including research on diseases/conditions that disproportionately affect women in addition to the evaluation of sex differences in the performance of and response to medical products. These important women's health issues are studied from a regulatory perspective, with a focus on improving and optimizing medical product development and the evaluation of product safety and efficacy in women. These findings have influenced industry direction, labeling, product discontinuation, safety notices, and clinical practice. In addition, OWH-funded research has addressed gaps in the knowledge about diseases and medical conditions that impact women across the life span such as cardiovascular disease, pregnancy, menopause, osteoporosis, and the safe use of numerous medical products.