Kentucky Outreach Service Kiosk (KyOSK) Study protocol: a community-level, controlled quasi-experimental, type 1 hybrid effectiveness study to assess implementation, effectiveness and cost-effectiveness of a community-tailored harm reduction kiosk on HIV, HCV and overdose risk in rural Appalachia.

INTRODUCTION: Many rural communities bear a disproportionate share of drug-related harms. Innovative harm reduction service models, such as vending machines or kiosks, can expand access to services that reduce drug-related harms. However, few kiosks operate in the USA, and their implementation, impact and cost-effectiveness have not been adequately evaluated in rural settings. This paper describes the Kentucky Outreach Service Kiosk (KyOSK) Study protocol to test the effectiveness, implementation outcomes and cost-effectiveness of a community-tailored, harm reduction kiosk in reducing HIV, hepatitis C and overdose risk in rural Appalachia. METHODS AND ANALYSIS: KyOSK is a community-level, controlled quasi-experimental, non-randomised trial. KyOSK involves two cohorts of people who use drugs, one in an intervention county (n=425) and one in a control county (n=325). People who are 18 years or older, are community-dwelling residents in the target counties and have used drugs to get high in the past 6 months are eligible. The trial compares the effectiveness of a fixed-site, staffed syringe service programme (standard of care) with the standard of care supplemented with a kiosk. The kiosk will contain various harm reduction supplies accessible to participants upon valid code entry, allowing dispensing data to be linked to participant survey data. The kiosk will include a call-back feature that allows participants to select needed services and receive linkage-to-care services from a peer recovery coach. The cohorts complete follow-up surveys every 6 months for 36 months (three preceding kiosk implementation and four post-implementation). The study will test the effectiveness of the kiosk on reducing risk behaviours associated with overdose, HIV and hepatitis C, as well as implementation outcomes and cost-effectiveness. ETHICS AND DISSEMINATION: The University of Kentucky Institutional Review Board approved the protocol. Results will be disseminated in academic conferences and peer-reviewed journals, online and print media, and community meetings. TRIAL REGISTRATION NUMBER: NCT05657106.

Drugs involved in Kentucky drug poisoning deaths and relation with antecedent controlled substance prescription dispensing.

BACKGROUND: The shift from prescription to illicit drugs involved in drug poisoning deaths raises questions about the current utility of prescription drug monitoring program (PDMP) data to inform drug poisoning (overdose) prevention efforts. In this study, we describe relations between specific drugs involved in Kentucky drug poisoning deaths and antecedent controlled substance (CS) dispensing. METHODS: The study used linked death certificates and PDMP data for 2,248 Kentucky resident drug poisoning deaths in 2021. Death certificate literal text analysis identified drugs mentioned with involvement (DMI) in drug poisoning deaths. We characterized the concordance between each DMI and the CS dispensing history for this drug at varying timepoints since 2008. RESULTS: Overall, 25.5% of all decedents had dispensed CS in the month before fatal drug poisoning. Over 80% of decedents were dispensed opioid(s) since 2008; the percentage was similar regardless of opioid involvement in the poisoning death. One-third of decedents had dispensed buprenorphine for treatment of opioid use disorder since 2008, but only 6.1% had dispensed buprenorphine in the month preceding death. Fentanyl/fentanyl analogs were DMI in 1,568 (69.8%) deaths, yet only 3% had received a fentanyl prescription since 2008. The highest concordance in the month preceding death was observed for clonazepam (43.6%). CONCLUSION: Overall, concordance between CS dispensing history and the drugs involved in poisoning deaths was low, suggesting a need to reevaluate the complex relationships between prescription medication exposure and overdose death and to expand harm reduction interventions both within and outside the healthcare system to reduce drug poisoning mortality.

Peer-based Retention Of people who Use Drugs in Rural Research (PROUD-R2): a multisite, randomised, 12-month trial to compare efficacy of standard versus peer-based approaches to retain rural people who use drugs in research.

INTRODUCTION: Rural communities bear a disproportionate share of the opioid and methamphetamine use disorder epidemics. Yet, rural people who use drugs (PWUD) are rarely included in trials testing new drug use prevention and treatment strategies. Numerous barriers impede rural PWUD trial engagement and advancing research methods to better retain rural PWUD in clinical trials is needed. This paper describes the Peer-based Retention Of people who Use Drugs in Rural Research (PROUD-R2) study protocol to test the effectiveness of a peer-driven intervention to improve study retention among rural PWUD. METHODS AND ANALYSIS: The PROUD-R2 study is being implemented in 21 rural counties in three states (Kentucky, Ohio and Oregon). People who are 18 years or older, reside in the study area and either used opioids or injected any drug to get high in the past 30 days are eligible for study inclusion. Participants are allocated in a 1:1 ratio to two arms, stratified by site to assure balance at each geographical location. The trial compares the effectiveness of two retention strategies. Participants randomised to the control arm provide detailed contact information and receive standard retention outreach by study staff (ie, contacts for locator information updates, appointment reminders). Participants randomised to the intervention arm are asked to recruit a 'study buddy' in addition to receiving standard retention outreach. Study buddies are invited to participate in a video training and instructed to remind their intervention participant of follow-up appointments and encourage retention. Assessments are completed by intervention, control and study buddy participants at 6 and 12 months after enrolment. ETHICS AND DISSEMINATION: The protocol was approved by a central Institutional Review Board (University of Utah). Results of the study will be disseminated in academic conferences and peer-reviewed journals, online and print media, and in meetings with community stakeholders. TRIAL REGISTRATION NUMBER: NCT03885024.

Professional societies can play a vital role in career development.

Ph.D.s in the life sciences are seeking nonacademic careers in large numbers, and private sector employment is reaching an all-time high. In this climate, trainees are seeking mentors and opportunities to understand and explore different career paths. Scientific societies such as the Society for Developmental Biology play vital roles in professional development to support members at all stages of their careers and promote a range of employment opportunities. To this end, the Professional Development and Education Committee of the society offers full day workshops and sessions at regional and annual meetings that support constituents throughout their careers. For example, a new GetHIRED! workshop the day before the 2019 annual society meeting was developed as an interactive job skills workshop for postdoctoral fellows to gain insights into the job application process. The committee also aims to advocate for innovative approaches to teaching and science literacy in both the classroom and through outreach activities. The activities offered by scientific societies can reach a broader audience than individual institutions, and have lasting impacts in the quality of their members' careers by augmenting professional development opportunities.

From bench to board-side: Academic teaching careers.

Teaching positions provide a rewarding career pathway for Ph.D.s wishing to stay in academia outside of the research-focused position. The balance of teaching and research expectations on faculty can vary greatly depending on the type of institution. Faculty at primarily undergraduate institutions may be required to be researchactive and mentor undergraduates in the laboratory, while teaching faculty at a research-centered university may not have a research lab. In addition, faculty are expected to actively contribute to the shared governance of the institution, in the name of service. The career in teaching has become highly competitive and offers unexpected rewards and benefits. Considered here are the differences found among teaching positions to serve as a guide when considering teaching as a career option. We include our personal career narratives to illustrate the driving forces that led each of us to this challenging yet fulfilling academic path.

Addressing Costs and Continuity of Care through Innovative Solutions for Infused Therapies: A Collaborative Experience with Infliximab.

BACKGROUND: Infused therapies are becoming more common as pharmaceutical and biotechnology companies increasingly focus their research and development efforts on biologic agents. OBJECTIVE: To understand how collaborative efforts among a health plan, providers, and specialty pharmacies can improve the efficiency of delivering infused therapies, using the example of a pilot program in southern Ohio for the administration of infliximab. METHODS: In October 2008, the authors conducted one-on-one, in-person interviews with representatives of a health plan, a specialty pharmacy, and the 3 largest gastroenterology practices in a southern Ohio community that collaborated to develop an innovative pilot program for delivering infliximab for patients with inflammatory bowel disease in a cost-effective manner in the office setting. The 2 health plan and 1 specialty pharmacy representatives were directly involved with the development and implementation of the program. Gastroenterology practice representatives included 3 practice managers, 2 infusion nurses, 2 billing managers, and 1 precertification specialist. RESULTS: The interviews revealed the opportunities and challenges associated with managing infused therapies, as well as the potential unintended consequences of unilateral action by health plans. As a result of changes introduced by a local health plan in southern Ohio, 3 of the largest gastroenterology practices in the region decided to discontinue in-office infliximab infusions for their patients and send them to local hospital outpatient infusion centers. However, before the implementation of this policy, a new collaboration between the health plan, the 3 practices, and the health plan's specialty pharmacy enabled these practices to continue to provide this medication in their offices. This collaboration avoided cost increases to all involved by preventing the shift of patients to hospital outpatient departments and allowing patients to continue their care in the office setting. CONCLUSION: It will become increasingly important for payers to develop and support cost-effective ways to provide physicians and patients with access to infused medications. This pilot program shows the benefits of collaboration among healthcare stakeholders to identify innovative solutions for delivering appropriate office-based infusion therapy. The specific approach that is most appropriate for a specific health plan will depend on the unique local market circumstances.

Oxidative metabolism of pyruvate is required for meiotic maturation of murine oocytes in vivo.

The requirement for oxidative metabolism of pyruvate during oogenesis in vivo was evaluated by inactivating Pdha1, a gene encoding an enzymatic subunit of pyruvate dehydrogenase complex, in murine oocytes at the beginning of the follicular growth phase. Immunohistochemical analysis revealed that Pdha1(-) oocytes have dramatically reduced amounts of pyruvate dehydrogenase enzyme by the secondary follicle stage. Despite this reduction, these oocytes grow to normal size, are ovulated, and can be fertilized. Pdha1(-) oocytes are, however, impaired in their ability to support embryonic development, as demonstrated by the failure of fertilized oocytes to develop beyond the one-cell zygote stage in vivo. Immunocytochemical evaluation showed that almost all (98.4%) ovulated Pdha1(-) oocytes have not completed meiotic maturation and/or have gross abnormalities of the meiotic spindle and chromatin. Meiotic maturation is even more compromised when these oocytes are matured in vitro in the absence of cumulus cells or in the presence of the gap junction inhibitor 18-alpha glycyrrhetinic acid, indicating that cumulus cells can partially compensate for this enzymatic deficiency through a gap junction-mediated mechanism. Ovulated Pdha1(-) oocytes were also shown to have reduced levels of total ATP content and NAD(P)H autofluorescence relative to oocytes without this enzymatic deficiency. These studies demonstrate that oxidative metabolism of pyruvate is essential for proper completion of oogenesis, serving as a vital source of energy during meiotic maturation. At earlier stages of oogenesis this metabolic pathway may not be necessary due to metabolic compensation by the granulosa cells.

Bisphenol A exposure in utero disrupts early oogenesis in the mouse.

Estrogen plays an essential role in the growth and maturation of the mammalian oocyte, and recent studies suggest that it also influences follicle formation in the neonatal ovary. In the course of studies designed to assess the effect of the estrogenic chemical bisphenol A (BPA) on mammalian oogenesis, we uncovered an estrogenic effect at an even earlier stage of oocyte development--at the onset of meiosis in the fetal ovary. Pregnant mice were treated with low, environmentally relevant doses of BPA during mid-gestation to assess the effect of BPA on the developing ovary. Oocytes from exposed female fetuses displayed gross aberrations in meiotic prophase, including synaptic defects and increased levels of recombination. In the mature female, these aberrations were translated into an increase in aneuploid eggs and embryos. Surprisingly, we observed the same constellation of meiotic defects in fetal ovaries of mice homozygous for a targeted disruption of ERbeta, one of the two known estrogen receptors. This, coupled with the finding that BPA exposure elicited no additional effects in ERbeta null females, suggests that BPA exerts its effect on the early oocyte by interfering with the actions of ERbeta. Together, our results show that BPA can influence early meiotic events and, importantly, indicate that the oocyte itself may be directly responsive to estrogen during early oogenesis. This raises concern that brief exposures during fetal development to substances that mimic or antagonize the effects of estrogen may adversely influence oocyte development in the exposed female fetus.

Effect of music on chronic osteoarthritis pain in older people.

BACKGROUND: Osteoarthritis is the most common degenerative disease in humans. It usually begins in middle age and is progressive. Chronic pain in older people presents a significant obstacle in maintaining function and independence. Previous studies have shown that music can improve motivation, elevate mood, and increase feelings of control in older people. PURPOSE: The purpose of this randomized clinical trial was to examine the influence of music as a nursing intervention on osteoarthritis pain in elders. METHOD: Data were collected using the short form of the McGill Pain Questionnaire with 66 elders suffering from chronic osteoarthritis pain. Differences in perceptions of pain were measured over 14 days in an experimental group who listened to music for 20 minutes daily and a control group who sat quietly for 20 minutes daily. All participants completed the Short Form McGill Pain Questionnaire (SF-MPQ) on day 1, 7, and 14 of the study. RESULTS: Results of t-tests indicated that those who listened to music had less pain on both the Pain Rating Index on day 1 (P = 0.001), day 7 (P = 0.001) and day 14 (P = 0.001) and on the Visual Analogue Scale on day 1 (P = 0.001), day 7 (P = 0.001) and day 14 (P = 0.001), when compared with those who sat quietly and did not listen to music. A repeated measure analysis of variance controlling for pretest measures demonstrated a significant decrease in pain among experimental group participants when compared with the control group on the pain descriptor section of the SF-MPQ (P = 0.001) and the visual analogue portion of the SF-MPQ (P = 0.001). CONCLUSION: Listening to music was an effective nursing intervention for the reduction of chronic osteoarthritis pain in the community-dwelling elders in this study.

Imatinib improves but may not fully reverse the poor prognosis of patients with CML with derivative chromosome 9 deletions.

Deletions of the derivative chromosome 9 occur in a subset of patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) and are associated with a poor prognosis on standard drug therapy. However, it is currently unknown if the presence of deletions influences the response to imatinib, an Abl-specific tyrosine kinase inhibitor, that has recently shown excellent hematologic and cytogenetic responses in patients with CML. We, therefore, compared hematologic and cytogenetic responses with imatinib in 397 patients with CML, and survival and progression in 354 of these patients, according to deletion status and disease phase. We found no difference in survival between patients with and without deletions, contrasting with previous reports in cohorts with a lower proportion of patients treated with imatinib. However, the time to disease progression on imatinib treatment was significantly shorter for patients with deletions, both in chronic phase (P =.02) and advanced phases (P =.02). Moreover, both in chronic phase and more advanced phases of CML, hematologic and cytogenetic responses were uniformly lower in patients with deletions, with significant differences seen for hematologic response (P =.04), for major cytogenetic response (P =.008) in chronic phase, and for hematologic response in advanced phases (P =.007) of CML. This finding suggests that differences in survival may become apparent with longer follow-up.

Quality assessment of genetic markers used for therapy stratification.

PURPOSE: Therapy stratification based on genetic markers is becoming increasingly important, which makes commitment to the highest possible reliability of the involved markers mandatory. In neuroblastic tumors, amplification of the MYCN gene is an unequivocal marker that indicates aggressive tumor behavior and is consequently used for therapy stratification. To guarantee reliable and standardized quality of genetic features, a quality-assessment study was initiated by the European Neuroblastoma Quality Assessment (ENQUA; connected to International Society of Pediatric Oncology) Group. MATERIALS AND METHODS: One hundred thirty-seven coded specimens from 17 tumors were analyzed in 11 European national/regional reference laboratories using molecular techniques, in situ hybridization, and flow and image cytometry. Tumor samples with divergent results were re-evaluated. RESULTS: Three hundred fifty-two investigations were performed, which resulted in 23 divergent findings, 17 of which were judged as errors after re-evaluation. MYCN analyses determined by Southern blot and in situ hybridization led to 3.7% and 4% of errors, respectively. Tumor cell content was not indicated in 32% of the samples, and 11% of seemingly correct MYCN results were based on the investigation of normal cells (eg, Schwann cells). Thirty-eight investigations were considered nonassessable. CONCLUSION: This study demonstrated the importance of revealing the difficulties and limitations for each technique and problems in interpreting results, which are crucial for therapeutic decisions. Moreover, it led to the formulation of guidelines that are applicable to all kinds of tumors and that contain the standardization of techniques, including the exact determination of the tumor cell content. Finally, the group has developed a common terminology for molecular-genetic results.

Expression and potential function of Rho family small G proteins in cells of the mammalian seminiferous epithelium.

Dynamic cellular rearrangements involving the actin cytoskeleton are required of both Sertoli and germ cells during spermatogenesis. Rho family small G proteins have been implicated in the control of the actin cytoskeleton in numerous cell types. Therefore, RhoA and Rac1 were investigated in Sertoli and germ cells. RhoA and Rac1 have been detected at both the mRNA and protein levels in these cells. In addition, Sertoli cell L-selectin is shown to interact with actin binding proteins, potentially providing a link between L-selectin and Rac1 signaling. Finally, inactivation of Sertoli cell Rho family proteins yields disruption of the actin cytoskeleton.