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In Indonesia, government-owned Community Health Centers (CHCs) spearhead tuberculosis (TB) care at the primary level, but a substantial proportion of individuals with pulmonary TB also seek care from Private Practitioners (PPs). However, little is known about PPs' practice in managing patients with TB-associated symptoms. To avoid bias associated with self-administered surveys, we used standardized patients (SPs) to evaluate PPs' adherence to the national TB guidelines. Four clinical scenarios of individuals presenting complaints suggestive of TB, accompanied by different sputum smear results or TB treatment histories were developed. We assigned 12 trained SPs to PPs practicing in 30 CHC catchment areas in Bandung city, Indonesia. For comparison, two scenarios were also presented to the CHCs. A total of 341 successful SP visits were made to 225 private general practitioners (GPs), 29 private specialists, and 30 CHCs. When laboratory results were not available, adherence to the recommended course of action, i.e., sputum examination, was low among private GPs (31%) and private specialists (20%), while it was requested in 87% of visits to the CHCs. PPs preferred chest X-ray (CXR) in all scenarios, with requests made in 66% of visits to private GPs and 84% of visits to private specialists (vs. 8% CHCs). Prescriptions of incorrect TB drug regimens were reported from 7% and 13% of visits to private GPs and specialists, respectively, versus none of the CHCs. Indonesian PPs have a clear preference for CXR over microbiological testing for triaging presumptive TB patients, and inappropriate prescription of TB drugs is not uncommon. These findings warrant actions to increase awareness among PPs about the importance of microbiological testing and of administering appropriate TB drug regimens. SP studies can be used to assess the impact of these interventions on providers' adherence to guidelines., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lestari et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Trisomy 21 (T21), a recurrent aneuploidy occurring in 1:800 births, predisposes to congenital heart disease (CHD) and multiple extracardiac phenotypes. Despite a definitive genetic etiology, the mechanisms by which T21 perturbs development and homeostasis remain poorly understood. We compared the transcriptome of CHD tissues from 49 patients with T21 and 226 with euploid CHD (eCHD). We resolved cell lineages that misexpressed T21 transcripts by cardiac single-nucleus RNA sequencing and RNA in situ hybridization. Compared with eCHD samples, T21 samples had increased chr21 gene expression; 11-fold-greater levels (P = 1.2 × 10-8) of SOST (chr17), encoding the Wnt inhibitor sclerostin; and 1.4-fold-higher levels (P = 8.7 × 10-8) of the SOST transcriptional activator ZNF467 (chr7). Euploid and T21 cardiac endothelial cells coexpressed SOST and ZNF467; however, T21 endothelial cells expressed 6.9-fold more SOST than euploid endothelial cells (P = 2.7 × 10-27). Wnt pathway genes were downregulated in T21 endothelial cells. Expression of DSCAM, residing within the chr21 CHD critical region, correlated with SOST (P = 1.9 × 10-5) and ZNF467 (P = 2.9 × 10-4). Deletion of DSCAM from T21 endothelial cells derived from human induced pluripotent stem cells diminished sclerostin secretion. As Wnt signaling is critical for atrioventricular canal formation, bone health, and pulmonary vascular homeostasis, we concluded that T21-mediated increased sclerostin levels would inappropriately inhibit Wnt activities and promote Down syndrome phenotypes. These findings imply therapeutic potential for anti-sclerostin antibodies in T21.

Background: Decision-making around birthplace is complex and multifactorial. The role of clinicians is to provide unbiased, evidence-based information to support women and birthing people to make decisions based on what matters to them. Some decisions may fall outside of clinical guidance and recommendations. Birth Choices Clinics can provide an opportunity for extended discussion and personalized birthplace planning. This study aimed to explore the rationale behind choosing birthplace "outside of guidance" and examine the outcomes for women who attended a Birth Choices Clinic., Methods: The study was descriptive using data extracted from clinical documentation and consultation. The data included demographic information, maternal characteristics, reason for choosing a midwifery-led birth setting, birthplace preference, and outcome., Results: Eighty-two women used the Birth Choices Clinic between April 2022 and February 2023 in one large maternity unit in the UK. Reasons for choosing birth in a midwifery-led setting included having access to a birthing pool, to reduce the chance of obstetric interventions and pragmatic reasons. Sixty-five percent of women experienced a spontaneous vaginal birth, 10% experienced an assisted vaginal birth, and 23% experienced a cesarean birth. Of the 33 women who ultimately commenced labor care in a midwifery-led setting, 76% (n = 25/33) birthed in this setting without complications. Transfer rates in labor were similar to those in a "low-risk" pregnant population., Discussion: Birth choice clinics may facilitate an understanding of material risk and support individualizing birth planning. There is evidence that women changed their planned birthplace, possibly in recognition of a move along the risk spectrum., (© 2024 The Authors. Birth published by Wiley Periodicals LLC.)

Background: No gold standard diagnostic test exists for latent tuberculosis infection (LTBI). The intra-dermal tuberculin skin test (TST) has known limitations and Interferon-gamma release assays (IGRA) have been developed as an alternative. We aimed to assess agreement between IGRA and TST, and risk factors for test positivity, in Indonesian healthcare students., Methods: Medical and nursing students starting their clinical training were screened using IGRA and TST. Agreement between the two tests was measured using Cohen's Kappa coefficient. Logistic regression was used to identify factors associated with test positivity., Results: Of 266 students, 43 (16.2%) were IGRA positive and 85 (31.9%) TST positive. Agreement between the two tests was 74.7% (kappa 0.33, 95% CI 0.21-0.45, P<0.0001). Students who had direct contact with family or friends with TB were less likely to be test positive using IGRA (AOR 0.18, 95% CI 0.05-0.64) and using TST (AOR 0.51, 95% CI 0.26-0.99)., Conclusion: Test positivity for LTBI was lower when measured by IGRA than by TST, with poor agreement between the two tests. Known close TB contact was unexpectedly negatively associated with positivity by either test. Longitudinal studies may be required to help determine the best test for LTBI in healthcare students in Indonesia., Competing Interests: NO authors have competing interests., (Copyright: © 2024 Apriani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: This study aimed to (1) collect and analyze statements about how to celebrate chiropractic in the present and roles that chiropractors may fulfill in the future, (2) identify if there was congruence among the themes between present and future statements, and (3) offer a model about the chiropractic profession that captures its complex relationships that encompass its interactions within microsystem, mesosystem, exosystem, and macrosystem levels., Methods: For this qualitative analysis, we used pattern and grounded theory approaches. A purposive sample of thought leaders in the chiropractic profession were invited to answer the following 2 open-ended questions: (1) envision the chiropractor of the future, and (2) recommendations on how to celebrate chiropractic. Information was collected during April 2023 using Survey Monkey. The information was entered into a spreadsheet and analyzed for topic clusters, which resulted in matching concepts with social-ecological themes. The themes between the responses to the 2 questions were analyzed for congruence. We used the Standards for Reporting Qualitative Research to report our findings., Results: Of the 54 experts invited, 32 (59%) participated. Authors represented 7 countries and have a median of 32 years of chiropractic experience, with a range of 5 to 51 years. Nineteen major topics in the future statements and 23 major topics in statements about celebrating chiropractic were combined in a model. The topics were presented using the 4 levels of the social-ecological framework. Individual (microsystem): chiropractors are competent, well-educated experts in spine and musculoskeletal care who apply evidence-based practices, which is a combination of the best available evidence, clinical expertise, and patient values. Interpersonal relationships (mesosystem): chiropractors serve the best interests of their patients, provide person-centered care, embrace diversity, equity, and inclusion, consider specific health needs and the health of the whole person. Community (exosystem): chiropractors provide care within integrated health care environments and in private practices, serve the best interests of the public through participation in their communities, participate through multidisciplinary collaboration with and within the health care system, and work together as a profession with a strong professional identity. Societal (macrosystem): chiropractors contribute to the greater good of society and participate on a global level in policy, leadership, and research. There was concordance between both the future envisioning statements and the present celebration recommendations, which suggest logical validity based on the congruence of these concepts., Conclusion: A sample of independent views, including the perceptions from a broad range of chiropractic thought leaders from various backgrounds, philosophies, diversity characteristics, and world regions, were assembled to create a comprehensive model of the chiropractic profession. The resulting model shows an array of intrinsic values and provides the roles that chiropractors may provide to serve patients and the public. This study offers insights into the roles that future chiropractors may fulfill and how these are congruent with present-day values. These core concepts and this novel model may have utility during dialogs about identity, applications regarding chiropractic in policy, practice, education, and research, and building positive relationships and collaborations., (© 2023 by National University of Health Sciences.)

Quality of life (QoL) in people living with HIV (PLHIV) is reportedly worse than in people without HIV, with many factors impacting on this. We aimed to investigate QoL in PLHIV in New Zealand (NZ). In-person interviews were conducted including socio-demographic, health, social connectedness, and stigma-related questions. QoL was measured using the 13-question PozQoL Scale - summed to give a score between 13 and 65. Univariate linear regression was used to investigate factors associated with differences in PozQoL scores. PLHIV ( n  = 188) of different ethnicities from throughout NZ participated. The mean age was 47 years; 65% were men; 61% were men who have sex with men; 61% had been living with HIV for ≥10 years. The mean summary PozQoL score was 47.16. Factors associated with a lower mean PozQol included no sex in the last 12 months (-9.03), inability to meet basic needs (-7.47), ever (-6.49) or recently (-5.03), experiencing stigma or discrimination, mental health condition (-5.74), HIV diagnosis <5 years (-5.48), poor health (-5.43), being unemployed (-5.02), not having support (-4.71), and greater internalised stigma (-2.81). Improving QoL will require investment in peer support and community welfare programmes to better support PLHIV, and stigma reduction campaigns targeting the broader community.

Purpose : There is poor reporting of the cost of simulation and greater transparency is needed. The primary study aim was to conduct a financial analysis of the university/training institution costs associated with a 5-day simulation-based learning program for speech-language pathology students. The secondary aim was to consider the economic costs of the model. Method : Costs associated with the delivery of a 5-day simulation-based learning program for speech-language pathology students from six Australian universities were collected regarding: (a) pre-program training, (b) personnel, (c) room hire, (d) equipment, and (e) consumables. Both financial costs and economic costs (Australian dollar, at June 2017) were calculated per university site, and per student. Result : The simulation program was run 21 times involving 176 students. Average total financial cost per program ranged from $4717 to $11 425, with cost variation primarily attributed to local labour costs and various use of in-kind support. Average financial cost per student was $859 (range $683-$1087), however this was almost double ($1461 per student, range $857-$2019) in the economic cost calculation. Personnel was the largest contributing cost component accounting for 76.6% of financial costs. Personnel was also the highest contributing cost in the economic analysis, followed by room hire. Conclusion : This study provides clarity regarding financial and economic costing for a 5-day simulation-based learning program. These data can help universities consider potential up-front financial costs, and well as strategies for financial cost minimisation, when implementing simulation-based learning within the university context.

Allied health clinical placements take place within an increasingly overstretched health care system where demand for services often exceeds availability of resources. Within this environment, student placements are often perceived as an additional burden to an already overwhelmed workforce. This study explored whether the quality of patient care was enhanced when services were re-designed using a collaborative partnership approach to more purposefully integrate students into delivery of care. Using an embedded multiple case study design, data were collected through focus groups and interviews, patient experience surveys, and secondary administrative data sources. Cases were across physiotherapy and occupational therapy in six different hospital settings. Perception of care provided by students was viewed positively by all stakeholders, including patients. Perceived health outcomes of faster improvement of health condition, improved mobility and function identified through our qualitative findings were supported by quantitative service delivery markers such as increased therapy sessions, more patients being discharged home instead of to other care facilities and reduced length of stay. Health care providers and students alike perceived improvements in service efficiencies whilst maintaining high quality care. This study has provided preliminary evidence towards improved patient care when a partnering approach is adopted whereby students are intentionally integrated into services that otherwise might not have been delivered. Furthermore, it has shifted the associated narrative from students as additional burden to students as benefit., (© 2022. Crown.)

Objectives: Animal models are needed to reliably separate the effects of mechanical joint instability and inflammation on posttraumatic osteoarthritis (PTOA) pathogenesis. We hypothesized that our modified intra-articular drilling (mIAD) procedure induces cartilage damage and synovial changes through increased inflammation without causing changes in gait., Methods: Twenty-four Yucatan minipigs were randomized into the mIAD (n=12) or sham control group (n=12). mIAD animals had two osseous tunnels drilled into each of the tibia and femur adjacent to the anterior cruciate ligament (ACL) attachment sites on the left hind knee. Surgical and contralateral limbs were harvested 15 weeks post-surgery. Cartilage degeneration was evaluated macroscopically and histologically. Synovial changes were evaluated histologically. Interleukin-1 beta (IL-1β), nuclear factor kappa B (NF-κB), and tumor necrosis factor alpha (TNF-α) mRNA expression levels in the synovial membrane were measured using quantitative real-time polymerase chain reaction. IL-1β and NF-κB levels in chondrocytes were assessed using immunohistochemistry. Load asymmetry during gait was recorded by a pressure-sensing walkway system before and after surgery., Results: The mIAD surgical knees demonstrated greater gross and histological cartilage damage than contralateral (P<.01) and sham knees (P<.05). Synovitis was present only in the mIAD surgical knee. Synovial inflammatory marker (IL-1β, NF-κB, and TNF-α) expression was three times higher in the mIAD surgical knee than the contralateral (P<.05). Chondrocyte IL-1β and NF-κB levels were highest in the mIAD surgical knee. In general, there were no significant changes in gait., Conclusions: The mIAD model induced PTOA through inflammation without affecting gait mechanics. This large animal model has significant applications for evaluating the role of inflammation in PTOA and for developing therapies aimed at reducing inflammation following joint injury., Competing Interests: Braden C. Fleming is a founder of Miach Orthopaedics, receives royalties from Springer Publishing, and receives a stipend from the American Journal of Sports Medicine. Brett D. Owens is a paid consultant for Conmed, Miach, Vericel, and Mitek, and receives inventor royalties from Conmed and a stipend from the American Journal of Sports Medicine., (AJTR Copyright © 2023.)

Background: Persistent enteral tube feeding beyond the point of medical and/or physical necessity provides important nutrition to a child but may have implications for their development, gastrointestinal tract and quality of life. Tube dependency can affect parent-child relationships and sibling and family dynamics and place additional medical demands upon parents. It is therefore important to transition children from tube to oral eating and drinking as soon as is medically safe to do so. Tube weaning requires a skilled team to support the transition to oral intake; however, access to experienced teams is inconsistent. Without transparent discussions with their treating teams, many parents are left to navigate tube weaning options independently., Methods: Fourteen parents were interviewed using semi-structured interviews. We explored the experiences of parents across their child's progression towards oral feeding, from the decision-making process to undertaking an intensive multi-disciplinary tube weaning programme. Thematic analysis of the parents' stories shaped the development of seven themes., Results: Parents were unaware that tube weaning would be required and how that would be facilitated. They expressed a strong belief that their child could learn to eat-if afforded an opportunity. Furthermore, parents are prepared to disengage from current services if they feel they are not respected members of their child's therapeutic team. Three key learnings were identified relating to the need for tube exit plans, parents as key team members and parents as change agents., Conclusions: Parenting a tube-fed child, initiating and engaging in tube weaning, is a stressful and emotional journey. However, by establishing care partnerships, parents are willing to put trust in a process if provided with options and afforded autonomy, empowerment, acknowledgement and relevant support., (© 2022 John Wiley & Sons Ltd.)

Smoking initiation is concentrated among young people which strongly influences future smoking prevalence. This study aimed to investigate the prevalence of smoking and other tobacco product use and potential determinants in a cross-sectional survey of 1 121 students aged 13 to 15 years in Dili, Timor-Leste. The prevalence of ever using a tobacco product was 40.4% (males 55.5%; females 23.8%) and of current use was 32.2% (males 45.3%; females 17.9%). In a logistic multivariable regression, factors associated with current use of any tobacco product were being male, ≥US$1 weekly pocket money, parents smoking, exposure at home, and exposure in other locations. The findings suggest that reducing the very high use of tobacco among adolescents in Timor-Leste will require new policy measures, enhanced enforcement of current legislation as well as a focused commitment to targeted smoke-free education campaigns, and community-based health promotion to support parents to quit smoking and not smoke around children.

For humans, acute and chronic overexposure to ultraviolet (UV) radiation can cause tissue damage in the form of sunburn and promote cancer(s). The immune-modulating properties of UV radiation and health-related consequences are not well known. Herein, we used the larvae of the wax moth Galleria mellonella, to determine UV-driven changes in cellular components of innate immunity. From immune cell (haemocyte) reactivity and the production of antimicrobial factors, these insects share many functional similarities with mammalian cellular innate immunity. After exposing insects to UVA or UVB for up to two hours, we monitored larval viability, susceptibility to infection, haemolymph (blood) physiology and faecal discharge. Prolonged exposure of larvae to UVB coincided with decreased survival, enhanced susceptibility to bacterial challenge, melanin synthesis in the haemolymph, compromised haemocyte functionality and changes in faecal (bacterial) content. We contend G. mellonella is a reliable in vivo model for assessing the impact of UV exposure at the whole organism and cellular levels., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Experiential learning opportunities, such as work integrated learning placements, are often challenging for health professional students. It is therefore imperative that students are adequately prepared before engaging in placement learning. Operationalising 'readiness for learning on placement' as a construct, is necessary for providing quality student feedback and assessment., Methods: An integrative mixed methods approach was adopted for this study, utilising a survey to canvass the perspectives of academics, students, and placement educators around the construct of readiness to inform potential assessment items. An assessment tool measuring student readiness for placement was then developed. Data from occupational therapy, physiotherapy and speech pathology programs were evaluated using Rasch analysis to explore the unidimensionality of this construct., Results: The online survey was completed by 64 participants, confirming the importance and measurability of foundational skills integral to readiness for placement learning. These foundational skills were then reflected in a pilot 20-item tool covering domains of professional and learner behaviour, communication, information gathering skills and reasoning. The Rasch analysis of 359 pre-registration student assessments confirmed unidimensionality, suggesting that the skills and attributes (operationalised as assessment items) that are considered part of 'readiness for placement' are components of this construct. Together, these findings provide support that the items on this tool are relevant and representative of the skills and behaviours that indicate readiness for placement learning. Two items regarding documentation and appropriate professional dress demonstrated some lower importance scores and interpretation variance warranting further investigation., Conclusion: Through the exploration of the construct of readiness for placement learning, we have created and subsequently revised, an innovative assessment tool that measures novice students' pre-placement capabilities. Further research is now needed to explore the psychometric properties of the tool., (© 2023. Crown.)

Background: Diffuse midline gliomas (DMG) are highly invasive brain tumors with rare survival beyond two years past diagnosis and limited understanding of the mechanism behind tumor invasion. Previous reports demonstrate upregulation of the protein ID1 with H3K27M and ACVR1 mutations in DMG, but this has not been confirmed in human tumors or therapeutically targeted., Methods: Whole exome, RNA, and ChIP-sequencing was performed on the ID1 locus in DMG tissue. Scratch-assay migration and transwell invasion assays of cultured cells were performed following shRNA-mediated ID1-knockdown. In vitro and in vivo genetic and pharmacologic [cannabidiol (CBD)] inhibition of ID1 on DMG tumor growth was assessed. Patient-reported CBD dosing information was collected., Results: Increased ID1 expression in human DMG and in utero electroporation (IUE) murine tumors is associated with H3K27M mutation and brainstem location. ChIP-sequencing indicates ID1 regulatory regions are epigenetically active in human H3K27M-DMG tumors and prenatal pontine cells. Higher ID1-expressing astrocyte-like DMG cells share a transcriptional program with oligo/astrocyte-precursor cells (OAPCs) from the developing human brain and demonstrate upregulation of the migration regulatory protein SPARCL1. Genetic and pharmacologic (CBD) suppression of ID1 decreases tumor cell invasion/migration and tumor growth in H3.3/H3.1K27M PPK-IUE and human DIPGXIIIP* in vivo models of pHGG. The effect of CBD on cell proliferation appears to be non-ID1 mediated. Finally, we collected patient-reported CBD treatment data, finding that a clinical trial to standardize dosing may be beneficial., Conclusions: H3K27M-mediated re-activation of ID1 in DMG results in a SPARCL1+ migratory transcriptional program that is therapeutically targetable with CBD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Although considerable research has targeted fall prevention among older adults with Parkinson's disease (PD), less is known about their ability to rise from the floor. The aim of the current exploratory study was to examine the relationship between floor rise and physical performance tests. A cross-sectional design was used. Twenty community-dwelling older adults with PD (mean age = 74.8 years, SD = 9.5 years) performed a standardized floor rise test and physical performance assessments in a structured task circuit. Mean time to rise from the floor was 14.9 seconds ( SD = 7.6 seconds). Fourteen (70%) participants used a quadruped strategy to rise to stand. Supine-to-stand performance time was significantly correlated with all physical performance measures. Findings serve as a catalyst for nursing and rehabilitation professionals to examine floor rise ability, prevent adverse effects of a critical fall, and instruct fall recovery techniques in clinical settings. [ Journal of Gerontological Nursing, 49( 1), 50-54.].

A hallmark of osteoarthritis (OA) is cartilage degeneration, which has been previously correlated with dramatic increases in inflammatory enzymes. Specifically, interleukin-1β (IL-1β) and subsequent upregulation of nuclear factor kappa B (NF-κB) is implicated as an important player in the development of posttraumatic osteoarthritis (PTOA). Alpha 2-macroglobulin (A2M) can inhibit this inflammatory pathway, making it a promising therapy for PTOA. Herein, we demonstrate that A2M binds and neutralizes IL-1β, blocking downstream NF-κB-induced catabolism seen in in vitro. Human chondrocytes (cell line C28) were incubated with A2M protein and then treated with IL-1β. A2M was labeled with VivoTag™ 680 to localize the protein postincubation. The degree of binding between A2M and IL-1β was evaluated through immunoprecipitation (IP). Catabolic proteins, including IL-1β and NF-kB, were detected by Western blot. Pro-inflammatory and chondrocyte-related gene expression was examined by qRT-PCR. VivoTag™ 680-labeled A2M was observed in the cytoplasm of C28 human chondrocytes by fluorescence microscopy. IP experiments demonstrated that A2M could bind IL-1β. Additionally, western blot analysis revealed that A2M neutralized IL-1β and NF-κB in a dose-dependent manner. Moreover, A2M decreased levels of MMPs and TNF-α and increased the expression of cartilage protective genes Col2, Type2, Smad4, and aggrecan. Mostly importantly, A2M was shown to directly neutralize IL-1β to downregulate the pro-inflammatory responses mediated by the NF-kB pathway. These results demonstrate a mechanism by which A2M reduces inflammatory catabolic activity and protects cartilage after joint injury. Further in vivo studies are needed to fully understand the potential of A2M as a novel PTOA therapy., (© 2022 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Competing Interests: Competing interests: MB is the Policy and Stakeholder Liaison Consultant for the Avoiding Brain Injury in Childbirth (ABC) collaboration. The guideline authors’ full declaration of interests can be viewed at https://www.nice.org.uk/guidance/ng229.

Objective: This study aimed to assess the feasibility of conducting a representative tuberculin skin test (TST) survey for Māori in Aotearoa New Zealand and to estimate the prevalence of latent tuberculosis (TB) infection., Methods: Participants were Māori in the Waikato region, recruited by a Māori nurse, through: 1) random household selection from the Electoral Roll; 2) randomly selected prison inmates; and 3) community and health settings. A TB history and symptoms questionnaire was completed, TST performed and investigation of those with TST induration ≥10mm., Results: Random household selection was resource intensive and only contributed 14 participants. Repeated random selection of prison lists were required to recruit 207 participants and there were no positive TST cases. Community and health settings yielded the highest participation (n=370) and the three people (0.5%) with TST ≥10mm. Age ≥45 years and history of contact with a TB case were associated with TST induration ≥5mm (n=39; 6.6%)., Conclusions: The community and health settings were the only feasible options for recruitment. The overall prevalence of a positive TST in the study population was low. A 5mm cut-off may be best to maximise sensitivity for future studies., Implications for Public Health: A mixture of sample selection processes that are more targeted are needed to identify Māori with latent TB infection., (© 2022 The Authors.)

Background: Functional gastrointestinal disorders (FGID) are linked to a variety of potential causes, and treatments include reassurance, life-style (including diet), psychological, or pharmacologic interventions., Aims: To assess whether a multidisciplinary integrated treatment approach delivered in a dedicated integrated care clinic (ICC) was superior to the standard model of care in relation to the gastrointestinal symptom burden., Methods: A matched cohort of 52 consecutive patients with severe manifestation of FGID were matched with 104 control patients based upon diagnosis, gender, age, and symptom severity. Patients in the ICC received structured assessment and 12-weeks integrated treatment sessions provided as required by gastroenterologist and allied health team. Control patients received standard medical care at the same tertiary center with access to allied health services as required but no standardized interprofessional team approach. Primary outcome was reduction in gastrointestinal symptom burden as measured by the Structured Assessment of Gastrointestinal Symptoms Scale (SAGIS). Secondary outcome was reduction in anxiety and depressive symptoms as measured by the Hospital Anxiety and Depression Scale (HADS)., Results: Mixed models estimated the within ICC change in SAGIS total as -9.7 (95% CI -13.6, -5.8; p < 0.0001), compared with -1.7 (95% CI -4.0, 0.6; p = 0.15) for controls. The difference between groups reached statistical significance, -7.6 (95% CI -11.4, -3.8; p < 0.0001). Total HADS scores in ICC patients were 3.4 points lower post-intervention and reached statistical significance (p = 0.001)., Conclusion: This matched cohort study demonstrates superior short-term outcomes of FGID patients in a structured multidisciplinary care setting as compared to standard care., (© 2022. Crown.)

Purpose: To assess the biomarker and functional role of the chromatin remodeling factor, bromodomain PHD finger transcription factor (BPTF), in breast cancer progression., Methods: BPTF copy number was assessed using fluorescence in situ hybridization. BPTF expression was regulated in breast cancer cells by shRNA/siRNA-mediated gene silencing and BPTF cDNA overexpression. The effects of regulating BPTF expression were examined on key oncogenic signaling pathways and on breast cancer cell proliferation, apoptosis, and cell cycle progression, as well as in xenograft models. The consequences of pharmacological bromodomain inhibition, alone or in combination with other targeted agents, on breast cancer progression were assessed in culture and in xenograft models., Results: BPTF copy number was gained in 34.1% and separately amplified in 8.2% of a breast cancer tissue cohort. Elevated BPTF copy number was significantly associated with increasing patient age and tumor grade and observed in both ER-positive and triple-negative breast cancer (TNBC) subtypes. BPTF copy number gain and amplification were also observed in The Cancer Genome Atlas (TCGA) breast cancer cohort. Stable shRNA-mediated silencing of BPTF significantly inhibited cell proliferation and induced apoptosis in TNBC and ER-positive human breast cancer cell lines. BPTF knockdown suppressed signaling through the phosphoinositide 3 kinase (PI3K) pathway, including reduced expression of phosphorylated AKT (Ser473), phosphorylated GSK-β (Ser9), and CCND1. These findings were confirmed following transient BPTF knockdown by a distinct siRNA in TNBC and ER-positive breast cancer cells. Stable suppression of BPTF expression significantly inhibited the in vivo growth of TNBC cells. Conversely, BPTF cDNA overexpression in TNBC and ER-positive breast cancer cells enhanced breast cancer cell proliferation and reduced apoptosis. BPTF targeting with the bromodomain inhibitor bromosporine, alone or in combination with the PI3K pathway inhibitor gedatolisib, produced significant anti-tumor effects against TNBC cells in vitro and in vivo ., Conclusion: These studies demonstrate BPTF activation in distinct breast cancer subtypes, identify pathways by which BPTF promotes breast cancer progression, and suggest BPTF as a rational target for breast cancer therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bezrookove, Khan, Nosrati, Miller, McAllister, Dar and Kashani-Sabet.)

Singing humpback whales are highly versatile vocalizers, producing complex sequences of sounds that they vary throughout adulthood. Past analyses of humpback whale song have emphasized yearly variations in structural features of songs made collectively by singers within a population with comparatively little attention given to the ways that individual singers vary consecutive songs. As a result, many researchers describe singing by humpback whales as a process in which singers produce sequences of repeating sound patterns. Here, we show that such characterizations misrepresent the degree to which humpback whales flexibly and dynamically control the production of sounds and sound patterns within song sessions. Singers recorded off the coast of Hawaii continuously morphed units along multiple acoustic dimensions, with the degree and direction of morphing varying across parallel streams of successive units. Individual singers also produced multiple phrase variants (structurally similar, but acoustically distinctive sequences) within song sessions. The precision with which individual singers maintained some acoustic properties of phrases and morphing trajectories while flexibly changing others suggests that singing humpback whales actively select and adjust acoustic elements of their songs in real time rather than simply repeating stereotyped sound patterns within song sessions., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Therapy of BRAF -mutant melanoma with selective inhibitors of BRAF (BRAFi) and MEK (MEKi) represents a major clinical advance but acquired resistance to therapy has emerged as a key obstacle. To date, no clinical approaches successfully resensitize to BRAF/MEK inhibition. Here, we develop a therapeutic strategy for melanoma using bromosporine, a bromodomain inhibitor. Bromosporine (bromo) monotherapy produced significant anti-tumor effects against established melanoma cell lines and patient-derived xenografts (PDXs). Combinatorial therapy involving bromosporine and cobimetinib (bromo/cobi) showed synergistic anti-tumor effects in multiple BRAFi-resistant PDX models. The bromo/cobi combination was superior in vivo to standard BRAFi/MEKi therapy in the treatment-naive BRAF -mutant setting and to MEKi alone in the setting of immunotherapy-resistant NRAS - and NF1 -mutant melanoma. RNA sequencing of xenografts treated with bromo/cobi revealed profound down-regulation of genes critical to cell division and mitotic progression. Bromo/cobi treatment resulted in marked DNA damage and cell-cycle arrest, resulting in induction of apoptosis. These studies introduce bromodomain inhibition, alone or combined with agents targeting the mitogen activated protein kinase pathway, as a rational therapeutic approach for melanoma refractory to standard targeted or immunotherapeutic approaches.

Objective: This tertiary centre study aims to identify factors associated with adverse outcomes in adult survivors with total cavopulmonary connection (TCPC) Fontan palliation for single ventricle., Methods: This retrospective review of medical records identified adult (≥18 years) survivors of TCPC Fontan palliation who were followed at a single tertiary centre between 1 January 2000 and 1 July 2019. Adverse outcomes were defined as arrhythmia, pacemaker/implantable cardioverter defibrillator placement, liver cirrhosis, protein losing enteropathy, hospitalisation for heart failure, thromboembolic complication and/or death., Results: 160 adult TCPC patients met the inclusion criteria: 117 (73.1%) extracardiac and 43 (26.9%) lateral tunnel. The median (IQR) duration of follow-up since TCPC palliation was 17.5 (11.8-21.3) years. An adverse outcome occurred in 87 (54.4%) patients. Adverse outcome-free survival rates at 10, 20 and 25 years post TCPC were 89% (95% CI 82% to 93%), 60% (95% CI 50% to 69%) and 24% (95% CI 15% to 35%), respectively. On multivariate analysis, extracardiac Fontan (HR 2.21, 95% CI 1.20 to 4.08, p=0.011) was observed to be an independent risk factor for adverse outcomes after adjusting for age, race, morphology of the systemic ventricle and history of fenestration., Conclusions: In this single-centre retrospective study of adult survivors of TCPC palliation, extracardiac Fontan was associated with an increased hazard for adverse outcomes. This finding could guide clinicians in developing risk modification strategies and management decisions to improve long-term outcomes in these patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Healthcare workers (HCWs), especially in high tuberculosis (TB) incidence countries, are at risk of Mycobacterium tuberculosis infection and TB disease, likely due to greater exposure to TB cases and variable implementation of infection control measures., Aim: We aimed to estimate the prevalence of tuberculin skin test (TST) positivity, history of TB and to identify associated risk factors in HCWs employed at a tertiary referral hospital in Bandung, Indonesia., Methods: A cross-sectional study was conducted from April to August 2018. A stratified sample of the HCWs were recruited, screened by TST, assessed for TB symptoms, history of TB disease and possible risk factors. Prevalence of positive TST included diagnosis with TB after starting work. HCWs with TB disease diagnosed earlier were excluded. Survey weights were used for all analyses. Possible risk factors were examined using logistic regression; adjusted odds ratios and 95% confidence intervals (CI) are presented., Results: Of 455 HCWs recruited, 42 reported a history of TB disease (25 after starting work) and 395 had a TST result. The prevalence of positive TST was 76.9% (95% CI 72.6-80.8%). The odds increased by 7% per year at work (95% CI 3-11%) on average, with a rapid rise in TST positivity up to 10 years of work and then a plateau with around 80% positive., Discussion: A high proportion of HCWs had a history of TB or were TST positive, increasing with longer duration of work. A package of TB infection control measures is needed to protect HCWs from Mycobacterium tuberculosis infection., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Background: Allowing students to access and document in electronic medical records (eMRs) during clinical placements is viewed as critical for ensuring that graduates have a high level of digital proficiency prior to entering the workforce. Limited studies have explored student access to eMRs in health disciplines outside of medicine and nursing., Objective: Our main objective was to examine allied health students' experiences and perceptions of the opportunity to develop eMR competencies during their placement, across a range of allied health disciplines and placement settings., Methods: An explanatory sequential design was used, comprising a quantitative survey ( n  = 102) followed by qualitative semi-structured interviews ( n  = 6) with senior allied health students to explore their experiences and perceptions of eMR access during placements., Results: Of the 93 students who responded to the question about their placement eMR, nine (10%) reported their placement site did not use an eMR and four students reported that they were not allowed to access the eMR during their placement. Most students (64%, 54 out of 84) accessed the system using their own credentials, but 31% (26 out of 84) used someone else's log-in and password. Students were satisfied with the eMR training and support received while on placement, but there was significant variability across sites on the level of training and support provided. All students believed that eMR access was beneficial for learning and preparation for work, improved delivery of care, taking ownership of work, and feeling responsible for patient care., Conclusion: Providing students with access to eMRs during placements is fundamental to the development of a student's professional identity and to recognizing their role in the delivery of interprofessional patient care. For graduates to be equipped to effectively contribute to multi-disciplinary care in a digital health environment, universities need to work with practice partners to standardize and formalize eMR access, registration, training, and support, and to provide students with early exposure and training on eMRs in university courses., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Health care workers (HCWs) in low- and middle-income countries (LMICs) continue to have an unacceptably high prevalence and incidence of Mycobacterium tuberculosis infection due to high exposure to tuberculosis (TB) cases at health care facilities and often inadequate infection control measures. This can contribute to an increased risk of transmission not only to HCWs themselves but also to patients and the general population., Aim: We assessed implementation of TB infection control measures in primary health centres (PHCs) in Bandung, Indonesia, and TB knowledge among HCWs., Methods: A cross-sectional study was conducted between May and November 2017 amongst a stratified sample of the PHCs, and their HCWs, that manage TB patients in Bandung . Questionnaires were used to assess TB infection control measures plus HCW knowledge. Summary statistics, linear regression and the Kruskal-Wallis test were used for analysis., Results: The median number of TB infection control measures implemented in 24 PHCs was 21 of 41 assessed. Only one of five management controls was implemented, 15 of 24 administrative controls, three of nine environmental controls and one of three personal respiratory protection controls. PHCs with TB laboratory facilities and high TB case numbers were more likely to implement TB infection control measures than other PHCs ( p =0.003). In 398 HCWs, the median number of correct responses for knowledge was 10 (IQR 9-11) out of 11., Discussion: HCWs had good TB knowledge. TB infection control measures were generally not implemented and need to be strengthened in PHCs to reduce M. tuberculosis transmission to HCWs, patients and visitors., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

The work-readiness skills and attributes that facilitate healthcare graduates to succeed in their new workplaces are not well defined. In particular, the perspectives of supervisors of graduates in the diverse hospital and community settings of healthcare practice are not well represented in research about work-readiness. Interview data from a case study of twenty-nine supervisors of speech-language pathology graduates was thematically analysed, using Boundary Critique Theory to interpret how the supervisors' understanding of graduate work-readiness was bounded within their understanding of their own system, needs and work environment. The four themes captured the skills that the supervisors perceived as critical for graduate work-readiness: Independence; Attitude; Teamwork; and Learning. A tension was identified within these themes, as supervisors' understanding of work-readiness was bounded by an expectation that graduates are able to moderate how they transfer and apply their graduate skills in their workplace according to the complexity of client needs and the workplace setting. This study increases the visibility of the supervisors' boundaries around what are and are not considered to be work-ready skills, attributes and expectations of a work ready speech-language pathology graduate. This knowledge can be used to facilitate speech-language pathology graduates to successfully transfer, apply and expand these skills as they transition to work, and may be useful for other health professions to explore., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Many institutions implemented telehealth initiatives to provide social support for patients during the SARS-CoV-2 (COVID-19) pandemic. Little is known about the impact of these programs on patient support persons and the trainees who facilitated them., Objective: To assess perceptions of a resident physician and medical student-driven video visit program., Methods: We designed and implemented a trainee-led video visit navigation program across three affiliated urban hospitals to facilitate video visits between patients and their support persons. We used descriptive statistics to understand the patient population served by the program and employed surveys for support persons and trainees to assess attitudes on the program., Results: From April to June 2020, a total of 443 video visits were completed. Surveys were conducted for 101 out of 184 (54.9%) support persons and 39 out of 65 (60.0%) of medical trainees. Surveys demonstrated that video visits helped alleviate the stress and anxiety of support persons having a hospitalized loved one they could not visit. For trainees, facilitating these connections helped mitigate stress and provided a mechanism to contribute to the pandemic response., Conclusion: Telehealth navigation programs provide high levels of connection for patients and their support persons during the COVID-19 pandemic and potentially beyond. Residents and medical students involved in these initiatives mobilized telehealth modalities to improve experiences with care delivery., (© 2022. The Author(s).)

Background: Medical and nursing students entering their clinical programmes are at increased risk for tuberculosis (TB) in TB-endemic settings. Relatively little is known about Mycobacterium tuberculosis infection among such students in high-endemic countries., Methods: We examined M. tuberculosis infection among medical and nursing students starting clinical training in Bandung, Indonesia using interferon-γ release assay (IGRA) QuantiFERON-TB Gold Plus. IGRA-negative students had a repeat test after 1 y and logistic regression was used to identify factors associated with IGRA positivity or conversion., Results: There were 379 students included in this study: 248 (65.4%) were medical students and 131 (34.6%) were nursing students. Of 379 students, 70 (18.5%) were IGRA positive at baseline. Of 293 IGRA-negative students with 1-y results, 26 (8.9%) underwent IGRA conversion. Being a medical student (adjusted relative risk [ARR] 5.15 [95% confidence interval {CI} 1.82 to 14.59], p=0.002) and participation in sputum collection or bronchoscopy were associated with IGRA conversion (ARR 2.74 [95% CI 1.29 to 5.79], p=0.008)., Conclusions: Medical and nursing students entering clinical training are at high risk of M. tuberculosis infection and need improved infection prevention and control strategies., (© The Author(s) 2021. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Aim: We describe the characteristics of women diagnosed with HIV and AIDS in Aotearoa New Zealand over the last 25 years, and of women living with HIV in New Zealand in order to guide the response for HIV prevention and care., Methods: Data on women diagnosed with HIV and AIDS in New Zealand (1996-2020) were collected through routine surveillance case reports from healthcare providers. CD4 cell count <350 cells/mm³ was considered a late diagnosis. Women living with HIV by 31 December 2020 included those first diagnosed in New Zealand and those previously diagnosed overseas., Results: A total of 634 women have been diagnosed with HIV (18% of all diagnoses in this time): most cases were acquired through heterosexual contact (82%). Twenty-eight percent (n=180/634) acquired HIV in New Zealand, of whom 43% were diagnosed late. AIDS was diagnosed in 128 women (72% within three months of HIV diagnosis). An estimated 570 women (77% aged >40 years) were living with diagnosed HIV at the end of 2020., Conclusion: The number of women diagnosed with HIV each year in New Zealand has remained steady over recent years. More timely testing and diagnosis is essential to ensure women with HIV have access to appropriate treatment and support., (© PMA.)

Setting: Newly diagnosed pulmonary TB with diabetes mellitus (DM) comorbidity attending clinics in Bandung City, Indonesia., Objective: To describe the effect of educational counselling on patients' knowledge about TB (transmission, treatment, risk factors) and DM (symptoms, treatment, complications, healthy lifestyle), adherence to medication, and to assess characteristics associated with knowledge., Design: All patients received counselling and were then randomised to either structured education on TB-DM, combined with clinical monitoring and medication adjustment (intervention arm), or routine care (control arm). Knowledge and adherence were assessed using a questionnaire., Results: Baseline and 6-month questionnaires were available for 108 of 150 patients randomised (60/76 in the intervention arm and 48/74 in the control arm). Patients knew less about DM than about TB. There was no significant difference in the proportion with knowledge improvement at 6 months, both for TB (difference of differences 14%; P = 0.20) or for DM (10%; P = 0.39) between arms. Intervention arm patients were more likely to adhere to taking DM medication, with fewer patients reporting ever missing oral DM drugs than those in the control arm (23% vs. 48%; P = 0.03). Higher education level was associated with good knowledge of both TB and DM., Conclusions: Structured education did not clearly improve patients' knowledge. It was associated with better adherence to DM medication, but this could not be attributed to education alone. More efforts are needed to improve patients' knowledge, especially regarding DM., (© 2021 The Union.)

In response to the COVID-19 pandemic, many medical schools suspended clinical clerkships and implemented newly adapted curricula to facilitate continued educational progress. While the implementation of these new curricula has been described, an understanding of the impact on student learning outcomes is lacking. In 2020, the authors followed Kern's 6-step approach to curricular development to create and evaluate a novel COVID-19 curriculum for medical students at the University of California San Francisco School of Medicine and evaluate its learning outcomes. The primary goal of the curriculum was to provide third- and fourth-year medical students an opportunity for workplace learning in the absence of clinical clerkships, specifically for students to develop clerkship-level milestones in the competency domains of practice-based learning and improvement, professionalism, and systems-based practice. The curriculum was designed to match students with faculty-mentored projects occurring primarily in virtual formats. A total of 126 students enrolled in the curriculum and completed a survey about their learning outcomes (100% response rate). Of 35 possible clerkship-level milestones, there were 12 milestones for which over half of students reported development in competency domains including practice-based learning and improvement, professionalism, and interpersonal and communication skills. Thematic analysis of students' qualitative survey responses demonstrated 2 central motivations for participating in the curriculum: identity as physicians-in-training and patient engagement. Six central learning areas were developed during the curriculum: interprofessional teamwork, community resources, technology in medicine, skill-building, quality improvement, and specialty-specific learning. This analysis demonstrates that students can develop competencies and achieve rich workplace learning through project-based experiential learning, even in virtual clinical workplaces. Furthermore, knowledge of community resources, technology in medicine, and quality improvement was developed through the curriculum more readily than in traditional clerkships. These could be considered as integral learning objectives in future curricular design., (Copyright © 2021 by the Association of American Medical Colleges.)

The role of human prostatic acid phosphatase (PAcP, P15309|PPAP&#95;HUMAN) in prostate cancer was investigated using a new proteomics tool termed signal sequence swapping (replacement of domains from the native cleaved amino terminal signal sequence of secretory/membrane proteins with corresponding regions of functionally distinct signal sequence subtypes). This manipulation preferentially redirects proteins to different pathways of biogenesis at the endoplasmic reticulum (ER), magnifying normally difficult to detect subsets of the protein of interest. For PAcP, this technique reveals three forms identical in amino acid sequence but profoundly different in physiological functions, subcellular location, and biochemical properties. These three forms of PAcP can also occur with the wildtype PAcP signal sequence. Clinical specimens from patients with prostate cancer demonstrate that one form, termed PLPAcP, correlates with early prostate cancer. These findings confirm the analytical power of this method, implicate PLPAcP in prostate cancer pathogenesis, and suggest novel anticancer therapeutic strategies., (© 2021 The Author(s).)

Introduction: The National Disability Insurance Scheme is the new consumer-controlled funding system for people with disability in Australia, and is expected to enhance participation outcomes of people with disability. This research explored participation opportunities for people with disability during the formative period of transition to the scheme, through stakeholder accounts of changes in allied health service contexts., Materials and Methods: Qualitative data were generated during interviews, workshops and meetings with industry, policy, practice and education stakeholders involved in scheme services. Inductive coding explored key themes within the data. The International Classification of Functioning model was then applied as a deductive coding framework to illuminate how the scheme was perceived to be impacting participation opportunities for recipients of scheme funding., Results and Discussion: Using the International Classification of Functioning helped us illuminate whether changes resulting from scheme transition posed participation opportunities or barriers for scheme recipients. Research participants often framed these changes negatively, even when examples suggested that changes had removed participation barriers for scheme recipients. Some participants viewed changes as obstructing equitable and quality professional practice. We explore potential opportunities to resolve tensions that also optimise the participation outcomes of individuals who receive services through individualised funding.IMPLICATIONS FOR REHABILITATIONThe introduction of individualised funding has removed barriers to participation for many National Disability Insurance Scheme recipients.Efforts must be made to build the trust of stakeholders involved in National Disability Insurance Scheme service provision regarding how fee-for-service funding can lead to good participation outcomes for scheme recipients.Transparency around the shared processes of clinical governance and equitable service access operating in Australia's individualized disability funding scheme are suggested to build trust.A visible commitment to maintaining a broad range of services is also indicated to build trust for stakeholders involved in the scheme.

Cholangiocarcinoma (CCA) is the second most common hepatobiliary cancer, an aggressive malignancy with limited therapeutic options. PARP (poly (ADP-ribose) polymerase) 1 and 2 are important for deoxyribonucleotide acid (DNA) repair and maintenance of genomic stability. PARP inhibitors (PARPi) such as niraparib have been approved for different malignancies with genomic alteration in germline BRCA and DNA damage response (DDR) pathway genes. Genomic alterations were analyzed in DDR genes in CCA samples employing The Cancer Genome Atlas (TCGA) database. Mutations were observed in various DDR genes, and 35.8% cases had alterations in at least one of three genes ( ARID1A , BAP1 and ATM ), suggesting their susceptibility to PARPi. Niraparib treatment suppressed cancer cell viability and survival, and also caused G2/M cell cycle arrest in patient-derived xenograft cells lines (PDXC) and established CCA cells harboring DDR gene mutations. PARPi treatment also induced apoptosis and caspase3/7 activity in PDXC and CCA cell lines, and substantially reduced expression of BCL2, BCL-XL and MCL1 proteins. Niraparib caused a significant increase in oxidative stress, and induced activation of DNA damage markers, phosphorylation of CHK2 and replication fork stalling. Importantly, niraparib, in combination with gemcitabine, produced sustained and robust inhibition of tumor growth in vivo in a patient-derived xenograft (PDX) model more effectively than either treatment alone. Furthermore, tissue samples from mice treated with niraparib and gemcitabine display significantly lower expression levels of pHH3 and Ki-67, which are a mitotic and proliferative marker, respectively. Taken together, our results indicate niraparib as a novel therapeutic agent alone or in combination with gemcitabine for CCA.

Homologous recombination DNA damage repair (HR-DDR) deficient patients with various solid tumors have been treated with PARP inhibitors. However, the clinical characteristics of patients with melanoma who have HR-DDR gene mutations and the consequences of PARP inhibition are poorly understood. We compared the commercially available next-generation sequencing data from 84 patients with melanomas from our institution with a dataset of 1,986 patients as well as 1,088 patients profiled in cBioportal. In total, 21.4% of patients had ≥1 functional HR-DDR mutation, most commonly involving BRCA1, ARID1A, ATM, ATR, and FANCA. Concurrent NF1, BRAF, and NRAS mutations were found in 39%, 39%, and 22% of cases, respectively. HR-DDR gene mutation was associated with high tumor mutational burden and clinical response to checkpoint blockade. A higher prevalence of HR-DDR mutations was observed in the datasets from Foundation Medicine (Cambridge, CA) and those from the Cancer Genome Atlas. Treatment of HR-DDR‒mutated patient-derived xenograft models of melanoma with PARP inhibitor produced significant antitumor activity in vivo and was associated with increased apoptotic activity. RNA sequencing analysis of PARP inhibitor-treated tumors indicated alterations in the pathways involving extracellular matrix remodeling, cell adhesion, and cell-cycle progression. Melanomas with HR-DDR mutations represent a unique subset, which is more likely to benefit from checkpoint blockade and may be targeted with PARP inhibitor., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Oxygen is vital in the treatment of illnesses in children and adults, yet is lacking in many low and middle-income countries health care settings. Oxygen concentrators (OCs) can increase access to oxygen, compared to conventional oxygen cylinders. We investigated the costs and critical success factors of OCs in three hospitals in Fiji, and extrapolated these to estimate the oxygen delivery cost to all Sub-Divisional hospitals (SDH) nationwide., Methods: Data sources included key personnel interviews, and data from SDH records, Ministry of Health and Medical Services, and a non-governmental organisation. We used Investment Logic Mapping (ILM) to define key issues. An economic case was developed to identify the investment option that optimised value while incorporating critical success factors identified through ILM. A fit-for-purpose analysis was conducted using cost analysis of four short-listed options. Sensitivity analyses were performed by altering variables to show the best or worst case scenario. All costs are presented in Fijian dollars., Results: Critical success factors identifed included oxygen availability, safety, ease of use, feasibility, and affordability. Compared to the status quo of having only oxygen cylinders, an option of having a minimum number of concentrators with cylinder backup would cost $434,032 (range: $327,940 to $506,920) over 5 years which would be 55% (range: 41 to 64%) of the status quo cost., Conclusion: Introducing OCs into all SDHs in Fiji would reduce overall costs, while ensuring identified critical success factors are maintained. This study provides evidence for the benefits of OCs in this and similar settings.

Nurse-patient therapeutic engagement on acute mental health wards is beneficial to service users' outcomes and nurses' job satisfaction. However, engagement is not always fulfilled in practice and interventions to improve engagement are sparse and ineffective. We explored the experiences of service users, carers, and clinicians drawing from 80 hours of non-participant observations in an acute mental health ward and semi-structured interviews with 14 service users, two carers, and 12 clinicians. Analysis of these data resulted in 28 touchpoints (emotionally significant moments) and eight overarching themes. Service users, carers, and clinicians identified a lack of high-quality, person-centred, collaborative engagement and recognized and supported efforts to improve engagement in practice. Potential solutions to inform future intervention development were identified. Our findings align with previous research highlighting negative experiences and support the need to develop multicomponent interventions through participatory methods., (© 2021 The Authors. International Journal of Mental Health Nursing published by John Wiley & Sons Australia, Ltd.)

Melanoma occurs as a consequence of inherited susceptibility to the disease and exposure to UV radiation (UVR) and is characterized by uncontrolled cellular proliferation and a high mutational load. The precise mechanisms by which UVR contributes to the development of melanoma remain poorly understood. Here we show that activation of nuclear receptor coactivator 3 (NCOA3) promotes melanomagenesis through regulation of UVR sensitivity, cell-cycle progression, and circumvention of the DNA damage response (DDR). Downregulation of NCOA3 expression, either by genetic silencing or small-molecule inhibition, significantly suppressed melanoma proliferation in melanoma cell lines and patient-derived xenografts. NCOA3 silencing suppressed expression of xeroderma pigmentosum C and increased melanoma cell sensitivity to UVR. Suppression of NCOA3 expression led to activation of DDR effectors and reduced expression of cyclin B1, resulting in G 2 -M arrest and mitotic catastrophe. A SNP in NCOA3 (T960T) reduced NCOA3 protein expression and was associated with decreased melanoma risk, given a significantly lower prevalence in a familial melanoma cohort than in a control cohort without cancer. Overexpression of wild-type NCOA3 promoted melanocyte survival following UVR and was accompanied by increased levels of UVR-induced DNA damage, both of which were attenuated by overexpression of NCOA3 (T960T). These results describe NCOA3-regulated pathways by which melanoma can develop, with germline NCOA3 polymorphisms enabling enhanced melanocyte survival in the setting of UVR exposure, despite an increased mutational burden. They also identify NCOA3 as a novel therapeutic target for melanoma. SIGNIFICANCE: This study explores NCOA3 as a regulator of the DDR and a therapeutic target in melanoma, where activation of NCOA3 contributes to melanoma development following exposure to ultraviolet light., (©2021 American Association for Cancer Research.)

Objectives: Our objectives were threefold: (1) describe a collaborative, theoretically driven approach to co-designing complex interventions; (2) demonstrate the implementation of this approach to share learning with others; and (3) develop a toolkit to enhance therapeutic engagement on acute mental health wards., Design and Participants: We describe a theory-driven approach to co-designing an intervention by adapting and integrating Experience-based Co-design (EBCD) with the Behaviour Change Wheel (BCW). Our case study was informed by the results of a systematic integrative review and guided by this integrated approach. We undertook 80 hours of non-participant observations, and semistructured interviews with 14 service users (7 of which were filmed), 2 carers and 12 clinicians from the same acute ward. The facilitated intervention co-design process involved two feedback workshops, one joint co-design workshop and seven small co-design team meetings. Data analysis comprised the identification of touchpoints and use of the BCW and behaviour change technique taxonomy to inform intervention development., Setting: This study was conducted over 12 months at an acute mental health organisation in England., Results: The co-designed Let's Talk toolkit addressed four joint service user/clinician priorities for change: (1) improve communication with withdrawn people; (2) nurses to help service users help themselves; (3) nurses to feel confident when engaging with service users; (4) improving team relations and ward culture. Intervention functions included training, education, enablement, coercion and persuasion; 14 behaviour change techniques supported these functions. We detail how we implemented our integrated co-design-behaviour change approach with service users, carers and clinicians to develop a toolkit to improve nurse-patient therapeutic engagement., Conclusions: Our theory-driven approach enhanced both EBCD and the BCW. It introduces a robust theoretical approach to guide intervention development within the co-design process and sets out how to meaningfully involve service users and other stakeholders when designing and implementing complex interventions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background. A significant proportion of tuberculosis (TB) patients globally make their initial visit for medical care to either an informal provider or a private practitioner, and many are not formally notified. Involvement of private practitioners (PPs) in a public-private mix for TB (TB-PPM) provides an opportunity for improving TB control. However, context-specific interventions beyond public-private agreements and mandatory notification are needed. In this study we will evaluate whether a tailored intervention package can increase TB notifications from PPs in Indonesia. Methods. This is a cluster-randomized trial of a multi-component public health intervention. 36 community health centre (CHC) areas will be selected as study locations and randomly allocated to intervention and control arms (1:1). PPs in the intervention areas will be identified using a mapping exercise and recruited into the study if they are eligible and consent. They will receive a tailored intervention package including in-person education about TB management along with bimonthly electronic refreshers, context-specific selection of referral pathways, and access to a TB-reporting app developed in collaboration with the National TB programme. The primary hypothesis is that the intervention package will increase the TB notification rate. The primary outcome will be measured by collecting notification data from the CHCs in intervention and control arms at the end of a 1-year observation period and comparing with the 1-year pre-intervention. The primary analysis will be intention-to-treat at the cluster level, using a generalised mixed model with repeated measures of TB notifications for 1 year pre- and 1 year post-intervention. Discussion. The results from this study will provide evidence on whether a tailored intervention package is effective in increasing the number of TB notifications, and whether the PPs refer presumptive TB cases correctly. The study results will guide policy in the development of TB-PPM in Indonesia and similar settings., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Hadisoemarto PF et al.)

Background: Kidney replacement therapy is controversial for patients with hepatorenal syndrome who may not be liver transplant candidates. Data surrounding the likelihood of recovery of kidney function and mortality after outpatient dialysis initiation in patients with dialysis-requiring hepatorenal syndrome could inform discussions between patients and providers., Methods: We performed a retrospective cohort study of patients with hepatorenal syndrome who were registered in the United States Renal Data System between 1996 and 2015 ( n =7830) as receiving maintenance dialysis. We characterized patients with hepatorenal syndrome by recovery of kidney function using Fine and Gray models. We also examined hazard of recovery of kidney function and death among those with hepatorenal syndrome versus those with acute tubular necrosis ( n =48,861) using adjusted Fine-Gray and Cox models, respectively., Results: Of the patients with hepatorenal syndrome, 11% recovered kidney function. Those with higher likelihood of recovery were younger, non-Hispanic White, and had a history of alcohol use. Compared with patients with acute tubular necrosis, patients with hepatorenal syndrome as the attributed cause of kidney disease had a lower hazard of recovery (HR, 0.22; 95% CI, 0.21 to 0.24) and higher hazard of death within 1 year (HR, 3.10; 95% CI, 2.99 to 3.23) in fully adjusted models., Conclusions: Patients with hepatorenal syndrome receiving chronic maintenance dialysis had a lower likelihood of recovery of kidney function and higher mortality risk compared with patients with acute tubular necrosis. Among patients with hepatorenal syndrome, those most likely to recover kidney function were younger, had a history of alcohol use, and lacked comorbid conditions. These data may inform prognosis and discussions surrounding treatment options when patients with hepatorenal syndrome need chronic maintenance dialysis therapy., Competing Interests: K.L. Johansen reports serving as a member of the steering committee for the GlaxoSmithKline prolyl hydroxylase inhibitor clinical trials program, and being an associate editor for JASN. E. Ku reports receiving research funding from CareDX. J.C. Lai reports being a scientific advisor for, or member of, the American Association for the Study of Liver Diseases, American Journal of Transplantation, American Society of Transplantation, and Liver Transplantation; and receiving research funding from Axcella Health, Inc., Genentech, and Vir Biotechnology. All remaining authors have nothing to disclose., (Copyright © 2021 by the American Society of Nephrology.)

Purpose: Simulation is increasingly used within speech-language pathology education. Research has primarily explored students' perceptions of learning in simulation. The aim of this study was to determine if speech-language pathology students achieved a statistically-equivalent level of competency when a mean of 20% of placement time was replaced with simulation compared to placements without a simulation component., Method: This non-inferiority randomised controlled trial involved students from six Australian universities. Students were randomised to either a simulation + traditional placement group attending 5 days of simulation prior to their traditional placement, or a traditional only placement group. Their end-placement clinical competency was assessed using Competency Assessment in Speech Pathology (COMPASS ® )., Result: Final data were available for 325 students: 150 students in traditional placements, 138 students in protocol-compliant simulation + traditional placements, and 37 students in non-protocol simulation + traditional placements. There were no statistically significant differences between groups (traditional vs protocol-compliant simulation + traditional Mann-Whitney-Wilcoxon z  = 1.23, df  = 286, p  = 0.22; traditional vs intention-to-treat simulation + traditional Mann-Whitney-Wilcoxon z  = 0.23, df  = 323, p  = 0.81)., Conclusion: This research contributes to the evidence base which suggests that simulation can partially replace traditional placement time for speech-language pathology students without loss of competency, substantiating its value as an alternative placement model in speech-language pathology programmes.

Objectives: We estimated the proportion of people reported with HIV in New Zealand between 2006 and 2017, and alive in 2017-2019, who were on antiretroviral therapy (ART) and had a suppressed viral load (VL), and explored their associated characteristics., Methods: Data were anonymously linked to information on ART and VL within the data collection period (January 2017 to August 2019) using the National Health Index (NHI), Ministry of Health and laboratory datasets, as well as information from clinical specialists. Logistic regression was used to test for associations. Sensitivity analyses were undertaken to estimate the range for the key proportions., Results: Overall, 2355 people were reported with HIV, of whom 116 (5%) had died, 337 (14%) were overseas, and 1701 (72%) were alive in New Zealand; for the remaining 201 (9%) the outcome was unknown. Clinical data were available for 1490 people (87.6%): 1408 (94.5%) were on ART, 11 (< 1%) were not on ART, and for 71 (4.8%) this was unknown. Of those on ART, 1156 (82.1%) had a suppressed VL (< 200 copies/mL), 34 (2.4%) were unsuppressed, and for 218 (15.5%) this was unknown. The estimate of the proportion on ART ranged from 99% to 78%, and those with a suppressed VL ranged from 98% to 78%., Conclusions: Among people with HIV in New Zealand who are under care, a high proportion were on ART and had suppressed VL. Increasing collection of NHIs and better linkage with laboratory information will reduce the number with unknown information and provide more complete VL results in the future., (© 2020 British HIV Association.)

Approaches to tube weaning enterally fed children and evaluating outcomes vary widely. This limits the utility of research for identifying both "what works" and successful implementation of research outcomes. We used a qualitative scoping review methodology to examine internationally published research. Our primary aim was to identify the main philosophies underpinning intervention design and the main outcome variables used to demonstrate success of existing programs. This information can be used to inform future research design and clinical practice. Literature up until June 2019 was sourced via Medline, Scopus, Ovid, and CINHAL databases; hand searching; and gray literature using Google Advanced Search. Three predominant approaches to tube-weaning interventions were identified: behavioral, child- and family-centered, and biomedical. A wide range of intervention variables were identified, with the level of parental involvement and the use of hunger provocation varying between approaches. Our Review also confirms that there is no consistency in outcome measures used, limiting comparability between programs. We suggest that the role of parents in the weaning process and its impact on both the child and the parent/carer while transitioning from enteral to oral eating are insufficiently understood. We discuss these findings in the context of a suggested framework for future research., (© 2020 American Society for Parenteral and Enteral Nutrition.)

It has been demonstrated that activated mast cells (MCs) are enriched in Kaposi sarcoma (KS) tumors and contribute to the inflammatory microenvironment. Mechanisms driving MC activation, however, are incompletely understood. We sought to understand whether immunoglobulin E (IgE), a potent activator of MCs, was associated with KS incidence and severity. In a cross-sectional study of untreated human immunodeficiency virus (HIV)-infected adults with or without KS in Uganda, we found that patients with KS had higher plasma IgE levels than those without KS. After adjustment for age, sex, CD4+ T-cell count, and HIV RNA levels, there was a dose-response relationship between plasma IgE levels and the presence and severity of KS. Higher eosinophil counts were also associated with IgE levels, and plasma interleukin 33 concentrations were higher in individuals with KS. These findings suggest that IgE-driven atopic inflammation may contribute the pathogenesis of KS. Therapies targeting IgE-mediated MC activation thus might represent a novel approach for treatment or prevention of KS., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective: This study is aimed to compare and evaluate any differences in clinical and radiological outcomes of different operative techniques of cranio-cervical decompression (CCD) performed in adults with symptomatic Chiari malformation type I (CM-1) within a single tertiary neurosurgical center., Methods: A retrospective review using the Hospital theatre management system (ORSOS) and records of patients who underwent CCD for CM-1 between January 2011 and October 2019 was performed. Patients were divided in three cohorts according to the operative technique used: an extradural osteo-ligamentous decompression (BD), BD followed by dural opening either without duraplasty (DOWD) or plus duroplasty (DOPD). The primary clinical outcome was measured by utilizing the Chicago Chiari Outcome Scale (CCOS). Syrinx outcome was measured on post-op MRI. Statistical analysis was performed using IBM SPSS 24 with α = 0.05., Results: 67 adults underwent 69 CCD: 10 BD, 29 DOWD and 30 DOPD. Median follow-up was 47.3 months (Interquartile Range (IQR) 26.3-73.7). Patients who underwent DOPD had a shorter median hospital stay (p-value 0.001), fewer unplanned readmissions (p-value 0.015), a higher median CCOS (p-value 0.001) and a lower post-operative complications rate (p-value 0.001) compared to patients who underwent DOWD. BD revealed a 40 % failure rate and was ineffective in cases with syringomyelia., Conclusion: Better clinical outcomes, lower complication risk, and short duration of hospital stay were associated with patients who underwent dural opening with augmentative watertight duraplasty. Bony decompression alone despite being a very safe technique, does not appear to be reliable and effective in controlling and relieving the clinical symptoms and the syringomyelia of adult patients with CM-1., (Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.)

Introduction: Clinical placements are central to the process of preparing future health professionals for practice. Health care environments are increasingly complex and demanding with clinical placements often being perceived as a burden on busy health professionals giving rise to a service-education tension. This tension creates a situation ripe for simplistic solutionist approaches. For example, characterising the problem of clinical placements as students negatively impacting on service productivity results in a reductionist solution such as universities compensating health services for student education. Challenges faced by placement seekers and placement providers are multifaceted and complex requiring a more sophisticated understanding and response to the challenges of involving students in the workplace to prepare them for the future workforce., Re-Conceptualisation: We argue that the health and education systems have become de-coupled. Learning and working are seen as distinct activities that are at odds with one another. Re-imagining the purposes and practices of clinical placements for the mutual benefit of patients, health services and students may fruitfully address this disconnect., Worked Example: We present a worked example using the conceptual and analytical tools of cultural-historical activity theory to articulate what we have learnt about this health-education disconnect. Our worked example draws on research involving a series of clinical education case studies within acute care contexts., Conclusion: Through the lens of cultural-historical activity theory, we highlight that solutionist approaches are entrenched in a de-coupling of health from education where the shared object of preparing the future workforce is fragmented. Successful re-coupling requires a partnership that is founded on a shared commitment to preparing the future workforce; recognises that learning and practice are inseparable; and understands that both activity systems are fluid and that collaboration to stay focused on the shared object of preparing the future workforce is complex, challenging and ongoing work., (© 2020 John Wiley & Sons Ltd and The Association for the Study of Medical Education.)

Background: Chemotherapy-induced peripheral neuropathy is a common and often severe side effect from many chemotherapeutic agents, with limited treatment options. There is no literature on the use of topical cannabinoids for chemotherapy-induced neuropathy., Case Presentations: The current manuscript presents a case series of patients presenting in oncology clinics at Sutter Health, CA and Mayo Clinic, Rochester, MN from April 2019 to December 2020 with chemotherapy-induced peripheral neuropathy who used topical creams containing the cannabinoids delta-nine-tetrahydrocannabinol (THC) and/or cannabidiol (CBD)., Conclusions: This case series suggests that topical cannabinoids may be helpful for patients with chemotherapy-induced peripheral neuropathy. This paper also discusses the potential mechanisms of action by which topical cannabinoids might alleviate established CIPN symptoms. A randomized placebo-controlled trial using a standardized product is planned to study the actual efficacy of such treatment.