Optimization of a Novel DEL Hit That Binds in the Cbl-b SH2 Domain and Blocks Substrate Binding.

We were attracted to the therapeutic potential of inhibiting Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b), a RING E3 ligase that plays a critical role in regulating the activation of T cells. However, given that only protein-protein interactions were involved, it was unclear whether inhibition by a small molecule would be a viable approach. After screening an ∼6 billion member DNA-encoded library (DEL) using activated Cbl-b, we identified compound 1 as a hit for which the cis-isomer (2) was confirmed by biochemical and surface plasmon resonance (SPR) assays. Our hit optimization effort was greatly accelerated when we obtained a cocrystal structure of 2 with Cbl-b, which demonstrated induced binding at the substrate binding site, namely, the Src homology-2 (SH2) domain. This was quite noteworthy given that there are few reports of small molecule inhibitors that bind to SH2 domains and block protein-protein interactions. Structure- and property-guided optimization led to compound 27, which demonstrated measurable cell activity, albeit only at high concentrations.

Investigating the role connective tissue fibroblasts play in the altered muscle anatomy associated with the limb abnormality, Radial Dysplasia.

Radial dysplasia (RD) is a congenital upper limb birth defect that presents with changes to the upper limb anatomy, including a shortened or absent radius, bowed ulna, thumb malformations, a radially deviated hand and a range of muscle and tendon malformations, including absent or abnormally shaped muscle bundles. Current treatments to address wrist instability caused by a shortened or absent radius frequently require an initial soft tissue distraction intervention followed by a wrist stabilisation procedure. Following these surgical interventions, however, recurrence of the wrist deviation remains a common, long-term problem following treatment. The impact of the abnormal soft connective tissue (muscle and tendon) anatomy on the clinical presentation of RD and the complications following surgery are not understood. To address this, we have examined the muscle, fascia and the fascial irregular connective tissue (ICT) fibroblasts found within soft connective tissues, from RD patients. We show that ICT fibroblasts isolated from RD patients are functionally abnormal when compared to the same cells isolated from control patients and secrete a relatively disordered extracellular matrix (ECM). Furthermore, we show that ICT fibroblast dysfunction is a unifying feature found in RD patients, even when the RD clinical presentation is caused by distinct genetic syndromes.

Fishing for oil and meat drives irreversible defaunation of deepwater sharks and rays.

The deep ocean is the last natural biodiversity refuge from the reach of human activities. Deepwater sharks and rays are among the most sensitive marine vertebrates to overexploitation. One-third of threatened deepwater sharks are targeted, and half the species targeted for the international liver-oil trade are threatened with extinction. Steep population declines cannot be easily reversed owing to long generation lengths, low recovery potentials, and the near absence of management. Depth and spatial limits to fishing activity could improve conservation when implemented alongside catch regulations, bycatch mitigation, and international trade regulation. Deepwater sharks and rays require immediate trade and fishing regulations to prevent irreversible defaunation and promote recovery of this threatened megafauna group.

Effect of donor HSD17B13 genotype on patient survival after liver transplant: a retrospective cohort study.

Background: Several genetic variants are associated with chronic liver disease. The role of these variants in outcomes after liver transplantation (LT) is uncertain. The aim of this study was to determine if donor genotype at risk-associated variants in PNPLA3 (rs738409 C>G, p.I148M) and HSD17B13 (rs72613567 T>TA; rs80182459, p.A192Lfs∗8) influences post-LT survival. Methods: In this retrospective cohort study, data on 2346 adults who underwent first-time LT between January 1, 1999 and June 30, 2020 and who had donor DNA samples available at five large Transplant Immunology Laboratories in Texas, USA, were obtained from the United Network for Organ Sharing (UNOS). Duplicates, patients with insufficient donor DNA for genotyping, those who were <18 years of age at the time of transplant, had had a previous transplant or had missing genotype data were excluded. The primary outcomes were patient and graft survival after LT. The association between donor genotype and post-LT survival was examined using Kaplan-Meier method and multivariable-adjusted Cox proportional hazards models. Findings: Median age of LT recipients was 57 [interquartile range (IQR), 50-62] years; 837 (35.7%) were women; 1362 (58.1%) White, 713 (30.4%) Hispanic, 182 (7.8%) Black/African-American. Median follow-up time was 3.95 years. Post-LT survival was not affected by donor PNPLA3 genotype but was significantly reduced among recipients of livers with two HSD17B13 loss-of-function (LoF) variants compared to those receiving livers with no HSD17B13 LoF alleles (unadjusted one-year survival: 82.6% vs 93.9%, P < 0.0001; five-year survival: 73.1% vs 82.9%, P = 0.0017; adjusted hazard ratio [HR], 2.25; 95% CI, 1.61-3.15 after adjustment for recipient age, sex, and self-reported ethnicity). Excess mortality was restricted to those receiving steroid induction immunosuppression (crude 90-day post-LT mortality, 9.3% [95% CI, 1.9%-16.1%] vs 1.9% [95% CI, 0.9%-2.9%] in recipients of livers with two vs no HSD17B13 LoF alleles, P = 0.0012; age, sex, and ethnicity-adjusted HR, 2.85; 95% CI, 1.72-4.71, P < 0.0001). No reduction was seen among patients who did not receive steroid induction (90-day mortality 3.1% [95% CI, 0%-7.3%] vs 2% [95% CI, 0.9%-3.1%], P = 0.65; adjusted HR, 1.17; 95% CI, 0.66-2.08, P = 0.60). Interpretation: Donor HSD17B13 genotype adversely affects post-LT survival in patients receiving steroid induction. Additional studies are required to confirm this association. Funding: The National Institutes of Health and American Society of Transplant Surgeons Collaborative Scientist Grant.

Managing Complexity: Black Older Adults With Multimorbidity.

BACKGROUND AND OBJECTIVES: Black older adults have higher rates of multimorbidity and receive less effective multimorbidity support than their white counterparts. Yet little is known about the experiences of Black older adults with multimorbidity that may be at the heart of those disparities and which are central to interventions and improving care for this population. In this study, we aimed to conceptualize the multimorbidity management (MM) experience for Black older adults. RESEARCH DESIGN AND METHODS: As part of a larger study on Black older adults' multimorbidity and physician empathy, we conducted in-depth qualitative interviews with 30 Black older adults living in a large midwestern city in the United States aged 65 years and older with self-reported multimorbidity. We used grounded theory analysis to distill findings into a core conceptual category as well as component domains and dimensions. RESULTS: "Managing complexity" emerged as the core category to describe MM in our sample. Managing complexity included domains of "social context," "daily logistics," "care time," and "care roles." DISCUSSION AND IMPLICATIONS: We discuss how managing complexity is distinct from patient complexity and how it is related to cumulative inequality and precarity. Study findings have potential implications for intervention around provider education and empathy as well as for enabling agency of Black older adults with MM.

Light-Driven Radiochemistry with Fluorine-18, Carbon-11 and Zirconium-89.

This review discusses recent advances in light-driven radiochemistry for three key isotopes: fluorine-18, carbon-11, and zirconium-89, and their applications in positron emission tomography (PET). In the case of fluorine-18, the predominant approach involves the use of cyclotron-produced [18F]fluoride or reagents derived thereof. Light serves to activate either the substrate or the fluorine-18 labeled reagent. Advancements in carbon-11 photo-mediated radiochemistry have been leveraged for the radiolabeling of small molecules, achieving various transformations, including 11C-methylation, 11C-carboxylation, 11C-carbonylation, and 11C-cyanation. Contrastingly, zirconium-89 photo-mediated radiochemistry differs from fluorine-18 and carbon-11 approaches. In these cases, light facilitates a postlabeling click reaction, which has proven valuable for the labeling of large biomolecules such as monoclonal antibodies (mAbs). New technological developments, such as the incorporation of photoreactors in commercial radiosynthesizers, illustrate the commitment the field is making in embracing photochemistry. Taken together, these advances in photo-mediated radiochemistry enable radiochemists to apply new retrosynthetic strategies in accessing novel PET radiotracers.

Sierra Nevada reference conditions: A dataset of contemporary reference sites and corresponding remote sensing-derived forest structure metrics for yellow pine and mixed-conifer forests.

Contemporary reference sites in California's Sierra Nevada represent areas where a frequent, low-intensity fire regime - an integral ecological process in temperate dry forests - has been reintroduced after several decades of fire suppression. Produced by an intact fire regime, forest structural patterns in these sites are likely more resilient to future disturbances and climate, and thus can provide reference conditions to guide management and ecological research. In this paper, we present a set of 119 delineated contemporary reference sites in the Sierra Nevada yellow pine and mixed-conifer zone along with a suite of key remote sensing-derived forest structure metrics representing conditions within these sites. We also provide a set of summary figures for individual reference sites and sites grouped by dominant climate class. We identified restored frequent-fire landscapes using a combination of fire history, burn severity, management history, and forest type datasets and we delineated individual polygons using catchment basins, fire perimeters, and imagery. Reference sites ranged in size from 101-966 ha with a mean size of 240 ha. Where available (for 59 sites), we used airborne lidar datasets to characterize a suite of key forest structure metrics within reference sites. Across all 119 sites, we provide a set of forest structure metrics produced by the California Forest Observatory. Reference sites were categorized based on their dominant climate class to assist users in identifying the most climatically relevant reference conditions for their project or study area. We encourage the use of the reference sites and associated forest structure datasets for guiding ecologically focused forest management and research in the Sierra Nevada.

Formation of giant iron oxide-copper-gold deposits by superimposed episodic hydrothermal pulses.

Iron oxide-copper-gold (IOCG) deposits are a globally important source of copper, gold and critical commodities. Despite their relevance, IOCG deposits remain an ill-defined clan, with a range of characteristics that has complicated development of the general genetic model. Here we focus on the Candelaria IOCG deposit in Chile and reveal that by using micro-textural and compositional variations in actinolite, a common alteration mineral found in many IOCG deposits, we can constrain the evolution of these systems. We demonstrate that Candelaria formed by the superposition of at least two pulses of mineralization with a late Cu-rich event overprinting and superimposed over an early, and probably higher temperature, iron oxide-apatite (IOA) mineralization event. These distinct pulses were likely caused by episodic injections of magmatic-hydrothermal fluids from crystallizing magmas at depth. Our data provide empirical evidence of grain-to-deposit scale compositional and potentially temperature changes in an IOCG system. The results support the use of actinolite chemistry as a novel approach to understand the formation of IOCG deposits and a potential tool for vectoring in exploration.

Racial Residential Segregation and the Health of Black Youth With Type 1 Diabetes.

OBJECTIVES: Black youth with type 1 diabetes (T1D) are at heightened risk for suboptimal glycemic control. Studies of neighborhood effects on the health of youth with T1D are limited. The current study investigated the effects of racial residential segregation on the diabetes health of young Black adolescents with T1D. METHODS: A total of 148 participants were recruited from 7 pediatric diabetes clinics in 2 US cities. Racial residential segregation (RRS) was calculated at the census block group level based on US Census data. Diabetes management was measured via self-report questionnaire. Hemoglobin A1c (HbA1c) information was gathered from participants during home-based data collection. Hierarchical linear regression was used to test the effects of RRS while controlling for family income, youth age, insulin delivery method (insulin pump versus syringe therapy), and neighborhood adversity. RESULTS: HbA1c was significantly associated with RRS in bivariate analyses, whereas youth-reported diabetes management was not. In hierarchical regression analyses, whereas family income, age, and insulin delivery method were all significantly associated with HbA1c in model 1, only RRS, age, and insulin delivery method were significantly associated with HbA1c in model 2. Model 2 explained 25% of the variance in HbA1c (P = .001). CONCLUSIONS: RRS was associated with glycemic control in a sample of Black youth with T1D and accounted for variance in HbA1c even after controlling for adverse neighborhood conditions. Policies to reduce residential segregation, along with improved screening for neighborhood-level risk, hold the potential to improve the health of a vulnerable population of youth.

Normothermic machine perfusion for older transplant recipients.

INTRODUCTION: Elderly patients (≥65 years old) are increasingly undergoing liver transplantation and are more likely to be removed from the waitlist. Normothermic machine perfusion (NMP) holds promise in expanding the number of livers available for transplant and improving outcomes for marginal donors and recipients. We aimed to determine the impact of NMP on outcomes in elderly recipients at our institution and nationally using the UNOS database. METHODS: The use of NMP on outcomes in elderly recipients was reviewed using both the UNOS/SRTR database (2016-2022) and institutional data (2018-2020). Characteristics and clinical outcomes were compared between the NMP and static cold (control) groups within both populations. RESULTS: Nationally, using the UNOS/SRTR database, we identified 165 elderly recipients from 28 centers who received a liver allograft undergoing NMP and 4270 that underwent traditional cold static storage. NMP donors were older (48.3 vs. 43.4 years, p < 0.01), had similar rates of steatosis (8.5% vs 8.5%, p = 0.58), were more likely to be from a DCD (41.8% vs 12.3%, p < 0.01), and had a higher donor risk index (DRI; 1.70 vs. 1.60, p < 0.02). NMP recipients had similar age but had a lower MELD score at transplant (17.9 vs. 20.7, p = 0.01). Despite increased marginality of the donor graft, NMP recipients had similar allograft survival and decreased length of stay, even after accounting for recipient characteristics including MELD. Institutional data showed that 10 elderly recipients underwent NMP and 68 underwent cold static storage. At our institution, NMP recipients had a similar length of stay, rates of complications, and readmissions. CONCLUSIONS: NMP may mitigate donor risk factors that are relative contraindications for transplantation in elderly liver recipients, increasing the donor pool. The application of NMP in older recipients should be considered.

Examining Racial/Ethnic Disparities in Coping and Stress Within an Environmental Riskscape.

Existing research on racial/ethnic differences in stress and coping is limited by small samples, single-item measures, and lack of inclusion of Mexican Americans. We address these gaps by analyzing data from the Texas City Stress and Health Study, a cross-sectional sample of Black (N = 257), White (N = 304), US-born (N = 689), and foreign-born (N = 749) Mexican Americans residing in proximity to a petrochemical complex. We compared active and avoidant coping by race/ethnicity and explored multivariable associations between coping and perceived stress. Black and foreign-born Mexican American respondents had the highest stressor exposure yet displayed different patterns of coping and perceived stress patterns. Active coping may be particularly effective for African Americans but may not offset extreme stress disparities. For Mexican Americans, the lack of association between coping and stress underscores the need for more work focused on the culturally diverse coping experiences.

Health Management Occupations During COVID-19: Experiences of Older African Americans With Multimorbidity.

Older African Americans with multimorbidity are at an especially high risk of adverse outcomes due to synergistic risks conferred by age, chronic disease burden and social determinants of health. Chronic condition self-management is one way older African Americans can use health management occupations and exercise agency to reduce their risk of becoming severely ill, and during the ongoing pandemic, of COVID-19 infection. The objective of this study was to understand how the COVID-19 pandemic shaped health management occupations of older African Americans. In-depth qualitative interviews were conducted with 30 African Americans aged 65 and older who reported having two or more chronic conditions. Data were analyzed using thematic analysis. Data suggest how key health management occupations (accessing care; managing medications, nutrition, and physical activity; and social and emotional health promotion and maintenance) were utilized and also shaped by the pandemic. Another key finding was perceived benefits of the pandemic on health and well-being.

Conifer water-use patterns across temporal and topographic gradients in the southern Sierra Nevada.

Climate change is increasing the severity and duration of drought events experienced by forest ecosystems. Because water is essential for tree physiological processes, the ability of trees to survive prolonged droughts will largely depend on whether they have access to reliable water sources. While many woody plant species exhibit the ability to shift water sources between different depths of soil and rock water in response to changes in climate and water availability, it is unclear if Sierra Nevada conifers exhibit this plasticity. Here we analysed the δ18O and δ13C values of annual tree rings to determine the water-use patterns of large Sierra Nevada conifers during the 2012-16 California drought and 4 years before this drought event (2004-07). We analysed four species (Pinus jeffreyi Grev. & Balf. (Jeffrey pine), Pinus lambertiana Dougl. (sugar pine), Abies concolor (Gord. & Glend.) Lindl. Ex Hilderbr (white fir) and Calocedrus decurrens (Torr.) Florin (incense-cedar)) across a range of topographic positions to investigate differences in water-use patterns by species and position on the landscape. We found no significant differences in δ18O and δ13C values for the pre-drought and drought periods. This stability in δ18O values suggests that trees did not shift their water-use patterns in response to the 2012-16 drought. We did find species-specific differences in water-use patterns, with incense-cedar exhibiting more depleted δ18O values than all other species. We also found trends that suggest the water source used by a tree may depend on topographic and growing environment attributes such as topographic wetness and the surrounding basal area. Overall, our results suggest that the water source used by trees varies by the species and topographic position, but that Sierra Nevada conifers do not switch their water-use patterns in response to the drought. This lack of plasticity could make Sierra Nevada conifers particularly vulnerable to drought mortality as their historically reliable water sources begin to dry out with climate change.

No Stone Left Unturned: Utilization of an Organ Procurement Organization Donor Surgeon at Procurement Reduces Discards of Marginal Liver Allografts.

BACKGROUND: The recent trend of organ procurement organizations (OPOs) employing independent surgeons for organ procurement has been developed with the goal of improving the supply of suitable organs for transplantation. We investigated the effects that the addition of an OPO-employed, organ-procurement specialist has on liver allograft discard rate, marginal organ utilization, and graft survival. METHODS: Organ Procurement and Transplant Network and OPO data were retrospectively studied between April 1, 2014' and July 31, 2019' within the Southwest Transplant Alliance donor service area. Liver procurements with an OPO-surgeon present (OPO-Present) were compared to those without the involvement of an OPO surgeon (OPO-Absent). Donor and recipient characteristics as well as outcomes were analyzed across groups using propensity score matching. RESULTS: In total 869 OPO-Present liver allografts had similar rates of discard (5.2%) compared to 771 OPO-Absent livers (5.8%). However, after adjusting for donor risk, OPO-Present livers had a lower propensity of discard compared to OPO-Absent (3.4% versus 7.6%, P < 0.05). OPO-Present livers were more likely to be shared nationally (11.0% versus 4.8%, P < 0.001). Outcome analysis showed allograft survival of OPO-Present livers at 5 y was comparable to OPO-Absent livers (79.5% versus 80%, P = 0.34). CONCLUSIONS: The presence of an OPO surgeon was associated with decreased liver allograft discard and increased utilization of marginal donor organs. The OPO surgeon's presence represents a potential strategy to increase organ utilization nationally.

Molecular Function and Contribution of TBX4 in Development and Disease.

Over the past decade, recognition of the profound impact of the TBX4 (T-box 4) gene, which encodes a member of the evolutionarily conserved family of T-box-containing transcription factors, on respiratory diseases has emerged. The developmental importance of TBX4 is emphasized by the association of TBX4 variants with congenital disorders involving respiratory and skeletal structures; however, the exact role of TBX4 in human development remains incompletely understood. Here, we discuss the developmental, tissue-specific, and pathological TBX4 functions identified through human and animal studies and review the published TBX4 variants resulting in variable disease phenotypes. We also outline future research directions to fill the gaps in our understanding of TBX4 function and of how TBX4 disruption affects development.

Ni-Catalyzed Reductive Cross-Coupling of Cyclopropylamines and Other Strained Ring NHP Esters with (Hetero)Aryl Halides.

A nickel-catalyzed reductive cross-coupling of cyclopropylamine NHP esters with (hetero)aryl halides is reported. This efficient protocol provides direct access to 1-arylcyclopropylamines, a bioisosteric motif commonly used in small molecule drug discovery. The reaction proceeds rapidly (<2 h) with excellent functional group tolerance and without requiring heat- or air-sensitive reagents. The method can also be extended to the arylation of four-membered strained rings. The NHP esters are easily obtained from the corresponding commercially available carboxylic acids in one step with high yields and no column chromatography.

Ginkgo biloba for tinnitus.

BACKGROUND: Tinnitus is a symptom defined as the perception of sound in the absence of an external source. In England alone there are an estimated ¾ million general practice consultations every year where the primary complaint is tinnitus, equating to a major burden on healthcare services. Clinical management strategies include education and advice, relaxation therapy, tinnitus retraining therapy (TRT), cognitive behavioural therapy (CBT), sound enrichment using ear-level sound generators or hearing aids, and drug therapies to manage co-morbid symptoms such as insomnia, anxiety or depression.  OBJECTIVES: To assess the effects of Ginkgo biloba for tinnitus in adults and children. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; CENTRAL (2022, Issue 6); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 7 June 2022. SELECTION CRITERIA: Randomised controlled trials (RCTs) recruiting adults and children with acute or chronic subjective tinnitus. We included studies where the intervention involved Ginkgo biloba and this was compared to placebo, no intervention, or education and information. Concurrent use of other medication or other treatment was acceptable if used equally in each group. Where an additional intervention was used equally in both groups, we analysed this as a separate comparison. The review included all courses of Ginkgo biloba, regardless of dose regimens or formulations, and for any duration of treatment. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were tinnitus symptom severity measured as a global score on a multi-item tinnitus questionnaire and serious adverse effects (bleeding, seizures). Our secondary outcomes were tinnitus loudness (change in subjective perception), tinnitus intrusiveness, generalised depression, generalised anxiety, health-related quality of life and other adverse effects (gastrointestinal upset, headache, allergic reaction). We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: This review included 12 studies (with a total of  1915 participants). Eleven studies compared the effects of Ginkgo biloba with placebo and one study compared the effects of Ginkgo biloba with hearing aids to hearing aids alone. All included studies were parallel-group RCTs. In general, risk of bias was high or unclear due to selection bias and poor reporting of allocation concealment and blinding of participants, personnel and outcome assessments. Due to heterogeneity in the outcomes measured and measurement methods used, only limited data pooling was possible.  Ginkgo biloba versus placebo When we pooled data from two studies for the primary outcome tinnitus symptom severity, we found that Ginkgo biloba may have little to no effect (Tinnitus Handicap Inventory scores) at three to six months compared to placebo, but the evidence is very uncertain (mean difference (MD) -1.35 (scale 0 to 100), 95% confidence interval (CI) -8.26 to 5.55; 2 studies; 85 participants) (very low-certainty). Ginkgo biloba may result in little to no difference in the risk of bleeding or seizures, with no serious adverse effects reported in either group (4 studies; 1154 participants; low-certainty). For the secondary outcomes, one study found that there may be little to no difference between the effects of Ginkgo biloba and placebo on tinnitus loudness measured with audiometric loudness matching at 12 weeks, but the evidence is very uncertain (MD -4.00 (scale -10 to 140 dB), 95% CI -13.33 to 5.33; 1 study; 73 participants) (very low-certainty). One study found that there may be little to no difference between the effects of Ginkgo biloba and placebo on health-related quality of life measured with the Glasgow Health Status Inventory at three months (MD -0.58 (scale 0 to 100), 95% CI -4.67 to 3.51; 1 study; 60 participants) (low-certainty). Ginkgo biloba may not increase the frequency of other adverse effects (gastrointestinal upset, headache, allergic reaction) at three months compared to placebo (risk ratio 0.91, 95% CI 0.52 to 1.60; 4 studies; 1175 participants) (low-certainty). None of the studies reported the other secondary outcomes of tinnitus intrusiveness or changes in depressive symptoms or depression, anxiety symptoms or generalised anxiety. Gingko biloba with concurrent intervention versus concurrent intervention only One study compared Ginkgo biloba with hearing aids to hearing aids only. It assessed the mean difference in the change in Tinnitus Handicap Inventory scores and tinnitus loudness using a 10-point visual analogue scale (VAS) at three months. The study did not report adverse effects, tinnitus intrusiveness, changes in depressive symptoms or depression, anxiety symptoms or generalised anxiety, or health-related quality of life. This was a single, very small study (22 participants) and for all outcomes the certainty of the evidence was very low. We were unable to draw meaningful conclusions from the numerical results. AUTHORS' CONCLUSIONS: There is uncertainty about the benefits and harms of Ginkgo biloba for the treatment of tinnitus when compared to placebo. We were unable to draw meaningful conclusions regarding the benefits and harms of Ginkgo biloba when used with concurrent intervention (hearing aids). The certainty of the evidence for the reported outcomes, assessed using GRADE, ranged from low to very low. Future research into the effectiveness of Ginkgo biloba in patients with tinnitus should use rigorous methodology. Randomisation and blinding should be of the highest quality, given the subjective nature of tinnitus and the strong likelihood of a placebo response. The CONSORT statement should be used in the design and reporting of future studies. We also recommend the use of validated, patient-centred outcome measures for research in the field of tinnitus.

Emergency First Responders and Professional Wellbeing: A Qualitative Systematic Review.

Emergency first responders (EFRs) such as police officers, firefighters, paramedics and logistics personnel often suffer high turnover due to work-related stress, high workloads, fatigue, and declining professional wellbeing. As attempts to counter this through resilience programmes tend to have limited success, there is a need for further research into how organisational policies could change to improve EFRs' professional wellbeing. AIM: To identify the factors that may contribute to or affect EFRs' professional wellbeing. METHODS: A systematic literature review has been carried out. Three databases (Science Direct, ProQuest, and PubMed) were searched using keywords developed based on the PICo (population, interest, and context) framework. A total of 984 articles were extracted. These were then critically appraised for the quality of the evidence presented, leading to a total of five being ultimately included for review. RESULTS: Thematic analysis revealed that although EFRs may be exposed daily to traumatic events, factors that contribute to a decline in professional wellbeing emerge from within the organisational environment, rather than from the event itself. CONCLUSION: The study concludes that organisational and team relations factors significantly impact EFRs ability to cope with stress. As such, organisational policy should evolve to emphasise team relations over resilience programmes.