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Introduction: The well-being of healthcare workers (HCWs) is critical to providing excellent care. Recent evidence concerns the well-being of emergency department (ED) HCWs in New Zealand, with high levels of burnout found in a 2020 survey. This threat to providing high-quality acute care warrants improvement interventions. The causes of burnout are complex and multifactorial, the solutions are not straightforward., Methods and Analysis: A prospective, multisite, before and after, mixed methods study assessing a multicomponent intervention, adaptable to local context, that targets three organisation levels (the individual, the group and the system levels) and meaningfully involves frontline HCWs may reduce HCW burnout and improve HCW well-being. Individual HCWs will choose from three individual-level psychological interventions and participate in those most appropriate for them. Local champions will decide which group-level intervention their ED will use. The system-level intervention will build capacity and capability for quality improvement (QI) with QI training and the establishment of a Quality Improvement Learning System. This system-level intervention has several important features that may ultimately empower HCWs to contribute to improving the quality of ED healthcare.We will enrol nine EDs, from which there will be at least 900 HCW participants. EDs will be enrolled in three waves from March 2023 to April 2024, with interventions taking place in each ED over 12 months.Methods of assessment will include baseline and repeat survey measures of burnout and well-being. Process evaluation at each ED will provide details of context, the intervention and the fidelity of the implementation., Ethics and Dissemination: Ethics committee approval was provided, with locality approval at each site.Individual site feedback will be provided to each ED and executive leadership. Dissemination of findings will be through publication in peer-reviewed journals, presentation at national and international scientific meetings and through national healthcare quality bodies., Trial Registration Number: Australia New Zealand Clinical Trials Registry (ACTRN12623000342617)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: With the rising costs for knee arthroplasty, therapies that allow patients to avoid or delay surgery following knee osteoarthritis (KOA) may help in reducing overall health care costs. Multiple intraarticular hyaluronic acid (HA) products are available on the market, varying by formulation, molecular weight, and number of injections, but clinical and economic benefits may differ by product. OBJECTIVES: To evaluate the all-cause and KOA-related health care resource utilization (HCRU) and costs among newly diagnosed patients with KOA treated with multi-injection HA., Methods: A retrospective cohort study using a large commercial claims database (Merative MarketScan database) to identify patients with KOA treated with high molecular weight (HMW) (n = 11,200), medium molecular weight (MMW) (n = 10,225), or low molecular weight (LMW) HAs (n = 8,473) between 2016 and 2019. KOA-related and all-cause HCRU and costs were compared within 12 months after the index HA treatment date. The association between outcomes and HA treatments was evaluated using a doubly robust method to adjust for confounding factors. HCRU and costs among the propensity score-weighted HA groups were compared using generalized linear models., Results: HMW HA patients were found to have lower adjusted KOA-related medical costs by $265.37 ( P < 0.001) and pharmacy costs by $19.90 ( P < 0.001) compared with LMW HA patients, as well as lower all-cause total medical costs by $130.42 ( P = 0.013) and pharmacy costs by $63.33 ( P < 0.001). HMW HA patients also had a lower adjusted KOA-related medical cost by $205.74 ( P < 0.001) and pharmacy cost by $14.39 ( P < 0.001) compared with MMW HA patients, as well as lower all-cause medical by $1,195.66 ( P < 0.001) and pharmacy by $196.99 ( P < 0.001). Three-injection treatment patients (HMW HA, 84%; MMW HA, 82%) had high completion rate, compared with the 5-injection treatment cohort (LMW HA, 48%)., Conclusions: HMW HA patients had statistically significantly lower adjusted all-cause and KOA-related medical and pharmacy costs at 1 year follow-up compared with MMW HA and LMW HA patients. It is unclear if this is related to differences in molecular weight or specific mechanism of actions.

SF3B1 mutations frequently occur in cancer yet lack targeted therapies. Clinical trials of XPO1 inhibitors, selinexor and eltanexor, in high-risk myelodysplastic neoplasms (MDS) revealed responders were enriched with SF3B1 mutations. Given that XPO1 (Exportin-1) is a nuclear exporter responsible for the export of proteins and multiple RNA species, this led to the hypothesis that SF3B1-mutant cells are sensitive to XPO1 inhibition, potentially due to altered splicing. Subsequent RNA sequencing after XPO1 inhibition in SF3B1 wildtype and mutant cells showed increased nuclear retention of RNA transcripts and increased alternative splicing in the SF3B1 mutant cells particularly of genes that impact apoptotic pathways. To identify novel drug combinations that synergize with XPO1 inhibition, a forward genetic screen was performed with eltanexor treatment implicating anti-apoptotic targets BCL2 and BCLXL, which were validated by functional testing in vitro and in vivo. These targets were tested in vivo using Sf3b1 K700E conditional knock-in mice, which showed that the combination of eltanexor and venetoclax (BCL2 inhibitor) had a preferential sensitivity for SF3B1 mutant cells without excessive toxicity. In this study, we unveil the mechanisms underlying sensitization to XPO1 inhibition in SF3B1-mutant MDS and preclinically rationalize the combination of eltanexor and venetoclax for high-risk MDS., (© 2024. The Author(s).)

Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase crucial for B cell development and function, acts downstream of the B cell receptor (BCR) in the BCR pathway. Other kinases involved downstream of the BCR besides BTK such as Syk, Lyn, PI3K, and Mitogen-activated protein (MAP) kinases also play roles in relaying signals from the BCR to provide pro-survival, activation, and proliferation cues. BTK signaling is implicated in various B-cell lymphomas such as mantle cell lymphoma, Waldenström Macroglobulinemia, follicular lymphoma, and diffuse large B cell lymphoma, leading to the development of transformative treatments like ibrutinib, the first-in-class covalent BTK inhibitor, and pirtobrutinib, the first-in-class noncovalent BTK inhibitor. However, kinase-deficient mutations C481F, C481Y, C481R, and L528W in the BTK gene confer resistance to both covalent and non-covalent BTK inhibitors, facilitating B cell survival and lymphomagenesis despite kinase inactivation. Further studies have revealed BTK's non-catalytic scaffolding function, mediating the assembly and activation of proteins including Toll-like receptor 9 (TLR9), vascular cell adhesion protein 1 (VCAM-1), hematopoietic cell kinase (HCK), and integrin-linked kinase (ILK). This non-enzymatic role promotes cell survival and proliferation independently of kinase activity. Understanding BTK's dual roles unveils opportunities for therapeutics targeting its scaffolding function, promising advancements in disrupting lymphomagenesis and refining B cell lymphoma treatments.

Background: HIV burden in the US among people who inject drugs (PWID) is driven by overlapping syndemic factors such as co-occurring health needs and environmental factors that synergize to produce worse health outcomes among PWID. This includes stigma, poverty, and limited healthcare access (e.g. medication to treat/prevent HIV and for opioid use disorder [MOUD]). Health services to address these complex needs, when they exist, are rarely located in proximity to each other or to the PWID who need them. Given the shifting drug use landscapes and geographic heterogeneity in the US, we evaluate a data-driven approach to guide the delivery of such services to PWID in local communities., Methods: We used a hybrid, type I, embedded, mixed method, data-driven approach to identify and characterize viable implementation neighborhoods for the HPTN 094 complex intervention, delivering integrated MOUD and HIV treatment/prevention through a mobile unit to PWID across five US cities. Applying the PRISM framework, we triangulated geographic and observational pre-implementation phase data (epidemiological overdose and HIV surveillance data) with two years of implementation phase data (weekly ecological assessments, study protocol meetings) to characterize environmental factors that affected the viability of implementation neighborhoods over time and across diverse settings., Results: Neighborhood-level drug use and geographic diversity alongside shifting socio-political factors (policing, surveillance, gentrification) differentially affected the utility of epidemiological data in identifying viable implementation neighborhoods across sites. In sites where PWID are more geographically dispersed, proximity to structural factors such as public transportation and spaces where PWID reside played a role in determining suitable implementation sites. The utility of leveraging additional data from local overdose and housing response systems to identify viable implementation neighborhoods was mixed., Conclusions: Our findings suggest that data-driven approaches provide a contextually relevant pragmatic strategy to guide the real-time implementation of integrated care models to better meet the needs of PWID and help inform the scale-up of such complex interventions. This work highlights the utility of implementation science methods that attend to the impact of local community environmental factors on the implementation of complex interventions to PWID across diverse drug use, sociopolitical, and geographic landscapes in the US., Trial Registration: ClincalTrials.gov, Registration Number: NCT04804072 . Registered 18 February 2021., (© 2024. The Author(s).)

Study Objectives: Obstructive sleep apnea (OSA) is associated with an increased risk of diabetes-related complications. Hence, it is plausible that continuous positive airway pressure (CPAP) could have a favorable impact on these complications. We assessed the feasibility of conducting a randomized control trial in patients with type 2 diabetes and OSA over 2 years., Methods: We conducted an open-label multicenter feasibility randomized control trial of CPAP vs no CPAP in patients with type 2 diabetes and OSA. Patients with resting oxygen saturation < 90%, central apnea index > 15 events/h, or Epworth Sleepiness Scale ≥ 11 were excluded. OSA was diagnosed using a multichannel portable device (ApneaLink Air, ResMed). The primary outcome measures were related to feasibility and the secondary outcomes were changes in various clinical and biochemical parameters related to diabetes outcomes., Results: Eighty-three (40 CPAP vs 43 no CPAP) patients were randomly assigned, with a median (interquartile range) follow-up of 645 (545, 861) days. CPAP compliance was inadequate, with a median usage of approximately 3.5 hours/night. Early CPAP use predicted longer-term compliance. The adjusted analysis showed a possible favorable association between being randomly assigned to CPAP and several diabetes-related end points (chronic kidney disease, neuropathy, and quality of life)., Conclusions: It was feasible to recruit, randomly assign, and achieve a high follow-up rate over 2 years in patients with OSA and type 2 diabetes. CPAP compliance might improve by a run-in period before randomization. A full randomized control trial is necessary to assess the observed favorable association between CPAP and chronic kidney disease , neuropathy, and quality of life in patients with type 2 diabetes., Clinical Trial Registration: Registry: ISRCTN; Name: The impact of sleep disorders in patients with type 2 diabetes; URL: https://www.isrctn.com/ISRCTN12361838; Identifier: ISRCTN12361838., Citation: Makhdom EA, Maher A, Ottridge R, et al. The impact of obstructive sleep apnea treatment on microvascular complications in patients with type 2 diabetes: a feasibility randomized controlled trial. J Clin Sleep Med . 2024;20(6):947-957., (© 2024 American Academy of Sleep Medicine.)

STK17A is a novel uncharacterized member of the death-associated protein family of serine and threonine kinases. Overexpression of STK17A is observed in many cancers. We identified a lead compound that is based on a quinazoline core. Optimizations of the lead compound led to the discovery of potent and selective STK17A/B inhibitors with drug-like properties and oral bioavailability. Compound 9 had an STK17A inhibitory IC 50 of 23 nM. Based on profiling studies against two wild-type kinase panels (375 and 398 kinases, respectively), compound 9 had strong inhibition of both STK17A and STK17B but moderate off-target inhibition only for AAK1, MYLK4, and NEK3/5. In addition, compound 9 had good oral bioavailability, paving the way for in vivo studies against various cancers., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Introduction: There are many intra-articular hyaluronic acid (IA-HA) products on the market that have known intrinsic differences in molecular size, source, and structure. The current review summarizes existing evidence describing and assessing these differences, while also identifying whether these differences have an impact on clinical outcomes., Methods: This systematic review summarized all literature that specifically addresses IA-HA product differences. Included studies summarized basic science and mechanism of action comparisons of IA-HA product differences, or systematic reviews that assess differences in clinical outcomes between IA-HA product differences., Results: A total of 20 investigations assessed basic science differences between IA-HA products, while 20 investigations provided assessments of the clinical outcome differences between IA-HA product characteristics. The published basic science literature provided a differentiation between low molecular weight (LMW) and high molecular weight (HMW) HA with regard to changes within the synovial fluid, driven by the interactions that these molecules have with receptors in the joint space. These differences in receptor interaction manifest within clinical outcomes, as meta-analyses comparing pain relief after IA-HA suggest that pain reduction is superior in patients who receive HMW HA as opposed to LMW HA., Conclusion: This review highlights differences between IA-HA characteristics, and how important the molecular weight, derivation of the product, and structure are to variances in reported clinical outcomes to treat osteoarthritis (OA) of the knee. HMW IA-HAs have shown greater efficacy compared to the alternative of LMW products, while avian-derived and cross-linked products have potentially demonstrated an increase in inflammatory events over non-avian-derived, non-cross-linked HAs., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: EF serves as a consultant for Arthrex and Ferring. MN, AM, and DM have nothing to disclose. MB serves as a consultant for Sanofi Aventis, Smith and Nephew, and AgNovos Healthcare. PS serves as a consultant for Arthrex and Pacira.

Objectives: ICU resource strain leads to adverse patient outcomes. Simple, well-validated measures of ICU strain are lacking. Our objective was to assess whether the "Activity index," an indicator developed during the COVID-19 pandemic, was a valid measure of ICU strain., Design: Retrospective national registry-based cohort study., Setting: One hundred seventy-five public and private hospitals in Australia (June 2020 through March 2022)., Subjects: Two hundred seventy-seven thousand seven hundred thirty-seven adult ICU patients., Interventions: None., Measurements and Main Results: Data from the Australian and New Zealand Intensive Care Society Adult Patient Database were matched to the Critical Health Resources Information System. The mean daily Activity index of each ICU (census total of "patients with 1:1 nursing" + "invasive ventilation" + "renal replacement" + "extracorporeal membrane oxygenation" + "active COVID-19," divided by total staffed ICU beds) during the patient's stay in the ICU was calculated. Patients were categorized as being in the ICU during very quiet (Activity index < 0.1), quiet (0.1 to < 0.6), intermediate (0.6 to < 1.1), busy (1.1 to < 1.6), or very busy time-periods (≥ 1.6). The primary outcome was in-hospital mortality. Secondary outcomes included after-hours discharge from the ICU, readmission to the ICU, interhospital transfer to another ICU, and delay in discharge from the ICU. Median Activity index was 0.87 (interquartile range, 0.40-1.24). Nineteen thousand one hundred seventy-seven patients died (6.9%). In-hospital mortality ranged from 2.4% during very quiet to 10.9% during very busy time-periods. After adjusting for confounders, being in an ICU during time-periods with higher Activity indices, was associated with an increased risk of in-hospital mortality (odds ratio [OR], 1.49; 99% CI, 1.38-1.60), after-hours discharge (OR, 1.27; 99% CI, 1.21-1.34), readmission (OR, 1.18; 99% CI, 1.09-1.28), interhospital transfer (OR, 1.92; 99% CI, 1.72-2.15), and less delay in ICU discharge (OR, 0.58; 99% CI, 0.55-0.62): findings consistent with ICU strain., Conclusions: The Activity index is a simple and valid measure that identifies ICUs in which increasing strain leads to progressively worse patient outcomes., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

This is a report on an outbreak of Panton-Valentine leucocidin-producing meticillin-resistant Staphylococcus aureus (PVL-MRSA) in an intensive care unit (ICU) during the COVID-19 pandemic that affected seven patients and a member of staff. Six patients were infected over a period of ten months on ICU by the same strain of PVL-MRSA, and a historic case identified outside of the ICU. All cases were linked to a healthcare worker (HCW) who was colonized with the organism. Failed topical decolonization therapy, without systemic antibiotic therapy, resulted in ongoing transmission and one preventable acquisition of PVL-MRSA. The outbreak identifies the support that may be needed for HCWs implicated in outbreaks. It also demonstrates the role of whole-genome sequencing in identifying dispersed and historic cases related to the outbreak, which in turn aids decision-making in outbreak management and HCW support. This report also includes a review of literature of PVL-MRSA-associated outbreaks in healthcare and highlights the need for review of current national guidance in the management of HCWs' decolonization regimen and return-to-work recommendations in such outbreaks., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

Introduction: The burden of chronic viral hepatitis (CVH) in the UK Nepali population is unknown. We aimed to determine knowledge of liver disease (LD) and prevalence of CVH in this community., Methods: This was a mixed method (qualitative and quantitative) study guided by a multidisciplinary stakeholder group. Focus groups (FG) led by Nepali community leaders explored LD knowledge. Thereafter, a prospective community-based cohort study utilising dried-blood spot testing was conducted. Thematic analysis explored FG data with categorical data analysed with Excel and R Studio., Results: FG data showed a lack of LD knowledge, with conflict between the roles of traditional and modern practices; 1,005 participants (525 male, 480 female) were tested for CVH, with a mean age of 63 years (range:19-86). Rates of CVH infection were low: 0.3% had current hepatitis B, with no active hepatitis C., Discussion: Key drivers for enthusiastic participation were development of peer support networks and advisory groups to disseminate information, including hepatitis B vaccine recommendations., (© Royal College of Physicians 2023. All rights reserved.)

Objectives: To investigate the prevalence and features of self-reported burnout among intensivists working in Australia and New Zealand, and evaluate potentially modifiable workplace stressors associated with increased risk of self-reported burnout. Methods: We performed an electronic survey among registered intensivists in Australia and New Zealand. Burnout and professional quality of life were measured using the Professional Quality of Life Scale version 5 (ProQOL-5). Socio-organisational factors were defined a priori and assessed using a five-point Likert scale. Thematic analysis was conducted on an open-ended question on workplace stressors. Results: 261 of 921 estimated intensivists responded (response rate, 28.3%). Overall, few participants (0.8%) demonstrated high scores (> 75th centile) for burnout, and 70.9% of participants scored in the average range for burnout. Of note, 98.1% of participants scored in the average to high range for compassion satisfaction. No association was found between sex, age, or years of practice with the level of burnout or compassion satisfaction. Seven themes emerged regarding intensivists' most stressful aspects of work: interpersonal interactions and workplace relationships (25.5%), workload and its impact (24.9%), resources and capacity (22.6%), health systems leadership and bureaucracy (16.1%), end-of-life issues and moral distress (8.4%), clinical management (4.9%), and job security and future uncertainty (1.3%). Conclusion: Fewer Australian and New Zealand intensivists experienced burnout than previously reported. Many self-reported work stressors do not relate to clinical work and are due to interpersonal interactions with other colleges and hospital administrators. Such factors are potentially modifiable and could be the focus of future interventions., Competing Interests: All authors declare that they do not have any potential conflict of interest in relation to this manuscript., (© 2022 College of Intensive Care Medicine of Australia and New Zealand.)

Introduction: Genetic manipulation of Aedes aegypti is key to developing a deeper understanding of this insects' biology, vector-virus interactions and makes future genetic control strategies possible. Despite some advances, this process remains laborious and requires highly skilled researchers and specialist equipment. Methods: Here we present two improved methods for genetic manipulation in this species. Use of transgenic lines which express Cre recombinase and a plasmid-based method for expressing PhiC31 when injected into early embryos. Results: Use of transgenic lines which express Cre recombinase allowed, by simple crossing schemes, germline or somatic recombination of transgenes, which could be utilized for numerous genetic manipulations. PhiC31 integrase based methods for site-specific integration of genetic elements was also improved, by developing a plasmid which expresses PhiC31 when injected into early embryos, eliminating the need to use costly and unstable mRNA as is the current standard. Discussion: Here we have expanded the toolbox for synthetic biology in Ae. aegypti . These methods can be easily transferred into other mosquito and even insect species by identifying appropriate promoter sequences. This advances the ability to manipulate these insects for fundamental studies, and for more applied approaches for pest control., 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 © 2023 Carabajal Paladino, Wilson, Tng, Dhokiya, Keen, Cuber, Larner, Rooney, Nicholls, Uglow, Williams, Anderson, Basu, Leftwich and Alphey.)

In mitosis, most transcription factors detach from chromatin, but some are retained and bookmark genomic sites. Mitotic bookmarking has been implicated in lineage inheritance, pluripotency and reprogramming. However, the biological significance of this mechanism in vivo remains unclear. Here, we address mitotic retention of the hemogenic factors GATA2, GFI1B and FOS during haematopoietic specification. We show that GATA2 remains bound to chromatin throughout mitosis, in contrast to GFI1B and FOS, via C-terminal zinc finger-mediated DNA binding. GATA2 bookmarks a subset of its interphase targets that are co-enriched for RUNX1 and other regulators of definitive haematopoiesis. Remarkably, homozygous mice harbouring the cyclin B1 mitosis degradation domain upstream Gata2 partially phenocopy knockout mice. Degradation of GATA2 at mitotic exit abolishes definitive haematopoiesis at aorta-gonad-mesonephros, placenta and foetal liver, but does not impair yolk sac haematopoiesis. Our findings implicate GATA2-mediated mitotic bookmarking as critical for definitive haematopoiesis and highlight a dependency on bookmarkers for lineage commitment., (© 2023. Springer Nature Limited.)

Purpose: To identify potential prognostic factors for patient-reported outcomes in an Icelandic cohort of ACL injured subjects., Methods: All knee MRI reports written in Iceland between the years 2001 to 2011 were read to identify individuals with a possible ACL injury. These individuals were contacted and asked to complete an online questionnaire regarding their injury and current knee related health. The questionnaire collected information on years since surgery, injury circumstance, brace use, physiotherapy, ACL surgery, second ACL injury and current smoking status. In addition, the baseline status of their meniscii were assessed from the original MRI report and medical records were used to identify any subsequent, non-ACL surgery. The patient-reported Knee Osteoarthritis and Injury Outcome Score (KOOS) was used assess current knee related health. A Bayesian proportional odds model was used to assess the effect of all potential prognostic factors above as well as age and sex on KOOS outcomes., Results: A total of 408 subjects completed the questionnaire indicating that they did rupture their ACL. The following variables were associated with worse outcomes across all KOOS subscales: having a subsequent arthroscopy, reinjury to your ACL, and smoking. Having physiotherapy for 9 months was associated with worse KOOS pain scores than having 6 months of physiotherapy. Conversely KOOS pain score tended to be higher if you injured your knee during sports., Conclusion: Reinjuring your ACL, smoking and having subsequent (non-ACLR) surgery predict your knee related health following an ACL injury. Strategies should be implemented to reduce the risk of secondary ACL injury, and patients should be strongly advised not to smoke., (© 2023. European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Introduction. Combination of PCR and Elek testing to identify toxigenic corynebacteria has revealed organisms described as non-toxigenic toxin-gene bearing (NTTB) Corynebacterium diphtheriae or C. ulcerans (i.e. PCR tox positive; Elek negative). These organisms carry part or all of tox , but are unable to express diphtheria toxin (DT) and present a challenge to clinical and public health case management. Gap analysis/Hypothesis. There are few data on the theoretical risk of NTTB reversion to toxigenicity. This unique cluster and subsequent epidemiologically linked isolates allowed the opportunity to determine any change in DT expression status. Aim. To characterize a cluster of infections due to NTTB in a skin clinic and subsequent cases in two household contacts. Methodology. Epidemiological and microbiological investigations were carried out according to existing national guidance at the time. Susceptibility testing used gradient strips. The tox operon analysis and multi-locus sequence typing (MLST) was derived from whole-genome sequencing. Alignment of the tox operon and phylogenetic analyses were performed using clustalW, mega, the public core-genome MLST (cgMLST) scheme and an in-house bioinformatic single nucleotide polymorphism (SNP) typing pipeline. Results. Isolates of NTTB C. diphtheriae were recovered from four cases (cases 1 to 4) with epidermolysis bullosa attending the clinic. Two further isolates were subsequently recovered from case 4, >18 months later, and from two household contacts (cases 5 and 6) after a further 18 months and 3.5 years, respectively. All eight strains were NTTB C. diphtheriae biovar mitis, belonged to the same sequence type (ST-336) with the same deletion in tox . Phylogenetic analysis showed relatively high diversity between the eight strains with 7-199 SNP and 3-109 cgMLST loci differences between them. The number of SNPs between the three isolates from case 4 and two household contacts (cases 5 and 6) was 44-70 with 28-38 cgMLST loci differences. Conclusions. We report a cluster of NTTB C. diphtheriae cases in a skin clinic and evidence of onward household transmission. We conclude the deletion in the tox was responsible for the non-expression of DT. There was no evidence of reversion to DT expression over the 6.5 year period studied. These data informed revision to guidance in the management of NTTB cases and their contacts in the UK.

Competing Interests: Intérêts concurrents: Shirley Huang est membre de la Société canadienne de gériatrie. Aucun autre intérêt concurrent n’a été déclaré.

Aim: To investigate the safety and efficacy of short recovery day-case pathway following lower-limb angioplasty in both intermittent claudication and critical limb ischaemia patients., Materials and Methods: A retrospective analysis was undertaken of the medical records of consecutive outpatients treated with lower-limb angioplasty over a 1-year period within an interventional radiology (IR) day-case unit in a high-volume vascular centre. Standard post-angioplasty care at York Teaching Hospital is discharge 3 h after puncture site haemostasis without the routine use of closure devices. The rates of successful same-day discharge, procedure success, complications, and re-admissions were calculated with 30-day follow-up., Results: The cohort included 301 patients (57% intermittent claudication and 43% critical limb ischaemia) undergoing 605 angioplasties using access sheath size ranging from 4 to 7 F. Closure devices were used in only 7% of patients. Successful same-day discharge achieved in 98% of patients (294/301), with seven admitted overnight because of complications. Eleven patients (3.6%) were re-admitted within 30 days. Technical success rates were 92%, and 96% when including partially successful interventions, with 4% technical failure. Twelve patients (4%) developed minor complications and four major complications (1%). There were no significant differences in complication rates between small and larger sheath sizes (p>0.05). No procedure-related death was recorded within 30 days., Conclusion: Lower-limb angioplasty can be performed safely as day-case procedure with a short recovery protocol within IR departments for both patients with intermittent claudication (IC) and critical limb ischaemia (CLI). This may significantly increase patient throughput and alleviate pressure on stretched hospital inpatient resources by safely discharging patients on the day of procedure., (Copyright © 2022 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Competing Interests: Competing interests: Shirley Huang is a member of the Canadian Geriatric Society. No other competing interests were declared.

Background: Limiting access to intra-articular knee injections, including hyaluronic acid (HA), has been advocated as a cost-containment measure in the treatment of knee osteoarthritis. The association between presurgical injections and post-surgical complications such as early periprosthetic joint infection and revision remained to be investigated. This study evaluated pre- and post-surgical costs and rates of post-surgical complications in knee arthroplasty (KA) patients with or without prior HA use., Methods: Commercial and Medicare Supplemental Claims Data (IBM MarketScan Research Databases) from January 1, 2012 to December 31, 2018 were used to identify unilateral KA patients. Those who completed a course of bio-fermentation derived HA (Bio-HA) as the first-line HA therapy comprised of the test group (n = 4091), while the control group did not use HA prior to KA (n = 118,659). Using multivariable regression with propensity score (PS) weighting, overall healthcare costs, readmission rates, and revision rates were assessed at six months following KA., Results: Healthcare costs following KA were significantly lower for the Bio-HA group ($10,021 ± $22,796) than No HA group ($12,724 ± $32,966; PS p < 0.001). Bio-HA patients had lower readmission rates (8.9% vs 14.0%; PS p < 0.001) and inpatient costs per readmitted patient ($43,846 ± $50,648 vs $50,533 ± $66,150; PS p = 0.005). There were no differences in revision rate for any reason (Bio-HA: 0.78% vs No HA: 0.67%; PS p = 0.361) and with PJI (Bio-HA: 0.42% vs No HA: 0.33%; PS p = 0.192). Costs in the six months up to and including the KA were similar for both groups (Bio-HA: $49,759 ± $40,363 vs No HA: $50,532 ± $43,183; PS p = 0.293)., Conclusion: Bio-HA use prior to knee arthroplasty did not appear to increase overall healthcare costs in the six months before and after surgery. Allowing access to HA injections provides a non-surgical therapeutic option without increasing cost or risk of post-surgical complications., Competing Interests: K Ong is an employee and shareholder of Exponent, a scientific and engineering consulting firm. Exponent has been paid fees for K Ong’s consulting services on behalf of Ferring Pharmaceuticals, during the conduct of the study; Exponent has been paid fees for K Ong’s consulting services on behalf of Bioventus, Medtronic, Stryker Orthopaedics, Sanofi, Pacira Pharmaceuticals, Paradigm Spine, St. Jude Medical, Relievant Medsystems, International Society for the Advancement of Spine Surgery, SI-Technology, LLC; Exponent has been paid fees for K Ong’s litigation consulting services on behalf of Zimmer Biomet, Joerns Healthcare, SpineFrontier, Ethicon, DJO, Ossur, Karl Storz Endoscopy-America, Rex Medical, Smith & Nephew and Covidien, outside the submitted work. S Kurtz reports grants from Ferring Pharmaceuticals, during the conduct of the study; grants from Stryker, Zimmer Biomet, Invibio, Wright Medical Technology, Ceramtec, Celanese, Ferring Pharmaceuticals, Formae, Lima Corporate, SINTX Technologies, Orthoplastics, Osteal Therapeutics, 3Spine, DJO Global, Carbofix, DePuy Synthes; is an employee and shareholder of Exponent, Inc, a scientific and engineering consulting firm. Exponent has been paid fees by companies and suppliers for S Kurtz consulting services on behalf of such companies and suppliers outside the submitted work. F Niazi reports being employed by Ferring Pharmaceuticals Inc. W Nelson was an employee of Ferring Pharmaceuticals. E Lau reports E Lau’s employer, Exponent Inc., received payment for consulting and other services to Ferring Pharmaceutical, Osteal Therapeutic, Ceramtec Inc. and Relievant Medsystem Inc., outside the submitted work., (© 2022 Nicholls et al.)

Background: In the face of the COVID-19 pandemic, the Defence Science and Technology Laboratory (Dstl) and Defence Pathology combined to form the Defence Clinical Lab (DCL), an accredited (ISO/IEC 17025:2017) high-throughput SARS-CoV-2 PCR screening capability for military personnel., Laboratory Structure and Resource: The DCL was modular in organisation, with laboratory modules and supporting functions combining to provide the accredited SARS-CoV-2 (envelope (E)-gene) PCR assay. The DCL was resourced by Dstl scientists and military clinicians and biomedical scientists., Laboratory Results: Over 12 months of operation, the DCL was open on 289 days and tested over 72 000 samples. Six hundred military SARS-CoV-2-positive results were reported with a median E-gene quantitation cycle (Cq) value of 30.44. The lowest Cq value for a positive result observed was 11.20. Only 64 samples (0.09%) were voided due to assay inhibition after processing started., Conclusions: Through a sustained effort and despite various operational issues, the collaboration between Dstl scientific expertise and Defence Pathology clinical expertise provided the UK military with an accredited high-throughput SARS-CoV-2 PCR test capability at the height of the COVID-19 pandemic. The DCL helped facilitate military training and operational deployments contributing to the maintenance of UK military capability. In offering a bespoke capability, including features such as testing samples in unit batches and oversight by military consultant microbiologists, the DCL provided additional benefits to the UK Ministry of Defence that were potentially not available from other SARS-CoV-2 PCR laboratories. The links between Dstl and Defence Pathology have also been strengthened, benefitting future research activities and operational responses., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To understand how researchers experience working in academia and the effects these experiences have on their mental health and well-being, through synthesizing published qualitative data., Method: A systematic review and qualitative meta-synthesis was conducted to gain a comprehensive overview of what is currently known about academic researchers' mental health and well-being. Relevant papers were identified through searching electronic databases, Google Scholar, and citation tracking. The quality of the included studies was assessed and the data was synthesised using reflexive thematic analysis., Results: 26 papers were identified and included in this review. Academic researchers' experiences were captured under seven key themes. Job insecurity coupled with the high expectations set by the academic system left researchers at risk of poor mental health and well-being. Access to peer support networks, opportunities for career progression, and mentorship can help mitigate the stress associated with the academic job role, however, under-represented groups in academia are at risk of unequal access to resources, support, and opportunities., Conclusion: To improve researchers' well-being at work, scientific/academic practice and the system's concept of what a successful researcher should look like, needs to change. Further high-quality qualitative research is needed to better understand how systemic change, including tackling inequality and introducing better support systems, can be brought about more immediately and effectively. Further research is also needed to better understand the experiences and support needs of post-doctoral and more senior researchers, as there is a paucity of literature in this area., Trial Registration: The review protocol was registered on PROSPERO (CRD42021232480)., Competing Interests: The authors have declared that no competing interests exist.

Progesterone receptor (PGR) activity is obligatory for mammalian ovulation; however, there is no established direct functional pathway explaining how progesterone receptor completely and specifically regulates oocyte release. This study examined the overarching cell- and isoform-specific effects of the PGR within each cellular compartment of the ovary, using mice null for the PGR (PRKO), as well as isoform-specific null mice. The PGR was expressed in ovarian granulosa and stromal cells and although PRKO ovaries showed no visible histological changes in preovulatory ovarian morphology, follicle rupture did not occur. Reciprocal ovarian transplant experiments established the necessity of ovarian PGR expression for ovulation. Cumulus-oocyte complexes of PRKO mice exhibited normal morphology but showed some altered gene expression. The examination of mitochondrial activity showed subtle differences in PRKO oocytes but no differences in granulosa cell respiration, glycolysis or β-oxidation. Concurrently, RNA-seq identified novel functional pathways through which the PGR may regulate ovulation. PGR-A was the predominant transcriptionally active isoform in granulosa cells and 154 key PGR-dependent genes were identified, including a secondary network of transcription factors. In addition, the PGR regulated unique gene networks in the ovarian stroma. Collectively, we establish the effector pathways activated by the PGR across the ovarian cell types and conclude that PGR coordinates gene expression in the cumulus, granulosa and stromal cells at ovulation. Identifying these networks linking the PGR to ovulation provides novel targets for fertility therapeutics and nonhormonal contraceptive development.

Objective: Obesity is a risk factor for idiopathic intracranial hypertension (IIH) and obstructive sleep apnoea (OSA). We aimed to determine the prevalence of OSA in IIH and evaluate the diagnostic performance of OSA screening tools in IIH. Additionally, we evaluated the relationship between weight loss, OSA and IIH over 12 months., Methods: A sub-study of a multi-centre, randomised controlled parallel group trial comparing the impact of bariatric surgery vs. community weight management intervention (CWI) on IIH-related outcomes over 12 months (IIH:WT). OSA was assessed using home-based polygraphy (ApneaLink Air, ResMed) at baseline and 12 months. OSA was defined as an apnoea-hypopnoea index (AHI) ≥ 15 or ≥ 5 with excessive daytime sleepiness (Epworth Sleepiness Scale ≥11 )., Results: Of the 66 women in the IIH: WT trial, 46 were included in the OSA sub-study. OSA prevalence was 47% (n = 19). The STOP-BANG had the highest sensitivity (84%) compared to the Epworth Sleepiness Scale (69%) and Berlin (68%) to detect OSA. Bariatric surgery resulted in greater reductions in AHI vs. CWI (median [95%CI] AHI reduction of  - 2.8 [ - 11.9, 0.7], p = 0.017). Over 12 months there was a positive association between changes in papilloedema and AHI (r = 0.543, p = 0.045), despite adjustment for changes in the body mass index (R 2  = 0.522, p = 0.017)., Conclusion: OSA is common in IIH and the STOP-BANG questionnaire was the most sensitive screening tool. Bariatric surgery improved OSA in patients with IIH. The improvement in AHI was associated with improvement in papilloedema independent of weight loss. Whether OSA treatment has beneficial impact on papilloedema warrants further evaluation., Trial Registration Number: IIH: WT is registered as ISRCTN40152829 and on ClinicalTrials.gov as NCT02124486 (28/04/2014)., (© 2021. The Author(s).)

Background: Subtotal cholecystectomy is occasionally the management of choice in the patient with a hostile Calot's triangle but when it is not considered safe to close the cystic duct this often leads to a biliary fistula. In order to reduce this morbidity a novel strategy to seal the cystic duct with cyanoacrylate glue was introduced. The outcome of the two strategies have been compared., Methods: Patients who had a laparoscopic subtotal cholecystectomy where the cystic duct was left open, the Unsecured group, were compared with those where the duct orifice was occluded with cyanoacrylate glue, the Glued group. The outcome of the two strategies have been compared by duration of biliary drainage, whether a leak was shown on ERCP, time to removal of the drain, length of hospital stay, the re-operation and readmission rates., Results: In 78 cases of laparoscopic subtotal cholecystectomy it was considered unsafe to close the cystic duct. 36 patients were managed without closure of the cystic duct, the Unsecured group and bile drainage continued for more than 3 days in 9 cases (25%) compared with 3 of 42 cases (7%) treated with glue, the Glued group (NS). Postoperative ERCP demonstrated a leak more frequently in the Unsecured group ( p  < 0.02). The length of stay was reduced in the Glued group. (0.9 compared with 3.0 days, p  < 0.01)., Conclusion: The results suggest that glue may be a safe option to occlude the cystic duct orifice and reduce hospital stay when this cannot safely be closed at subtotal cholecystectomy.

Background: Multiple interventions may be used to treat symptomatic knee osteoarthritis (OA), but concerns have been raised about the safety and efficacy of some therapies. Clinical trials have shown that hyaluronic acid (HA) can provide pain relief up to 6 months and possibly to 12 months, while real-world data has shown that pain medication and intra-articular corticosteroid (CS) injection utilization are reduced within 6 months after HA., Objective: To examine changes in prescription pain medication and CS utilization during 1 year after multimodal therapy that included high molecular weight, bio-fermentation derived HA (Bio-HA) use for knee OA., Methods: Commercial and Medicare Supplemental claims data (IBM MarketScan Research Databases) (1 January 2012, through 31 December 2018) was used to identify unilateral Bio-HA patients using multimodal therapy (any combination of CS injection, opioids, and non-opioid pain medication). Monthly therapy utilization was compared in the 12 months after Bio-HA therapy initiation to the 4-month intra-multimodal period., Results: A total of 13,999 patients underwent Bio-HA therapy with concurrent multimodal therapy. The number of filled opioid prescriptions decreased from 2,913.0/month to 2,861.5/month after Bio-HA, with a reduction in mean monthly prescriptions from 0.60 to 0.43 per user ( p  < 0.001). A number of opioid days supplied also decreased from 48,914/month to 39,730/month, with a decrease from 10.1/month to 6.0/month per user ( p  < 0.001). Bio-HA patients had prescription pain medication-free days for 71% of the time post-multimodal period compared to 53% during the intra-multimodal period ( p  < 0.001). The proportion of patients with CS injections after Bio-HA decreased from 53.8% to 29.6% ( p  < 0.001). Total monthly CS injections decreased from 2,292 to 663., Conclusions: Our data suggest that high molecular weight Bio-HA, as part of multimodal therapy, may be effective in providing longer-term pain relief with the reduction in pain therapy (CS injections and opioids) and increase in prescription pain medication-free days.