Traumatic chylothorax following blunt thoracic trauma.

Background: Chylothorax occurs when chyle from the thoracic duct leaks into the pleural space. While majority of cases are iatrogenic, traumatic chylothorax can occur when rib or vertebral fractures disrupt the thoracic duct. These occurrences are exceedingly rare, particularly following blunt traumatic insult. Methods: We performed a retrospective review of a case of chylothorax following blunt trauma. Data was extracted from the electronic medical record. Case: A 60-year-old female presented to the trauma bay after a motor vehicle crash as a restrained driver with bilateral chest pain. Of note, patient had three left rib fractures from fall five days prior. She was neurologically and hemodynamically normal on arrival. Physical exam was notable for chest wall tenderness. Computed tomography revealed the following: bilateral hemopneumothoraces, pneumomediastinum, manubrium fracture, retrosternal hematoma, left 2-10 and right 1-2 rib fractures along with multiple orthopedic injuries. Left tube thoracostomy yielded 150 mL of blood. She was admitted to the intensive care unit. Patient had a 48-h period of cardiogenic shock requiring vasopressors and aggressive fluid resuscitation. On post-injury day (PID) 2, the chest tube drained milky fluid. Pleural fluid sampling was significant for triglyceride levels of 1292 mg/dL. Hemodynamics then improved. Due to low output (<500 mL/day), patient was managed conservatively a fat-restricted diet supplemented with medium-chain fatty acids. Chest tube was removed PID-7 once chyle leak resolved. Repeat chest radiograph PID-10 was negative for effusion. She was discharged to rehabilitation PID-13. At one-week follow-up, repeat CXR showed a small, loculated left lateral pleural effusion. Patient had no complaints and was maintaining adequate oxygen saturations on room air. Discussion: We present a case of delayed chylothorax after blunt trauma precipitated by increased central venous pressure secondary to right heart failure, aggressive fluid resuscitation and vasopressor use. Traumatic chylothorax should be considered in patients with pleural effusion in the setting of blunt chest trauma as sudden hyperextension of the spine can disrupt the thoracic duct. Delayed diagnosis is not uncommon due to an average latency period of 2-10 days. Pleural fluid with triglyceride level > 110 mg/dL and chylomicrons is diagnostic. Initial management consists of chyle reduction through diet modification (high protein/restricted fat diet). Octreotide can be used as a pharmacological adjunct. Refractory or high-output cases (>1000 mL/day) may require surgical ligation of the thoracic duct. Early identification and intervention are paramount as untreated chylothorax is associated with significant morbidity and mortality rates up to 50 %.

Paediatric laceration repair in the emergency department: post-discharge pain and maladaptive behavioural changes.

BACKGROUND: Paediatric laceration repair procedures are common in the ED; however, post-discharge recovery remains understudied. Perioperative research demonstrates that children exhibit maladaptive behavioural changes following stressful and painful medical procedures. This study examined post-discharge recovery following paediatric laceration repair in the ED. METHODS: This prospective observational study included a convenience sample of 173 children 2-12 years old undergoing laceration repair in a paediatric ED in Orange, California, USA between April 2022 and August 2023. Demographics, laceration and treatment data (eg, anxiolytic medication), and caregiver-reported child pre-procedural and procedural pain (Numerical Rating Scale (NRS)) were collected. On days 1, 3, 7 and 14 post-discharge, caregivers reported children's pain and new-onset maladaptive behavioural changes (eg, separation anxiety) via the Post Hospitalization Behavior Questionnaire for Ambulatory Surgery. Univariate and logistic regression analyses were conducted to identify variables associated with the incidence of post-discharge maladaptive behavioural change. RESULTS: Post-discharge maladaptive behavioural changes were reported in 43.9% (n=69) of children. At 1 week post-discharge, approximately 20% (n=27) of children exhibited maladaptive behavioural changes and 10% (n=13) displayed behavioural changes 2 weeks post-discharge. Mild levels of pain (NRS ≥2) were reported in 46.7% (n=70) of children on post-discharge day 1, 10.3% (n=14) on day 7 and 3.1% (n=4) on day 14. An extremity laceration (p=0.029), pre-procedural midazolam (p=0.020), longer length of stay (p=0.043) and post-discharge pain on day 1 (p<0.001) were associated with incidence of maladaptive behavioural changes. Higher pain on post-discharge day 1 was the only variable independently associated with an increased likelihood of maladaptive behavioural change (OR=1.32 (95% CI 1.08 to 1.61), p=0.001). CONCLUSION: Over 40% of children exhibited maladaptive behavioural changes after ED discharge. Although the incidence declined over time, 10% of children continued to exhibit behavioural changes 2 weeks post-discharge. Pain on the day following discharge emerged as a key predictor, highlighting the potential critical role of proactive post-procedural pain management in mitigating adverse behavioural changes.

SHH regulates penile morphology and smooth muscle through a mechanism involving BMP4 and GREM1.

BACKGROUND: The cavernous nerve (CN) is frequently damaged in prostatectomy and diabetic patients with erectile dysfunction (ED), initiating changes in penile morphology including an acute and intense phase of apoptosis in penile smooth muscle and increased collagen, which alter penile architecture and make corpora cavernosa smooth muscle less able to relax in response to neurotransmitters, resulting in ED. AIM: Sonic hedgehog (SHH) is a critical regulator of penile smooth muscle, and SHH treatment suppresses penile remodeling after CN injury through an unknown mechanism; we examine if part of the mechanism of how SHH preserves smooth muscle after CN injury involves bone morphogenetic protein 4 (BMP4) and gremlin1 (GREM1). METHODS: Primary cultures of smooth muscle cells were established from prostatectomy, diabetic, hypertension and Peyronie's (control) (N = 18) patients. Cultures were characterized by ACTA2, CD31, P4HB, and nNOS immunohistochemical analysis. Patient smooth muscle cell growth was quantified in response to BMP4 and GREM1 treatment. Adult Sprague Dawley rats underwent 1 of 3 surgeries: (1) uninjured or CN-injured rats were treated with BMP4, GREM1, or mouse serum albumin (control) proteins via Affi-Gel beads (N = 16) or peptide amphiphile (PA) (N = 26) for 3 and 14 days, and trichrome stain was performed; (2) rats underwent sham (N = 3), CN injury (N = 9), or CN injury and SHH PA treatment for 1, 2, and 4 days (N = 9). OUTCOMES: Western analysis for BMP4 and GREM1 was performed; (3) rats were treated with 5E1 SHH inhibitor (N = 6) or IgG (control; N = 6) for 2 and 4 days, and BMP4 and GREM1 localization was examined. Statistics were performed by analysis of variance with Scheffé's post hoc test. RESULTS: BMP4 increased patient smooth muscle cell growth, and GREM1 decreased growth. In rats, BMP4 treatment via Affi-Gel beads and PA increased smooth muscle at 3 and 14 days of treatment. GREM1 treatment caused increased collagen and smooth muscle at 3 days, which switched to primarily collagen at 14 days. CN injury increased BMP4 and GREM1, while SHH PA altered Western band size, suggesting alternative cleavage and range of BMP4 and GREM1 signaling. SHH inhibition in rats increased BMP4 and GREM1 in fibroblasts. CLINICAL IMPLICATIONS: Understanding how SHH PA preserves and regenerates penile morphology after CN injury will aid development of ED therapies. STRENGTHS AND LIMITATIONS: SHH treatment alters BMP4 and GREM1 localization and range of signaling, which can affect penile morphology. CONCLUSION: Part of the mechanism of how SHH regulates corpora cavernosa smooth muscle involves BMP4 and GREM1.

Chlamydia retesting remains low among young women in Australia: an observational study using sentinel surveillance data, 2018-2022.

BACKGROUND: Chlamydia remains the most notified bacterial sexually transmissible infection in Australia with guidelines recommending testing for re-infection at 3months post treatment. This paper aimed to determine chlamydia retesting and repeat positivity rates within 2-4months among young women in Australia, and to evaluate what factors increase or decrease the likelihood of retesting. METHODS: Chlamydia retesting rates among 16-29-year-old women were analysed from Australian Collaboration for Coordinated Enhanced Sentinel Surveillance of sexually transmissible infection and bloodborne virus (ACCESS) sentinel surveillance data (n =62 sites). Among women with at least one positive test between 1 January 2018 and 31 August 2022, retesting counts and proportions within 2-4months were calculated. Logistic regression was performed to assess factors associated with retesting within 2-4months. RESULTS: Among 8758 women who were positive before 31 August 2022 to allow time for follow up, 1423 (16.2%) were retested within 2-4months, of whom 179 (12.6%) tested positive. The odds of retesting within 2-4months were 25% lower if tested in a coronavirus disease 2019 (COVID-9) pandemic year (2020-2022) (aOR=0.75; 95% CI 0.59-0.95). Among 9140 women with a positive test before 30 November 2022, 397 (4.3%) were retested too early (within 7days to 1month) and 81 (20.4%) of those were positive. CONCLUSIONS: Chlamydia retesting rates remain low with around a sixth of women retested within 2-4months in line with guidelines. Re-infection is common with around one in eight retesting positive. An increase in retesting is required to reduce the risk of reproductive complications and onward transmission.

Negative pressure dressings and the impact on pain management on thoracic incisions in patients undergoing oesophagectomy: a pilot study.

BACKGROUND: Pain control is recognised as a crucial post-operative measure for patients undergoing oesophagectomy with a thoracotomy incision for oesophageal cancer, where ineffective breathing due to pain is directly correlated with increased morbidity. The analgesic benefits of negative pressure wound therapy (NPWT) appear to be a relatively new and emerging finding. This pilot study aims to investigate the effects of NPWT on post-operative pain control and determine the feasibility of a larger trial. METHOD: Ten consecutive patients undergoing oesophagectomy were prospectively enrolled to have a PREVENA Incision Management System placed over a closed thoracotomy wound. This dressing was changed at post-operative day 5 and removed after day 10. Post-operative morbidity was recorded and analgesia was prescribed by the Acute Pain Service who were blinded to the study aims. Analgesia requirements were recorded in oral morphine equivalents (OME) and compared to 30 patients that had previously undergone oesophagectomy via thoracotomy. RESULTS: One patient was withdrawn from the study and there was no significant differences in patient demographics. The study group had less average daily analgesia requirements and reduced overall reported pain. Patients in the study group were less likely to develop pneumonia (44% and 57%) and less likely to require re-operation for complications of their surgery (0% and 10%). CONCLUSION: This pilot study shows reduced post-operative analgesia requirements and reduced morbidity when using NPWT over a closed thoracotomy wound, and affirms the feasibility of a future randomized control trial.

DNA mismatch repair deficient cancer - Emerging biomarkers of resistance to immune checkpoint inhibition.

The DNA mismatch repair pathway is involved in the identification, excision, and repair of base-base mismatches and indel loops in the genome. Mismatch repair deficiency occurs in approximately 20% of all cancers and results in a type of DNA damage called microsatellite instability. In 2017, the immune checkpoint inhibitor, Pembrolizumab, an anti-PD-1 therapy, was approved for use in all unresectable or metastatic tumours that were mismatch repair deficient or had high microsatellite instability regardless of tissue origin. This landmark approval was the first time a drug had been approved in a site agnostic way, but accumulating data has revealed that up to 50% of mismatch repair deficient tumours are refractory to treatment and there is a huge amount of variability in the therapeutic benefit amongst responders. Several mechanisms of resistance to immune checkpoint blockade for mismatch repair deficient cancers have been identified but our understanding of what is driving resistance in a proportion of patients remains lacking. In this review article, we discuss the emerging mechanisms of resistance which may enable optimal stratification of patients for treatment with immune checkpoint inhibitors in the future.

In Vitro Effects of Methylprednisolone over Oligodendroglial Cells: Foresight to Future Cell Therapies.

The implantation of oligodendrocyte precursor cells may be a useful therapeutic strategy for targeting remyelination. However, it is yet to be established how these cells behave after implantation and whether they retain the capacity to proliferate or differentiate into myelin-forming oligodendrocytes. One essential issue is the creation of administration protocols and determining which factors need to be well established. There is controversy around whether these cells may be implanted simultaneously with corticosteroid treatment, which is widely used in many clinical situations. This study assesses the influence of corticosteroids on the capacity for proliferation and differentiation and the survival of human oligodendroglioma cells. Our findings show that corticosteroids reduce the capacity of these cells to proliferate and to differentiate into oligodendrocytes and decrease cell survival. Thus, their effect does not favour remyelination; this is consistent with the results of studies with rodent cells. In conclusion, protocols for the administration of oligodendrocyte lineage cells with the aim of repopulating oligodendroglial niches or repairing demyelinated axons should not include corticosteroids, given the evidence that the effects of these drugs may undermine the objectives of cell transplantation.

Microtubule-associated proteins MAP7 and MAP7D1 promote DNA double-strand break repair in the G1 cell cycle phase.

The DNA-damage response is a complex signaling network that guards genomic integrity. The microtubule cytoskeleton is involved in the repair of DNA double-strand breaks; however, little is known about which cytoskeleton-related proteins are involved in DNA repair and how. Using quantitative proteomics, we discovered that microtubule associated proteins MAP7 and MAP7D1 interact with several DNA repair proteins including DNA double-strand break repair proteins RAD50, BRCA1 and 53BP1. We observed that downregulation of MAP7 and MAP7D1 leads to increased phosphorylation of p53 after γ-irradiation. Moreover, we determined that the downregulation of MAP7D1 leads to a strong G1 arrest and that the downregulation of MAP7 and MAP7D1 in G1 arrested cells negatively affects DNA repair, recruitment of RAD50 to chromatin and localization of 53BP1 to the sites of damage. These findings describe for the first time a novel function of MAP7 and MAP7D1 in cell cycle regulation and repair of DNA double-strand breaks.

Assessment of suitable referral, effectiveness and long-term outcomes of standard vs intensive pain management programmes for people with chronic pain.

Background: Chronic pain is a leading cause of disability, often requiring multidisciplinary management. 2021 NICE guidance has questioned the quality of the evidence surrounding the efficacy of pain management programmes (PMPs), with only minor benefit demonstrated in psychological and physical outcomes. There is need for further high-quality evidence for the efficacy of PMPs for a range of chronic pain conditions and to identify barriers to successful management of chronic pain. Objective: This service evaluation utilised routinely collected outcome data of 508 PMP attendees to investigate change in pain- and patient-related outcomes across two distinct PMPs; a standard and an intensive PMP, and establish their longer-term efficacy and appropriateness for patients with differing degrees of need. Results: More people with chronic widespread pain, fibromyalgia, and osteoarthritis were referred to the intensive PMP (reflecting greater disability and distress in these conditions). Those referred to the intensive PMP demonstrated greater distress (such as more severe depression and anxiety), lower pain acceptance and poorer physical function. Improvements were observed in all outcomes across both PMPs (including physical function, pain catastrophising and pain acceptance). Depression and disability demonstrated clinically meaningful improvements in the intensive PMP, and pain severity showed clinically meaningful improvement in both PMPs. However, depression severity, disability, pain severity, and pain interference significantly deteriorated at 6-month follow-up for those on the intensive PMP, with pain severity increasing to a clinically meaningful degree (by more than 10%), though these outcomes remained better than at baseline. Conclusion: This evaluation identified that people with chronic pain most at risk of deterioration in physical and psychological wellbeing after completing a PMP require early identification to mitigate such deterioration. Established and emerging PMPs need to be tailored to the needs of this group, particularly at follow-up to reduce risks of pain severity increasing, alongside establishing/reinforcing safeguards against deterioration post-PMP.

Catalytic site mutations confer multiple states of G protein activation.

Heterotrimeric guanine nucleotide-binding proteins (G proteins) that function as molecular switches for cellular growth and metabolism are activated by GTP and inactivated by GTP hydrolysis. In uveal melanoma, a conserved glutamine residue critical for GTP hydrolysis in the G protein α subunit is often mutated in Gαq or Gα11 to either leucine or proline. In contrast, other glutamine mutations or mutations in other Gα subtypes are rare. To uncover the mechanism of the genetic selection and the functional role of this glutamine residue, we analyzed all possible substitutions of this residue in multiple Gα isoforms. Through cell-based measurements of activity, we showed that some mutants were further activated and inactivated by G protein-coupled receptors. Through biochemical, molecular dynamics, and nuclear magnetic resonance-based structural studies, we showed that the Gα mutants were functionally distinct and conformationally diverse, despite their shared inability to hydrolyze GTP. Thus, the catalytic glutamine residue contributes to functions beyond GTP hydrolysis, and these functions include subtype-specific, allosteric modulation of receptor-mediated subunit dissociation. We conclude that G proteins do not function as simple on-off switches. Rather, signaling emerges from an ensemble of active states, a subset of which are favored in disease and may be uniquely responsive to receptor-directed ligands.

Characteristics of Human Immunodeficiency Virus (HIV) Seroconversions in a Large Prospective Implementation Cohort Study of Oral HIV Preexposure Prophylaxis in Men Who Have Sex with Men (EPIC-NSW).

BACKGROUND: Most human immunodeficiency virus (HIV) seroconversions in people who have initiated preexposure prophylaxis (PrEP) occur in the context of insufficient adherence. We describe participants who seroconverted after being dispensed PrEP in a large PrEP implementation study in Australia. METHODS: Expanded PrEP Implementation in Communities in New South Wales was an implementation study of daily oral PrEP in individuals aged ≥18 years at high risk for acquiring HIV. HIV seroconversions were defined as a positive HIV test by either antigen, antibody, or detectable HIV viral load after enrollment. Insufficient adherence, measured by dispensing logs or participant self-report, was defined as <4 PrEP doses per week. RESULTS: A total of 9596 participants were enrolled and dispensed PrEP between 1 March 2016 and 30 April 2018; 30 were diagnosed with HIV by 31 March 2019. The median (interquartile range [IQR]) age was 31 (25-38) years, all identified as male, 29 (97%) identified as gay or homosexual, and 20 (69%) lived in a postcode with a low concentration of gay male residents. The median (IQR) days from first PrEP dispensing to diagnosis was 409 (347-656). There was no evidence that participants who seroconverted had been sufficiently adherent to PrEP. Nineteen (63%) participants who seroconverted were diagnosed with chlamydia, gonorrhoea, syphilis, or new hepatitis C infection. One participant had resistance to emtricitabine (M184V mutation) at diagnosis. CONCLUSIONS: Participants who seroconverted were insufficiently adherent to PrEP despite being at high risk for acquiring HIV. Understanding the reasons for poor PrEP adherence in individuals who subsequently acquire HIV is critical to improving PrEP effectiveness.

A Rare Case of Primary Follicular Dendritic Cell Sarcoma of the Kidney.

The objective of this case report is to describe a rare case of primary follicular dendritic cell sarcoma (FDCS) of the kidney. FDCS is a rare soft tissue malignancy that most often presents intranodally with lymphadenopathy of the neck, mediastinum, and axilla. One-third of cases present extranodally and most commonly affect the liver, lung, and tonsils. To date, there have been few reports of retroperitoneal FDCS and, to the best of our knowledge, only two other reported cases with primary renal involvement. We present a 56-year-old female with end-stage renal disease on hemodialysis who presented to the hospital with a hypertensive emergency. Computed tomography (CT) of the abdomen was obtained revealing a left-sided renal mass and she subsequently underwent left radical nephrectomy. The pathologic features of the mass revealed oval to spindle cells with eosinophilic cytoplasm, dispersed vesicular chromatin, and small nucleoli found arranged in fascicles, whorls, and storiform patterns with occasional multinucleate forms. The neoplastic cells were immunoreactive to vimentin and expressed cell markers for CD23, CD35, and CD68. These features confirmed a final pathologic diagnosis of primary FDCS of the kidney. To our knowledge, this is the third case of primary renal FDCS reported in the literature. Extranodal FDCS is rare but does occur and needs to be on the differential diagnosis if pathologic features point to its diagnosis.

Availability of Central α4ß2* Nicotinic Acetylcholine Receptors in Human Obesity.

PURPOSE: Obesity is thought to arise, in part, from deficits in the inhibitory control over appetitive behavior. Such motivational processes are regulated by neuromodulators, specifically acetylcholine (ACh), via α4ß2* nicotinic ACh receptors (nAChR). These nAChR are highly enriched in the thalamus and contribute to the thalamic gating of cortico-striatal signaling, but also act on the mesoaccumbal reward system. The changes in α4ß2* nAChR availability, however, have not been demonstrated in human obesity thus far. The aim of our study was, thus, to investigate whether there is altered brain α4ß2* nAChR availability in individuals with obesity compared to normal-weight healthy controls. METHODS: We studied 15 non-smoking individuals with obesity (body mass index, BMI: 37.8 ± 3.1 kg/m2; age: 39 ± 14 years, 9 females) and 16 normal-weight controls (non-smokers, BMI: 21.9 ± 1.7 kg/m2; age: 28 ± 7 years, 13 females) by using PET and the α4ß2* nAChR selective (-)-[18F]flubatine, which was applied within a bolus-infusion protocol (294 ± 16 MBq). Volume-of-interest (VOI) analysis was performed in order to calculate the regional total distribution volume (VT). RESULTS: No overall significant difference in VT between the individuals with obesity and the normal-weight volunteers was found, while the VT in the nucleus basalis of Meynert tended to be lower in the individuals with obesity (10.1 ± 2.1 versus 11.9 ± 2.2; p = 0.10), and the VT in the thalamus showed a tendency towards higher values in the individuals with obesity (26.5 ± 2.5 versus 25.9 ± 4.2; p = 0.09). CONCLUSION: While these first data do not show greater brain α4ß2* nAChR availability in human obesity overall, the findings of potentially aberrant α4ß2* nAChR availability in the key brain regions that regulate feeding behavior merit further exploration.

Implementação Clínica de Diferentes Estratégias para Reabilitação Baseada em Exercícios em Receptores de Transplante de Rim e Fígado: Um Estudo Piloto / Clinical Implementation of Different Strategies for Exercise-Based Rehabilitation in Kidney and Liver Transplant Recipients: A Pilot Study

Resumo Fundamento: A doença cardiovascular está entre as principais causas de morte entre pacientes transplantados. Embora esses pacientes possam teoricamente se beneficiar de programas de reabilitação baseada em exercícios (RBE), sua implementação ainda é um desafio. Objetivo: Apresentamos nossa experiência inicial em diferentes modos de realização de um programa piloto de RBE em receptores de transplante de rim e fígado. Métodos: Trinta e dois pacientes transplantados renais ou hepáticos foram convidados para um programa de RBE de 6 meses realizado na academia do hospital, na academia comunitária ou em casa, de acordo com a preferência do paciente. O nível de significância adotado foi de 5%. Resultados: Dez pacientes (31%) não completaram o programa. Entre os 22 que completaram, 7 treinaram na academia do hospital, 7 na academia comunitária e 8 em casa. O efeito geral foi um aumento de 11,4% nos METs máximos (tamanho do efeito de Hedges g = 0,39). O grupo de academia hospitalar teve um aumento nos METs de 25,5% (g = 0,58, tamanho de efeito médio) versus 10% (g = 0,25) e 6,5% (g = 0,20) para os grupos de academia comunitária e em casa, respectivamente. Houve efeito benéfico nas pressões arteriais sistólica e diastólica, maior para os grupos academia hospitalar (g= 0,51 e 0,40) e academia comunitária (g= 0,60 e 1,15) do que para os pacientes treinando em casa (g= 0,07 e 0,10). Nenhum evento adverso significativo foi relatado durante o seguimento. Conclusão: Programas de RBE em receptores de transplante de rim e fígado devem ser incentivados, mesmo que sejam realizados fora da academia do hospital, pois são seguros com efeitos positivos na capacidade de exercício e nos fatores de risco cardiovascular.

Abstract Background: Cardiovascular disease is among the leading causes of death in solid organ transplant recipients with a functional graft. Although these patients could theoretically benefit from exercise-based rehabilitation (EBR) programs, their implementation is a challenge. Objective: We present our initial experience on different delivery modes of a pilot EBR program in kidney and liver transplant recipients. Methods: Thirty-two kidney or liver transplant recipients were invited for a 6-month EBR program delivered at the hospital gym, community gym or at home, according to the patient's preference. The significance level adopted was 5%. Results: Ten patients (31%) did not complete their program. Among the 22 who did, 7 trained at the hospital gym, 7 at the community gym, and 8 at home. The overall effect was an 11.4% increase in maximum METs (Hedges' effect size g = 0.39). The hospital gym group had an increase in METs of 25.5% (g= 0.58, medium effect size) versus 10% (g= 0.25), and 6.5% (g= 0.20) for the community gym and home groups, respectively. There was a beneficial effect on systolic and diastolic blood pressures, greater for the hospital gym (g= 0.51 and 0.40) and community gym (g= 0.60 and 1.15) groups than for the patients training at home (g= 0.07 and 0.10). No significant adverse event was reported during the follow-up. Conclusion: EBR programs in kidney and liver transplant recipients should be encouraged, even if they are delivered outside a hospital gym, since they are safe with positive effects on exercise capacity and cardiovascular risk factors.

Is non-occupational HIV Post Exposure Prophylaxis (nPEP) still used? An exploration of nPEP use since widespread availability of HIV PrEP.

BACKGROUND: Non-occupational Post-Exposure Prophylaxis (nPEP) is an effective HIV prevention strategy in gay and bisexual men (GBM) taken after possible exposure. HIV Pre-Exposure Prophylaxis (PrEP) is also a highly effective HIV prevention strategy. METHODS: A retrospective audit of medical records of GBM presenting to a sexual health centre and provided with nPEP compared two periods to determine if nPEP usage changed following availability of PrEP. In the first period (P1) PrEP was available through extended trials. In the second period (P2) PrEP became more accessible through the Australian Pharmaceutical Benefits Scheme (PBS). Period comparisons were performed using a two-population test of proportions with one-tailed testing and significance set at P < .05 using SPSS Statistics Version 25. RESULTS: There were 232 GBM provided with nPEP in P1, and 202 in P2. A two-population test of proportions demonstrated that GBM presentations for nPEP decreased significantly from 302/4779 (6.3%) of GBM visits in P1 to 221/7205 (3.1%) in P2 when PrEP was more accessible (Z=8.53, P < .001). PrEP uptake after presenting for nPEP increased from 30 (12.9%) of total GBM visits in P1 to 69 (34.2%) in P2 (Z=5.26, p < .001). CONCLUSIONS: GBM accessing nPEP decreased with statistical significance post introduction of PBS PrEP.

Statin Treatment as a Targeted Therapy for APC-Mutated Colorectal Cancer.

Background: Mutations in the tumor suppressor gene Adenomatous Polyposis Coli (APC) are found in 80% of sporadic colorectal cancer (CRC) tumors and are also responsible for the inherited form of CRC, Familial adenomatous polyposis (FAP). Methods: To identify novel therapeutic strategies for the treatment of APC mutated CRC, we generated a drug screening platform that incorporates a human cellular model of APC mutant CRC using CRISPR-cas9 gene editing and performed an FDA-approved drug screen targeting over 1000 compounds. Results: We have identified the group of HMG-CoA Reductase (HMGCR) inhibitors known as statins, which cause a significantly greater loss in cell viability in the APC mutated cell lines and in in vivo APC mutated patient derived xenograft (PDX) models, compared to wild-type APC cells. Mechanistically, our data reveals this new synthetic lethal relationship is a consequence of decreased Wnt signalling and, ultimately, a reduction in the level of expression of the anti-apoptotic protein Survivin, upon statin treatment in the APC-mutant cells only. This mechanism acts via a Rac1 mediated control of beta-catenin. Conclusion: Significantly, we have identified a novel synthetic lethal dependence between APC mutations and statin treatment, which could potentially be exploited for the treatment of APC mutated cancers.

Do we DARE? Improving digital ano-rectal examination in men who have sex with men living with HIV: a quality improvement initiative.

Men who have sex with men (MSM) living with HIV are at increased risk of anal cancer and annual screening via digital ano-rectal examination (DARE) is recommended. Baseline audit (Cycle 1) was undertaken of the medical records of MSM living with HIV aged ≥50years (n =85) from 1 January 2017 to 31 December 2018, in line with guidelines at the time. Data collection included whether DARE was discussed and offered, and whether DARE was accepted or declined. We provided staff training and altered clinic proformas aiming to increase DARE. Audit Cycle 2 (Cycle 2) was undertaken of eligible MSM (n =86) who attended between 1 January 2019 to 31 December 2020. DARE frequency increased from 4.7% in Cycle 1 to 41.8% in Cycle 2 (P <0.001) and discussion and offer of DARE increased from 8% to 64% in Cycle 2 (P <0.001).

Sonic Hedgehog Signaling in Primary Culture of Human Corpora Cavernosal Tissue From Prostatectomy, Diabetic, and Peyronie's Patients.

BACKGROUND: Cavernous nerve (CN) injury causes penile remodeling, including smooth muscle apoptosis and increased collagen, which results in erectile dysfunction (ED), and prevention of this remodeling is critical for novel ED therapy development. AIM: We developed 2 peptide amphiphile (PA) hydrogel delivery vehicles for Sonic hedgehog (SHH) protein to the penis and CN, which effectively suppress penile distrophic remodeling (apoptosis and fibrosis), in vivo in a rat CN injury model, and the aim of this study is to determine if SHH PA can be used to regenerate human corpora cavernosal smooth muscle deriving from multiple ED origins. METHODS: Corpora cavernosal tissue was obtained from prostatectomy, diabetic, hypertension, cardiovascular disease and Peyronie's (control) patients (n = 21). Primary cultures (n = 21) were established, and corpora cavernosal cells were treated with SHH protein, MSA (control), 5E1 SHH inhibitor, and PBS (control). Growth was quantified by counting the number of cells at 3-4 days. Statistics were performed by ANOVA with Scheffe's post hoc test. Concentration of SHH protein for maximal growth was optimized, and a more active SHH protein examined. OUTCOMES: Cultures were characterized by immunohistochemical analysis with ACTA2, CD31, nNOS and P4HB, and smooth muscle was quantified in comparison to DAPI. RESULTS: Cultures established were >97% smooth muscle. SHH protein increased growth of smooth muscle cells from prostatectomy, diabetic, and Peyronie's patients in a similar manner (49%-51%), and SHH inhibition decreased growth (20%-33%). There was no difference in growth using 25 ug and 10 ug SHH protein, suggesting a threshold concentration of SHH protein above which smooth muscle growth is enhanced. A more active lipid modified SHH peptide further enhanced growth (15%), indicating a more robust growth response. SHH increased growth in smooth muscle cells from hypertension (37%) and cardiovascular disease (32%) patients. SHH protein increased growth under normal and high glucose conditions, suggesting that high glucose conditions that may be present in under controlled diabetic patients would not detract from SHH regenerative capacity. CLINICAL IMPLICATIONS: SHH PA would be beneficial to enhance smooth muscle regeneration in patients with ED of multiple etiologies. STRENGTHS AND LIMITATIONS: Understanding how human corpora cavernosal tissue responds to SHH treatment is critical for clinical translation of SHH PA to ED patients. CONCLUSION: Corpora cavernosal smooth muscle from all ED patients responded to SHH treatment with increased growth. Stupp, SI. Sonic Hedgehog Signaling in Primary Culture of Human Corpora Cavernosal Tissue From Prostatectomy, Diabetic, and Peyronie's Patients. J Sex Med 2022;19:1228-1242.

A Drug Screening Revealed Novel Potential Agents against Malignant Pleural Mesothelioma.

The lack of effective therapies remains one of the main challenges for malignant pleural mesothelioma (MPM). In this perspective, drug repositioning could accelerate the identification of novel treatments. We screened 1170 FDA-approved drugs on a SV40-immortalized mesothelial (MeT-5A) and five MPM (Mero-14, Mero-25, IST-Mes2, NCI-H28 and MSTO-211H) cell lines. Biological assays were carried out for 41 drugs, showing the highest cytotoxicity and for whom there were a complete lack of published literature in MPM. Cytotoxicity and caspase activation were evaluated with commercially available kits and cell proliferation was assayed using MTT assay and by clonogenic activity with standard protocols. Moreover, the five most effective drugs were further evaluated on patient-derived primary MPM cell lines. The most active molecules were cephalomannine, ouabain, alexidine, thonzonium bromide, and emetine. Except for alexidine, these drugs inhibited the clonogenic ability and caspase activation in all cancer lines tested. The proliferation was inhibited also on an extended panel of cell lines, including primary MPM cells. Thus, we suggest that cephalomannine, ouabain, thonzonium bromide, and emetine could represent novel candidates to be repurposed for improving the arsenal of therapeutic weapons in the fight against MPM.

Predictors of prolonged admission after outpatient female pelvic reconstructive surgery.

OBJECTIVES: This study aimed to determine factors associated with prolonged hospital admission following outpatient female pelvic reconstructive surgery (FPRS) and associated adverse clinical outcomes. METHODS: Using the National Surgical Quality Improvement Program database, we identified outpatient FPRS performed 2011-2016. Isolated hysterectomy without concurrent prolapse repair was excluded. Surgeries were classified as major or minor for analysis. The primary outcome was prolonged length of stay (LOS), defined as admission of ≥2 days. Secondary outcomes included complications, readmission and reoperation associated with prolonged LOS. We abstracted data on covariates, and following univariable analysis, performed backward stepwise regression analysis. RESULTS: A total of 29645 women were included: 12311 (41.5%) major and 17334 (58.5%) minor procedures. A total of 6.9% (2033) had a prolonged LOS. On full cohort multivariable regression analysis, patient characteristics associated with prolonged LOS were older age (odds ratio [OR]: 1.1 per 10 years, confidence interval [CI]: 1.06-1.1, p < 0.001), frailty (OR: 1.8, 95% CI: 1.3-2.6, p = 0.001), and Caucasian race (OR: 1.2, CI: 1.02-1.3, p = 0.024). Associated surgical factors included having a major surgical procedure (OR: 1.3, CI: 1.2-1.4, p < 0.001), use of general anesthesia (OR: 2.0, CI: 1.5-2.6, p < 0.001) and longer operative time (OR: 2.0, CI: 1.8-2.2, p < 0.001). The occurrence of any complication (10.3% vs. 4.7%, p < 0.001), hospital readmission (4.3% vs. 1.7%, p < 0.001), and reoperation (2.7% vs. 1.0%, p < 0.001) were more likely with prolonged LOS. CONCLUSIONS: After outpatient FPRS, 6.9% of patients experience an admission of ≥2 days. Prolonged LOS is more common in patients who are older, frail and Caucasian, and in those who have major surgery with long operative time and general anesthesia.