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Abstract Background Indoleamine 2,3-dioxygenase 1 (IDO1) levels correlate with poor outcomes in urothelial carcinoma (UC). IDO1 and programmed death-ligand 1 (PD-L1) are often co-expressed. Epacadostat is a potent and highly selective inhibitor of IDO1. In a subgroup analysis of patients with advanced UC participating in a phase I/II study, epacadostat-pembrolizumab treatment produced an objective response rate (ORR) of 35%. Methods ECHO-303/KEYNOTE-698 was a double-blinded, randomized phase III study of adults with metastatic or unresectable locally advanced UC with recurrence or progression following first-line platinum-based chemotherapy. Participants were randomized to epacadostat 100 mg twice daily (BID) plus pembrolizumab or placebo plus pembrolizumab until completion of 35 pembrolizumab infusions, disease progression, or unacceptable toxicity. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors version 1.1. Results Target enrollment was 648 patients; enrollment was halted early based on efficacy results from the phase III ECHO-301/KEYNOTE-252 study in metastatic melanoma. Forty-two patients were randomized to each treatment arm. Median duration of follow-up was 62 days in each arm. The investigator-assessed ORR (unconfirmed) was 26.2% (95% CI 16.35–48.11) for epacadostat plus pembrolizumab and 11.9% (95% CI 4.67–29.50) for placebo plus pembrolizumab. Two complete responses were reported, both in the placebo-plus-pembrolizumab arm. Circulating kynurenine levels increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and numerically decreased in the epacadostat-plus-pembrolizumab arm. The safety profile of epacadostat plus pembrolizumab was similar to that of pembrolizumab monotherapy, although a numerically greater proportion of patients in the combination vs. control arm experienced treatment-related grade ≥ 3 adverse events (16.7% vs. 7.3%). One patient in each arm died due to cardiovascular events, which were not deemed drug-related. No new safety concerns were identified for either agent. Conclusions Epacadostat plus pembrolizumab demonstrated anti-tumor activity and was generally tolerable as second-line treatment of patients with unresectable locally advanced or recurrent/progressive metastatic UC. Epacadostat 100 mg BID, when administered with pembrolizumab, did not normalize circulating kynurenine in most patients. Further study of combined IDO1/PD-L1 inhibition in this patient population, particularly with epacadostat doses that result in durable normalization of circulating kynurenine, may be warranted. Trial registration ClinicalTrials.gov, NCT03374488. Registered 12/15/2017.

Abstract Background Indoleamine 2,3- dioxygenase 1 (IDO1) is an immunosuppressive enzyme that has been correlated with shorter disease-specific survival in patients with urothelial carcinoma (UC). IDO1 may counteract the antitumor effects of immune checkpoint inhibitors. Epacadostat is a potent and highly selective inhibitor of IDO1. In the phase I/II ECHO-202/KEYNOTE-037 study, epacadostat plus pembrolizumab resulted in a preliminary objective response rate (ORR) of 35% in a cohort of patients with advanced UC. Methods ECHO-307/KEYNOTE-672 was a double-blinded, randomized, phase III study. Eligible adults had confirmed locally advanced/unresectable or metastatic UC of the urinary tract and were ineligible to receive cisplatin-based chemotherapy. Participants were randomly assigned (1:1) to receive epacadostat (100 mg twice daily) plus pembrolizumab (200 mg every 3 weeks) or placebo plus pembrolizumab for up to 35 pembrolizumab infusions. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors (version 1.1). Results A total of 93 patients were randomized (epacadostat plus pembrolizumab, n = 44; placebo plus pembrolizumab, n = 49). Enrollment was stopped early due to emerging data from the phase III ECHO-301/KEYNOTE-252 study. The median duration of follow-up was 64 days in both arms. Based on all available data at cutoff, ORR (unconfirmed) was 31.8% (95% CI, 22.46–55.24%) for epacadostat plus pembrolizumab and 24.5% (95% CI, 15.33–43.67%) for placebo plus pembrolizumab. Circulating kynurenine levels numerically increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and decreased in the epacadostat-plus-pembrolizumab arm. Epacadostat-plus-pembrolizumab combination treatment was well tolerated with a safety profile similar to the placebo arm. Treatment discontinuations due to treatment-related adverse events were more frequent with epacadostat (11.6% vs. 4.1%). Conclusions Treatment with epacadostat plus pembrolizumab resulted in a similar ORR and safety profile as placebo plus pembrolizumab in cisplatin-ineligible patients with previously untreated locally advanced/unresectable or metastatic UC. At a dose of 100 mg twice daily, epacadostat did not appear to completely normalize circulating kynurenine levels when administered with pembrolizumab. Larger studies with longer follow-up and possibly testing higher doses of epacadostat, potentially in different therapy settings, may be warranted. Trial registration ClinicalTrials.gov identifier: NCT03361865, retrospectively registered December 5, 2017.

ObjectiveIn the phase 3 CELESTIAL trial, cabozantinib improved overall survival (OS) and progression-free survival (PFS) compared with placebo in patients with previously treated advanced hepatocellular carcinoma (HCC). This subgroup analysis evaluated cabozantinib in patients who had received sorafenib as the only prior systemic therapy.MethodsCELESTIAL randomised (2:1) patients with advanced HCC and Child-Pugh class A liver function to treatment with cabozantinib (60 mg daily) or placebo. Eligibility required prior treatment with sorafenib, and patients could have received ≤2 prior systemic regimens. The primary endpoint was OS. Outcomes in patients who had received sorafenib as the only prior therapy were analysed by duration of prior sorafenib (

Abstract Introduction Several systemic therapies have demonstrated a survival advantage in metastatic castration resistant prostate cancer (mCRPC). Access to these medications varies significantly worldwide. In Australia until recently, patients must have received docetaxel first, unless unsuitable for chemotherapy, despite no evidence suggesting superiority over androgen receptor signalling inhibitors (ARSIs). Our study investigated real‐world systemic treatment patterns in Australian patients with mCRPC. Methods The electronic CRPC Australian Database (ePAD) was interrogated to identify mCRPC patients. Clinicopathological features, treatment and outcome data, stratified by first‐line systemic therapies, were extracted. Comparisons between groups utilised Kruskal–Wallis tests and Chi‐Square analyses. Time‐to‐event data were calculated using Kaplan–Meier methods and groups compared using log‐rank tests. Factors influencing overall survival (OS) and time to treatment failure (TTF) were analysed through Cox proportional hazards regression models. Results We identified 578 patients who received first‐line systemic therapy for mCRPC. Enzalutamide (ENZ) was most commonly prescribed (n = 240, 41%), followed by docetaxel (DOC, n = 164, 28%) and abiraterone (AA, n = 100, 17%). Patients receiving ENZ or AA were older (79, 78.5 years respectively) compared with DOC (71 years, p = 0.001) and less likely to have ECOG performance status 0 (45%, 44%, 59% in ENZ, AA and DOC groups respectively p 12 months was independently associated with longer TTF (HR 0.67, p

The band gaps of three forms of polyaniline (PANI) are calculated using the DFT method with the B3LYP functional and SV(P) basis set. This marks the first time that the band gap for this polymer has been calculated using this DFT method. The calculations include an investigation of the effect of varying the benzoid--quinoid structural units, the effect of increasing oligomer length, and the inclusion of Michael's addition structures, which could be residual in the polymer depending on the chosen synthetic method. All results were compared with the experimentally determined band gap of 1.5 eV as typically reported in the literature. A commonly used structural motif of alternating benzoid-quinoid units and a ratio of 0.5:0.5 benzoid--quinoid resulted in a computed band gap of 1.9 eV. Inclusion of one extra quinoid unit gave rise to a band gap of 1.3 eV. Incorporation of a Michael's addition structure was found to dominate the band gap calculation, yielding a localized LUMO and a band gap of 1.3 eV that was insensitive to the polymer chain length and composition. Key words: polyaniline, B3LYP/def SV(P), band gap, computational chemistry, TurboMol. Nous avons calculé les bandes interdites de trois formes de polyaniline (PANI) à l'aide de la méthode DFT avec la fonctionnelle B3LYP et la base SV(P). Les calculs de la bande interdite avec cette méthode DFT constituent une première pour ce polymère. Ces calculs permettent d'étudier les effets de la variation des unités structurales benzoïdes et quinoïdes et de l'augmentation de la longueur des oligomères, ainsi que l'inclusion des structures d'addition de Michael qui pourraient être présentes à titre résiduel dans le polymère selon la méthode synthétique choisie. Tous les résultats ont été comparés à la bande interdite déterminée expérimentalement de 1,5 eV, qui correspond à la valeur généralement rapportée dans la littérature. Le résultat du calcul de la bande interdite effectué avec un motif structural communément utilisé, qui consiste à alterner les unités benzoïdes et quinoïdes, et un rapport benzoïde-quinoïde de 0,5 : 0,5 était de 1,9 eV. Cette valeur s'est établi à 1,3 eV avec l'inclusion d'une unité quinoïde supplémentaire. Nous avons constaté que l'effet de l'incorporation d'une structure d'addition de Michael était majeur dans le calcul de la bande interdite, donnant lieu à une LUMO localisée et à une bande interdite de 1,3 eV indépendante de la longueur et de la composition de la chaîne de polymère. [Traduit par la Rédaction] Mots-clés : polyaniline, B3LYP/def SV(P), bande interdite, chimie computationnelle, TurboMol., 1. Introduction Polyaniline (PANI) is an intrinsically conductive organic polymer. It is one of the more robust organic conductive polymers, as it is air stable and convenient to synthesize. PANI [...]

The COVID-19 pandemic has imposed significant mental health burdens upon the general population worldwide, either directly owing to the disease or indirectly through aggressive public health measures to control spread of the virus that causes COVID-19. In this narrative review, we used a systematic approach to summarize the impact of restrictive lockdown measures on the general mental health of people living in Victoria, Australia during 2020 and to identify the groups with an increased risk of adverse mental health outcomes. A systematic database search (Ovid Medline, PsycINFO, Embase) for articles examining the mental health of Victorians in the context of the COVID-19 pandemic during 2020 yielded 88 articles, of which 15 articles were finally included in this review. We found that the general mental health of Victorians was negatively affected by COVID-19 restrictions during 2020. Although studies reported heterogeneous mental health outcomes, we found that the general population consistently used coping strategies and demonstrated mental health help-seeking behaviors in response to the restrictions. Women, children, young people, carers, people who became unemployed owing to the pandemic, and those with pre-existing psychiatric conditions had a higher risk of adverse mental health consequences during the COVID-19 pandemic in 2020.

Background Surgical decompression of the carpal tunnel is considered the method of choice for its treatment with satisfactory results documented. Various methods and suturing materials have been used for closure of the surgical wound. In the present study, we compared interrupted mattress closure by means of nylon suture to running subcuticular closure with vicryl rapide suture. As far as we know, there is no similar study in the literature. Methods A total of twenty patients were included in the study. Ten of them had their surgical wound closed with 3.0 nylon suture in an interrupted fashion and for the rest, a running subcuticular 3.0 vicryl rapide was used. All patients filled in a questionnaire about VAS perceived pain and a Quick DASH score sheet, preoperatively, at two and six weeks postoperatively. The cosmesis of the scar was assessed using the POSAS v2.0 system at two and six weeks after surgery and overall incidence of infections was noted as well. Results There was no statistically important difference between the two groups of patients in regards to postoperative VAS pain levels at two and six weeks. Likewise, no statistically significant difference was evident as far as Quick DASH score, POSAS score and infections were concerned. Conclusions Our results suggest that the use of running subcuticular vicryl rapide suture is an attractive alternative to interrupted nylon sutures for closure after open carpal tunnel decompression, lacking any significant drawbacks. Lay Summary Surgery for carpal tunnel decompression is considered the method of choice for its treatment with documented satisfactory results. Various methods and suturing materials have been used for closure of the surgical wound. In the present study, we compared the use of a non-absorbable suture, placed intermittently to an absorbable continuous intradermal suture. A total of twenty patients were included in the study. Half of them had their wound closed with the absorbable suture and the other half with the non-absorbable suture, as described above. All patients were evaluated as far as pain, scar characteristics, functional outcomes of the operated hand and incidence of infection, at two and six weeks after surgery. After analysis of the data, no significant differences were found between the two groups, suggesting that both of these techniques are equally safe and efficacious.

We examined whether environmentally relevant concentrations of different types of microplastics, with or without PCBs, directly affect freshwater prey and indirectly affect their predators. Asian clams (Corbicula fluminea) were exposed to environmentally relevant concentrations of polyethylene terephthalate (PET), polyethylene, polyvinylchloride (PVC) or polystyrene with and without polychlorinated biphenyls (PCBs) for 28 days. Their predators, white sturgeon (Acipenser transmontanus), were exposed to clams from each treatment for 28 days. In both species, we examined bioaccumulation of PCBs and effects (i.e., immunohistochemistry, histology, behavior, condition, mortality) across several levels of biological organization. PCBs were not detected in prey or predator, and thus differences in bioaccumulation of PCBs among polymers and biomagnification in predators could not be measured. One of the main objectives of this study was to test the hypothesis that bioaccumulation of PCBs would differ among polymer types. Because we could not answer this question experimentally, a bioaccumulation model was run and predicted that concentrations of PCBs in clams exposed to polyethylene and polystyrene would be greater than PET and PVC. Observed effects, although subtle, seemed to be due to microplastics rather than PCBs alone. For example, histopathology showed tubular dilation in clams exposed to microplastics with PCBs, with only mild effects in clams exposed to PCBs alone.

The beneficial effect of adding 8.4% sodium bicarbonate (NaHCO3) to local anaesthesia, making it less painful to inject, is documented in the literature. However, few doctors actually put this knowledge into practice. With this study, we quantify this effect in the Maltese population and justify its use in our day to day practice. In addition, we take this opportunity to elaborate on the additional factors that improve patient comfort when injecting local anaesthesia. Method A total of 150 patients having a procedure under local anaesthesia at the Plastic Surgery and Burns Unit, at Mater Dei Hospital, Malta, were included in this study. 75 patients were injected with lidocaine alone and another 75 patients were injected with lidocaine mixed with 8.4% sodium bicarbonate. Results The commonest age group was the 70-79 age group in both cohorts. The minimum pain score was 0 in both groups. The highest score was 9 in the group without sodium bicarbonate and 8 in the group with sodium bicarbonate. The mean pain score was 3.93 in the cohort without sodium bicarbonate and 2.55 in the cohort with sodium bicarbonate. The median value was 4 in the group of patients injected without sodium bicarbonate and 2 in the group injected with sodium bicarbonate. The p-value was <0.05, making these results statistically significant. Conclusion Alkalinisation of local anaesthetic solutions improves the pain of infiltration of the local anaesthetic at a minimal cost. This increases patient compliance and patient comfort and thus allowing more surgeries to be performed under local anaesthesia. [ABSTRACT FROM AUTHOR]

Background: Hyperbaric oxygen therapy (HBOT) involves patients breathing 100% oxygen in a pressurized chamber, above 1 atmosphere. Many centers are now promoting the use of HBOT for skin rejuvenation. However, the current indications for HBOT do not encompass aesthetic applications. Aim: The aim of this evidence‐based review was to assess the existing literature regarding the utilization of HBOT in medical aesthetics and rejuvenation, evaluate its effectiveness and safety, and conduct a cost analysis. Materials and Methods: PubMed Interface, Cochrane Library, Google Scholar, and Embase searches were carried out. The Best Bets methodology was used, and the risk of bias was appraised using the Quality Assessment Tool for Quantitative Studies. Results and Main Findings: This review included a total of 17 human studies with a total of 766 participants. Three studies were classified as level II evidence, three studies were of level III evidence, and 11 were of level IV evidence. All the included studies were judged at high risk of bias. The most relevant findings supported by level II evidence were that HBOT decreased the shedding rate post‐FUE hair transplant (27.6 ± 2.6% vs. 69.1 ± 2.4%) but this did not affect the final outcome between HBOT (96.9 ± 0.5%) and the control (93.8 ± 0.6%). Moreover, level III evidence demonstrated that following HBOT, there was a significant increase in elastic fiber length (p ≤ 0.0001, effect size = 2.71) and a significant decrease in fiber fragmentation (p = 0.012). There was also a significant increase in collagen fiber density following HBOT (p = 0.0001, effect size = 1.10). However, there was no significant effect of antioxidant vitamins A, C, and E with HBOT. The inflammatory response significantly decreased after 7 days of HBOT with a decreased expression of IL‐12p40, MIP‐1β, and PDGF‐BB and a higher expression of IL‐1Ra. Moreover, HBOT was used prophylactically prior to abdominoplasty to decrease the risk of complications. In this study, complications were decreased from 32.6% (89 patients) to 8.4% (7 patients) with a p < 0.001, and in a multivariate analysis, preoperative HBOT was an independent protective factor against postoperative complications (p < 0.001). Conclusion and Recommendations: There is conflicting evidence on how the method of action of HBOT can have a beneficiary effect in aesthetic and whether the treatment is justifiable. To our knowledge, this is the first comprehensive review discussing the available evidence regarding the use of HBOT in many aesthetic clinical scenarios, including preventive, medical, and surgical settings. However, randomized clinical trials with longer follow‐up and better patient selection are needed to be able to generate a reliable conclusion. [ABSTRACT FROM AUTHOR]

Insulin receptor signaling governs central physiological functions related to cell growth and metabolism. Here the authors use protein complex purification and super-resolution microscopy to show that insulin receptor activity requires association with dystrophin glycoprotein complex and plakoglobin.

Background: Tuberculosis (TB) incidence is decreasing in the Northern Territory (NT) but still exceeds rates elsewhere in Australia. Deaths and morbidity from advanced TB continue, with delay in diagnosis a contributor to adverse outcomes. Aims: We aimed to describe the delay in diagnosis of TB, identify risk factors for delay and examine the associations between delay and clinical outcomes. Methods: We conducted a historical cohort analysis which included adult inpatients diagnosed with TB at the Royal Darwin Hospital from 2010 to 2020. Patient delay was measured as time from symptom onset to first seeking care, and health system delay was quantified as time from first relevant clinical contact to diagnosis. The sum of these two periods was the total delay. Ethics approval was granted by NT HREC (2020‐3852). Results: Eighty‐four cases were included; the median total delay was 90 days (interquartile range (IQR): 60–121), patient delay was 53 days (IQR: 30–90), and health system delay was 21 days (IQR: 12–45). Patient delay was longer among patients with extrapulmonary (median: 100 days (IQR: 90–105) compared with pulmonary TB patients (39 days (IQR: 27–54), P < 0.0001). Health system delay was longer in those aged ≥45 years (30 days (IQR: 16–51) vs younger patients (14 days (IQR: 8–30), P = 0.007) and among non‐smokers (31 days (IQR: 21–55) vs 21 days (IQR: 10–40), P = 0.048). Median delay was longer among patients with non‐drug‐related complications of disease (P < 0.0001), those admitted to critical care (P < 0.0001), and those with respiratory failure (P = 0.001). Conclusion: The patient delays we report are longer than reported elsewhere in Australia. The next steps will require concerted efforts to improve community awareness of TB and strategies to strengthen health systems through better resourcing and healthcare provider support. [ABSTRACT FROM AUTHOR]

The immobilization of zerovalent iron nanoparticles (nZVI) is a way to facilitate their use in continuous flow systems for the treatment of aqueous pollutants. In this work, two types of nZVI (powdered, NSTAR; and slurry suspended, N25) were immobilized in millimetric alginate beads (AL) by coagulation, forming nanocomposites (NCs). These NCs, N25@AL and NSTAR@AL, were structurally studied and tested for Cr(VI) removal. For both NCs types, SEM analysis showed a uniform distribution of the nanoparticles in micron-scale agglomerates, and XRD analysis revealed the preservation of α-Fe as the main iron phase of the immobilized nanoparticles. Additionally, Raman spectroscopy results evidenced a partial oxidation of the initially present magnetite. For both nZVI types, the Cr(VI) removal efficiency increased with temperature, decreased with pH, and did not show any significant change in anoxic or oxic conditions. On the other hand, N25@AL resulted a faster removal agent than NSTAR@AL; however, both materials had the same maximum removal capacity: 133 mg of Cr(VI) per gram of nZVI at pH 3. Cr(III) formed during the removal of Cr(VI) was retained by the alginate matrix, constituting a clear advantage against the use of free nZVI in suspension at acidic pH.