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Introduction: ALK-positive lung cancers represent a molecularly diverse disease. With drug exposure, driving selection pressure, and resistance pathways, disease relapse will emerge. There is compelling rationale to investigate novel treatment strategies, informed by dynamic circulating tumor DNA (ctDNA) monitoring. Methods: The single-arm, pilot study ALKTERNATE investigated fixed alternating cycles of lorlatinib intercalated with crizotinib in individuals resistant to second-generation ALK inhibitors. Dynamic ctDNA explored the correlation with disease response and disease recurrence and defined disease resistance. The primary outcome was time-to-treatment failure, a composite of tolerability, feasibility, and efficacy. Secondary outcomes included standard survival measures, toxicity, pharmacokinetic analysis, and patient-reported outcomes. Tertiary outcomes were proteogenomic analyses of tissue and plasma. Results: A total of 15 individuals were enrolled; three encountered primary resistance to lorlatinib induction. There were 12 participants who received alternating therapy, and this approach revealed safety, feasibility, and effectiveness. Patient-reported outcomes were maintained or improved on therapy, and toxicity was consistent with previous reports. The pharmacokinetic measures were similar to the single-arm drug experience. Median time-to-treatment failure was 10 months; overall survival was 23 months. ctDNA profiles indicated inferior survival in those with preexistent TP53 mutations and those without clear or cleared ctDNA at trial induction. The study defined a vastly heterogeneous population with an abundance of ALK coexisting with non-ALK resistance variants. Conclusions: ALKTERNATE revealed feasibility with a novel alternating ALK inhibitor strategy in ALK-positive NSCLC. Results support progressing inquiry into this approach and propose a flexible design with drug(s) selected and alternating time frames, informed by real-time plasma profiling. Moving this concept to treatment naive may also optimize impact.

Abstract In this phase II, single arm trial (ACTRN12617000720314), we investigate if alternating osimertinib and gefitinib would delay the development of resistance to osimertinib in advanced, non-small cell lung cancer (NSCLC) with the epidermal growth factor receptor (EGFR) T790M mutation (n = 47) by modulating selective pressure on resistant clones. The primary endpoint is progression free-survival (PFS) rate at 12 months, and secondary endpoints include: feasibility of alternating therapy, overall response rate (ORR), overall survival (OS), and safety. The 12-month PFS rate is 38% (95% CI 27.5–55), not meeting the pre-specified primary endpoint. Serial circulating tumor DNA (ctDNA) analysis reveals decrease and clearance of the original activating EGFR and EGFR-T790M mutations which are prognostic of clinical outcomes. In 73% of participants, loss of T790M ctDNA is observed at progression and no participants have evidence of the EGFR C797S resistance mutation following the alternating regimen. These findings highlight the challenges of treatment strategies designed to modulate clonal evolution and the clinical importance of resistance mechanisms beyond suppression of selected genetic mutations in driving therapeutic escape to highly potent targeted therapies.

Purpose: Perilunate fracture dislocation (PLFD) injuries are associated with the development of acute carpal tunnel syndrome (CTS). The purpose of our study was to identify the factors that increase the likelihood of developing CTS in patients with PLFD. Additionally, we attempted to classify patients who did not initially undergo carpal tunnel release (CTR) at the time of injury but eventually underwent CTR within the follow-up period. Methods: Patients presenting to a level-1 trauma center with isolated PLFDs (Mayfield III–IV) were retrospectively identified by using CPT and ICD-10 codes. Polytraumatized patients, those with a history of previous wrist trauma, or those with previous carpal tunnel symptoms or surgery were excluded. Outcomes of interest included the development of acute CTS, pre- and post-reduction changes in CTS symptoms, and associated hand and wrist fractures. Chi-square tests, Kruskal–Wallis tests, and multivariate logistic regression were used to examine the predictors of developing CTS after a PLFD. Results: In total, 43 patients were included in the final cohort, with a mean age of 44 years, of which 77% were men. The most common fracture of the carpus included scaphoid fractures (9/43, 21%). The average time from presentation to reduction was 636 minutes. Acute CTS symptoms before reduction were present in 26% of the patients and increased post-reduction to 28%. No difference exists between the time to sedation and the presence of acute carpal tunnel symptoms (P >.05). During initial surgical intervention, 79% underwent CTR (27/34). Of the seven patients who did not initially undergo a CTR, 57% (4/7) required a CTR within the follow-up period. Conclusion: Reduction of PLFDs did not significantly improve the number of patients with acute CTS. More than 50% of the patients who did not undergo a CTR at the initial surgery required a CTR within the follow-up period. Type of study/level of evidence: Prognostic III.

Bone is continuously in a state of building and renewal, though the process of remodeling that takes place at many sites asynchronously throughout the skeleton, with bone formation and resorption equal at these sites (bone multicellular units). Remodeling takes place on bone surfaces, both on trabeculae and in the cortex, and serves the purposes of replacing old bone or that damaged by microfractures throughout the skeleton. The bone loss and consequent osteoporotic fractures that result from excess resorption over formation have mainly been prevented or treated by antiresorptive drugs that inhibit osteoclast formation and/or activity. Virtually all of the evidence leading to acceptance of antiresorptive drugs as treatment has depended upon their prevention of vertebral fractures. In recent decades, new prospects came of anabolic treatments that partly restore bone volume and microstructure restore bone that has been lost. The first of these was parathyroid hormone (PTH), shown by daily injection to increase markers of bone formation and prevent fractures. This field of interest enlarged with the discovery of PTH-related protein (PTHrP), so closely related in structure and action to PTH. The structural relationship between PTH and PTHrP is important in assessing their physiological and pharmacological roles, with the N-terminal domains of the 2 having virtually equal actions on target cells. Abaloparatide, a peptide analogue based on the structures of PTHrP and PTH, has been approved in some countries as a therapy for osteoporosis. Treatment through the PTH receptor activation pathway, and probably with any anabolic therapy, needs to be followed by antiresorptive treatment in order to maintain bone that has been restored. No matter how effective anabolic therapies for the skeleton become, it seems highly likely that there will be a continuing need for antiresorptive drugs.

Tungsten-based scandate dispenser cathodes are promising next-generation thermionic electron sources for vacuum electron devices, due to their excellent emission performance at temperatures lower than those required for conventional cathodes. There has been a significant recent effort to understand scandate cathode performance and to characterize the tungsten and other materials on the emitting surface, primarily via the study of cathodes before and after emission testing. Moreover, these scandate cathodes have typically been characterized at room temperature only. In situ observations of scandate cathodes is challenging, as these devices are thermionic emitters that operate in a high-vacuum environment, and because the sizes of relevant material features range from the micron (2.0 µm) to the nanometer (in situ heating experiments was conducted on un-activated impregnated scandate cathode fragments, utilizing a micro-electro-mechanical system-based heater chip in a scanning electron microscope, enabling the real-time observation of cathode material evolution at elevated temperature (up to 1200 °C) under a pressure of 10−6 to 10−7 mbar. This study revealed how impregnant materials grow and migrate within the cathode matrix at elevated temperatures, and these observations are key to a thorough understanding of the behavior of scandate cathode materials. It also enabled direct observation of the incipient faceting of tungsten surfaces at high temperature while surrounded by impregnant materials. These are the first in situ observations of scandate cathode material evolution in relevant environmental conditions and at sufficiently high resolution to provide insights into the morphological and phase changes that occur in the near-surface regions of scandate cathodes.

The neuronal activity has a unique genetic signature that can be used for personal identification and authentication. Continuous authentication of individuals is required in the field involving high security, such as military services, intelligence organizations and secret agencies. Electroencephalogram (EEG) based authentication method is favorable due to its uniqueness and the fact that it can be used even when the person is unconscious. In this study, we investigated the number of samples per subject required to reliably develop a biometric trait authentication system. Initially, we extracted the background EEG signals from the publicly available Temple University Hospital (TUH) database. A total of 46 statistical and frequency domain features were extracted from each EEG signal per subject. The classification was performed using the extreme Gradient Boosting (XGBoost) classifier. We varied the number of EEG signal segments per subject from 5 to 127 with an increment of 5 segments per trial. Finally, the performance parameters such as accuracy, sensitivity, specificity, precision and F-measure were obtained in each case for the biometric authentication system using the test data. Our model achieved the highest accuracy of 100% when more than 75 EEG signals per subject were considered for the analysis. We also identified alpha band power as the most efficient feature for authentication. Our results show that EEG signals can be effectively used for personal identification and authentication.

Background In CheckMate 9LA, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy regardless of tumor PD-L1 expression or histology. We report updated efficacy and safety in all randomized patients with a minimum 4-year follow-up and an exploratory treatment-switching adjustment analysis in all treated patients who received chemotherapy and subsequent immunotherapy.Methods Adults with stage IV/recurrent non-small cell lung cancer (NSCLC), no sensitizing EGFR/ALK alterations, and ECOG performance status ≤1 were randomized 1:1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with chemotherapy (two cycles) or chemotherapy (four cycles, with optional maintenance pemetrexed for the nonsquamous population). Assessments included OS, progression-free survival, and objective response rate. Exploratory analyses included efficacy by tumor PD-L1 expression and histology and in patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events (TRAEs), and a treatment-switching adjustment analysis using inverse probability of censoring weighting.Results With a 47.9-month minimum follow-up for OS, nivolumab plus ipilimumab with chemotherapy continued to prolong OS over chemotherapy in all randomized patients (HR 0.74, 95% CI 0.63 to 0.87; 4-year OS rate: 21% versus 16%), regardless of tumor PD-L1 expression (HR (95% CI): PD-L1

A 50-year-old woman living with untreated HIV and injection drug use presented with right shoulder pain. The shoulder exam and computed tomography (CT) scan were concerning for septic arthritis. She was started on empiric vancomycin and cefepime and underwent right shoulder debridement and humeral head resection. Bone cultures grew methicillin sensitive Staphylococcus aureus (MSSA); empiric broad-spectrum antibiotics were changed to cefazolin. The patient subsequently developed severe anemia refractory to blood transfusions approximately 6 days later. Further evaluation disclosed hemolytic anemia attributable to cefazolin. Antibiotic therapy was switched from cefazolin to daptomycin, and the patient was started on prednisone. She had sustained improvement in hemoglobin values above 6 g/dL without requiring further transfusions prior to hospital discharge. Drug-induced immune hemolytic anemia from cefazolin is rare but has been reported primarily in the perioperative setting. Here, we present a case following initiation of treatment for septic arthritis.

This paper presents a unique control system to regulate power exchanges and load bus voltage in a networked microgrid (NMG) system comprising AC and DC microgrids. During the islanding of a microgrid in this NMG system, load voltage and power balance can get disturbed. A control system and associated converter and inverter control methods are presented to rectify these issues. An efficient model predictive control (MPC) method, which gives a tracking error of 50% lower than a conventional proportional-integral (PI) controller, is used to control multiple inverters in the NMG system. Simulation studies are conducted to test the NMG in islanding and load change scenarios. With the help of these studies, it is verified that the MPC-controlled inverters can provide better tracking accuracy in achieving desired power flows in the NMG system.

Life-prolonging central nervous system active systemic therapies for metastatic NSCLC have increased the complexity of managing brain metastases (BMs). Australian medical oncologists, radiation oncologists, and neurosurgeons discussed the evidence guiding the diverse clinical approaches to the management of BM in NSCLC. The Australian context is broadly applicable to other jurisdictions; therefore, we have documented these discussions as principles with broader applications. Patient management was stratified according to clinical and radiologic factors under two broad classifications of newly diagnosed BMs: symptomatic and asymptomatic. Other important considerations include the number and location of metastases, tumor histotypes, molecular subtype, and treatment purpose. Careful consideration of the pace and burden of symptoms, risk of worsening neurologic function at a short interval, and extracranial disease burden should determine whether central nervous system active systemic therapies are used alone or in combination with local therapies (surgery with or without radiation therapy). Most clinical trial evidence currently focuses on historical treatment options or a single treatment modality rather than the optimal sequencing of multiple modern therapies; therefore, an individualized approach is key in a rapidly changing therapeutic landscape.

In the phase III AURA3 study (NCT02151981), the third-generation epidermal growth factor receptor tyrosine kinase inhibitor osimertinib prolonged progression-free survival versus platinum-doublet chemotherapy in patients with EGFR T790M advanced NSCLC. Here, by next-generation sequencing of circulating tumor DNA, the authors assess candidate mechanisms of acquired resistance to osimertinib in patients from the AURA3 trial.

Abstract Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.

Nanoporous structures with 3D interconnected networks are traditionally made by dealloying a binary precursor. Certain approaches for fabricating these materials have been applied to refractory multi-principal element alloys (RMPEAs), which can be suitable candidates for high-temperature applications. In this study, nanoporous refractory multi-principal element alloys (np-RMPEAs) were fabricated from magnesium-based thin films (VMoNbTaMg) that had been prepared by magnetron sputtering. Vacuum thermal dealloying (VTD), which involves sublimation of a higher vapor pressure element, is a novel technique for synthesizing nanoporous refractory elements that are prone to oxidation. When VMoNbTaMg was heated under vacuum, a nanoporous structure was created by the sublimation of the highest vapor pressure element (Mg). X-ray photoelectron spectroscopy depth profiling indicated significantly less ligament oxidation during VTD as compared to traditional dealloying methods. Furthermore, np-RMPEAs exhibited outstanding stability against coarsening, retaining smaller ligaments (~25 nm) at elevated temperature (700 °C) for a prolonged period (48 h).

Pelaksanaan kegiatan pengabdian kepada masyarakat ini bertujuan untuk menghasilkan suatu dokumen bagi Yayasan Pendidikan Kristen, Sekolah GMIT, dan Gereja Masehi Injili di Timor (GMIT) untuk mendorong dan memfasilitasi upaya peningkatan mutu unggul Sekolah GMIT; menyediakan rujukan bagi intervensi, pengendalian, dan evaluasi mutu Sekolah GMIT; meningkatkan daya saing sekolah GMIT di kanca nasional dan global. Metode pelaksanaan kegiatan Pengabdian kepada Masyarakat, dilakukan dalam beberapa tahapan yakni: (1) penyusunan kerangka kerja tim, (2) studi dokumen, (3) analisis kebutuhan, (4) penyusunan draf, (5) validasi, (6) revisi/penyempurnaan draf, dan (6) pelaporan. Pelaksanaan kegiatan penyusunan standar sekolah dapat dikatakan berhasil secara signifikan 100%. Indikatornya, terlihat jelas dengan tersedianya standar sekolah unggul GMIT untuk satuan pendidikan dasar GMIT dan satuan pendidikan menengah Kristen dan meningkatnya atensi serta terjadi perubahan pola pikir Yapenkris dan Sekolah GMIT terkait urgensi, subtansi, dan prosedur pengembangan standar sekolah unggul GMIT. Hal ini diikuti dengan penetapan sejumlah sekolah GMIT, baik di tingkat dasar maupun menengah oleh GMIT untuk dikembangkan menjadi sekolah unggul GMIT. Selanjutnya dokumen standar sekolah unggul GMIT sudah dapat digunakan dalam pengembangan Sekolah Unggul GMIT.

Sorting nexins (SNX) are a family of proteins containing the Phox homology domain, which shows a preferential endo-membrane association and regulates cargo sorting processes. Here, we established that SNX32, an SNX-BAR (Bin/Amphiphysin/Rvs) sub-family member associates with SNX4 via its BAR domain and the residues A226, Q259, E256, R366 of SNX32, and Y258, S448 of SNX4 that lie at the interface of these two SNX proteins mediate this association. SNX32, via its PX domain, interacts with the transferrin receptor (TfR) and Cation-Independent Mannose-6-Phosphate Receptor (CIMPR), and the conserved F131 in its PX domain is important in stabilizing these interactions. Silencing of SNX32 leads to a defect in intracellular trafficking of TfR and CIMPR. Further, using SILAC-based differential proteomics of the wild-type and the mutant SNX32, impaired in cargo binding, we identified Basigin (BSG), an immunoglobulin superfamily member, as a potential interactor of SNX32 in SHSY5Y cells. We then demonstrated that SNX32 binds to BSG through its PX domain and facilitates its trafficking to the cell surface. In neuroglial cell lines, silencing of SNX32 leads to defects in neuronal differentiation. Moreover, abrogation in lactate transport in the SNX32-depleted cells led us to propose that SNX32 may contribute to maintaining the neuroglial coordination via its role in BSG trafficking and the associated monocarboxylate transporter activity. Taken together, our study showed that SNX32 mediates the trafficking of specific cargo molecules along distinct pathways.

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer death worldwide. Immunotherapy with immune checkpoint inhibitors (ICI) has significantly improved outcomes in some patients, however 80-85% of patients receiving immunotherapy develop primary resistance, manifesting as a lack of response to therapy. Of those that do have an initial response, disease progression may occur due to acquired resistance. The make-up of the tumour microenvironment (TME) and the interaction between tumour infiltrating immune cells and cancer cells can have a large impact on the response to immunotherapy. Robust assessment of the TME with accurate and reproducible methods is vital to understanding mechanisms of immunotherapy resistance. In this paper we will review the evidence of several methodologies to assess the TME, including multiplex immunohistochemistry, imaging mass cytometry, flow cytometry, mass cytometry and RNA sequencing.

Introduction: Over the past decade, ALK tyrosine kinase inhibitors have delivered unprecedented survival for individuals with ALK-positive (ALK+) lung cancers. Real-world data enhance the understanding of optimal drug sequencing and expectations for survival. Methods: Multicenter real-world study of individuals with pretreated advanced ALK+ lung cancers managed on a lorlatinib access program between 2016 and 2020. Key outcomes were lorlatinib efficacy, tolerability, and treatment sequencing. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method among all individuals (PFSa and OSa), with at least 30 days (one-cycle) lorlatinib exposure (PFSb and OSb), and with good performance status (PFSc and OSc). Subgroups of interest were analyzed to assess signals of potential clinical applicability. Two OS index dates were analyzed, from lorlatinib initiation and advanced ALK+ diagnosis. Results: The population (N = 38, 10 sites) was heavily pretreated (23 had ≥2 previous treatment lines) with a high disease burden (26 had 2–4 sites and 11 had >4 sites of metastatic disease, 19 had brain metastases). The overall response rate was 44% and the disease control rate was 81%. Lorlatinib dose reduction (18%), interruption (16%), and discontinuation (3%) were consistent with the trial experience. From advanced ALK+ diagnosis, the median OS for populations a, b, and c was 45.0 months, 69.9 months and 61.2 months respectively. From lorlatinib initiation, the median PFSa, PFSb and PFSc was 7.3 months, 13.2 months and 27.7 months and the median OSa, OSb and OSc was 19.9 months, 25.1 months and 27.7 months. The median PFSa with versus without brain metastases was 34.6 months versus 5.8 months (p = 0.09). The intracranial median PFS was 14.2 months. Previous good response versus poor response to the first ALK-directed therapy median PFSa was 27.7 months versus 4.7 months with a hazard ratio of 0.3 (p = 0.01). Conclusions: Lorlatinib is a potent, highly active brain-penetrant third-generation ALK tyrosine kinase inhibitors with benefits for most individuals in the later-line setting in a real-world evaluation, consistent with clinical trial data.

Abstract Immune checkpoint inhibitors and related molecules can achieve tumour regression, and even prolonged survival, for a subset of cancer patients with an otherwise dire prognosis. However, it remains unclear why some patients respond to immunotherapy and others do not. PET imaging has the potential to characterise the spatial and temporal heterogeneity of both immunotherapy target molecules and the tumor immune microenvironment, suggesting a tantalising vision of personally-adapted immunomodulatory treatment regimens. Personalised combinations of immunotherapy with local therapies and other systemic therapies, would be informed by immune imaging and subsequently modified in accordance with therapeutically induced immune environmental changes. An ideal PET imaging biomarker would facilitate the choice of initial therapy and would permit sequential imaging in time-frames that could provide actionable information to guide subsequent therapy. Such imaging should provide either prognostic or predictive measures of responsiveness relevant to key immunotherapy types but, most importantly, guide key decisions on initiation, continuation, change or cessation of treatment to reduce the cost and morbidity of treatment while enhancing survival outcomes. We survey the current literature, focusing on clinically relevant immune checkpoint immunotherapies, for which novel PET tracers are being developed, and discuss what steps are needed to make this vision a reality.

Background: Previous researchers have used a 30-min eutectic mixture of local anesthetic (EMLA) test, which assesses the sympathetically mediated vasomotor function, in diagnosing carpal tunnel syndrome (CTS). However, its specificity was low, limiting its clinical diagnostic utility. In this study, we assessed the efficiency of 90-min extended EMLA-induced stimulated skin-wrinkling (SSW) test in CTS diagnosis. Methods: A cross-sectional study was designed among patients clinically diagnosed with CTS. Hands of healthy volunteers and the asymptomatic hands of selected patients served as control. The Boston symptom severity scale (SSS) and the neuropathic pain severity inventory (NPSI) were used to assess symptom severity, and nerve conduction study (NCS) was used to assess electrophysiological severity. EMLA-induced SSW was visually graded after 90 min of application and correlated with symptom and NCS severities. Results: Forty-two symptomatic hands and 30 asymptomatic hands were enrolled as cases and controls, respectively. The diagnostic efficiency of the extended EMLA test was found to be 83.4% for digit 2 and 87.3% for the lateral 4 digits (mean), whereas the diagnostic efficiency of standard NCS was 88.1%. Boston SSS and NPSI were better correlated with EMLA positivity than NCS positivity. A linear regression analysis showed negative correlation of wrinkling grade with NCS grade. Conclusion: With its improved diagnostic efficiency, the 90-min extended EMLA test can feasibly be used as an alternative to NCS, especially in general practice settings. Its potential clinical utility should be explored in a large population of CTS patients showing varying clinical and electrophysiological severities.

Background ImmunoPET is a multicentre, single arm, phase 0–1 study that aims to establish if 89Zr-durvalumab PET/CT can be used to interrogate the expression of PD-L1 in larger, multicentre clinical trials.Methods The phase 0 study recruited 5 PD-L1+ patients with metastatic non-small cell lung cancer (NSCLC). Patients received 60MBq/70 kg 89Zr-durva up to a maximum of 74 MBq, with scan acquisition at days 0, 1, 3 or 5±1 day. Data on (1) Percentage of injected 89Zr-durva dose found in organs of interest (2) Absorbed organ doses (µSv/MBq of administered 89Zr-durva) and (3) whole-body dose expressed as mSv/100MBq of administered dose was collected to characterise biodistribution.The phase 1 study will recruit 20 patients undergoing concurrent chemoradiotherapy for stage III NSCLC. Patients will have 89Zr-durva and FDG-PET/CT before, during and after chemoradiation. In order to establish the feasibility of 89Zr-durva PET/CT for larger multicentre trials, we will collect both imaging and toxicity data. Feasibility will be deemed to have been met if more than 80% of patients are able complete all trial requirements with no significant toxicity.Ethics and dissemination This phase 0 study has ethics approval (HREC/65450/PMCC 20/100) and is registered on the Australian Clinical Trials Network (ACTRN12621000171819). The protocol, technical and clinical data will be disseminated by conference presentations and publications. Any modifications to the protocol will be formally documented by administrative letters and must be submitted to the approving HREC for review and approval.Trial registration number Australian Clinical Trials Network ACTRN12621000171819.

Vacuum thermal dealloying is a recently developed technique and was newly introduced to produce nanoporous metals, due to its intriguing advantages, i.e., preventing oxidation and producing no chemical waste, etc. Here, we report on the fabrication of nanoporous stainless steel films by vacuum thermal dealloying of sputtered stainless steel–magnesium precursor films. It was found that crack-free nanoporous stainless steel films can be successfully attained under a broad temperature range of 450–600 °C, with a dealloying time of 0.5–2 h. The resulting structure and ligaments were temperature- and time-dependent, and moreover, the condition of “600 °C + 2 h” generated the most homogeneous structure. Moreover, small amounts of residual Mg were found at pore sites in the resultant structures, suggesting that the dealloying was not fully complete.

Blood flow in the microcirculatory system is crucially affected by intrinsic red blood cell (RBC) properties, such as their deformability. In the smallest vessels of this network, RBCs adapt their shapes to the flow conditions. Although it is known that the age of RBCs modifies their physical properties, such as increased cytosol viscosity and altered viscoelastic membrane properties, the evolution of their shape-adapting abilities during senescence remains unclear. In this study, we investigated the effect of RBC properties on the microcapillary in vitro flow behavior and their characteristic shapes in microfluidic channels. For this, we fractioned RBCs from healthy donors according to their age. Moreover, the membranes of fresh RBCs were chemically rigidified using diamide to study the effect of isolated graded-membrane rigidity. Our results show that a fraction of stable, asymmetric, off-centered slipper-like cells at high velocities decreases with increasing age or diamide concentration. However, while old cells form an enhanced number of stable symmetric croissants at the channel centerline, this shape class is suppressed for purely rigidified cells with diamide. Our study provides further knowledge about the distinct effects of age-related changes of intrinsic cell properties on the single-cell flow behavior of RBCs in confined flows due to inter-cellular age-related cell heterogeneity.

Abstract Background The Australian Pancreatic Cancer Screening Program (APCSP) offers endoscopic ultrasound surveillance for individuals at increased risk of pancreatic ductal adenocarcinoma (PDAC) with all participants requiring assessment by a Familial Cancer Service before or after study enrolment. Methods Individuals aged 40–80 years (or 10 years younger than the earliest PDAC diagnosis) were eligible for APCSP study entry if they had 1) ≥ two blood relatives with PDAC (at least one of first-degree association); 2) a clinical or genetic diagnosis of Hereditary Pancreatitis or Peutz-Jeghers syndrome irrespective of PDAC family history; or 3) a known PDAC predisposition germline pathogenic variant (BRCA2, PALB2, CDKN2A, or Lynch syndrome) with ≥one PDAC-affected first- or second-degree relative. Retrospective medical record review was conducted for APCSP participants enrolled at the participating Australian hospitals from January 2011 to December 2019. We audited the genetic investigations offered by multiple Familial Cancer Services who assessed APCSP participants according to national guidelines, local clinical protocol and/or the availability of external research-funded testing, and the subsequent findings. Descriptive statistical analysis was performed using Microsoft Excel. Results Of 189 kindreds (285 participants), 50 kindreds (71 participants) had a known germline pathogenic variant at enrolment (BRCA2 n = 35, PALB2 n = 6, CDKN2A n = 3, STK11 n = 3, PRSS1 n = 2, MLH1 n = 1). Forty-eight of 136 (35%) kindreds with no known germline pathogenic variant were offered mutation analysis; 89% was clinic-funded, with increasing self-funded testing since 2016. The relatively low rates of genetic testing performed reflects initial strict criteria for clinic-funded genetic testing. New germline pathogenic variants were detected in five kindreds (10.4%) after study enrolment (BRCA2 n = 3 kindreds, PALB2 n = 1, CDKN2A n = 1). Of note, only eight kindreds were reassessed by a Familial Cancer Service since enrolment, with a further 21 kindreds identified as being suitable for reassessment. Conclusion Germline pathogenic variants associated with PDAC were seen in 29.1% of our high-risk cohort (55/189 kindreds; 82/285 participants). Importantly, 10.4% of kindreds offered genetic testing were newly identified as having germline pathogenic variants, with majority being BRCA2. As genetic testing standards evolve rapidly in PDAC, 5-yearly reassessment of high-risk individuals by Familial Cancer Services is warranted.

Budidaya rumput laut yang dilakukan oleh petani rumput laut di Desa Allumang, Kecamatan Pantar Barat Laut, Kabupaten Alor, Propinsi Nusa Tenggara Timur, belum sepenuhnya memperhatikan biofouling yang tumbuh bersama rumput laut, baik pada thallus rumput laut maupun pada tali atau longline yang digunakan untuk mengikat benih rumput laut dari awal budidaya, serta setelah panen. Hal ini berdampak pada penurunan kualitas rumput laut karena pertumbuhannya terhambat akibat adanya kompetisi unsur hara antara rumput laut dan biofouling. Kegiatan Pengabdian Kepada Masyarakat ini bertujuan untuk meningkatkan pengetahuan dan pemahaman masyarakat mengenai penanganan biofouling sebagai pesaing dalam pengambilan sumberdaya (nutrisi) untuk meningkatkan mutu atau mutu rumput laut. Metode pelaksanaan kegiatan pengabdian masyarakat ini dilakukan dalam beberapa tahapan, antara lain: (1) Tahap Persiapan; (2) tahap pelaksanaan kegiatan; (3) tahap evaluasi. Pelaksanaan kegiatan sosialisasi ini ditujukan kepada pembudidaya rumput laut di Desa Alumang yang berjumlah 582 KK dan perkembangannya dikatakan berhasil secara signifikan yaitu 100% karena secara kognitif psikologis terjadi perubahan pola pikir petani mengenai penanganan biofouling. untuk meningkatkan mutu atau mutu rumput laut karena berkorelasi dengan mutu rumput laut yang dihasilkan. Selanjutnya untuk lebih memastikan pemahaman pembudidaya rumput laut, dilakukan contoh kegiatan demonstrasi penanganan biofouling di lokasi budidaya.

Introduction: Entrectinib is an approved tyrosine kinase inhibitor (TKI) for ROS1 fusion–positive NSCLC. An updated integrated analysis of entrectinib from the ALKA-372-001, STARTRK-1, and STARTRK-2 trials is presented, with substantially longer follow-up, more patients, and the first description of the median overall survival (OS). An exploratory analysis of entrectinib in ROS1 fusion–positive NSCLC with the central nervous system (CNS)–only progression post-crizotinib is reported. Methods: Adults with ROS1 fusion–positive, locally advanced or metastatic NSCLC who received at least one dose of entrectinib and had 12 months or longer of follow-up were included in the analysis. Co-primary end points were confirmed objective response rate (ORR) and duration of response (DoR) by blinded independent central review. The data cutoff was on August 31, 2020. Results: The efficacy-assessable population comprised 168 ROS1 TKI–naïve patients. The median survival follow-up was 29.1 months (interquartile range, 21.8–35.9). The ORR was 68% (95% confidence interval [CI]: 60.2–74.8); the median DoR was 20.5 months. The median progression-free survival (PFS) was 15.7 months and the median OS was 47.8 months. In the 25 patients with measurable baseline CNS metastases, the intracranial ORR was 80% (95% CI: 59.3–93.2), median intracranial DoR was 12.9 months, and median intracranial PFS was 8.8 months. Among 18 patients with CNS-only progression on previous crizotinib treatment, two achieved a partial response (11%) and four had stable disease (22%). In seven patients with measurable CNS disease from this cohort, the intracranial ORR was 14% (1 partial response). Conclusions: Entrectinib is active and achieves prolonged survival in ROS1 TKI–naïve patients with ROS1 fusion–positive NSCLC. Modest activity is seen in patients with CNS-only progression post-crizotinib.

Abstract Malignant pleural mesothelioma (MPM) is an aggressive cancer with treatment limited to Cisplatin and Pemetrexed chemotherapy. Recently, we showed that drugs targeting the BCL-2-regulated apoptosis pathway could kill MPM cell lines in vitro, and control tumor growth in vivo. These studies showed BCL-XL was the dominant pro-survival BCL-2 family member correlating with its high-level expression in cells and patient tumor samples. In this study we show another inhibitor, AZD4320 that targets BCL-XL (and BCL-2), can also potently kill MPM tumor cells in vitro (EC50 values in the 200 nM range) and this effect is enhanced by co-inhibition of MCL-1 using AZD5991. Moreover, we show that a novel nanoparticle, AZD0466, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer, was as effective as standard-of-care chemotherapy, Cisplatin, at inhibiting tumor growth in mouse xenograft studies, and this effect was enhanced when both drugs were combined. Critically, the degree of thrombocytopenia, an on-target toxicity associated with BCL-XL inhibition, was significantly reduced throughout the treatment period compared to other BCL-XL-targeting BH3-mimetics. These pre-clinical findings provide a rationale for the future clinical evaluation for novel BH3-mimetic formulations in MPM, and indeed, other solid tumor types dependent on BCL-XL.

Milk is a complex liquid, and the concentrations of many of its components are under genetic control. Many genes and pathways are known to regulate milk composition, and the purpose of this review is to highlight how the discoveries of quantitative trait loci (QTL) for milk phenotypes can elucidate these pathways. The main body of this review focuses primarily on QTL discovered in cattle (Bos taurus) as a model species for the biology of lactation, and there are occasional references to sheep genetics. The following section describes a range of techniques that can be used to help identify the causative genes underlying QTL when the underlying mechanism involves the regulation of gene expression. As genotype and phenotype databases continue to grow and diversify, new QTL will continue to be discovered, and although proving the causality of underlying genes and variants remains difficult, these new data sets will further enhance our understanding of the biology of lactation.

Background: Carpal tunnel syndrome (CTS) predominantly affects women. Previous studies observed more intense symptoms among women without a corresponding increase in disease severity and attributed it to reporting bias. In this study, we examined whether women are inherently more vulnerable to work related median nerve dysfunction at wrist and whether reported CTS symptoms among women correspond to the degree of median neuropathy at wrist. Methods: A cross-sectional study was designed for outpatients (aged 25-59 years) diagnosed with CTS. Occupational categorisation was done based on the analysis of their individual job tasks. Symptom severity (Boston Symptom Severity Scale – SSS), functional disability (Boston Functional Status Scale - FSS), and clinical (Hi – Ob scale) and neurophysiological severity (NCS grade) were determined, compared among occupational groups and were statistically analysed. Results: A total of 454 patients (348 women and 106 men; F: M ratio 3.28:1) were included. Among them, 191 were housewives. Female manual workers and housewives reported significantly more intense symptoms with a corresponding increase in clinical and electrophysiological severity (p < 0.001) when compared to female non-manual workers. However, no significant difference in symptoms, clinical or neurophysiological severity was found between male non-manual and manual workers. Among manual workers, women were more symptomatic than men, but clinical and neurophysiological severities were significantly higher only in the older age groups. Conclusion: The differential vulnerability of the female population to hand-intensive work predisposes them to severe median nerve dysfunction at wrist with proportionately higher CTS symptoms. Therefore, working women need focussed attention for remedial measures.

Budaya temong merupakan media rekonsiliasi, walaupun budaya temong sangat bermanfaat dalam menyelesaikan pertikaian tetapi budaya ini mulai ditinggalkan karena tergerus oleh kemajuan zaman setiap persoalan langsung dilimpahkan ke kepolisian. melalui metode wawancara dan diskusi bersama sesama anggota temong, tokoh adat, tokoh masyarakat, tokoh agama dan pemerintah ditemukan pola dan faktor-faktor yang mendorong peristiwa rekonsiliasi. adapun pola yang mendorong peristiwa rekonsiliasi antara lain: (a) saat kegiatan temong berlangsung ada ikatan emosional, merasa senasib dan sepenanggungan sehingga perasan bathin antar sesama anggota temong lebih terbuka; (b) ketika kegiatan temong berlangsung ada perasaan sukacita, bergembira bersama sehingga melalui kebersamaan yang ada, suasana bathin para anggota lebih ebih menerima satu dengan yang lain dan saling memaafkan jika ada pertikaian mealui guyonan, berbalas berpantun; (c) setelah kegiatan temong berakhir dilanjutkan dengan makan bersama sehingga jika masih ada persoalan yang tersimpan dibathin dapat segera lebur karena semua anggota saling melayani, menerima kekurangan dan kelebihan antar anggota. selanjutnya ditemukan faktor yang mendorong peristiwa rekonsiliasi dapat berlangsung, seperti (a) keinginan memegang teguh nilai adatia yang diwariskan oleh leluhur melalui budaya temong; (b) apabila rekonsiliasi berhasil dengan mendamaikan pertikaian oleh beberapa pihak saat pelaksanaan kegiatan temong biasanya akan menghasilkan hasil panen yang melimpah; (c) apabila rekonsiliasi berhasil dengan mendamaikan pertikaian oleh beberapa pihak saat pelaksanaan kegiatan temong, di ladang (kebun) tersebut biasanya terbebas dari hama yang dapat merusak tanaman perkebunan. melalui kegiatan pengabdian masyarakat, kami melakukan pendampingan kepda masyarakat untuk tetap menggunakan budaya temong sebagai media rekonsiliasi.

The ability to maintain relevant information on a daily basis is negatively impacted by aging. However, the neuronal mechanism manifesting memory persistence in young animals and memory decline in early aging is not fully understood. A novel event, when introduced around encoding of an everyday memory task, can facilitate memory persistence in young age but not in early aging. Here, we investigated in male rats how sub-regions of the hippocampus are involved in memory representation in behavioral tagging and how early aging affects such representation by combining behavioral training in appetitive delayed-matching-to-place tasks with the “cellular compartment analysis of temporal activity by fluorescence in situ hybridization” technique. We show that neuronal assemblies activated by memory encoding were also partially activated by novelty, particularly in the distal CA1 and proximal CA3 subregions in young male rats. In early aging, both encoding- and novelty-triggered neuronal populations were significantly reduced with a more profound effect in encoding neurons. Thus, memory persistence through novelty facilitation engages overlapping hippocampal assemblies as a key cellular signature, and cognitive aging is associated with underlying reduction in neuronal activation.

The erythrocyte sedimentation rate (ESR) is one of the oldest medical diagnostic tools. However, currently there is some debate on the structure formed by the cells during the sedimentation process. While the conventional view is that erythrocytes sediment as separate aggregates, others have suggested that they form a percolating gel, similar to other colloidal suspensions. However, visualization of aggregated erythrocytes, which would settle the question, has always been challenging. Direct methods usually study erythrocytes in 2D situations or low hematocrit (∼1%). Indirect methods, such as scattering or electric measurements, provide insight on the suspension evolution, but cannot directly discriminate between open or percolating structures. Here, we achieved a direct probing of the structures formed by erythrocytes in blood at stasis. We focused on blood samples at rest with controlled hematocrit of 45%, from healthy donors, and report observations from three different optical imaging techniques: direct light transmission through thin samples, two-photon microscopy and light-sheet microscopy. The three techniques, used in geometries with thickness from 150 μm to 3 mm, highlight that erythrocytes form a continuous network with characteristic cracks, i.e., a colloidal gel. The characteristic distance between the main cracks is of the order of ∼100 μm. A complete description of the structure then requires a field of view of the order of ∼1 mm, in order to obtain a statistically relevant number of structural elements. A quantitative analysis of the erythrocyte related processes and interactions during the sedimentation need a further refinement of the experimental set-ups.

Background: Rising population of elder people and associated rise in health problems, frailty and disabilities have significant socioeconomic and health care implications. Mental health related disability contributes significantly in the global disability statistics and is an important health and quality of life indicator. Assessment of disabilities in elderly is essential part of routine evaluation, further it also helps the clinicians in identifying current functional status and choosing and monitoring therapeutic interventions and need for social welfare schemes. Methods: In order to understand the process of disability assessment in geriatric psychiatry and to gather information about social welfare schemes a literature review in Google Scholar and PubMed electronic database, and website of various ministries under Government of India was done, using developed key search terms for articles published up to February 2021. The identified eligible articles were reviewed for ideas and concepts, which were then integrated and categorized under broader themes. Finally, the broad categories were discussed briefly based on the above framework. Results: Review findings are summarized under the following headings: concept of ageing and disability, assessment of disability, process of certification, and social welfare schemes. Conclusions: The process of disability assessment comprises of comprehensive clinical evaluation, use of standardized rating instruments and disability certification wherever warranted or asked for. It is now being acknowledged worldwide by provisions of various social welfare benefits, that living with disability and increased care needs should be an integral part of definition of successful ageing.

Abstract Antiphospholipid syndrome (APS) is an autoimmune disease that demonstrates antiphospholipid antibodies that cause hypercoagulability and leads to venous and arterial thrombosis. Autoantibodies to a disintegrin‐like and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS 13) play a role in the microthrombosis of thrombotic thrombocytopenic purpura in APS patients.

Introduction With growing health care costs, high-value care is an increasingly important subject for medical training. Many resident and medical student curricula have incorporated lectures-based material about this topic. However, practical-type experiences are needed to refine critical-thinking skills essential for high-value care. Methods To provide such practical experiences, we developed an instructional game for resident-level education that incorporated cost-constraint-based approaches in the workup of anemia. To play the game, teams of learners were given patients with anemia of unknown cause. To pay for their diagnostic tests of choice, teams earned money by correctly answering internal medicine resident-level anemia questions. The first team to successfully work up and diagnose three patients won. Results Resident learners had very positive reviews of our game. As a team, groups of residents across all levels were able to develop cost-effective strategies for diagnosis. Our game also served as a resource for anemia education. Residents on average felt the game enhanced their ability to apply medical knowledge and clinical reasoning (M = 4.7 out of 5, where 5 = strongly agree), as well as high-value care (4.6), and should remain in the program for the high-value care curriculum (4.9). Discussion Game-based learning provides a fun, orthogonal approach to learning critical-thinking skills used during anemia diagnostic patient workups. Although we did not quantify change in diagnostic test ordering, according to resident-learners, our high-value care game improved their ability to integrate cost-effective strategies into their practice of medicine.

(1) Background: When red blood cells are centrifuged in a continuous Percoll-based density gradient, they form discrete bands. While this is a popular approach for red blood cell age separation, the mechanisms involved in banding were unknown. (2) Methods: Percoll centrifugations of red blood cells were performed under various experimental conditions and the resulting distributions analyzed. The age of the red blood cells was measured by determining the protein band 4.1a to 4.1b ratio based on western blots. Red blood cell aggregates, so-called rouleaux, were monitored microscopically. A mathematical model for the centrifugation process was developed. (3) Results: The red blood cell band pattern is reproducible but re-centrifugation of sub-bands reveals a new set of bands. This is caused by red blood cell aggregation. Based on the aggregation, our mathematical model predicts the band formation. Suppression of red blood cell aggregation reduces the band formation. (4) Conclusions: The red blood cell band formation in continuous Percoll density gradients could be explained physically by red blood cell aggregate formation. This aggregate formation distorts the density-based red blood cell age separation. Suppressing aggregation by osmotic swelling has a more severe effect on compromising the RBC age separation to a higher degree.

Nivolumab is an immune checkpoint inhibitor used to treat multiple solid-organ malignancies. While many of its immune-related adverse events are well established, nivolumab-induced sclerosing cholangitis remains poorly characterised, with no defined diagnostic criteria. Moreover, data regarding long-term outcomes are particularly lacking. We present a biopsy-proven case of nivolumab-induced sclerosing cholangitis, which uniquely captures 18 months of follow-up post-treatment. Our case highlights key features of intrahepatic subtype sclerosing cholangitis and suggests durable response to corticosteroid therapy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The technical and financial feasibility of small-scale distributed Concentrating Solar Thermal Power (CSP) systems for urban areas in Johannesburg, South Africa, is investigated. The University of the Witwatersrand (Wits), located in central Johannes-burg, is used as the basis of a case study for the im-plementation of these systems. A number of proven CSP technologies were identified and a technology screening was performed to identify suitable technologies for possible implementation, for a reference output of 120 kW(e). From these, a number of systems were chosen for more detailed evaluation and the hourly energy production of these systems was analysed, using local weather data. The Compound Linear Fresnel Reflector system (CLFR) proved to be most suitable because of the space and cost benefits it offers. Systems that integrate organic Rankine cycles (ORC) as well as thermal storage and hybridisation were also investigated. The levelised cost of electricity (LEC) was predicted to be between R4.31 and R3.18 per kWh. Currently these technologies cannot compete financially with the price of local, fossil produced electricity, but with the increase in electricity tariffs and demand for clean reliable power CSP technologies, may become competitive in distributed generation systems in urban areas.

The success of immunotherapeutics over the past decade has fundamentally altered the therapeutic landscape in melanoma and non-small cell lung (NSCLC) cancer care. Multiple clinical trials have confirmed significant improvements in survival with a variety of immunotherapeutic strategies. The careful and appropriate selection of standard of care (SOC) therapies is key to the successful design and interpretation of these trials. To date immunotherapeutic trials have used best supportive care, matched placebo, chemotherapy, targeted therapy or, more recently, established immunotherapeutics in melanoma clinical trials as SOCs. Each of these SOC choices has a fundamental impact on the selection and validity of response assessment criteria and clinical endpoints. As yet there is no established approach, thus new data must be interpreted with an understanding of the limitations of the current paradigm. Additionally, the pace of development has mandated the use of novel clinical trial designs, answering multiple therapeutic questions simultaneously and designed to expedite regulatory approval. This review addresses the most important challenges in the selection of SOC in immunotherapeutic trials and the current and future challenges in trial design.