A phase II study of tepotinib in patients with advanced solid cancers harboring MET exon 14 skipping mutations or amplification (KCSG AL19-17).

BACKGROUND: We evaluated the efficacy and safety of tepotinib in patients with various solid cancers harboring MET exon 14 skipping mutation (METex14) or MET gene amplification. PATIENTS AND METHODS: A phase II, multicenter study was conducted in patients with advanced or metastatic solid cancers who progressed after standard treatment, harboring either METex14 or MET amplification detected in tissue-based next-generation sequencing (NGS). The primary endpoint was objective response rate (ORR). For exploratory analyses, we analyzed the gene profiles using plasma NGS test. RESULTS: Thirty-five patients were enrolled. The ORR was 57.6% for all patients, 52.2% for those with METex14, and 70% for those with MET amplification. Median progression-free survival (PFS) was 8 months [95% confidence interval (CI) 4.5-11.5 months] and median overall survival (OS) was 14 months (95% CI 7.8-20.2 months) in all patients. For patients with non-small-cell lung cancer with METex14, the median PFS was 9 months (95% CI 4.7-13.4 months) and the median OS was 17 months [95% CI not applicable (NA)-NA]. For patients with MET amplification, the median PFS was 7 months (95% CI 1.5-12.5 months) and the median OS was 10 months (95% CI 5.8-14.2 months). The ORR of patients with MET dysregulation detected by plasma NGS was 72.2%, whereas the ORR was 30% in those without detection. The most common adverse events were peripheral edema, asthenia, transaminase elevation, and anorexia, mostly grade 1 or 2. CONCLUSIONS: Tepotinib demonstrated consistent antitumor activity in patients with METex14, and promising antitumor activity in various cancers with MET amplification. Detection of MET dysregulation by plasma NGS may predict the response to tepotinib.

Reduction of Displaced Acetabular Fracture with Central Hip Dislocation using Vector Traction: A Case Report.

Fracture-dislocations of the hip is the result of high-energy trauma which necessitates urgent reduction. Closed reduction is usually attempted first and if failed, open reduction is indicated and may require more than one surgical approach. However, there is also the option of managing it with vector traction. This case report details the treatment of a middle-aged gentleman who sustained a left hip central dislocation which was gradually reduced with vector traction prior to surgery and in doing so, diminished the risk of him developing several potentially debilitating complications known to be associated with surgical fixation of such injuries.

Nosocomial outbreak of Achromobacter spp. bacteremia due to germicide contamination: a systematic review.

OBJECTIVE: Achromobacter spp. are aerobic, non-fermentative Gram-negative bacilli that can be widely found in aquatic environments. Nosocomial outbreaks and pseudo-outbreaks of Achromobacter spp. bacteremia have been recognized for decades. Notably, commonly used germicides in hospital settings constitute important sources for these outbreaks. This review aims at summarizing the latest studies and presents the characteristics of nosocomial outbreaks of Achromobacter spp. bacteremia caused by germicide contamination. MATERIALS AND METHODS: A systematic search of the PubMed and EMBASE databases was conducted for articles published in English between January 1, 2000, and June 10, 2022. RESULTS: Overall, 170 articles were retrieved, and 7 studies were finally included in the systematic review. Whether true or pseudo-bacteremia, positive blood culture results were most commonly reported in immunosuppressed patients or those with indwelling catheters. The most commonly reported contaminated germicide was chlorhexidine solution used as both an antiseptic and disinfectant. Atomizers, dispensers, and various product containers were identified as reservoirs. The prognoses of the affected patients were generally favorable. CONCLUSIONS: Awareness about the high survival ability of Achromobacter spp. in germicides and the possible hospital reservoirs of these microbes will help to improve infection control and prevent nosocomial outbreaks or pseudo-outbreaks caused by Achromobacter spp.

Fluctuation of BCR-ABL1 qPCRIS level beyond 0.1%IS after stopping tyrosine kinase inhibitor in chronic myeloid leukaemia patients with deep molecular response for at least two years.

Fluctuation of BCR-ABL1 real-time quantitative polymerase chain reaction in International Scale (qPCRIS) level below major molecular response (MMR) (0.1%IS) is a known phenomenon after stopping tyrosine kinase inhibitor (TKI) in chronic myeloid leukaemia (CML) patients who are attempting treatment free remission (TFR). We report here four cases of fluctuation beyond MMR during conduct of a Malaysia Stop TKI Trial (MSIT) to examine the validity of the commonly used relapse criterion - loss of MMR for one reading - aiming to provide evidence in setting relapse criteria for future CML patients who want to attempt TFR.

Knowledge, attitudes and behaviour towards needlestick injuries among junior doctors.

BACKGROUND: Needlestick injuries (NSIs) are common healthcare-related injuries and possible consequences include blood-borne infections. Despite that, a large proportion of NSIs are not reported. AIMS: To estimate the prevalence of under-reporting of NSIs and to evaluate the knowledge, attitude and behaviour towards NSIs among junior doctors in a tertiary hospital in Singapore. METHODS: An explanatory sequential mixed-methods design was employed. Quantitative data were collected through questionnaires completed by 99 junior doctors. Descriptive statistics and bivariate analysis were performed to evaluate socio-demographic characteristics, NSI history and NSI reporting practices. Qualitative data were collected through 12 in-depth interviews. Participants were purposively recruited, and semi-structured topic guides were developed. Data were analysed using a thematic approach. RESULTS: Fifty-two per cent of respondents had history of NSI. Of those with history of NSI, 31% did not report injury. NSI reporters were 1.52 times as likely to be aware of how to report injury (P < 0.05), and 1.63 times as likely to feel that reporting benefits their health (P < 0.01) compared with non-reporters. NSI reporters were 83% more likely to report a clean NSI (P = 0.05). For non-reporters, the main reasons for not reporting were perceived low risk of transmission (41%) and lack of time to report (35%). Themes identified in the qualitative data include perceived benefits, perceived barriers, perceived threats, cues to action and organizational culture. CONCLUSION: Under-reporting of NSIs may have significant implications for patients and healthcare workers. Addressing identified factors and instituting targeted interventions will help to improve reporting rates.

Astrocytic water channel aquaporin-4 modulates brain plasticity in both mice and humans: a potential gliogenetic mechanism underlying language-associated learning.

The role of astrocytes in brain plasticity has not been extensively studied compared with that of neurons. Here we adopted integrative translational and reverse-translational approaches to explore the role of an astrocyte-specific major water channel in the brain, aquaporin-4 (AQP4), in brain plasticity and learning. We initially identified the most prevalent genetic variant of AQP4 (single nucleotide polymorphism of rs162008 with C or T variation, which has a minor allele frequency of 0.21) from a human database (n=60 706) and examined its functionality in modulating the expression level of AQP4 in an in vitro luciferase reporter assay. In the following experiments, AQP4 knock-down in mice not only impaired hippocampal volumetric plasticity after exposure to enriched environment but also caused loss of long-term potentiation after theta-burst stimulation. In humans, there was a cross-sectional association of rs162008 with gray matter (GM) volume variation in cortices, including the vicinity of the Perisylvian heteromodal language area (Sample 1, n=650). GM volume variation in these brain regions was positively associated with the semantic verbal fluency. In a prospective follow-up study (Sample 2, n=45), the effects of an intensive 5-week foreign language (English) learning experience on regional GM volume increase were modulated by this AQP4 variant, which was also associated with verbal learning capacity change. We then delineated in mice mechanisms that included AQP4-dependent transient astrocytic volume changes and astrocytic structural elaboration. We believe our study provides the first integrative evidence for a gliogenetic basis that involves AQP4, underlying language-associated brain plasticity.

Serologic evidence of West Nile virus and Usutu virus infections in Eurasian coots in the Netherlands.

West Nile virus (WNV) and Usutu virus (USUV) are arboviruses that are maintained in enzootic transmission cycles between mosquitoes and birds and are occasionally transmitted to mammals. As arboviruses are currently expanding their geographic range and emerging in often unpredictable locations, surveillance is considered an important element of preparedness. To determine whether sera collected from resident and migratory birds in the Netherlands as part of avian influenza surveillance would also represent an effective source for proactive arbovirus surveillance, a random selection of such sera was screened for WNV antibodies using a commercial ELISA. In addition, sera of jackdaws and carrion crows captured for previous experimental infection studies were added to the selection. Of the 265 screened serum samples, 27 were found to be WNV-antibody-positive, and subsequent cross-neutralization experiments using WNV and USUV confirmed that five serum samples were positive for only WNV-neutralizing antibodies and seven for only USUV. The positive birds consisted of four Eurasian coots (Fulica atra) and one carrion crow (Corvus corone) for WNV, of which the latter may suggest local presence of the virus, and only Eurasian coots for USUV. As a result, the screening of a small selection of serum samples originally collected for avian influenza surveillance demonstrated a seroprevalence of 1.6% for WNV and 2.8% for USUV, suggesting that this sustained infrastructure could serve as a useful source for future surveillance of arboviruses such as WNV and USUV in the Netherlands.

Gastrointestinal inflammation by gut microbiota disturbance induces memory impairment in mice.

In this study, we tested our hypothesis regarding mechanistic cross-talk between gastrointestinal inflammation and memory loss in a mouse model. Intrarectal injection of the colitis inducer 2,4,6-trinitrobenzenesulfonic acid (TNBS) in mice caused colitis via activation of nuclear factor (NF)-κB and increase in membrane permeability. TNBS treatment increased fecal and blood levels of lipopolysaccharide (LPS) and the number of Enterobacteriaceae, particularly Escherichia coli (EC), in the gut microbiota composition, but significantly reduced the number of Lactobacillus johnsonii (LJ). Indeed, we observed that the mice treated with TNBS displayed impaired memory, as assessed using the Y-maze and passive avoidance tasks. Furthermore, treatment with EC, which was isolated from the feces of mice with TNBS-induced colitis, caused memory impairment and colitis, and increased the absorption of orally administered LPS into the blood. Treatment with TNBS or EC induced NF-κB activation and tumor necrosis factor-α expression in the hippocampus of mice, as well as suppressed brain-derived neurotrophic factor expression. However, treatment with LJ restored the disturbed gut microbiota composition, lowered gut microbiota, and blood LPS levels, and attenuated both TNBS- and EC-induced memory impairment and colitis. These results suggest that the gut microbiota disturbance by extrinsic stresses can cause gastrointestinal inflammation, resulting in memory impairment.

Light chain multiple myeloma: an evaluation of its biochemical investigations.

Multiple myeloma is a type of plasma cell dyscrasia, characterised by presence of paraprotein or monoclonal (M)-protein in serum or urine. The M-protein may consist of an intact immunoglobulin, the heavy chain only or the light chain only. The latter, designated as light chain multiple myeloma (LCMM) makes up almost 20% of myelomas. Clinical manifestation is often heralded by hypercalcaemia, renal impairment, normocytic normochromic anaemia and bone lesions, reflecting end-organ damage, collectively known as the acronym CRAB. In particular, free light chain nephrotoxicity accounts for the high prevalence of renal impairment seen in LCMM. This case illustrates a typical presentation of LCMM with focal discussion on its initial and diagnostic, as well as prognostic biochemical investigations.

Determination of the 99th percentile upper reference limit for high-sensitivity cardiac troponin I in Malaysian population.

Introduction of high-sensitivity cardiac troponin I (hscTn I) assays for routine clinical use in Malaysia requires determination of the 99th percentile upper reference limit (URL) for each assay to suit local context. Hence, this study aimed to determine the 99th percentile URL for hscTn I in the Malaysian population. A total of 250 (120 males and 130 females) healthy Malaysian blood donors aged 18 to 60 years old were recruited. Blood samples for hscTn I were measured using Abbott Diagnostics hscTn I assay on Architect i2000sr analyser. The 99th percentile was calculated using a non-parametric method and gender specific results were compared. The 99th percentile URL for hscTn I for the overall population was 23.7 ng/L, with gender specific values being 29.9 ng/L and 18.6 ng/L for male and female, respectively. Females had significantly lower hscTn I compared to males. This study confirms the use of gender specific 99th percentile URL for hscTn I for clinical use in a multi-ethnic Malaysian population.

Lactobacillus fermentum IM12 attenuates inflammation in mice by inhibiting NF-κB-STAT3 signalling pathway.

In the present study, we isolated Lactobacillus fermentum IM12 from human gut microbiota, which strongly inhibited interleukin (IL)-6 expression and STAT3 activation in lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages, and examined its anti-inflammatory effect in mice with carrageenan-induced hind-paw oedema (CIE) or 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis (TIC). Oral administration of IM12 (0.2×109, 1×109 or 5×109 cfu/mouse, once a day for 3 days) in mice with CIE significantly suppressed the increase of oedema volume and thickness, as well as myeloperoxidase activity and IL-6, IL-17, NO, and prostaglandin E2 levels in the carrageenan-stimulated paw. Treatment with IM12 (1×109 cfu/mouse, once a day for 3 days) in mice with TIC significantly suppressed colon shortening, and myeloperoxidase activity and IL-6 and IL-17 levels. Treatment with IM12 in mice with CIE or TIC also suppressed the expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2, as well as activation of nuclear factor kappa beta (NF-κB) and signal transducer and activator of transcription 3 (STAT3). Furthermore, IM12 significantly inhibited the expression of iNOS, and COX-2, as well as activation of NF-κB in LPS-stimulated mouse peritoneal macrophages. The inflammatory effect of heat-inactivated IM12 was significantly different to that of live IM12 in mice with TIC, although anti-inflammatory effect of IM12 was reduced by heat treatment. Based on these findings, IM12 may attenuate inflammation by inhibiting NF-κB-STAT3 signalling pathway.

Pediococcus acidilactici LAB4 and Lactobacillus plantarum LAB12 assimilate cholesterol and modulate ABCA1, CD36, NPC1L1 and SCARB1 in vitro.

There is growing interest in the use of probiotic lactic acid bacteria (LAB) for prevention of hypercholesterolaemia. This study assessed the cholesterol lowering ability of Pediococcus acidilactici LAB4 and Lactobacillus plantarum LAB12 in growth media. Both LAB yielded >98% (39.2 µg/ml) cholesterol lowering in growth media. Nile Red staining indicated direct assimilation of cholesterol by the LAB. The LAB were then explored for their prophylactic (pre-treatment of HT29 cells with LAB prior to cholesterol exposure) and biotherapeutic (treatment of HT29 cells with LAB after exposure to cholesterol) use against short and prolonged exposure of HT29 cells to cholesterol, respectively. For HT29 cells pre-treated with LAB, cholesterol lowering was accompanied by down-regulation of ATP-binding cassette family transporter-type A1 (ABCA1), cluster of differentiation 36 (CD36) and scavenger receptor class B member 1 (SCARB1). HT29 cells treated with LAB after prolonged exposure to cholesterol source, on the other hand, was associated with up-regulation of ABCA1, restoration of CD36 to basal level and down-regulation of Neimann-Pick C1-Like 1 (NPC1L1). The present findings implied the potential use of LAB4 and LAB12 as part of the strategies in prevention and management of hypercholesterolaemia.

Posterior Elbow Dislocation with Brachial Artery Thrombosis Treated Non-surgically: A Case Report.

The brachial artery is rarely injured in closed posterior dislocation of the elbow, unlike the high rate of vascular injury seen after dislocation of the knee. Despite the anatomical proximity of the brachial artery to the elbow joint, most cases of brachial artery injury after dislocation of the elbow are related to an associated fracture, an open injury or high-energy trauma. A high index of suspicion should be maintained as well as a thorough neurovascular examination with regards this potentially disastrous complication. We describe an unusual case of complete thrombosis of the brachial artery presenting with a posterior elbow dislocation following a fall (low energy trauma) that was treated nonoperatively. At three months follow-up, patient had good circulation over the affected limb, no complaints of ischemic pain or cold intolerance, no signs of Volkmann's ischemic contracture, and a range of motion that was comparable to the contralateral limb.

Comparison of cytotoxicity test models for evaluating resin-based composites.

OBJECTIVES: This study compared different cytotoxicity test models for evaluating resin-based composites (RBCs) and assessed the biocompatibility of standard and bulk-fill RBCs. METHODS: A standard (spectrum TPH) and a bulk-fill (smart dentin replacement (SDR)) RBC were selected. Disc-shaped specimens (7 mm diameter) of 2 and 4 mm thickness were polymerized for 20 s with a LED curing light of 700 mW/cm2 irradiance. The specimens ( n = 5) were subjected to micro-hardness testing and three cytotoxicity test models (direct contact, indirect contact and extract tests) with the established L-929 cell line. Hardness ratios of top and bottom surfaces of specimens were computed to assess the effectiveness of cure. For the direct and indirect contact tests, the cells were stained and zones of inhibition were analyzed after material contact for 24 h. For the extract test, cells were exposed to extracts for 24 h, and cell viability was measured. Data was analyzed using analysis of variance/Scheffe's post hoc test and Pearson's correlation ( p < 0.05). RESULTS: The lowest mean hardness ratio and highest cytotoxicity were observed for TPH at 4 mm. At 4-mm thickness, SDR was found to be biocompatible with all three models. Correlations between hardness ratio and cell viability ranged from r = 0.89-0.96 for the various tests. A significant correlation ( r = 0.97) was also observed between the three test models. CONCLUSION: Our data indicated consistency between direct contact, indirect contact and extract test models for cytotoxicity testing of RBCs. Bulk placement and curing at 4 mm for the bulk-fill RBC evaluated did not result in undue cytotoxicity.

An improved reprogrammable mouse model harbouring the reverse tetracycline-controlled transcriptional transactivator 3.

Reprogrammable mouse models engineered to conditionally express Oct-4, Klf-4, Sox-2 and c-Myc (OKSM) have been instrumental in dissecting molecular events underpinning the generation of induced pluripotent stem cells. However, until now these models have been reported in the context of the m2 reverse tetracycline-controlled transactivator, which results in low reprogramming efficiency and consequently limits the number of reprogramming intermediates that can be isolated for downstream profiling. Here, we describe an improved OKSM mouse model in the context of the reverse tetracycline-controlled transactivator 3 with enhanced reprogramming efficiency (>9-fold) and increased numbers of reprogramming intermediate cells albeit with similar kinetics, which we believe will facilitate mechanistic studies of the reprogramming process.

Predisposition to and effects of methamphetamine use on the adolescent brain.

Adolescence is a period of heightened vulnerability both to addictive behaviors and drug-induced brain damage. Yet, only limited information exists on the brain mechanisms underlying these adolescent-specific characteristics. Moreover, distinctions in brain correlates between predisposition to drug use and effects of drugs in adolescents are unclear. Using cortical thickness and diffusion tensor image analyses, we found greater and more widespread gray and white matter alterations, particularly affecting the frontostriatal system, in adolescent methamphetamine (MA) users compared with adult users. Among adolescent-specific gray matter alterations related to MA use, smaller cortical thickness in the orbitofrontal cortex was associated with family history of drug use. Our findings highlight that the adolescent brain, which undergoes active myelination and maturation, is more vulnerable to MA-related alterations than the adult brain. Furthermore, MA-use-related executive dysfunction was greater in adolescent MA users than in adult users. These findings may provide explanation for the severe behavioral complications and relapses that are common in adolescent-onset drug addiction. Additionally, these results may provide insights into distinguishing the neural mechanisms that underlie the predisposition to drug addiction from effects of drugs in adolescents.