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.

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.

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.

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.

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.

Three-dimensional modelling and concurrent measurements of root anatomy in mandibular first molar mesial roots using micro-computed tomography.

AIM: To obtain concurrent radicular measurements in the mesiobuccal (MB) and mesiolingual (ML) canals of mandibular first molars using scanned data of micro-computed tomography (µCT) with novel software. METHODOLOGY: The scanned data from 37 mandibular first molar mesial roots were reconstructed and analysed with custom-developed software (Kappa2). For each canal, three-dimensional (3D) surface models were re-sliced at 0.1-mm intervals perpendicular to the central axis. Dentine thicknesses, canal widths and 3D curvatures were measured automatically on each slice. Measurements were analysed statistically with anova for differences at each direction and at different levels of both canals. RESULTS: Lateral dentine thicknesses were significantly higher than mesial and distal thicknesses, at all the levels of both canals (P < 0.001). Mesial thicknesses were significantly higher than distal thicknesses in the coronal third of both canals (P < 0.001). Thinnest dentine thicknesses were mainly located on the disto-inside of both canals. Narrowest canal widths were 0.24 ± 0.10 and 0.22 ± 0.09 mm in MB and ML canals, respectively. Canal curvatures were greatest in the apical third of both canals (P < 0.001), and they were greater in the MB canals than in the ML canals (P < 0.05). CONCLUSIONS: Micro-computed tomography with novel software provided valuable anatomical information for optimizing instrumentation and minimizing mishaps in nonsurgical root canal treatment.

Alterations in white matter microstructures and cognitive dysfunctions in benign childhood epilepsy with centrotemporal spikes.

BACKGROUND AND PURPOSE: Although benign childhood epilepsy with centrotemporal spikes (BECTS) is known to have good prognosis, patients often manifest neuropsychological impairments. This study aimed to investigate cognitive dysfunctions and their relationship with white matter microstructural changes in BECTS patients. METHODS: Nineteen BECTS and 25 normal subjects aged 7-16 years were included. Neuropsychological performances were assessed by the Wechsler Intelligence Scale for Children III, executive function tests, verbal and visuospatial memory tests, the verbal fluency and Boston naming tests. Diffusion tensor imaging (DTI) was performed to measure the fractional anisotropy (FA), axial (AD), radial (RD), and mean diffusivities (MD). The voxel-wise tract-based spatial statistics and region of interest methods were used for DTI, and their correlations with cognitive variables were analyzed. RESULTS: Patients with BECTS had lower intelligence quotient (IQ) scores compared with those of the control group. Higher AD and MD values were found in the left superior longitudinal fasciculus, the retrolenticular part of the internal capsule, posterior thalamic radiation, sagittal stratum and the body of the corpus callosum in BECTS patients compared with controls. Lower performances in verbal IQ, freedom from distractibility and processing speed were correlated with higher AD in the left superior fronto-occipital fasciculus, and lower verbal IQ scores were correlated with decreased FA values in the splenium of the corpus callosum in these patients. CONCLUSIONS: White matter microstructural changes predominantly in the left hemisphere might contribute to their cognitive abnormalities especially verbal IQ in BECTS patients.

Antimicrobial and in vitro wound healing properties of novel clay based bionanocomposite films.

The present study investigates the development of methyl cellulose (MC)-sodium alginate (SA)-montmorillonite (MMT) clay based bionanocomposite films with interesting wound healing properties. The differential scanning calorimetry analysis of the composite films revealed presence of single glass transition temperature (Tg) confirming the miscible nature of the ternary blended films. The increase in MMT ratio in the composite films reduced the mobility of biopolymer chains (MC/SA) which increased the Tg of the film. Thermogravimetric analysis showed that dispersion of clay (MMT) at nano level significantly delayed the weight loss that correlated with higher thermal stability of the composite films. It was observed that the developed films were able to exhibit antimicrobial activity against four typical pathogenic bacteria found in the presence of wound. The developed films were able to significantly inhibit (10 mg/ml) the growth of Enterococcus faecium and Pseudomonas aeruginosa. In vitro scratch assay indicated potential wound closure activities of MC-2-4 bionanocomposite films at their respective highest subtoxic doses. In conclusion, these ternary bionanocomposite films were found to be promising systems for wound healing applications.

Short communication: antiviral activity of subcritical water extract of Brassica juncea against influenza virus A/H1N1 in nonfat milk.

Subcritical water extract (SWE) of Brassica juncea was studied for antiviral effects against influenza virus A/H1N1 and for the possibility of application as a nonfat milk supplement for use as an "antiviral food." At maximum nontoxic concentrations, SWE had higher antiviral activity against influenza virus A/H1N1 than n-hexane, ethanol, or hot water (80°C) extracts. Addition of 0.5mg/mL of B. juncea SWE to culture medium led to 50.35% cell viability (% antiviral activity) for Madin-Darby canine kidney cells infected with influenza virus A/H1N1. Nonfat milk supplemented with 0.28mg/mL of B. juncea SWE showed 39.62% antiviral activity against influenza virus A/H1N1. Thus, the use of B. juncea SWE as a food supplement might aid in protection from influenza viral infection.

Autotransplantation of mesiodens for missing maxillary lateral incisor with cone-beam CT-fabricated model and orthodontics.

AIM: Autotransplantation is a viable treatment option for a missing tooth when there is a suitable donor, especially in adolescents with remaining facial growth. This report presents the aesthetic restoration of a missing maxillary lateral incisor through orthodontic treatment and autotransplantation of a mesiodens using a CBCT-fabricated rapid-prototyping model. SUMMARY: A 14-year-old male patient with a congenitally missing maxillary lateral incisor was referred from the Department of Orthodontics. The teeth were moved orthodontically to regain space for the missing lateral incisor and to close the space of the mesiodens after transplantation. A replica of the donor tooth was fabricated from a cone-beam computed tomography scan through a rapid-prototyping machine before autotransplantation surgery. The model was used to create a socket for the graft tooth, thereby shortening the extra-oral time and minimizing the damage to the root surface. After transplantation and orthodontic tooth movement, the mesiodens was finally restored with an aesthetic laminate restoration. Over 3 years, the aesthetics remained excellent, and the transplant functioned normally without any signs or symptoms of root resorption. KEY LEARNING POINT: Missing anterior teeth may be replaced through a combination of orthodontics, autotransplantation with a rapid-prototyping model and prosthodontic restoration, in growing patients.

The frequency and impact of ROS1 rearrangement on clinical outcomes in never smokers with lung adenocarcinoma.

BACKGROUND: To determine the frequency and predictive impact of ROS1 rearrangements on treatment outcomes in never-smoking patients with lung adenocarcinoma. PATIENTS AND METHODS: We concurrently analyzed ROS1 and ALK rearrangements and mutations in the epidermal growth factor receptor (EGFR), and KRAS in 208 never smokers with lung adenocarcinoma. ROS1 and ALK rearrangements were identified by fluorescent in situ hybridization. RESULTS: Of 208 tumors screened, 7 (3.4%) were ROS1 rearranged, and 15 (7.2%) were ALK-rearranged. CD74-ROS1 fusions were identified in two patients using reverse transcriptase-polymerase chain reaction. The frequency of ROS1 rearrangement was 5.7% (6 of 105) among EGFR/KRAS/ALK-negative patients. Patients with ROS1 rearrangement had a higher objective response rate (ORR; 60.0% versus 8.5%; P = 0.01) and a longer median progression-free survival (PFS; not reached versus 3.3 months; P = 0.008) to pemetrexed than those without ROS1/ALK rearrangement. The PFS to EGFR-tyrosine kinase inhibitors in patients harboring ROS1 rearrangement was shorter than those without ROS1/ALK rearrangement (2.5 versus 7.8 months; P = 0.01). CONCLUSIONS: The frequency of ROS1 rearrangements in clinically selected patients is higher than that reported for unselected patients, suggesting that ROS1 rearrangement is a druggable target in East-Asian never smokers with lung adenocarcinoma. Given the different treatment outcomes to conventional therapies and availability of ROS1 inhibitors, identification of ROS1 rearrangement can lead to successful treatment in ROS1-rearranged lung adenocarcinomas.

A multicenter, phase II trial of everolimus in locally advanced or metastatic thyroid cancer of all histologic subtypes.

BACKGROUND: This phase II study investigated the efficacy and safety of everolimus, an inhibitor of mammalian target of rapamycin (mTOR), in locally advanced or metastatic thyroid cancer. PATIENTS AND METHODS: Patients with thyroid cancer of any histology that was resistant or not appropriate for (131)I received everolimus 10 mg daily orally until unacceptable toxicity or disease progression. The primary end point was disease control rate [partial response (PR) + stable response ≥12 weeks]. Secondary end points included response rates, clinical benefit (PD + durable stable disease (SD)], progression-free survival (PFS), overall survival, duration of response, and safety. RESULTS: Thirty-eight of 40 enrolled patients were evaluable for efficacy. The disease control rate was 81% and two (5%) patients achieved objective response; their duration of response was 21+ and 24+ weeks. Stable disease (SD) and progressive disease was reported in 76% and 17% of patients, respectively. Seventeen (45%) patients showed durable SD (≥24 weeks) and clinical benefit was reported in 19 (50%) patients. Median PFS was 47 weeks [95% confidence interval (CI) 14.9-78.5]. Calcitonin, CEA, and thyroglobulin concentrations were ≥50% lower than baseline in three (30%) and four (44%) patients with medullary thyroid cancer and five (33%) patients with PTC, respectively. The most common treatment-related adverse events were mucositis (84%), anorexia (44%), and aspartate transaminase/alanine transaminase elevation (26%). CONCLUSIONS: Everolimus had a limited activity with low response rate in locally advanced or metastatic thyroid cancer. Reasonable clinical benefit rate and safety profile may warrant further investigation. CLINICALTRIALSGOV NUMBER: NCT01164176.

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.

INS(GFP/w) human embryonic stem cells facilitate isolation of in vitro derived insulin-producing cells.

AIMS/HYPOTHESIS: We aimed to generate human embryonic stem cell (hESC) reporter lines that would facilitate the characterisation of insulin-producing (INS⁺) cells derived in vitro. METHODS: Homologous recombination was used to insert sequences encoding green fluorescent protein (GFP) into the INS locus, to create reporter cell lines enabling the prospective isolation of viable INS⁺ cells. RESULTS: Differentiation of INS(GFP/w) hESCs using published protocols demonstrated that all GFP⁺ cells co-produced insulin, confirming the fidelity of the reporter gene. INS-GFP⁺ cells often co-produced glucagon and somatostatin, confirming conclusions from previous studies that early hESC-derived insulin-producing cells were polyhormonal. INS(GFP/w) hESCs were used to develop a 96-well format spin embryoid body (EB) differentiation protocol that used the recombinant protein-based, fully defined medium, APEL. Like INS-GFP⁺ cells generated with other methods, those derived using the spin EB protocol expressed a suite of pancreatic-related transcription factor genes including ISL1, PAX6 and NKX2.2. However, in contrast with previous methods, the spin EB protocol yielded INS-GFP⁺ cells that also co-expressed the beta cell transcription factor gene, NKX6.1, and comprised a substantial proportion of monohormonal INS⁺ cells. CONCLUSIONS/INTERPRETATION: INS(GFP/w) hESCs are a valuable tool for investigating the nature of early INS⁺ progenitors in beta cell ontogeny and will facilitate the development of novel protocols for generating INS⁺ cells from differentiating hESCs.

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.

Long-term residence of a graft is an insufficient stimulus for the induction of tolerance. Investigating the role of cyclosporine in class I-disparate heart grafts in the rat.

This study demonstrates that the induction of tolerance is possible across a class I only antigenic barrier that fails to produce heart graft rejection. However, the long-term residence alone of such a graft per se, does not necessarily lead to the establishment of systemic tolerance in the recipient. The important finding in this study with regard to the biology of allograft tolerance, is that while the class I antigen provides the stimulus, its presence alone is not sufficient for the induction of tolerance; indeed, the action of the Cyclosporine A (CyA) is a necessary adjunct to its induction.

The effects of acute temperature change on cost of transport at maximal labriform speed in bluegill Lepomis macrochirus.

The effects of acute temperature change on the cost of bluegill Lepomis macrochirus swimming were quantified. At 14 degrees C, maximum labriform swimming speed (U(lab,max)) was reduced relative to that at the acclimation temperature of 22 degrees C, but total cost of transport (T(TC)) remained unchanged. At 30 degrees C, U(lab,max) was the same as at 22 degrees C, but T(TC) was 66% greater.