Biallelic EPCAM deletions induce tissue-specific DNA repair deficiency and cancer predisposition.

We report a case of Mismatch Repair Deficiency (MMRD) caused by germline homozygous EPCAM deletion leading to tissue-specific loss of MSH2. Through the use of patient-derived cells and organoid technologies, we performed stepwise in vitro differentiation of colonic and brain organoids from reprogrammed EPCAMdel iPSC derived from patient fibroblasts. Differentiation of iPSC to epithelial-colonic organoids exhibited continuous increased EPCAM expression and hypermethylation of the MSH2 promoter. This was associated with loss of MSH2 expression, increased mutational burden, MMRD signatures and MS-indel accumulation, the hallmarks of MMRD. In contrast, maturation into brain organoids and examination of blood and fibroblasts failed to show similar processes, preserving MMR proficiency. The combined use of iPSC, organoid technologies and functional genomics analyses highlights the potential of cutting-edge cellular and molecular analysis techniques to define processes controlling tumorigenesis and uncovers a new paradigm of tissue-specific MMRD, which affects the clinical management of these patients.

Differential impact of COVID-19 on mental health and burnout.

BACKGROUND: There may be differential impact of the COVID-19 pandemic on mental health and burnout rates of healthcare professionals (HCPs) performing different roles. AIMS: To examine mental health and burnout rates, and possible drivers for any disparities between professional roles. METHODS: In this cohort study, online surveys were distributed to HCPs in July-September 2020 (baseline) and re-sent 4 months later (follow-up; December 2020) assessing for probable major depressive disorder (MDD), generalized anxiety disorder (GAD), insomnia, mental well-being and burnout (emotional exhaustion and depersonalization). Separate logistic regression models (at both phases) compared the risk of outcomes between roles: healthcare assistants (HCAs), nurses and midwives (nurses), allied health professionals (AHPs) and doctors (reference group). Separate linear regression models were also developed relating the change in scores to professional role. RESULTS: At baseline (n = 1537), nurses had a 1.9-fold and 2.5-fold increased risk of MDD and insomnia, respectively. AHPs had a 1.7-fold and 1.4-fold increased risk of MDD and emotional exhaustion, respectively. At follow-up (n = 736), the disproportionate risk between doctors and others worsened: nurses and HCAs were at 3.7-fold and 3.6-fold increased risk of insomnia, respectively. Nurses also had a significantly increased risk of MDD, GAD, poor mental well-being and burnout. Nurses also had significantly worsened anxiety, mental well-being and burnout scores over time, relative to doctors. CONCLUSIONS: Nurses and AHPs had excess risk of adverse mental health and burnout during the pandemic, and this difference worsened over time (in nurses especially). Our findings support adoption of targeted strategies accounting for different HCP roles.

Magnetically recoverable Fe3O4 nanocatalyst for the synthesis of biodynamically significant 1H-pyrazolo[1,2-b]phthalazine-5,10-diones derivatives and its DFT study.

An environmentally sustainable and proficient method is reported for the synthesis of medicinally important pyrazolo[1,2-b] phthalazine dione derivatives by aqueous micellar medium catalysed by Fe3O4 NPs. Dialkyl acetylenedicarboxylate with isocyanides in the presence of phthalhydrazide is used as starting material. The main advantages of this protocol are the availability of starting materials, short reaction times, green solvents and practical simplicity.

Glycemic Status among Pregnant Women during 24th to 28th Gestational Age.

Gestational diabetes mellitus (GDM) is a heterogeneous group of metabolic disorder, which result in varying degrees of maternal hyperglycemia and pregnancy associated risk. Glucose intolerance usually returns to normal range within 6 weeks after delivery. This study was undertaken to determine the glycemic status who attended for antenatal care. This study enrolled pregnant women, with their gestational age between 24th - 28th weeks. This analytical cross sectional study was carried out in the department of Biochemistry, BIRDEM General Hospital, Dhaka, Bangladesh from July 2014 to June 2015. Total 135 subjects were selected to evaluate the glycemic status among Bangladeshi pregnant women attending BIRDEM General Hospital. Among them 41 were GDM subjects and 94 were non GDM subjects. The mean fasting plasma glucose values (mmol/L) and 2 hours after 75gm glucose values of GDM were 6.06±1.26 and 9.78±2.74 respectively compared to non GDM patients were 4.82±0.38 and 7.26±0.41 respectively and the mean of HbA1C (%) of GDM and non GDM were 5.87±0.73 and 5.43±0.31 respectively.

Efficient one-pot synthesis of substituted diphenyl 1, 3-thiazole through multicomponent reaction by using green and efficient Iron-catalyst via Cross-Dehydrogenative Coupling(CDC).

A clean and efficient, multi-component strategy for the synthesis of biologically important trisubstituted thiazole via the reaction of readily available barbituric acid, acetophenone, and aryl thioamides is reported in the presence of FeCl3.6H2O / O2(Air) in DMF solvent. The advantages of the present methodology include a one-pot reaction, environment-friendly approach, cost-effectiveness, broad substrate scope, operational simplicity, short reaction time, easy workup procedure, and high yields.

BF3-etherate promoted facile access to vinyloxyimidazopyridines: a metal-free sustainable approach.

A convenient and metal-free synthesis of vinyloxyimidazopyridine derivatives has been attained via BF3.OEt2 promoted one-pot multicomponent approach. This procedure involves a facile coupling of 2-aminopyridine derivatives with arylglyoxal and alkyne derivatives. BF3.OEt2 complexation has successfully catalyzed the reaction at room temperature. Utilization of transition metal-free catalyst, mild reaction conditions, easy handling and operational simplicity are key features of developed process.

Procalcitonin as a predictor of severity and mortality in a cohort of patients hospitalised with COVID-19.

INTRODUCTION: To evaluate the association of Procalcitonin (PCT) with severity in Coronavirus disease 2019 (COVID-19), hospitalised patients and to test the hypothesis that it is an independent predictor of mortality. MATERIALS AND METHODS: This study was conducted at Chemical Pathology, Department of Pathology and Laboratory Medicine and Department of Medicine, Aga Khan University (AKU), Karachi Pakistan. Electronic medical records of all in-patients including both genders and all age groups with documented COVID-19 from March to August 2020 were reviewed and recorded on a pre-structured performa. The subjects were divided into two categories severe and non-severe COVID-19; and survivors and non-survivors. Between-group differences were tested using the Chi-square and Mann-Whitney's U-test. The receiver operating characteristic curve was plotted for serum PCT with severity and mortality. A binary logistic regression was used to identify variables independently associated with mortality. The data was analysed using SPSS. RESULTS: 336 patients were reviewed as declared COVID-19 positive during the study duration, and 136 were included in the final analysis including 101 males and 35 females. A statistically significant difference in PCT was found between severe and non-severe COVID-19 (p value=0.01); and survivors and nonsurvivors (p value<0.0001). PCT, older age and increased duration of hospital stay were revealed as variables independently associated with mortality. On ROC analysis, an AUC of 0.76 for mortality prediction was generated for PCT. CONCLUSION: Baseline serum PCT concentration is a promising predictor of mortality and severity in COVID-19 cases when considered in combination with clinical details and other laboratory tests.

Metal-free visible-light-mediated organophotoredox catalysis: synthesis of 3-functionalized indole via C-C, C-N bond formation.

A visible-light-mediated, mild and one-pot three-component reaction in the presence of organophotoredox catalyst Eosin Y using EtOH:H2O as reaction medium for the synthesis of 3-functionalized indole derivatives was developed. Visible light used in the protocol is green, inexpensive, readily available energy source. The sustainable reagents make the protocol compatible with green chemistry demands.

Visible-light-mediated one-pot efficient synthesis of 1-aryl-1H,3H-thiazolo[3,4-a]benzimidazoles: a metal-free photochemical approach in aqueous ethanol.

A new metal-free approach to construct medicinally valuable 1-aryl-1H,3H-thiazolo[3,4-a]benzimidazoles under visible light irradiation in aqueous ethanol medium at room temperature has been developed. The present process was performed with 1,2-phenylenediamines, aromatic aldehydes and 2-mercaptoacetic acid utilizing a simple household 22 W compact fluorescent lamp to generate C-S, C-N bonds through radical intermediates. This visible-light-promoted synthesis provides lower cost, operation simplicity and high functional groups tolerating ability with short reaction time and high yield under mild reaction conditions.

Bridging the gap between micro- and macro-scales in medical imaging with textural analysis - A biological basis for CT radiomics classifiers?

INTRODUCTION: Studies suggest there is utility in computed tomography (CT) radiomics for pancreatic disease; however, the precise biological interpretation of its features is unclear. In this manuscript, we present a novel approach towards this interpretation by investigating sub-micron tissue structure using digital pathology. METHODS: A classification-to attenuation (CAT) function was developed and applied to digital pathology images to create sub-micron linear attenuation maps. From these maps, grey level co-occurrence matrix (GLCM) features were extracted and compared to pathology features. To simulate the spatial frequency loss in a CT scanner, the attenuation maps were convolved with a point spread function (PSF) and subsequently down-sampled. GLCM features were extracted from these down-sampled maps to assess feature stability as a function of spatial frequency loss. RESULTS: Two GLCM features were shown to be strongly and positively correlated (r = 0.8) with underlying characteristics of the tumor microenvironment, namely percent pimonidazole staining in the tumor. All features underwent marked change as a function of spatial frequency loss; progressively larger spatial frequency losses resulted in progressively larger inter-tumor standard deviations; two GLCM features exhibited stability up to a 100 µm pixel size. CONCLUSION: This work represents a necessary step towards understanding the biological significance of radiomics. Our preliminary results suggest that cellular metrics of pimonidazole-detectable hypoxia correlate with sub-micron attenuation coefficient texture; however, the consistency of these textures in face of spatial frequency loss is detrimental for robust radiomics. Further study in larger data sets may elucidate additional, potentially more robust features of biologic and clinical relevance.

Total compared with partial pancreatectomy for pancreatic adenocarcinoma: assessment of resection margin, readmission rate, and survival from the U.S. National Cancer Database.

Introduction: Total pancreatectomy for pancreatic ductal adenocarcinoma has historically been associated with substantial patient morbidity and mortality. Given advancements in perioperative and postoperative care, evaluation of the surgical treatment options for pancreatic adenocarcinoma should consider patient outcomes and long-term survival for total pancreatectomy compared with partial pancreatectomy. Methods: The U.S. National Cancer Database was queried for patients undergoing total pancreatectomy or partial pancreatectomy for pancreatic adenocarcinoma during 1998-2006. Demographics, tumour characteristics, operative outcomes, 30-day mortality, 30-day readmission, additional treatment, and Kaplan-Meier survival curves were compared. Results: The database query returned 807 patients who underwent total pancreatectomy and 5840 who underwent partial pancreatectomy. More patients who underwent total pancreatectomy than a partial pancreatectomy had a margin-negative resection (p < 0.0001). Mortality and readmission rates were similar in the two groups, as was long-term survival on Kaplan-Meier curves (p = 0.377). A statistically significant difference in the rate of surgery only (without additional treatment) was observed for patients in the total pancreatectomy group (p = 0.0003). Conclusions: Although total compared with partial pancreatectomy was associated with a higher rate of margin-negative resection, median survival was not significantly different for patients undergoing either procedure. Patients who underwent total pancreatectomy were significantly less likely to receive adjuvant therapy.

Motivated to do well: an examination of the relationships between motivation, effort, and cognitive performance in schizophrenia.

The uncertain relationship between negative symptoms, and specifically motivational deficits, with cognitive dysfunction in schizophrenia is in need of further elucidation as it pertains to the interpretation of cognitive test results. Findings to date have suggested a possible mediating role of motivational deficits on cognitive test measures, although findings from formal examinations of effort using performance validity measures have been inconsistent. The aim of this study was to examine the relationships between motivation, effort exerted during cognitive testing, and cognitive performance in schizophrenia. Sixty-nine outpatients with schizophrenia or schizoaffective disorder were evaluated for psychopathology, severity of motivational deficits, effort exerted during cognitive testing, and cognitive performance. Motivation and degree of effort exerted during cognitive testing were significantly related to cognitive performance, specifically verbal fluency, verbal and working memory, attention and processing speed, and reasoning and problem solving. Further, effort accounted for 15% of the variance in cognitive performance, and partially mediated the relationship between motivation and cognitive performance. Examining cognitive performance profiles for individuals exerting normal or reduced effort revealed significant differences in global cognition, as well as attention/processing speed and reasoning and problem solving. These findings suggest that cognitive domains may be differentially affected by impairments in motivation and effort, and highlight the importance of understanding the interplay between motivation and cognitive performance deficits, which may guide the appropriate selection of symptom targets for promoting recovery in patients.

Developing Objective Metrics for Unit Staffing (DOMUS) study.

OBJECTIVE: Safe midwifery staffing levels on delivery suites is a priority area for any maternity service. Escalation policies are tools that provide an operational response to emergency pressures. The aim of this study was to assess the feasibility of using a scoring system to contemporaneously assess the required staffing level based on demand and use this to determine delivery suite escalation level and utilise the information generated regarding clinical activity (Demand) and staffing levels (Capacity) to generate unit-specific calculation for the actual number of midwifery staff required. SETTING: A maternity unit of a university-affiliated tertiary referral hospital. DESIGN: Over a 12-month period, specifically designed scoring sheets were completed by delivery suite shift co-ordinators four times a day (04:00, 10:00, 16:00 and 22:00). Based on the dependency score (Demand) and the number of midwifery staff available (Capacity), an escalation level was determined for each shift. The 80th centile of the demand was used to determine optimal capacity. RESULTS: A total of 1160 scoring sheets were completed. Average staff number throughout the year on any shift was 7 (range 3-11). Average dependency score was 7 (range 1-14). The 80th centile for demand was calculated to be 11. CONCLUSIONS: This study stresses the importance and usefulness of a simple tool that can be used to determine the level of escalation on delivery suite based on an objective scoring system and can also be used to determine the appropriate staffing on delivery suite.

Synthetic seed production and physio-biochemical studies in Cassia angustifolia Vahl. - a medicinal plant.

Synthetic seed technology is an alternative to traditional micropropagation for production and delivery of cloned plantlets. Synthetic seeds were produced by encapsulating nodal segments of C. angustifolia in calcium alginate gel. 3% (w/v) sodium alginate and 100 mM CaCl2 · 2H2O were found most suitable for encapsulation of nodal segments. Synthetic seeds cultured on half strength Murashige and Skoog medium supplemented with thidiazuron (5.0 µM) + indole-3-acetic acid (1.0 µM) produced maximum number of shoots (10.9 ± 0.78) after 8 weeks of culture exhibiting (78%) in vitro conversion response. Encapsulated nodal segments demonstrated successful regeneration after different period (1-6 weeks) of cold storage at 4 °C. The synthetic seeds stored at 4 °C for a period of 4 weeks resulted in maximum conversion frequency (93%) after 8 weeks when placed back to regeneration medium. The isolated shoots when cultured on half strength Murashige and Skoog medium supplemented with 1.0 µM indole-3-butyric acid (IBA), produced healthy roots and plantlets with well-developed shoot and roots were successfully hardened off in plastic pots containing sterile soilrite inside the growth chamber and gradually transferred to greenhouse where they grew well with 85% survival rate. Growth performance of 2 months old in vitro-raised plant was compared with in vivo seedlings of the same age. Changes in the content of photosynthetic pigments, net photosynthetic rate (PN), superoxide dismutase and catalase activity in C. angustifolia indicated the adaptation of micropropagated plants to ex vitro conditions.

Pre-culturing of nodal explants in thidiazuron supplemented liquid medium improves in vitro shoot multiplication of Cassia angustifolia.

An in vitro propagation system for Cassia angustifolia Vahl. has been developed. Due to the presence of sennosides, the demand of this plant has increased manyfold in global market. Multiple shoots were induced by culturing nodal explants excised from mature plants on a liquid Murashige and Skoog [8] medium supplemented with 5-100 µM of thidiazuron (TDZ) for different treatment duration (4, 8, 12 and 16 d). The optimal level of TDZ supplemented to the culture medium was 75 µM for 12 d induction period followed by subculturing in MS medium devoid of TDZ as it produced maximum regeneration frequency (87%), mean number of shoots (9.6 ± 0.33) and shoot length (4.4 ± 0.46 cm) per explant. A culture period longer than 12 d with TDZ resulted in the formation of fasciated or distorted shoots. Ex vitro rooting was achieved when the basal cut end of regenerated shoots was dipped in 200 µM indole-3-butyric acid (IBA) for half an hour followed by their transplantation in plastic pots filled with sterile soilrite where 85% plantlets grew well and all exhibited normal development. The present findings describe an efficient and rapid plant regeneration protocol that can further be used for genetic transformation studies.

[MRI investigations in patients with problems due to metal-on-metal implants]. / Magnetresonanztomographische Untersuchungen bei Problemen mit Metall-auf-Metall-Implantaten.

Until recently, metal-on-metal (MoM) hip implants were commonly used for joint replacement and resurfacings. Their use has rapidly declined following reports of Frühversagen and soft tissue disease caused by the release of metal debris from the prosthesis. Detection of these soft tissue lesions has proven difficult using conventional imaging techniques and blood metal ion tests. Current guidelines recommend the use of imaging modalities including metal artefact reduction sequence (MARS) magnetic resonance imaging (MRI), computed tomography and ultrasound but provide little indication which is best. MARS significantly reduces the susceptibility artefact induced by the presence of metal objects, thereby producing diagnostic quality images that can be shared with other physicians and compared over time. The clinical interpretation of MRI findings of solid pseudotumours and severe muscle atrophy is straightforward: revision is usually recommended. However, the most common MRI findings are of a cystic pseudotumour and minor muscle wasting. In these cases decision-making is difficult and we currently use multi-disciplinary and multi-colleague based meetings to make decisions regarding patient management. This article presents a comparison of imaging modalities and an update on the interpretation of MARS MRI for the investigation of patients with MoM hip implants.The English full-text version of this article is available at Springer Link (under "Supplemental").

Attentional bias for alcohol-related stimuli among belief based and non-belief based non-drinkers.

BACKGROUND/AIMS: Research has provided evidence for an association between attentional biases for substance-related stimuli and the development and maintenance of a variety of addictive behaviours. Attempts at reducing attentional bias amongst harmful and dependent drinkers have provided evidence to suggest that reduced attentional bias in heavy drinkers would lead to necessary reductions in alcohol intake. We tested one aspect of this assumption by measuring attentional bias amongst non-drinkers who, if the link between attentional bias and actual drug use is causal, should demonstrate no attentional bias for alcohol-related stimuli. METHODS: An alcohol Stroop task was administered to belief-based abstainers, non-belief based abstainers and light social drinkers to measure attentional biases for alcohol-related words compared to neutral words. RESULTS: Belief-based abstainers demonstrated significant attentional bias for alcohol-related stimuli, whilst non-belief based abstainers and light social drinkers did not. CONCLUSION: Attentional biases towards alcohol-related stimuli are not specific to harmful and problem drinkers, which has implications for interventions based on attentional bias change.