Association of Baseline Frailty with Patient-Reported Outcomes in Systemic Lupus Erythematosus at 1 Year.

The relationship of baseline frailty with subsequent patient-reported outcomes in systemic lupus erythematosus (SLE) remains unclear. We assessed these associations in a pilot prospective cohort study. Frailty based on the FRAIL scale and the Fried phenotype and patient-reported outcomes, namely Patient Reported Outcomes Measurement Information System computerized adaptive tests and Valued Life Activities disability, were measured at baseline and 1 year among women aged 18-70 years with SLE enrolled at a single center. Differences in Patient Reported Outcomes Measurement Information System computerized adaptive tests between frail and non-frail participants were evaluated using Wilcoxon rank sum tests, and the association of baseline frailty with self-report disability at 1 year was estimated using linear regression. Of 51 participants, 24% (FRAIL scale) and 16% (Fried phenotype) met criteria for frailty at baseline despite median age of 55.0 and 56.0 years, respectively. Women with (versus without) baseline frailty using either measure had worse 1-year Patient Reported Outcomes Measurement Information System computerized adaptive test scores across multiple domains and greater self-report disability. Baseline frailty was significantly associated with self-report disability at 1 year (FRAIL scale: parameter estimate 0.55, 95% confidence interval (CI) 0.21-0.89, p<0.01; Fried phenotype: parameter estimate 0.61, 95% CI 0.22-1.00, p<0.01), including only slight attenuation after adjustment for SLE cumulative organ damage (FRAIL scale: parameter estimate 0.45, 95% CI 0.09-0.81, p=0.02; Fried phenotype: parameter estimate 0.49, 95% CI 0.09-0.90, p=0.02). These preliminary findings support frailty as an independent risk factor for clinically relevant patient-reported outcomes, including disability onset, among women with SLE.

A Possible Novel Protective Effect of Piceatannol against Isoproterenol (ISO)-Induced Histopathological, Histochemical, and Immunohistochemical Changes in Male Wistar Rats.

Dry mouth is characterized by lower saliva production and changes in saliva composition. In patients with some salivary gland function remaining, pharmaceutical treatments are not recommended; therefore, new, more effective methods of promoting saliva production are needed. Hence, this study aimed to provide an overview of the histological changes in the salivary gland in the model of isoproterenol (ISO)-induced degenerative changes in male Wistar rats and to evaluate the protective effect of piceatannol. Thirty-two male Wistar rats were randomly divided into four groups: the control group, the ISO group, and the piceatannol (PIC)-1, and -2 groups. After the third day of the experiment, Iso (0.8 mg/100 g) was injected intraperitoneally (IP) twice daily into the animals. PIC was given IP in different daily doses (20 and 40 mg/kg) for three days before ISO and seven days with ISO injection. The salivary glands were rapidly dissected and processed for histological, histochemical, immunohistochemical (Ki-67), and morphometric analysis. Upon seven days of treatment with ISO, marked hypertrophy was observed, along with an increased number of positive Ki-67 cells. Proliferation was increased in some endothelial cells as well as in ducts themselves. Despite the significant decrease in proliferation activity, the control group did not return to the usual activity level after treatment with low-dose PIC. Treatment with a high dose of PIC reduced proliferative activity to the point where it was substantially identical to the results seen in the control group. An ISO-driven xerostomia model showed a novel protective effect of piceatannol. A new era of regenerative medicine is dawning around PIC's promising role.

Exploring accommodations along the education to employment pathway for deaf and hard of hearing healthcare professionals.

BACKGROUND: Deaf and hard of hearing (DHH) people are an underserved population and underrepresented among healthcare professionals. A major barrier to success for DHH healthcare professionals is obtaining effective accommodations during education and employment. Our objective: describe DHH individuals' experiences with accommodations in healthcare education. METHODS: We used an online survey and multipronged snowball sampling to recruit participants who identify as DHH and who had applied to a U.S. health professional school (regardless of acceptance status). One hundred forty-eight individuals representing multiple professions responded; 51 had completed their training. Over 80% had been accepted to, were currently enrolled, or had completed health professions schools or residency programs, and/or were employed. The survey included questions addressing experiences applying to health professions programs and employment; satisfaction with accommodations in school and training; having worked with a disability resource professional (DRP); and depression screening. RESULTS: Use and type of accommodation varied widely. While in school, respondents reported spending a mean of 2.1 h weekly managing their accommodations. Only 50% were highly satisfied with the accommodations provided by their programs. Use of disability resource providers (DRPs) for accommodations was highest during school (56%) and less frequent during post-graduate training (20%) and employment (14%). Respondents who transitioned directly from school to employment (versus via additional training) were more satisfied with their accommodations during school and were more likely to find employment (p = 0.02). Seventeen respondents screened positive for risk of depression; a positive screen was statistically associated with lower school accommodation satisfaction. CONCLUSIONS: DHH people study and practice across many health professions. While respondents were mostly successful in entering health professions programs, accommodation experiences and satisfaction varied. Satisfaction with accommodations was related to successful employment and wellness. Low satisfaction was associated with higher likelihood of depression symptoms. To increase representation in the workforce, healthcare professional schools, training programs, and employers should enhance support for the learning and working climates for people with disabilities.

Mechanotransductive Mechanisms of Biomimetic Hydrogel Cues Modulating Meckel's Cartilage Degeneration.

Meckel's cartilage, a cartilage rod present in the mandible during developmental stages, shows a unique developmental fate: while the anterior and posterior portions undergo ossification, the middle part degenerates. Previously, it was shown that a stiff environment promoted cartilage degeneration in the middle region, while a soft environment enhanced the mineralization in the anterior region of Meckel's cartilage. This study aims to elucidate the spatio-temporal changes in the mechanosensing properties of Meckel's cartilage during its early developmental stages and clarify the mechanotransduction-related mechanisms involved in its degeneration. The results show that the expression of Hippo pathway effector yes-associated protein (YAP) is only detectable in the Meckel's cartilage onward embryonic day (E)14.5, indicating that mechanosensing is dependent on the tissue developmental stage. Consistently, microenvironmental stiffness-induced cartilage degeneration can only be induced in cartilages onward E14.5, but not in those at earlier developmental stages. Expressions of integrin-ß1 and cartilage matrix-degrading enzymes, matrix metalloproteinase 1 (MMP-1) and MMP-13, are significantly enhanced in the degeneration area. Moreover, verteporfin (YAP inhibitor) and integrin-ß1 antibody block the substrate stiffness-induced degeneration by suppressing the expressions of MMP-1 and MMP-13. These data provide new insights into the interplay between biochemical and mechanical cues determining the fate of Meckel's cartilage.

Impact of the fear of Covid-19 infection on intent to breastfeed; a cross sectional survey of a perinatal population in Qatar.

OBJECTIVES: Infection control measures during the Covid-19 pandemic have focused on limiting physical contact and decontamination by observing cleaning and hygiene rituals. Breastfeeding requires close physical contact and observance of hygienic measures like handwashing. Worries around contamination increase during the perinatal period and can be expressed as increase in obsessive compulsive symptoms. These symptoms have shown to impact breastfeeding rates. This study attempts to explore any relationship between the Covid-19 pandemic and perinatal obsessive-compulsive symptomatology and whether the Covid-19 pandemic has any impact on intent to breastfeed. METHODS: A cross sectional survey of perinatal women attending largest maternity centre in Qatar was carried out during the months of October to December 2020. Socio-demographic information, intent to breastfeed and information around obsessive compulsive thoughts around Covid-19 pandemic were collected using validated tools. RESULTS: 15.7% respondents report intent to not breastfeed. 21.4% respondents reported obsessive-compulsive symptoms. 77.3% respondents believed the biggest source of infection was from others while as only 12% of the respondents believed that the source of infection was through breastfeeding and 15.7% believed the vertical transmission as the main source of risk of transmission. CONCLUSIONS: The rates of Obsessive-compulsive symptoms were increased and the rates of intent to breastfeed were decreased when compared with pre pandemic rates. The obsessive-compulsive symptoms and the intent to not breastfeed were significantly associated with fear of infection to the new-born. Obsessive-compulsive symptoms were not significantly correlated with intent to breastfeed and can be seen as adaptive strategies utilized by women to continue breastfeeding in the context of fear of infection.

Emergency department presentations of alcohol and other substance misuse: first cross-sectional national study in Qatar.

OBJECTIVES: This study attempts the first in a series of investigations into the misuse of alcohol and substances in Qatar. This study explores the emergency presentations of alcohol and substance abuse to all the state funded emergency departments (EDs) in the country which serve around 90% of the population over a 22-month period. Due to legal penalties for alcohol and substance use, and lack of subsidised community-based facilities, ED presentations are a good starting point to explore this burden. DESIGN AND PARTICIPANTS: A retrospective population-based, cross-sectional study, analysing electronic patient records of all state funded EDs spanning a period of 22 months, from 1 January 2019 to 31 October 2020 was carried out. The study included all eligible individuals aged 18 or over. Primary reason/diagnosis for presentation containing any of the alcohol or substance use key words were included in the study using composite data capture forms by trained clinicians. RESULTS: An overwhelming majority (95.5%) of the total 1495 cases presenting to the EDs with substance abuse were using alcohol. Only 2.1% of the cases were females. Those of Asian (non-Arab) constituted 70% of this group. Qatari citizens presented with highest proportion of substance abuse other than alcohol (23%). Overall, 2.26% of all presentations to the EDs were related to alcohol and substance abuse and this amounted to 3 ED visits per 10 000 of population per year. 56.6% of the cases presented over the weekend. Less than 1% were referred to psychiatry and no other meaningful rehabilitative interventions were offered to others. CONCLUSION: As Qatar moves towards establishing community-based rehabilitative resources for alcohol and substances abuse, the findings from this study will help in shaping these developments. These can include ED-based routine screening for alcohol abuse and referral to rehabilitation services without fear of legal penalties.

Qatar Healthcare Workers' COVID-19 Vaccine Hesitancy and Attitudes: A National Cross-Sectional Survey.

Introduction: Healthcare workers are the critical frontline workforce of the COVD-19 pandemic and are considered a target group for vaccination. Hesitancy to vaccinate is a major concern that can jeopardize the vaccination programme. The hesitancy rates in the general population and healthcare workers (HCWs) vary globally, and more importantly, hesitancy in HCWs is of particular concern, as it can influence the wider population. Materials and Methods: The present study evaluated the vaccine hesitancy rate and its sociodemographic and attitudinal factors among the HCWs in the state of Qatar. We conducted a national cross-sectional survey using a validated hesitancy measurement tool between October 15 and November 15, 2020. A total of 7,821 adults above the age of 18 years out of the 2.3 million adult Qatari residents completed the survey. While majority of the participants were from the general public, 1,546 participants were HCWs. Sociodemographic data, along with attitudes and beliefs around COVID-19 vaccination, were collected from the respondents. Results: We found that 12.9% of the study participants showed vaccine hesitancy, defined as definitely or probably will not take the vaccine if offered, and 25.31% reported that they were unsure about the uptake of the COVID-19 vaccine. Female respondents were more hesitant toward the vaccine. Safety and efficacy concerns of vaccine were the significant predictors of vaccine hesitancy. The primary predictor for vaccine acceptance was a better understanding of the disease and vaccine. Discussion: Overall, 1 in 8 HCWs were reluctant to get vaccinated against COVID-19, mainly due to concerns about the vaccine's efficacy and safety. Education about the vaccine's safety and efficacy can potentially improve acceptance among healthcare workers.

Burnout and job satisfaction among psychiatrists in the Mental Health Service, Hamad Medical Corporation, Qatar.

BACKGROUND: Job satisfaction is a critical concern among medical staff and directly affects patient safety and quality of health care services. Burnout has been reported to be correlated with job satisfaction. AIMS: This study aimed to determine the prevalence of burnout and level of job satisfaction among psychiatrists working in the Mental Health Service, Hamad Medical Corporation, Qatar, and examine correlations among socio-demographic variables, burnout, and job satisfaction. METHOD: A cross-sectional survey was conducted using a socio-demographic questionnaire, the Maslach Burnout Inventory (MBI), and the Job Descriptive Index (JDI). RESULTS: One-third of psychiatrists reported high levels of emotional exhaustion, with a similar proportion describing low levels of personal accomplishment. Less than 20 % demonstrated high levels of depersonalization. Trainees were more burned out than senior psychiatrists. Opportunities for promotion was the only factor with which the majority of psychiatrists were not satisfied. CONCLUSIONS: The prevalence of high burnout in psychiatrists remains lower in Qatar than in other countries. Lower levels of satisfaction with co-workers, work, supervision, opportunities for promotion, and the job in general increased emotional exhaustion and depersonalization. Interestingly, satisfaction with salary did not have a significant effect on burnout.

SIRT3, a metabolic target linked to ataxia-telangiectasia mutated (ATM) gene deficiency in diffuse large B-cell lymphoma.

Inactivation of Ataxia-telangiectasia mutated (ATM) gene results in an increased risk to develop cancer. We show that ATM deficiency in diffuse large B-cell lymphoma (DLBCL) significantly induce mitochondrial deacetylase sirtuin-3 (SIRT3) activity, disrupted mitochondrial structure, decreased mitochondrial respiration, and compromised TCA flux compared with DLBCL cells expressing wild type (WT)-ATM. This corresponded to enrichment of glutamate receptor and glutamine pathways in ATM deficient background compared to WT-ATM DLBCL cells. ATM-/- DLBCL cells have decreased apoptosis in contrast to radiosensitive non-cancerous A-T cells. In vivo studies using gain and loss of SIRT3 expression showed that SIRT3 promotes growth of ATM CRISPR knockout DLBCL xenografts compared to wild-type ATM control xenografts. Importantly, screening of DLBCL patient samples identified SIRT3 as a putative therapeutic target, and validated an inverse relationship between ATM and SIRT3 expression. Our data predicts SIRT3 as an important therapeutic target for DLBCL patients with ATM null phenotype.

Sociodemographic and clinical characteristics of patients with recurrent psychiatric readmissions in Qatar.

OBJECTIVE: To examine the sociodemographic and clinical characteristics of psychiatric patients with recurrent psychiatric readmissions (RPR). METHODS: A retrospective study was conducted at Hamad General Hospital in Qatar on psychiatric patients with recurrent readmissions from August 2018 to January 2019. RESULTS: Of 380 psychiatric patients admitted during the study period, 40 (10.5%) were readmitted within 30 days of discharge. Most of the patients who were readmitted were single, male and unemployed. Psychotic spectrum disorder was the most frequent psychiatric condition and was diagnosed in 18 (45%) patients. A total of 30% of the patients were receiving treatment with anti-psychotics, and a similar number received more than one medication. Most patients showed poor or no compliance. Only 12.5% of patients stayed in the hospital for more than 5 weeks in their last admission during the study period. CONCLUSIONS: Poor compliance, male sex and single status were the most common demographic and clinical features of patients with RPR. Post-discharge psychiatric care should be tailored to meet the requirements of patients prone to RPR.

Circumventing cellular immunity by miR142-mediated regulation sufficiently supports rAAV-delivered OVA expression without activating humoral immunity.

Recombinant adeno-associated virus (rAAV)-mediated gene delivery can efficiently target muscle tissues to serve as "biofactories" for secreted proteins in prophylactic and therapeutic scenarios. Nevertheless, efficient rAAV-mediated gene delivery is often limited by host immune responses against the transgene product. The development of strategies to prevent anti-transgene immunity is therefore crucial. The employment of endogenous microRNA (miRNA)-mediated regulation to detarget transgene expression from antigen presenting cells (APCs) has shown promise for reducing immunogenicity. However, the mechanisms underlying miRNA-mediated modulation of anti-transgene immunity by APC detargeting are not fully understood. Using the highly immunogenic ovalbumin (OVA) protein as a proxy for foreign antigens, we show that rAAV vectors containing miR142 binding sites efficiently repress co-stimulatory signals in dendritic cells, significantly blunt the cytotoxic T cell response, allow for sustained transgene expression in skeletal myoblasts, and attenuate clearance of transduced muscle cells in mice. Furthermore, the blunting of humoral immunity against circulating OVA correlates with detargeting of OVA expression from APCs. This demonstrates that incorporating APC-specific miRNA binding sites into rAAV vectors provides an effective strategy for reducing transgene-specific immune response. This approach holds promise for clinical applications where the safe and efficient delivery of a prophylactic or therapeutic protein is desired.

Hesperidin promotes lysosomal biogenesis in chronically ethanol-induced cardiotoxicity in rats: A proposed mechanisms of protection.

Alcohol consumption is a major global risk factor for mortality and morbidity. We aimed to delineate the mechanisms underlying the potential ameliorative effects of hesperidin against chronically ethanol-induced cardiotoxicity. Sixty male albino rats were divided into normal control group, hesperidin-treated control group, untreated alcoholic group, and hesperidin-treated alcoholic group. Transcription factor-EB (TFEB) expression levels were estimated using real-time reverse transcription-polymerase chain reaction. Peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1-α), macrophage inflammatory protein-1 α, poly-(ADP-ribose)-polymerase-1 (PARP-1) activity, and tenascin C levels in cardiac tissues were estimated by enzyme-linked immunosorbent assay; while tissue malondialdehyde and total antioxidant capacity were evaluated spectrophotometrically. Our data portrayed promoting lysosomal biogenesis, as judged by upregulation of TFEB expression and its target PGC1-α, as well as decreased PARP-1 activity and offsetting inflammation, oxidative stress, and tissue injury as the principal culprits mediating the cardioprotective effect of hesperidin in alcohol-induced cardiotoxicity. In conclusion, hesperidin can be used as a cardioprotective agent in chronically ethanol-induced cardiotoxicity.

Human papillomavirus genotypes in Pacific Islander cervical cancer patients.

OBJECTIVE: The role of human papillomavirus (HPV) in the development of invasive cervical cancers is widely known. Few HPV studies have targeted geographically isolated regions. The objective of this study was to determine the HPV genotypes in cervical cancer patients from the Pacific Islands referred to Tripler Army Medical Center (TAMC). METHODS: All cases of invasive cervical cancer treated at TAMC through the Pacific Island Health Care Project between January 2004 and October 2014 were identified through a review of pathology specimens. DNA was extracted from paraffin-embedded tissue blocks. PCR was performed using PLEX-ID plates to isolate and amplify HPV-specific DNA. Mass spectrometry was subsequently performed to identify specific HPV genotypes. RESULTS: Thirty-five patients had their pathology specimens analyzed. Ten patients had localized disease (Stage 1); 21 had regional disease (Stages 2 and 3); and 4 had distant disease (Stage 4). Thirty-three squamous cell carcinomas and 3 adenocarcinomas were identified. The most common HPV subtypes found were 16 (6, 24%), 45 (6, 24%), and 52 (6, 24%). Other HPV subtypes isolated included 18 (1, 4%), 33 (3, 12%), 39 (2, 8%), 54 (1, 4%), and 67 (1, 4%). In 10 samples, HPV was not isolated. CONCLUSION: Pacific Islanders referred to TAMC present with a disproportionally higher rate of regional and advanced disease. Significantly, only 28% of invasive cervical cancers in the Pacific Island population sampled could have been potentially be prevented using the available quadrivalent vaccine targeting HPV 16/18; however, 88% could be covered by the recently licensed nonavalent vaccine.

Author Correction: Role of hypoxia in Diffuse Large B-cell Lymphoma: Metabolic repression and selective translation of HK2 facilitates development of DLBCL.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Fatty Acid Synthase induced S6Kinase facilitates USP11-eIF4B complex formation for sustained oncogenic translation in DLBCL.

Altered lipid metabolism and aberrant protein translation are strongly associated with cancerous outgrowth; however, the inter-regulation of these key processes is still underexplored in diffuse large B-cell lymphoma (DLBCL). Although fatty acid synthase (FASN) activity is reported to positively correlate with PI3K-Akt-mTOR pathway that can modulate protein synthesis, the precise impact of FASN inhibition on this process is still unknown. Herein, we demonstrate that attenuating FASN expression or its activity significantly reduces eIF4B (eukaryotic initiation factor 4B) levels and consequently overall protein translation. Through biochemical studies, we identified eIF4B as a bonafide substrate of USP11, which stabilizes and enhances eIF4B activity. Employing both pharmacological and genetic approaches, we establish that FASN-induced PI3K-S6Kinase signaling phosphorylates USP11 enhancing its interaction with eIF4B and thereby promoting oncogenic translation.

Role of hypoxia in Diffuse Large B-cell Lymphoma: Metabolic repression and selective translation of HK2 facilitates development of DLBCL.

Published molecular profiling studies in patients with lymphoma suggested the influence of hypoxia inducible factor-1 alpha (HIF1α) targets in prognosis of DLBCL. Yet, the role of hypoxia in hematological malignancies remains unclear. We observed that activation of HIF1α resulted in global translation repression during hypoxic stress in DLBCL. Protein translation efficiency as measured using 35S-labeled methionine incorporation revealed a ≥50% reduction in translation upon activation of HIF1α. Importantly, translation was not completely inhibited and expression of clinically correlated hypoxia targets such as GLUT1, HK2, and CYT-C was found to be refractory to translational repression under hypoxia in DLBCL cells. Notably, hypoxic induction of these genes was not observed in normal primary B-cells. Translational repression was coupled with a decrease in mitochondrial function. Screening of primary DLBCL patient samples revealed that expression of HK2, which encodes for the enzyme hexokinase 2, was significantly correlated with DLBCL phenotype. Genetic knockdown studies demonstrated that HK2 is required for promoting growth of DLBCL under hypoxic stress. Altogether, our findings provide strong support for the direct contribution of HK2 in B-cell lymphoma development and suggest that HK2 is a key metabolic driver of the DLBCL phenotype.

Analysis of the CRISPR-Cas system in bacteriophages active on epidemic strains of Vibrio cholerae in Bangladesh.

CRISPR-Cas (clustered regularly interspersed short palindromic repeats-CRISPR-associated proteins) are microbial nuclease systems involved in defense against phages. Bacteria also resist phages by hosting phage-inducible chromosomal islands (PICI) which prevent phage reproduction. Vibrio cholerae which causes cholera epidemics, interacts with numerous phages in the environment and in cholera patients. Although CRISPR-Cas systems are usually carried by bacteria and archea, recently V. cholerae specific ICP1 phages were found to host a CRISPR-Cas system that inactivates PICI-like elements (PLE) in V. cholerae. We analyzed a collection of phages and V. cholerae isolated during seasonal cholera epidemics in Bangladesh, to study the distribution, and recent evolution of the phage-encoded CRISPR-Cas system. Five distinct but related phages carrying the CRISPR-Cas system, and possible CRISPR-Cas negative progenitor phages were identified. Furthermore, CRISPR arrays in the phages were found to have evolved by acquisition of new spacers targeting diverse regions of PLEs carried by the V. cholerae strains, enabling the phages to efficiently grow on PLE positive strains. Our results demonstrate a continuing arms-race involving genetic determinants of phage-resistance in V. cholerae, and the phage-encoded CRISPR-Cas system in the co-evolution of V. cholerae and its phages, presumably fostered by their enhanced interactions during seasonal epidemics of cholera.

Mechanistic insights into the effects of quercetin and/or GLP-1 analogue liraglutide on high-fat diet/streptozotocin-induced type 2 diabetes in rats.

BACKGROUND: The development of complementary treatment strategies that focuses on achieving a balance between adaptive and apoptotic unfolded protein response (UPR), enhancing endoplasmic reticulum (ER) homeostasis, and thus preserving ß cell mass and function is particularly warranted. AIM: This study was designed to investigate the effectiveness of the combined treatment by Quercetin (QUE) and Liraglutide (LIRA) in modulating hyperglycemia, insulin-insensitivity, UPR/ER stress markers, apoptosis, oxidative stress and inflammation using a high-fat diet/streptozotocin -induced type 2 diabetic rat model. METHODS: Sixty male albino rats were allocated into five equal groups: normal control, diabetic control, LIRA treated diabetic; QUE treated diabetic and combined treatment diabetic groups. Fasting glucose, insulin, CHOP, macrophage inflammatory protein -1 α (MIP-1α) and Bax, Bcl2 levels were estimated by ELISA; mRNA expression levels of the spliced X-box binding protein 1 (XBP1) were estimated using quantitative real-time RT-PCR, while MDA, advanced oxidation protein products, reduced glutathione levels and protein disulfide isomerase (PDI) activity were evaluated spectrophotometrically. Pancreatic tissues were also subjected to histopathological examination. RESULTS: The combined treatment with both LIRA and QUE causes significant improvements in all the studied parameters; including XBP1 splicing, CHOP, MIP-1α, Bax/Bcl2 ratio, PDI activity, as well as oxidative stress markers as compared to either treatment alone. It also attenuated pancreatic histopathological damage. IN CONCLUSION: Our study nominates this combination to be used in T2DM to achieve adequate glycaemic control and to preserve optimal ß cell function.

EBV-negative Aggressive NK-cell Leukemia/Lymphoma: Clinical, Pathologic, and Genetic Features.

Aggressive natural killer cell leukemia (ANKL) is a systemic NK-cell neoplasm, almost always associated with Epstein-Barr virus (EBV). Rare cases of EBV-negative ANKL have been described, and some reports suggested more indolent behavior. We report the clinicopathologic, immunophenotypic, and molecular characteristics of 7 EBV-negative ANKL. All patients were adults, with a median age of 63 years (range 22 to 83 y) and an M:F ratio of 2.5:1. Five patients were White, 1 Black, and 1 Asian. All patients presented acutely, with fever (6/7), cytopenias (6/7), and splenomegaly (4/7). Four patients had lymphadenopathy, 4 had extranodal disease. Bone marrow involvement was present in 5, with hemophagocytosis in 3. Peripheral blood was involved in 5 with the neoplastic cells containing prominent azurophilic granules. By immunohistochemistry and/or flow cytometry, the tumor cells lacked surface CD3 and were positive for CD56 (7/7), CD2 (5/5), CD8 (3/7), CD30 (4/5), and granzyme-B (6/6). They were negative for CD4, CD5, ßF1, TCRγ, LMP1, and EBV-encoded RNA. Polymerase chain reaction for TCRG clonality was polyclonal. Mutational analysis revealed missense mutations in the STAT3 gene in both cases studied. Median survival was 8 weeks from the onset of disease. One patient received allogeneic bone marrow transplant and is alive with no disease (follow-up 15 mo). EBV-negative ANKL exists but is rare. It tends to occur in older patients and is indistinguishable clinically and pathologically from EBV-positive ANKL, with a similar fulminant clinical course. The high prevalence of Asian patients seen with EBV-positive disease seems less evident with EBV-negative cases.

Radicular anatomy of permanent mandibular second molars in an Iranian population: A preliminary study.

BACKGROUND: Root morphology is of utmost importance to endodontic sciences. Since there are a few studies on the morphology of mandibular second molars' roots, and some anatomical variables are not evaluated before, the aim of this study was to investigate thoroughly radicular anatomy of this tooth. MATERIALS AND METHODS: This ex vivo study was performed on 150 intact mandibular second molars. After access cavity preparation and ensuring canal patency, Indian ink was injected into root canals from the orifices. The teeth became transparent using methyl salicylate storage. Then, they were inspected by an endodontist under a ×10 stereomicroscope regarding numerous root morphological variables. Data were analyzed using chi-square test and analysis of variance (α = 0.05). RESULTS: About 86.7% of teeth had two roots and 13.3% were single-rooted (P = 0.0001), of which, 50% were C-shaped (6.7% of all teeth, P = 0.0001). 86.7% of mesial roots were double canalled, whereas 75.3% of distal roots were single canalled (P = 0.0001). 71.45% and 95.3% of the mesial and distal roots had one apical foramen, respectively (P = 0.0001). Apical foramens were mostly central followed by lingual in most cases. Distances between apical foramen and apical constriction ranged between 0.27 and 0.40 mm (P = 0.0545). Distances between apical foramen and root apices ranged between 0.30 and 0.47 mm (P = 0.0001). Vertucci classifications of mesial canals were Type II in 62.6% and Type IV in 37.4%. 86.2% of single-canal distal roots were Type I. 66.7% of double-canal distal roots were Type II and 33.3% were Type IV (P = 0.0001). The mean root lengths from cervical to apex of mesial, distal, and single roots were 14.02 ± 0.85 (95% confidence interval [CI] = 13.87-14.17), 13.35 ± 0.91 (95% CI = 13.19-13.50), and 14.25 ± 0.72 mm (95% CI = 13.91-14.58), respectively. The extents of canal curvatures varied between 20° and 31° buccolingually (P = 0.0000), and between 19° and 27° mesiodistally (P = 0.0000). CONCLUSION: There was a considerable rate of eccentric apical foramen in mandibular second molars.