The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial.

The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian cancer. Here we report the activity of CHK1i in platinum-resistant high-grade serous ovarian carcinoma (HGSOC) with measurable and biopsiable disease (cohort 5), or without biopsiable disease (cohort 6). The primary endpoint was objective response rate (ORR). Secondary outcomes were safety and progression-free survival (PFS). 49 heavily pretreated patients were enrolled (24 in cohort 5, 25 in cohort 6). Among the 39 RECISTv1.1-evaluable patients, ORR was 33.3% in cohort 5 and 28.6% in cohort 6. Primary endpoint was not evaluable due to early stop of the trial. The median PFS was 4 months in cohort 5 and 6 months in cohort 6. Toxicity was manageable. Translational research was an exploratory endpoint. Potential biomarkers were investigated using pre-treatment fresh biopsies and serial blood samples. Transcriptomic analysis revealed high levels of DNA replication-related genes (POLA1, POLE, GINS3) associated with lack of clinical benefit [defined post-hoc as PFS < 6 months]. Subsequent preclinical experiments demonstrated significant cytotoxicity of POLA1 silencing in combination with CHK1i in platinum-resistant HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation.

AKT1 interacts with DHX9 to Mitigate R Loop-Induced Replication Stress in Ovarian Cancer.

PARP inhibitor (PARPi)-resistant BRCA-mutant (BRCAm) high-grade serous ovarian cancer (HGSOC) represents a new clinical challenge with unmet therapeutic needs. Here, we performed a quantitative high-throughput drug combination screen that identified the combination of an ATR inhibitor (ATRi) and an AKT inhibitor (AKTi) as an effective treatment strategy for both PARPi-sensitive and PARPi-resistant BRCAm HGSOC. The ATRi and AKTi combination induced DNA damage and R loop-mediated replication stress (RS). Mechanistically, the kinase domain of AKT1 directly interacted with DHX9 and facilitated recruitment of DHX9 to R loops. AKTi increased ATRi-induced R loop-mediated RS by mitigating recruitment of DHX9 to R loops. Moreover, DHX9 was upregulated in tumors from patients with PARPi-resistant BRCAm HGSOC, and high coexpression of DHX9 and AKT1 correlated with worse survival. Together, this study reveals an interaction between AKT1 and DHX9 that facilitates R loop resolution and identifies combining ATRi and AKTi as a rational treatment strategy for BRCAm HGSOC irrespective of PARPi resistance status. SIGNIFICANCE: Inhibition of the AKT and ATR pathways cooperatively induces R loop-associated replication stress in high-grade serous ovarian cancer, providing rationale to support the clinical development of AKT and ATR inhibitor combinations. See related commentary by Ramanarayanan and Oberdoerffer, p. 793.

Type 2 Diabetes and Precursors in Community Dwelling Asian Indian Adult Youth.

Background: Recent studies have shown a high prevalence of Type-2-diabetes (T2DM) (24%) and prediabetes (18.1%) in Kerala. There is no community based study from South Asia regarding the prevalence of type 2 diabetes and its precursors in the young adult population. This community based study was done to find the prevalence of type 2 diabetes and its precursors in South Indian adult youth (18-30 years age) of Thiruvananthapuram district. Research Design and Methods: Cross sectional design was used for this study. Multistage cluster sampling was used to enrol community dwelling youth of 18 to 30 years, residing in Thiruvananthapuram district. Six panchayath wards from rural and urban regions and 4 from coastal area were randomly selected as the primary sampling units. Trained staff nurses conducted the survey with the help of accredited-social-health-activists (ASHA). Socio-demographic data, anthropometry, clinical features of insulin resistance, and random capillary glucose (CG) and blood pressure were assessed and recorded. Oral Glucose tolerance test or HbA1c was done for participants with a CG ≥130 mg/dl for diagnosis of diabetes and prediabetes. Results: A total of 1031 participants were included from the rural (n = 394), coastal (n = 269) and urban (n = 368) areas. Prevalence of hyperglycaemia i.e., T2DM and pre-diabetes was 0.48% (n = 5) and 2.4% (n = 25) respectively. Family-history of T2DM was present in 35.1% subjects. Prevalence of overweight, obesity and abdominal-obesity was 28.2%, 16.1% and 28.4% respectively. Clinical-features of insulin resistance (CFIR) were present in 27.1% subjects (acanthosis [17.7%], skin tags [1.7%] and PCOS phenotype [10.7%]). Among various anthropometric measurements and their derivatives, CFIR correlated best (r = 0.24, P < 0.01) with the product of BMI and the sum of abdominal circumference and hip circumference (Trivandrum Medical College [TMC] -adiposity-index), which is a newly proposed parameter. Hyperglycaemia was more common in males, did not correlate with waist hip ratio, and correlated best again with TMC-adiposity-index ((r = 0.13, P < 0.01). Conclusions: The burden of insulin resistance in the young South Indian population, hitherto unknown in any community based study, has been studied for the first time. The prevalence of precursors of T2DM is high in this population. Early identification of 'at risk' individuals could provide a window of opportunity for preventing or delaying future diabetes and its long term complications. TMC adiposity index could become a valuable tool in the anthropometric assessment for predicting future T2DM.

Reference range for glycated haemoglobin in full term non diabetic pregnant women: a multicentric cross sectional study.

BACKGROUND: There are no large studies to define the normal value of glycated haemoglobin (HbA1c) measured in full term pregnant women measured at the time of delivery. RESEARCH DESIGN AND METHODS: The study was conducted at three government hospitals in South India. Clinical data, maternal blood sample and foetal cord blood sample were collected from women admitted for safe confinement. Mean (± SD) of HbA1c in participants with no known diabetes (gestational or pregestational) or any complications (maternal or fetal) is described, 2.5th-97.5th centile reference range was derived. RESULTS: From 3 centres, 2004 women participated in the study. Data from 1039 participants who had no history of diabetes or any maternal or fetal complication were used to determine the reference range for HbA1c at term pregnancy. The mean HbA1c in subjects devoid of diabetes and its known complications was 5.0 (± 0.39) %. The reference range for normal HbA1c at term in these women was found to be 4.3-5.9%. Maternal HbA1c at term pregnancy in non-diabetic pregnant women is associated with pre-pregnancy BMI, maternal age and 2-h plasma glucose level of 2nd trimester oral glucose tolerance test (OGTT). CONCLUSIONS: The mean HbA1c at term pregnancy in non-diabetic women admitted for safe confinement is 5.00 (± 0.39) %. An HbA1c of 5.9% or more at term should be considered abnormal and women with such a value may be kept at a close surveillance for development of diabetes.

BLM overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor-resistant BRCA-mutant ovarian cancer.

Poly(ADP-ribose) polymerase inhibitors (PARPis) have changed the treatment paradigm in breast cancer gene (BRCA)-mutant high-grade serous ovarian carcinoma (HGSC). However, most patients eventually develop resistance to PARPis, highlighting an unmet need for improved therapeutic strategies. Using high-throughput drug screens, we identified ataxia telangiectasia and rad3-related protein/checkpoint kinase 1 (CHK1) pathway inhibitors as cytotoxic and further validated the activity of the CHK1 inhibitor (CHK1i) prexasertib in PARPi-sensitive and -resistant BRCA-mutant HGSC cells and xenograft mouse models. CHK1i monotherapy induced DNA damage, apoptosis, and tumor size reduction. We then conducted a phase 2 study (NCT02203513) of prexasertib in patients with BRCA-mutant HGSC. The treatment was well tolerated but yielded an objective response rate of 6% (1 of 17; one partial response) in patients with previous PARPi treatment. Exploratory biomarker analyses revealed that replication stress and fork stabilization were associated with clinical benefit to CHK1i. In particular, overexpression of Bloom syndrome RecQ helicase (BLM) and cyclin E1 (CCNE1) overexpression or copy number gain/amplification were seen in patients who derived durable benefit from CHK1i. BRCA reversion mutation in previously PARPi-treated BRCA-mutant patients was not associated with resistance to CHK1i. Our findings suggest that replication fork-related genes should be further evaluated as biomarkers for CHK1i sensitivity in patients with BRCA-mutant HGSC.

Significance of microbial genome in environmental remediation.

Environmental pollutants seriously threaten the ecosystem and health of various life forms, particularly with the rapid industrialization and emerging population. Conventionally physical and chemical strategies are being opted for the removal of these pollutants. Bioremediation, through several advancements, has been a boon to combat the existing threat faced today. Microbes with enzymes degrade various pollutants and utilize them as a carbon and energy source. With the existing demand and through several research explorations, Genetically Engineered Microorganisms (GEMs) have paved to be a successful approach to abate pollution through bioremediation. The genome of the microbe determines its biodegradative nature. Thus, methods including pure culture techniques and metagenomics are used for analyzing the genome of microbes, which provides information about catabolic genes. The information obtained along with the aid of biotechnology helps to construct GEMs that are cost-effective and safer thereby exhibiting higher degradation of pollutants. The present review focuses on the role of microbes in the degradation of environmental pollutants, role of evolution in habitat and adaptation of microbes, microbial degenerative genes, their pathways, and the efficacy of recombinant DNA (rDNA) technology for creating GEMs for bioremediation. The present review also provides a gist of existing GEMs for bioremediation and their limitations, thereby providing a future scope of implementation of these GEMs for a sustainable environment.

Cough remedy leading to chronic cough: An unusual airway foreign body-Clove.

The spectrum of presentation of airway foreign body can vary from having mild symptoms to sudden death. Smaller foreign body in distal airways, especially if the patient is unaware of aspiration can result in chronic symptoms mimicking asthma. Clove, has been used traditionally for its medicinal values and commonly used as a cough remedy. In this case series, we report four cases of this unusual airway foreign body which were essentially consumed with an intention to prevent cough, but unfortunately became the reason for their cough.

Monitoring of Harmful Algal Bloom (HAB) of Noctiluca scintillans (Macartney) along the Gulf of Mannar, India using in-situ and satellite observations and its impact on wild and maricultured finfishes.

In the Gulf of Mannar, Noctiluca scintillans blooms have been observed three times in September 2019, September and October 2020, and October 2021. It was determined and measured how the bloom period affects ichthyo-diversity. Noctiluca cell density varied slightly from year to year, ranging from1.8433 × 103 cells/L to 1.3824 x 106cells/L. In surface and sea bottom waters, high ammonia levels and low dissolved oxygen levels were noted. During the bloom period a significant increase in chlorophyll concentration was found. The amount of chlorophyll in GOM was extremely high, according to remote sensing photos made using MODIS-Aqua 4 km data. Acute hypoxia caused the death of wild fish near coral reefs and also in fish reared in sea cages. The decay of the bloom resulted in significant ammonia production, a dramatic drop in the amount of dissolved oxygen in the water, and ultimately stress, shock, and mass mortality of fishes.

A Case Report of Rare Vocal Cord Hemangioendothelioma in a Paediatric Larynx.

Hemangioendothelioma (HEM) is a vascular tumour which is locally aggressive with a low-grade malignant potential. We present a rare case of HEM arising from the vocal cord of a 10-year-old female child. Video laryngoscopy clearly showed a large vocal cord polyp-like mass attached to middle one-third of left cord. Histopathological examination showed fragments of tissue with a neoplasm composed of spindle cells arranged diffusely admixed with numerous small vascular channels. These specific cells were positive for CD31, CD34, vimentin and ERG. Flexiblescopy and narrow band imaging were performed 3 weeks after surgery which showed no residual mass. Treatment of HEM is hampered by lack of proper guidelines and protocol. In this case of localized vocal cord lesion, a wide excision with regular follow up is considered ideal.

Hyperfunctional Laryngeal Behavior: Is It the Cause or Consequence of Vocal Fold Polyps?

OBJECTIVES: To evaluate the relationship between arytenoid adduction asymmetry (AAA) and the demographic and morphological characteristics of true vocal fold (TVF) polyps and establish the cause and effect relationship between AAA and TVF polyps. METHODS: Videolaryngostroboscopic findings of 163 patients with TVF polyps were retrospectively reviewed and categorized into Group 1 with AAA or Group 2 without AAA. Demographic details, clinicomorphological polyp characteristics, supraglottic phenomena, and AAA attributes were analyzed. RESULTS: Group 1 was younger than Group 2 (fourth vs fifth decade; P = .0066). Polyp characteristics showed no significant intergroup differences. The association between AAA and false vocal fold (FVF) adduction (65.28% vs 47.62% in Group 1 and 2 respectively; P = .0441) was significant. In relation to TVF polyp laterality, contralateral and bilateral AAA and FVF adduction respectively, was significant. CONCLUSION: AAA is a compensatory laryngeal adaptation akin to a FVF adduction muscle tension pattern. With a concomitant laryngeal pathology and high vocal demand, AAA is a consequence and not the cause for underlying laryngeal pathology which hinders glottic closure.

Distinct roles of treatment schemes and BRCA2 on the restoration of homologous recombination DNA repair and PARP inhibitor resistance in ovarian cancer.

Poly (ADP-ribose) polymerase inhibitors (PARPis) represent a major advance in ovarian cancer, now as a treatment and as a maintenance therapy in the upfront and recurrent settings. However, patients often develop resistance to PARPis, underlining the importance of dissecting resistance mechanisms. Here, we report different dosing/timing schemes of PARPi treatment in BRCA2-mutant PEO1 cells, resulting in the simultaneous development of distinct resistance mechanisms. PARPi-resistant variants PEO1/OlaJR, established by higher initial doses and short-term PARPi treatment, develops PARPi resistance by rapidly restoring functional BRCA2 and promoting drug efflux activity. In contrast, PEO1/OlaR, developed by lower initial doses with long-term PARPi exposure, shows no regained BRCA2 function but a mesenchymal-like phenotype with greater invasion ability, and exhibits activated ATR/CHK1 and suppressed EZH2/MUS81 signaling cascades to regain HR repair and fork stabilization, respectively. Our study suggests that PARPi resistance mechanisms can be governed by treatment strategies and have a molecular basis on BRCA2 functionality. Further, we define different mechanisms that may serve as useful biomarkers to assess subsequent treatment strategies in PARPi-resistant ovarian cancer.

Colistimethate sodium-chitosan hydrogel for treating Gram-negative bacterial wound infections.

The drug resistance is higher among Gram-negative bacteria and demands the usage of strong antibiotics which can in turn result in systemic toxicity. In the treatment of the chronic wounds harboring pathogenic Gram-negative bacteria, the demand for an antimicrobial product that can be topically administered has been on the rise. In an effort to address the above issue, we have developed Colistimethate sodium (a high-end antibiotic) loaded chitosan hydrogel and characterized. The prepared hydrogel is very stable and observed to be bio- and hemo-compatible in nature. The antibacterial activity of the prepared hydrogel was studied against both ATCC (American Type Culture Collection) strains and clinical isolates of Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae. The CMS incorporated hydrogel is also capable of inhibiting the biofilm formation. The developed hydrogel can be potentially being used for the treatment of Gram-negative bacterial infected wounds.

Antiseptic chitosan bandage for preventing topical skin infections.

Infections on the wound surface are the major problem in restricting the healing process. To reduce the transmission and treat the infection, we have developed 0.05% and 0.1% octenidine dihydrochloride (Ocd) incorporated chitosan (Cs) based flexible bandages. Ocd is extensively used skin antiseptic for its mode of action over a broad spectrum of antimicrobial activity. The prepared antiseptic Cs-Ocd bandage was characterized using Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscope (SEM). In addition, swelling, degradation, cytocompability, antibacterial, and anti-biofilm property of the developed bandages were studied. This highly porous nature of Cs-Ocd bandage showed enhanced swelling property, slow degradation profile and controlled release of Ocd. The prepared antiseptic bandage exhibited synergistic effect showing good hemostatic potential with Cs, excellent antimicrobial and anti-biofilm activity with Ocd against Staphylococcus aureus (S. aureus) and Candida auris (C. auris). Thus, the developed Cs-Ocd bandage can be used as potential antiseptic bandage for skin infections.

Hydrogels: A potential platform for induced pluripotent stem cell culture and differentiation.

Induced pluripotent stem cells (iPSCs) can be used to generate desired types of cells that belong to the three germ layers (i.e., ectoderm, endoderm and mesoderm). These cells possess great potential in regenerative medicine. Before iPSCs are used in various biomedical applications, the existing xenogeneic culture methods must be improved to meet the technical standards of safety, cost effectiveness, and ease of handling. In addition to commonly used 2D substrates, a culture system that mimics the native cellular environment in tissues will be a good choice when culturing iPS cells and differentiating them into different lineages. Hydrogels are potential candidates that recapitulate the native complex three-dimensional microenvironment. They possess mechanical properties similar to those of many soft tissues. Moreover, hydrogels support iPSC adhesion, proliferation and differentiation to various cell types. They are xeno-free and cost-effective. In addition to other substrates, such as mouse embryonic fibroblast (MEF), Matrigel, and vitronectin, the use of hydrogel-based substrates for iPSC culture and differentiation may help generate large numbers of clinical-grade cells that can be used in potential clinical applications. This review mainly focuses on the use of hydrogels for the culture and differentiation of iPSCs into various cell types and their potential applications in regenerative medicine.

Melanotic Neuroectodermal Tumor of Infancy in the Ulna of an Infant: A Very Rare Tumor: A Case Report.

CASE: A 4-month-old boy presented with a nontender swelling of the right proximal forearm of 2 months' duration. Radiological evaluation showed lytic lesion surrounded by sclerotic bone in the ulna with soft-tissue extension. Histopathological examination showed tumor of round and epithelioid cells containing melanin, interpreted as melanotic neuroectodermal tumor. The patient underwent a wide excision of the shaft of the ulna with creation of radioulnar synostosis. There is no recurrence 6 years after surgery. CONCLUSION: Melanotic neuroectodermal tumor is rare in the appendicular skeleton and has to be differentiated from other round cell tumors and osteomyelitis. As far as we know, this is the first reported case in the ulna.

"Innocent" arytenoid adduction asymmetry: An etiological survey.

PURPOSE: To estimate the incidence of "innocent" arytenoid adduction asymmetry (AAA) among patients presenting at a laryngology clinic, identify its association with demographic characteristics, symptomatology and various clinical/pathological conditions and thereby determine its clinical significance. METHODS: A prospective comparative observational clinical study was conducted. Group 1 included patients presenting at the Department of Laryngology, identified with a primary diagnosis and coexisting "innocent" AAA i.e., an overriding arytenoid with normal vocal fold mobility on laryngoscopy. Group 2 included an equal number of randomly selected patients fulfilling the same criteria, without AAA. Demographic and clinical details were recorded and analyzed. RESULTS: 110 cases were included in each group. The incidence of innocent AAA was 12.7%. Males were predominant in both Groups, with the gender difference significant in Group 1. Patients in Group 1 were significantly younger than in Group 2. Professional voice users, namely singers, were significantly greater in Group 1. Symptoms associated with Group 1 (i.e. AAA) were high pitch strain while singing (p = 0.01) and unilateral throat pain (p = 0.01), and the associated diagnoses were Singing Voice Dysphonia (p = 0.005), Vocal Process Granuloma (p = 0.04) and Ventricular Band Dysphonia (p = 0.047). As a definitive diagnosis was made in all patients, the presenting complaints were not attributed to AAA. Right sided preponderance of AAA was significant. Among the diagnoses with a laterality (e.g. vocal process granuloma), AAA was observed contralateral to the pathology in 70.7% and ipsilaterally in 29.3% (p = 0.0058). CONCLUSION: Innocent AAA is common among males in the 3rd-4th decades, in singers among professional voice users, and in those with the muscle tension dysphonia spectrum and vocal process granuloma, thereby suggesting that it is an acquired habit/response to greater vocal demand. The observation of AAA contralateral to laryngeal lesions, highlights its compensatory nature, attempting to optimize glottic closure.

Lipid Profile in Indian Patients With Type 2 Diabetes: The Scope for Atherosclerotic Cardiovascular Disease Risk Reduction.

OBJECTIVE: Reduction of atherosclerotic cardiovascular disease (ASCVD) risk in patients with diabetes requires proper management of lipid parameters. This study aimed to find the pattern of dyslipidemia and scope of ASCVD risk reduction in patients with diabetes by lipid management. METHODS: Clinical, biochemical, and medication profiles of all patients with diabetes attending a tertiary diabetes care hospital over a 2-year period were collected. The prevalence of various lipid abnormalities was determined after excluding patients with thyroid dysfunction and those on lipid-lowering medications. Patients were stratified according to LDL cholesterol, HDL cholesterol, and triglyceride levels, and other clinical parameters were compared among the groups. The adequacy of statin treatment was assessed based on American Diabetes Association guidelines. RESULTS: Nine hundred and seventy-one patients were included. The prevalence of hyperlipidemia was 40.0%, of whom 14.6% were newly diagnosed. The most common lipid abnormality was elevated LDL cholesterol. Higher A1C and fasting blood glucose values were found to be associated with higher LDL cholesterol levels. Twenty-seven percent of patients with indications for treatment with statins were receiving them. Of those being treated with statins, 42.6% had an LDL cholesterol level ≥100 mg/dL. CONCLUSION: In South Indian patients with type 2 diabetes and fair glycemic control, high LDL cholesterol is the predominant lipid abnormality. There remains a huge potential for ASCVD risk reduction in this population if the knowledge practice gap is addressed.

Targeting the PI3K/mTOR Pathway Augments CHK1 Inhibitor-Induced Replication Stress and Antitumor Activity in High-Grade Serous Ovarian Cancer.

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic malignancy in industrialized countries and has limited treatment options. Targeting ataxia-telangiectasia and Rad3-related/cell-cycle checkpoint kinase 1 (CHK1)-mediated S-phase and G2-M-phase cell-cycle checkpoints has been a promising therapeutic strategy in HGSOC. To improve the efficacy of CHK1 inhibitor (CHK1i), we conducted a high-throughput drug combination screening in HGSOC cells. PI3K/mTOR pathway inhibitors (PI3K/mTORi) showed supra-additive cytotoxicity with CHK1i. Combined treatment with CHK1i and PI3K/mTORi significantly attenuated cell viability and increased DNA damage, chromosomal breaks, and mitotic catastrophe compared with monotherapy. PI3K/mTORi decelerated fork speed by promoting new origin firing via increased CDC45, thus potentiating CHK1i-induced replication stress. PI3K/mTORi also augmented CHK1i-induced DNA damage by attenuating DNA homologous recombination repair activity and RAD51 foci formation. High expression of replication stress markers was associated with poor prognosis in patients with HGSOC. Our findings indicate that combined PI3K/mTORi and CHK1i induces greater cell death in HGSOC cells and in vivo models by causing lethal replication stress and DNA damage. This insight can be translated therapeutically by further developing combinations of PI3K and cell-cycle pathway inhibitors in HGSOC. SIGNIFICANCE: Dual inhibition of CHK1 and PI3K/mTOR pathways yields potent synthetic lethality by causing lethal replication stress and DNA damage in HGSOC, warranting further clinical development.

Incidence of New-Onset Diabetes and PostTransplant Metabolic Syndrome after Liver Transplantation - A Prospective Study from South India.

BACKGROUND AND AIMS: Liver transplantation has become an effective therapy for patients with end-stage liver disease. The risk of new-onset diabetes after transplantation (NODAT) and posttransplant metabolic syndrome (PTMS) is high among patients after liver transplantation. These are thought to be associated with increased risks of graft rejection, infection, cardiovascular disease, and death. Our study aimed to document the incidence of NODAT and PTMS and analyze pre and posttransplant predictive factors for their development in patients undergoing a liver transplant. METHODS: This was a prospective comparative study on 51 patients who underwent live donor liver transplantation. They were evaluated at baseline, 3 and 6 months after transplantation with fasting glucose, lipids, serum insulin levels, C-peptide, and HbA1C. They were followed up at 5 years to document any cardiovascular events or rejection. RESULTS: The incidence of preoperative diabetes mellitus (DM) in the study group was 25/51 (49%). The incidence of NODAT was 38.5% (10/26 patients) and PTMS 29% (10/35), respectively. Age (47.7 ± 5.4 vs 41.5 ± 12.7 years), HOMA2 - IR (2.3 ± 1.8 vs 2.1 ± 1.6), serum insulin (16.1 ± 12.0 vs 17.9 ± 14.5), and C-peptide (4.6 ± 0.5 vs 4.8 ± 0.7) were similar at baseline in the NODAT group compared to those who did not develop it. Mean tacrolimus levels were higher in PTMS group (6.8 ± 2.9 vs 5.0. ± 2.0 P value = 0.042). By the end of 5 years, 7 patients expired; 6 due to rejection and one due to cardiovascular disease. Moreover, 2 of these patients had preexisting DM and 2 had NODAT. CONCLUSIONS: None of the baseline metabolic factors in patients undergoing liver transplant were predictive of the development of NODAT or PTMS. Mean tacrolimus levels were significantly higher in the PTMS group. A 5-year follow-up showed no excess risk of cardiovascular events or rejection in those with preexisting DM or in those who developed NODAT.