Comparative assessment of immunogenicity of recombinant insulin Aspart from BioGenomics and its originator NovoRapid® in adult patients with type 2 diabetes mellitus.

OBJECTIVES: To assess and compare the immunogenicity of recombinant Insulin Aspart [manufactured by BioGenomics Limited (BGL-ASP)] with its originator NovoRapid® (manufactured by Novo Nordisk) in adult patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: BGL-IA-CTP301 study was a randomized, open label, parallel group, multicenter phase-III clinical study to compare the efficacy and safety of recombinant Insulin Aspart 100 U/mL [manufactured by BioGenomics Limited (BGL-ASP)] with its reference medicinal product (RMP); NovoRapid® [manufactured by Novo Nordisk], in adult patients with Type 2 diabetes mellitus (T2DM). The primary objective of the study was to compare the immunogenicity of BGL-ASP and RMP; NovoRapid® in patient serum samples collected from phase-III clinical study. Immunogenicity was studied as the incidence of patients positive for anti-insulin Aspart (AIA) antibodies, developed against BGL-ASP/RMP at baseline, end of 12 week and end of 24 week of the treatment period. The changes in incidence of patients positive for AIA antibodies post-baseline were also studied to assess and compare the treatment-emergent antibody response (TEAR) between the treatment groups (BGL-ASP and RMP). Statistical evaluation was done by Fisher's exact test to compare the overall incidence of patients positive for AIA antibodies and the TEAR positives observed post-baseline in both the treated groups. An in-vitro neutralizing antibody assay (Nab assay) was also performed to study the effect of AIA antibodies in neutralizing the biological activity/metabolic function of the insulin. The neutralizing potential of AIA was studied by its effect on %glucose uptake. We also evaluated the association between AIA antibody levels and its impact on biological activity by studying the correlation between them. RESULTS: Analysis of immunogenicity data suggested that the percentage of patients positive for AIA antibodies until week 24 was similar and comparable in both the treatment groups, BGL-ASP and RMP; NovoRapid®. The changes in incidence of patients positive for AIA post-baseline in terms of TEAR positives were also similar and comparable between the treatment groups. The results of the Nab assay with confirmed positive AIA samples from BGL-ASP- and RMP-treated groups did not have any negative impact on %glucose uptake by the cells in Nab assay, confirming the absence of neutralizing antibodies in both the treatment groups. The correlation studies also showed absence of association between AIA antibody levels and percentage glucose uptake in both BGL-ASP and RMP-NovoRapid® treatment groups. CONCLUSIONS: The immunogenicity assessment based on the overall incidence of patients positive for AIA, changes in incidence of patients positive for AIA post-baseline, TEAR rates and absence of neutralizing antibodies, were found to be apparently similar and comparable in both the treatment groups (BGL-ASP and RMP). We conclude from our studies that the immunogenicity of BGL-ASP is similar and comparable to RMP and the observed immunogenicity in terms of anti-insulin Aspart antibody levels had no impact on the biological activity of insulin.

On the Fundamental Polymer Chemistry of Inverse Vulcanization for Statistical and Segmented Copolymers from Elemental Sulfur.

In this concept review, the fundamental and polymerization chemistry of inverse vulcanization for the preparation of statistical and segmented sulfur copolymers, which have been actively developed and advanced in various applications over the past decade is discussed. This concept review delves into a discussion of step-growth polymerization constructs to describe the inverse vulcanization process and discuss prepolymer approaches for the synthesis of segmented sulfur polyurethanes. Furthermore, this concept review discusses the advantages of inverse vulcanization in conjunction with dynamic covalent polymerization and post-polymerization modifications to prepare segmented block copolymers with enhanced thermomechanical and flame retardant properties of these materials.

Incidence and Outcomes of Early Cancers After Kidney Transplantation.

Outcomes of early cancers after kidney transplantation are not well-understood. We included recipients of first live and deceased donor kidney transplants who developed de novo cancers in Australia and New Zealand between 1980-2016. We compared the frequency and stage of specific cancer types that developed early (≤12-months) and late (>12-months) post-transplantation. Risk factors for death were evaluated using multivariable Cox regression analyses. Of 2,759 recipients who developed de novo cancer, followed-up for 40,035 person-years, 243 (8.8%) patients were diagnosed with early cancer. Post-transplant lymphoproliferative disease, urinary cancers and melanoma were the most common cancer types (26%, 18%, and 12%) and the majority were either in-situ or locally invasive lesions (55%, 84%, and 86%). Tumors arising early from the gastrointestinal and respiratory systems were uncommon but aggressive, with 40% presenting with metastatic disease at time of diagnosis. Overall, 32% of patients with early cancers died within a median of 4.7 months (IQR:0.6-16) post-diagnosis and 91% were cancer-related deaths. Older recipient and donor age were associated with an increased risk of all-cause death. Early cancers, though infrequent in kidney transplant recipients, are associated with poor outcomes, as nearly 1 in 3 died from cancer-related death; with majority of deaths occurring within 12-months of cancer diagnosis.

Urinary adenosine triphosphate and nitric oxide levels in patients with underactive bladder: a preliminary study.

INTRODUCTION: Various in vitro and in vivo animal studies have shown that adenosine triphosphate (ATP) has a stimulatory role and nitric oxide (NO) has an inhibitory role in modulating bladder contractility. However, it is not known what happens to the urinary levels of ATP and NO in humans with underactive bladder (UAB). METHODS: In this prospective case-control study, we compared ATP and NO levels in twenty six male patients of UAB with a bladder contractility index (BCI) of < 100 and 18 healthy male volunteers without any lower urinary tract symptoms (LUTS). RESULTS: The mean urinary ATP levels were significantly lower in cases compared to controls (546.1 ± 37.3 pg/µl vs. 610.7 ± 24.9 pg/µl, p value < 0.001) and the mean NO levels were significantly higher in cases compared to controls (1233.4 ± 91.2 pg/µl vs. 1126.3 ± 91.3.4 pg/µl, p value < 0.001). The mean NO/ATP ratio in cases was significantly higher than that of controls (2.26 ± 0.2 vs. 1.84 ± 0.18, p value < 0.000). Using receiver operating curve (ROC) analysis, we noted the area under the curve (AUC) for NO/ATP ratio to be 0.91 in the diagnosis of cases. A cut-off value of 2.06 for NO/ATP ratio had sensitivity, specificity and diagnostic accuracy of 88.5%, 88.9% and 88.6%, respectively, in diagnosing patients with UAB. CONCLUSION: Patients with UAB have significantly higher levels of urinary NO and decreased levels of urinary ATP. Urinary NO/ATP levels can be considered as a noninvasive alternate test for diagnosing bladder underactivity.

Microbial and physicochemical assessment of irrigation water treatment methods.

AIMS: The presence of foodborne pathogens in preharvest agricultural water has been identified as a potential contamination source in outbreak investigations, driving markets and auditing bodies to begin requiring water treatment for high-risk produce. Therefore, it is essential that we identify water treatment methods which are effective as well as practical in their application on farm. METHODS AND RESULTS: In this work, we evaluated two sanitizers which are most prominent in preharvest agricultural water treatment (calcium hypochlorite (free chlorine: 3-5 ppm) and peracetic acid (PAA: 5 ppm)), an EPA registered antimicrobial device (ultraviolet light (UV)), in addition to a combination approach (chlorine + UV, PAA + UV). Treatments were evaluated for their ability to inactivate total coliforms and generic Escherichia coli and consistency in treatment efficacy over 1 h of operation. Physicochemical variables were measured along with microbial populations at 0, 5, 15, 30, 45 and 60 min of operation. Escherichia coli and coliform counts showed a significant (P < 0·05) reduction after treatment, with combination and singular treatments equally effective at inactivating E. coli and coliforms. A significant increase (P < 0·05) in oxidation-reduction potential was seen during water treatment (Chlorine; UV + Chlorine), and a significant reduction (P < 0·05) in pH was seen after PAA and PAA + UV treatments (60 min). CONCLUSION: Overall, the results indicate that all treatments evaluated are equally efficacious for inactivating E. coli and coliforms present in surface agricultural water. SIGNIFICANCE AND IMPACT OF THE STUDY: This information when paired with challenge studies targeting foodborne pathogens of interest can be used to support grower decisions when selecting and validating a preharvest agricultural water treatment programme.

Relationship between corneal confocal microscopy and markers of peripheral nerve structure and function in Type 2 diabetes.

AIMS: To investigate changes in corneal nerve morphology in Type 2 diabetes and to establish relationships between in vivo corneal confocal microscopy and markers of peripheral nerve structure and function. PARTICIPANTS AND METHODS: We recruited 57 participants with Type 2 diabetes and 26 healthy controls of similar age and sex distribution. We also recruited a disease control group of 54 participants with Type 1 diabetes. All participants were assessed for distal symmetrical polyneuropathy using the Total Neuropathy Score. In vivo corneal confocal microscopy was used to assess corneal nerve fibre length, corneal nerve fibre density, corneal nerve branch density and inferior whorl length. Peripheral nerve structure was assessed using median nerve ultrasonography. Large fibre function was assessed according to median nerve axonal excitability. Small fibre function was assessed using SudoscanTM and the Survey of Autonomic Symptoms. RESULTS: Corneal nerve fibre length, fibre density and branch density and inferior whorl length were significantly lower in individuals with Type 2 diabetes compared to controls (P<0.001 for all). In the Type 2 diabetes cohort, correlations were observed between neuropathy severity and corneal nerve fibre density (P=0.004), corneal nerve branch density (P=0.003), corneal nerve fibre length (P=0.002) and inferior whorl length (P=0.01). Significant correlations were observed between corneal confocal outcomes and axonal excitability measurements. No association was found between corneal confocal microscopy and median nerve cross-sectional area, Sudoscan measurements or the Survey of Autonomic Symptoms. CONCLUSIONS: This study demonstrated significant changes in corneal nerves in individuals with Type 2 diabetes. Reductions in corneal nerve measures correlated with increasing neuropathy severity. Associations were found between corneal confocal microscopy and markers of voltage-gated potassium channel function.

Associations between acute glucose control and peripheral nerve structure and function in type 1 diabetes.

AIM: To examine the associations between continuous overlapping net glycaemic action (CONGA), percentage time in hyperglycaemia (%HG) or normoglycaemia (%NG) and peripheral nerve structure and function in type 1 diabetes. METHODS: Twenty-seven participants with type 1 diabetes underwent continuous glucose monitoring followed by corneal confocal microscopy and nerve excitability assessments. CONGA, %HG (> 10.0 mmol/l) and %NG (3.9-10.0 mmol/l) were correlated against corneal nerve fibre length and density in the central cornea and inferior whorl region, corneal microneuromas, and a nerve excitability score while controlling for age, sex, diabetes duration and HbA1c . RESULTS: An increase in CONGA [median 2.5 (2.0-3.1) mmol/l] or %HG (mean 46 ± 18%) was associated with a worse nerve excitability score (r = -0.433, P = 0.036 and r = -0.670, P = 0.0012, respectively). By contrast, greater %NG (51 ± 17%) correlated with better nerve excitability scores (r = 0.672, P = 0.0011). Logistic regression revealed that increasing %HG increased the likelihood of abnormal nerve function [odds ratio (OR) 1.11, 95% confidence interval (CI) 1.01-1.23; P = 0.037). An increase in CONGA and %HG were associated with worsening nerve conduction measures, whereas longer %NG correlated with improved nerve conduction variables. CONGA and %HG were associated with inferior whorl corneal nerve fibre length (r = 0.483, P = 0.034 and r = 0.591, P = 0.021, respectively) and number of microneuromas (r = 0.433, P = 0.047 and r = 0.516, P = 0.020, respectively). CONCLUSIONS: Short-term measures of glucose control are associated with impaired nerve function and alterations in corneal nerve morphology.

Sonographic assessment of nerve blood flow in diabetic neuropathy.

AIMS: To undertake sonographic assessment of nerve blood flow in people with Type 2 diabetes and correlate the findings with neuropathy severity scores and electrophysiological measurements. METHODS: Median and tibial nerve ultrasound scans were undertaken in 75 people with diabetes and 30 aged-matched controls without diabetes, using a high-resolution linear probe at non-entrapment sites. Nerve blood flow was quantified using power Doppler techniques to obtain the vessel score and the maximum perfusion intensity. Neuropathy severity was assessed using a total neuropathy score. RESULTS: Diabetic nerves had higher rates of nerve blood flow detection (28%) compared to the control group (P < 0.0001). Significant correlations were found between nerve blood flow measurements and nerve size (P <0.001), reported sensory symptoms (P < 0.05) and neuropathy severity scores (P < 0.001). The cohort with diabetes had significantly larger median (8.5 ± 0.3 mm2 vs 7.2 ± 0.1 mm2 ; P < 0.05) and tibial nerves (18.0 ± 0.9 mm2 vs 12.8 ± 0.5 mm2 ; P < 0.05) compared with controls. CONCLUSION: Peripheral nerve hypervascularity is detectable by ultrasonography in moderate to severe diabetic neuropathy with prominent sensory dysfunction.

Azomethine ylide cycloaddition: a versatile tool for preparing novel pyrrolizidino-spiro-oxindolo hybrids of the doubly conjugated alkamide piperine.

A facile, multicomponent (MCR) atom-economic synthesis of novel spiro-oxindolo pyrrolizidine adducts of piperine has been achieved via an intermolecular 1,3-dipolar azomethine ylide cycloaddition reaction. Either of the two conjugated double bonds in piperine takes part in the reaction to produce two regioisomeric adducts in racemic form. Acenaphthoquinone, ninhydrin and different isatin derivatives were reacted with proline and piperine to afford a never before reported library of 22 compounds. The structures of the products were determined by 1D/2D NMR, mass spectral analysis and confirmed by X-ray crystallography of selected products. Chiral HPLC separation was performed to measure the specific rotation and CD spectra of the enantiomers for two racemic compounds.

Conduction block in immune-mediated neuropathy: paranodopathy versus axonopathy.

BACKGROUND AND PURPOSE: Conduction block is a pathognomonic feature of immune-mediated neuropathies. The aim of this study was to advance understanding of pathophysiology and conduction block in chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). METHODS: A multimodal approach was used, incorporating clinical phenotyping, neurophysiology, immunohistochemistry and structural assessments. RESULTS: Of 49 CIDP and 14 MMN patients, 25% and 79% had median nerve forearm block, respectively. Clinical scores were similar in CIDP patients with and without block. CIDP patients with median nerve block demonstrated markedly elevated thresholds and greater threshold changes in threshold electrotonus, whilst those without did not differ from healthy controls in electrotonus parameters. In contrast, MMN patients exhibited marked increases in superexcitability. Nerve size was similar in both CIDP groups at the site of axonal excitability. However, CIDP patients with block demonstrated more frequent paranodal serum binding to teased rat nerve fibres. In keeping with these findings, mathematical modelling of nerve excitability recordings in CIDP patients with block support the role of paranodal dysfunction and enhanced leakage of current between the node and internode. In contrast, changes in MMN probably resulted from a reduction in ion channel density along axons. CONCLUSIONS: The underlying pathologies in CIDP and MMN are distinct. Conduction block in CIDP is associated with paranodal dysfunction which may be antibody-mediated in a subset of patients. In contrast, MMN is characterized by channel dysfunction downstream from the site of block.

Prolonged Ischemic Time, Delayed Graft Function, and Graft and Patient Outcomes in Live Donor Kidney Transplant Recipients.

The association between prolonged cold ischemic time (CIT) and graft and patient outcomes in live donor kidney transplant recipients remains unclear. The aims of this study were to examine the association of CIT with delayed graft function and graft loss in live donor kidney transplant recipients and those who participated in the Australian Paired Kidney Exchange program using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry. Of 3717 live donor transplant recipients between 1997 and 2012 who were followed for a median of 6.6 years (25 977 person-years), 224 (25%) experienced CIT >4-8 h. Donor age was an effect modifier between CIT and graft outcomes. In recipients who received kidneys from older donors aged >50 years, every hour of increase in CIT was associated with adjusted odds of 1.28 (95% confidence interval [CI] 1.07-1.53, p = 0.007) for delayed graft function, whereas CIT >4-8 h was associated with adjusted hazards of 1.93 (95% CI 1.21-3.09, p = 0.006) and 1.91 (95% CI 1.05-3.49, p = 0.035) for overall and death-censored graft loss, respectively, compared with CIT of 1-2 h. Attempts to reduce CIT in live donor kidney transplants involving older donor kidneys may lead to improvement of graft outcomes.

Paper-based archiving of biological samples from fish for detecting betanodavirus.

This study was carried out to evaluate the efficiency of the Flinders Technology Associates (FTA(®)) card (Whatman(®)) as a sampling device and storage platform for RNA from betanodavirus-infected biological samples (viz., larvae, broodstock, cell culture supernatants and rearing seawater spiked with infected materials). The study showed that FTA cards can be used to detect betanodaviruses by reverse transcription-polymerase chain reaction (RT-PCR). The diagnostic efficiency of RT-PCR from all sample types on FTA cards decreased after 21 days of storage at 4 °C, although the virus could be detected up to 28 days by nested RT-PCR. The FTA card protocol thus provides a supplementary method for quick and easy collection of samples, preservation of RNA on a dry storage basis, and detection of betanodavirus-infected fish.

Peripheral neuron plasticity is enhanced by brief electrical stimulation and overrides attenuated regrowth in experimental diabetes.

Peripheral nerve regrowth is less robust than commonly assumed, particularly when it accompanies common clinical scenarios such as diabetes mellitus. Brief extracellular electrical stimulation (ES) facilitates the regeneration of peripheral nerves in part through early activation of the conditioning injury response and BDNF. Here, we explored intrinsic neuronal responses to ES to identify whether ES might impact experimental diabetes, where regeneration is attenuated. ES altered several regeneration related molecules including rises in tubulin, Shh (Sonic hedgehog) and GAP43 mRNAs. ES was associated with rises in neuronal intracellular calcium but its strict linkage to regrowth was not confirmed. In contrast, we identified PI3K-PTEN involvement, an association previously linked to diabetic regenerative impairment. Following ES there were declines in PTEN protein and mRNA both in vitro and in vivo and a PI3K inhibitor blocked its action. In vitro, isolated diabetic neurons were capable of mounting robust responsiveness to ES. In vivo, ES improved electrophysiological and behavioral indices of nerve regrowth in a chronic diabetic model of mice with pre-existing neuropathy. Regrowth of myelinated axons and reinnervation of the epidermis were greater following ES than sham stimulation. Taken together, these findings identify a role for ES in supporting regeneration during the challenges of diabetes mellitus.

Teaching community medicine to medical undergraduates-learning by doing: our experience of rural posting at All India Institute of Medical Sciences, New Delhi, India.

BACKGROUND: The goal of medical education is to ensure that the medical graduate has acquired broad public health competencies needed to solve the health problems of the community. We present the current teaching of community medicine to medical students of the All India Institute of Medical Sciences (AIIMS), New Delhi during their 5-week posting at the rural centre at Ballabgarh, Haryana. METHODS: The teaching activities consist of field visits to different levels of health facilities and meeting with health workers, epidemiological exercises, a community-based exercise, posting in inpatient and outpatient departments of a secondary hospital, and domiciliary visits to families of patients. These are spread over 80 sessions of about 200 hours. There is very little didactic teaching and the assessment is broad-based. The evaluation of the posting was based on comparison of blinded pre- and post-posting assessments as well as anonymous feedback of the posting by the students. RESULTS: There was a significant increase in the mean scores of all components of the posting-epidemiology (5.1 to 8.4), health systems (6.8 to 9.3) and clinical (8.0 to 10.8). The posting did not result in a better understanding of a public health approach as compared to a clinical approach. The feedback provided by students was generally positive for all activities with 94% of them rating it as good or very good. CONCLUSION: The teaching of community medicine can be made more practical and interesting without compromising on learning. However, despite such a programme, getting medical students to develop a public health approach is a daunting task.

Familial adult myoclonus epilepsy: a pragmatic approach.

Familial Adult Myoclonus Epilepsy (FAME), with a prevalence of < 1/35 000, is known under different acronyms. The disease is transmitted in an autosomal dominant manner and is characterized by the occurrence of cortical myoclonic tremor, overt myoclonus, and rare bilateral tonic-clonic seizures. FAME is considered neurodegenerative, although it is relatively slow in progression. Diagnosis is based on specific neurophysiological testing, namely jerk-locked back-averaging, somatosensory evoked potentials, long latency reflex, and motor evoked potentials, among others. Imaging data, including functional magnetic resonance imaging, indicate a cortical origin of the cortical myoclonic tremor and decreased cerebellar activation. Cerebellar changes in Purkinje cells have been noted, from few neuropathology reports, in patients from isolated pedigrees. The differential diagnosis includes essential tremor, some forms of genetic generalized epilepsy, and progressive myoclonus epilepsies. Treatment is mainly symptomatic.

Patient costs for drug-resistant TB diagnosis and pre-treatment evaluation in North India.

INTRODUCTION: India's National TB Elimination Programme (NTEP) aims to eliminate TB-related catastrophic expenditure by offering free diagnosis and treatment. However, 3.9% of TB patients have drug-resistant TB (DR-TB) and are facing higher costs. OBJECTIVE: To assess DR-TB patients' diagnosis and pre-treatment evaluation costs, catastrophic cost incidence, and its relation to patient characteristics. METHODS: The study included DR-TB patients from three District Drug-Resistant TB Centres in Delhi and Faridabad (October 2021-June 2022). Socio-economic and clinical characteristics and direct medical and non-medical costs from drug susceptibility testing eligibility to the start of DR-TB treatment were collected using patient interviews and records. Indirect costs were calculated via the human capital approach, defining catastrophic costs as expenses over 20% of household annual income. Multivariable regression was used to estimate the effects of patient characteristics on catastrophic costs. RESULTS: Of 158 patients, 37.3% were aged 19-30 years, and 55.7% were women. Median total cost was USD326.6 (IQR 132.7-666.7), with 48.2% for diagnosis and 66.0% indirect. 32% faced catastrophic costs, with manual labourers at higher risk (adjusted OR 4.4). CONCLUSION: Despite free diagnosis and treatment, a significant portion of DR-TB households in India incur catastrophic costs, mainly from indirect expenses, indicating a need for targeted policy and programme interventions.

INTRODUCTION: Le Programme national Indien d'élimination de la TB (NTEP) a pour objectif de réduire les dépenses catastrophiques liées à la TB en offrant un diagnostic et un traitement gratuits. Cependant, 3,9% des patients atteints de TB présentent une TB résistante aux médicaments (DR-TB) et doivent faire face à des coûts plus élevés. OBJECTIF: Évaluer les coûts de diagnostic et d'évaluation pré-thérapeutique chez les patients atteints de DR-TB, ainsi que l'impact des coûts catastrophiques et leur corrélation avec les caractéristiques des patients. MÉTHODES: L'étude a porté sur les patients atteints de DR-TB provenant de trois Centres de lutte contre la TB résistante aux médicaments des districts de Delhi et de Faridabad, Inde (octobre 2021­juin 2022). Les données relatives aux caractéristiques socio-économiques et cliniques, ainsi qu'aux coûts directs médicaux et non médicaux, ont été collectées lors de l'évaluation de l'éligibilité à l'antibiogramme au début du traitement de la DR-TB, à travers des entretiens avec les patients et l'analyse des dossiers. Les coûts indirects ont été évalués en utilisant l'approche du capital humain, définissant les coûts catastrophiques comme dépassant 20 % du revenu annuel du ménage. Une régression multivariable a été réalisée pour estimer l'impact des caractéristiques des patients sur les coûts catastrophiques. RÉSULTATS: Sur un échantillon de 158 patients, 37,3% avaient entre 19 et 30 ans et 55,7% étaient des femmes. Le coût médian total s'élevait à 326,6 USD (IQR 132,7­666,7), dont 48,2% pour le diagnostic et 66,0% pour les coûts indirects. En outre, 32% des patients ont été confrontés à des coûts catastrophiques, les travailleurs manuels étant les plus touchés (OR ajusté 4,4). CONCLUSION: Bien que le diagnostic et le traitement soient gratuits, de nombreux ménages indiens touchés par la DR-TB doivent faire face à des coûts élevés, en particulier des dépenses indirectes, soulignant ainsi le besoin d'interventions politiques et programmatiques ciblées.

Investigation of PNPLA3 and IL28B genotypes on diabetes and obesity after liver transplantation: insight into mechanisms of disease.

To identify genetic risks for obesity and diabetes postliver transplantation (LT), LT recipients underwent genotyping for IL28B rs12979860 (n = 295) and PNPLA3 rs738409 (n = 205) polymorphism in both donors and recipients. The development of obesity and diabetes/impaired fasting glucose (IFG) was determined 1-5 years post-LT. Recipient PNPLA-3 genotype was independently associated with obesity (BMI > 30) at 3 years posttransplant (genotype CC 33.7%, CG 48.3% and GG 82.4%, p = 0.002), with an odds ratio (OR 2.54, CI 1.38-4.66, p = 0.003), associated with the G allele. Diabetes/IFG diagnosed within 5 years posttransplant associated with PNPLA-3 non-CC genotype (HR 1.59, 1.12-2.26, p = 0.010), but not IL28B TT genotype (HR 1.46, 0.94-2.27, p = 0.092). No genotype variable was independently predictive of diabetes/IFG. The combination of PNPLA-3 non-CC and IL28B TT genotype was associated with increased risk of diabetes/IFG compared to PNPLA-3 CC, IL28B non-TT (HR 2.64, CI 1.30-5.39, p = 0.008). Donor genotypes were not associated with any of the outcomes analyzed. In conclusion, PNPLA-3 non-CC genotype is associated with posttransplant obesity but not independently with diabetes/IFG. The lack of donor related risk suggests a peripheral rather than central mechanism of insulin resistance in liver transplant recipients.

Association between calcineurin inhibitor treatment and peripheral nerve dysfunction in renal transplant recipients.

Neurotoxicity is a significant clinical side effect of immunosuppressive treatment used in prophylaxis for rejection in solid organ transplants. This study aimed to provide insights into the mechanisms underlying neurotoxicity in patients receiving immunosuppressive treatment following renal transplantation. Clinical and neurophysiological assessments were undertaken in 38 patients receiving immunosuppression following renal transplantation, 19 receiving calcineurin inhibitor (CNI) therapy and 19 receiving a calcineurin-free (CNI-free) regimen. Groups were matched for age, gender, time since transplant and renal function and compared to normal controls (n = 20). The CNI group demonstrated marked differences in nerve excitability parameters, suggestive of nerve membrane depolarization (p < 0.05). Importantly, there were no differences between the two CNIs (cyclosporine A or tacrolimus). In contrast, CNI-free patients showed no differences to normal controls. The CNI-treated patients had a higher prevalence of clinical neuropathy and higher neuropathy severity scores. Longitudinal studies were undertaken in a cohort of subjects within 12 months of transplantation (n = 10). These studies demonstrated persistence of abnormalities in patients maintained on CNI-treatment and improvement noted in those who were switched to a CNI-free regimen. The results of this study have significant implications for selection, or continuation, of immunosuppressive therapy in renal transplant recipients, especially those with pre-existing neurological disability.

Non-specific sex-differential effect of DTP vaccination may partially explain the excess girl child mortality in Ballabgarh, India.

OBJECTIVE: To test the hypothesis that a gender differential exists in the effect on child mortality of BCG, DTP, measles vaccine as administered under programme conditions in Ballabgarh HDSS area. METHODS: All live births in 28 villages of Ballabgarh block in North India from 2006 to 2011 were followed until 31 December 2011 or 36 months of age whichever was earlier. The period of analysis was divided into four time periods based on eligibility for vaccines under the national immunisation schedule (BCG for tuberculosis, primary and booster doses of diphtheria-tetanus-pertussis and measles). Cox proportional hazards regression was used to assess the association between sex and risk of mortality by vaccination status using age as the timescale in survival analysis and adjusting for wealth index, access to health care, the presence of a health facility in the village, parental education, type of family, birth order of the child and year of birth. RESULTS: 702 deaths (332 boys and 370 girls) occurred among 12,142 children in the cohort in the 3 years of follow-up giving a cumulative mortality rate of 57.5 per 1000 live births with 35% excess girl child mortality. Age at vaccination for the four vaccines did not differ by sex. There was significant excess mortality among girls after immunisation with DTP, for both primary (HR 1.65; 95% CI:1.17-2.32) and DTPb (2.21; 1.24-3.93) vaccinations. No significant excess morality among girls was noted after exposure to BCG 1.06 (0.67-1.67) or measles 1.34 (0.85-2.12) vaccine. CONCLUSION: This study supports the contention that DTP vaccination is partially responsible for higher mortality among girls in this study population.

Fetal and neonatal atrial arrhythmias: an association with maternal diabetes and neonatal macrosomia.

OBJECTIVE: To determine if the incidence of maternal diabetes mellitus or neonatal macrosomia is more frequent in fetuses and neonates with atrial arrhythmias than the general population. METHODS: Fetuses and neonates <30 days of age with atrial flutter or ectopic atrial tachycardia and structurally normal hearts were identified retrospectively through the cardiology databases. Electrocardiograms, echocardiograms, and medical records of mothers and infants were reviewed. RESULTS: Thirty-one patients (15 fetuses, 12 diagnosed in-utero) were identified. Infants with atrial flutter or ectopic atrial tachycardia were more likely to be macrosomic or to be born to diabetic mothers than the general population. Two had left atrial dimension z-scores above +2, and two had interventricular thickness z-scores above +2. Eighteen of 19 had abnormal mitral E/A ratios, suggesting left ventricular diastolic dysfunction. CONCLUSIONS: Fetuses and neonates with atrial flutter or ectopic atrial tachycardia were more likely to be macrosomic or be born to diabetic mothers than the general population. Postnatal echocardiography suggests that there may be abnormal diastolic left ventricular filling in some babies with these arrhythmias. Independent of ventricular hypertrophy, we speculate that isolated, non-recurrent fetal or neonatal atrial flutter, or ectopic atrial tachycardia may be caused by cardiac diastolic dysfunction and atrial stretch in utero.