Phase 1b/2a randomized study of heterologous ChAdOx1-HBV/MVA-HBV therapeutic vaccination (VTP-300) as monotherapy and combined with low-dose nivolumab in virally-suppressed patients with chronic hepatitis B.

BACKGROUND AND AIM: The induction of effective CD8+ T cells is thought to play a critical role in the functional cure of chronic hepatitis B (CHB). Additionally, the use of checkpoint inhibitors is being evaluated to overcome T cell dysfunction during CHB. APPROACH AND RESULTS: A chimpanzee adenoviral vector (ChAdOx1-HBV) and a Modified vaccinia Ankara boost (MVA-HBV) encoding the inactivated polymerase, core, and S region from a consensus genotype C HBV were studied. The trial enrolled 55 patients with virally-suppressed CHB virus infection and HBsAg <4,000 IU/mL Group 1 received MVA-HBV intramuscularly (IM) on Day 0 and 28, Group 2 received ChAdOx1-HBV on Day 0/MVA-HBV on Day 28 (VTP-300), Group 3 received VTP-300 + low-dose nivolumab (LDN) on Day 28, and Group 4 received VTP-300 plus LDN with both injections. VTP-300 alone and in combination with LDN was well tolerated with no treatment-related serious adverse events. Reductions of HBsAg were demonstrated in the VTP-300 group 2: 3 of 18 patients with starting HBsAg < 50 IU/ml had durable log10 declines > 0.7 log10 2 months post last-dose. Group 3 (N=18) had reductions in HBsAg of 0.76 log10 and 0.80 log10 3 (p<0.001) at 2 and 7 months post last dose. Two developed persistent non-detectable HBsAg levels. CD4+ and CD8+ antigen-specific T cell responses were generated and there was a correlation between IFN-y ELISpot response and HBsAg decline in Group 2. CONCLUSIONS: VTP-300 induced CD4+ and CD8+ T cells and lowered HBsAg in a subset of patients with baseline values below 100 IU/ml. The addition of LDN resulted in significant reduction in surface antigen. VTP-300 is a promising immunotherapeutic to move forward alone or in combination therapies. IMPACT AND IMPLICATIONS: The induction of potent, durable CD8+ T cells may be critical to achieving a functional cure in chronic hepatitis B virus infection. A prime-boost immunotherapeutic consisting of an adenoviral-vector encoding hepatitis B antigens followed by a pox virus boost was shown to induce CD8+ T cells and to lower HBsAg in CHB patients, either alone or more impactfully when administered in conjunction with a checkpoint inhibitor. The use of immunotherapeutics CLINTRIALS: NCT047789.

Work-related injuries among farm workers engaged in agricultural operations in India: a cross-sectional study.

PURPOSE: We aim to investigate nature, risk factors as well as magnitude of farm injuries and fatalities among agricultural workers in rural India. METHODS: An Agricultural Injury Study (AIS) was conducted using selected 1703 villages in eight states of rural India based on statistical consideration using unstructured proforma for 3086 victims/respodents, who were mostly agricultural workers or farmers. Injury incidence rate (IIR) was estimated per 1000 machines/tools per year for farm machinery and hand tools injuries, and per 100 000 workers per year for other sources. Questions about the injuries involved in farming tasks were used. RESULTS: About 36.2% fatalities were caused by farm machinery that involves tractors. The IIR per year of farm machinery, hand tools and injuries due to other sources were 3.2 per 1000 machines, 0.7 per 1000 tools and 77 per 100 000 workers, respectively. Correlation between number of injury-prone agricultural machines and number of farm machinery injury is r=0.80 (number of injuries increases with increase in number of machines). The χ²=72.53; p<0.01 of number of hand tools and number of farm hand tools-related injuries, that is, they are statistically significant. CONCLUSION: Exposures to agricultural machineries during farming operations can result in injuries confounding that may be fatal or non-fatal. Mapping down the cause and taking preventive measure to reduce the losses are of major concern. Also, customised safety programme as well as legislative awareness is needed to be raised for the higher injury incidence group.

The road map toward an hepatitis C virus-free transplant population.

Antiviral therapy to eradicate hepatitis C virus (HCV) infection improves outcomes in patients undergoing liver transplantation (LT) for advanced chronic HCV with or without hepatocellular carcinoma. Traditionally, antiviral therapy focused on the use of interferon (IFN)-based regimens, with antiviral treatment initiated in the posttransplant period once recurrent HCV disease with fibrosis in the allograft was identified. The use of IFN-based therapy was limited in pretransplant patients with advanced liver disease. Earlier intervention, either before transplantation or early after LT, is now feasible with the advent of second-generation direct-acting antiviral agents (DAAs) with superior tolerability and efficacy to IFN-based therapy. These agents have the potential to reduce the number of patients developing HCV-related complications requiring LT and retransplantation, as well as reducing the demand for donor organs. We discuss the pros and cons of pretransplant, peritransplant, and posttransplant therapy with current DAAs, citing available data from clinical trials and real-world experience.

HBsAg and HBcrAg as predictors of HBeAg seroconversion in HBeAg-positive patients treated with nucleos(t)ide analogues.

HBeAg seroconversion marks an important spontaneous change and treatment end-point for HBeAg-positive patients and is a pre-requisite for HBsAg loss or functional cure. In this retrospective analysis, we aimed to identify predictors of seroconversion using serum quantitative HBsAg and HBcrAg, in HBeAg-positive patients treated with nucleos(t)ide analogues (NA). Data and samples from 118 HBeAg-positive adults (genotypes A-G) started on NA between Jan 2005 and Sept 2016 were retrospectively analysed at several time-points. The predictive power of on-treatment levels of HBsAg and HBcrAg was determined using receiver operating curve (ROC) analysis and cut-off values determined by maximized Youden's index. About 36.4% of patients achieved HBeAg seroconversion after a median of 39 months' treatment. On treatment kinetics of HBV DNA, HBsAg and HBcrAg differed between HBeAg seroconverters and nonseroconverters. A combination of HBsAg and HBcrAg had the greatest predictive value for HBeAg seroconversion: at 6 months, HBsAg of 3.9 log10  IU/mL and HBcrAg of 5.7 log10 U/mL had a sensitivity of 71.4%, specificity of 79.5%, positive predictive value (PPV) of 65.2% and negative predictive value (NPV) of 83.8%, with AUROC of 0.769 (0.668, 0.869; 95%CI), and at 12 months, HBsAg 3.8 log10  IU/mL and HBcrAg 5.5 log10 U/mL had a sensitivity of 73.7%, specificity of 79.5%, PPV of 63.6% and NPV of 86.1%, with AUROC 0.807 (0.713, 0.901; 95% CI). In conclusion, our results may be used to identify patients who are unlikely to achieve treatment end-points, which will be important as the future management of chronic hepatitis B looks to therapies that offer functional cure.

Serum NGAL can act as an early renal safety biomarker during long-term nucleos(t)ide analogue antiviral therapy in chronic hepatitis B.

Tubular renal toxicity is a side-effect of long-term therapy with nucleos(t)ide analogue(s) (NA) in chronic hepatitis B (CHB). There are no established surrogate markers in plasma of early NA-related toxicity. Neutrophil gelatinase-associated lipocalin (NGAL) is a protein produced by tubular cells following renal damage. We aimed therefore to retrospectively compare conventional renal markers (estimated glomerular filtration rates (eGFR) and urinary protein/creatinine ratio uPCR) with a sensitive biomarker (NGAL) in CHB patients on long-term NA therapy and assess the ability of new markers to predict NA-related renal toxicity (new onset of nonalbumin proteinuria). A total of 192 naïve CHB patients (median age 41 years, 78% males, 25% HBeAg+, 35% cirrhosis) were NA treated for at least 5 years (median 8.34 years, range 5.54-11.1 years). The eGFR and uPCR were compared at baseline and last clinical visit with serum NGAL concentrations measured by ELISA at same time-points and assessed according to the presence/absence of nonalbumin proteinuria at last visit. While baseline and last visit eGFR were similar (median:78 vs 84 mL/min), serum NGAL concentrations increased during therapy (median:9.4 vs 16.4 ng/mL, P < .05). The proportion of patients with proteinuria (uPCR > 15) increased between baseline and last visit (4.6% vs 21.4%, P < .05), with 30 (16%) patients having de novo nonalbumin proteinuria at last visit. High baseline NGAL concentrations were exclusive to patients with de novo nonalbumin proteinuria (median:31.7 vs 7.8 ng/mL, P < .01) and baseline NGAL levels >25 mg/mL were predictive of nonalbumin proteinuria at last visit (AUROC = 0.813). In conclusion, serum NGAL can act as a surrogate marker of early renal injury (de novo nonalbumin proteinuria) in CHB on long-term NA therapy.

Efficacy and safety results of patients with HCV genotype 2 or 3 infection treated with ombitasvir/paritaprevir/ritonavir and sofosbuvir with or without ribavirin (QUARTZ II-III).

The efficacy and safety of an investigational combination of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) plus sofosbuvir (SOF) ± ribavirin (RBV) in patients with HCV genotype 2 or 3 infection with or without cirrhosis was evaluated. Patients with HCV genotype 3 infection without cirrhosis were randomized to receive OBV/PTV/r + SOF ± RBV for 12 weeks; OBV/PTV/r + SOF + RBV was administered to genotype 3-infected patients with cirrhosis for 12 weeks and to genotype 2-infected patients without cirrhosis for either 6 or 8 weeks. Efficacy was assessed by sustained virologic response [HCV RNA <25 IU/mL] 12 weeks post-treatment (SVR12). Safety was assessed in all treated patients. In patients with genotype 3 infection with or without cirrhosis treated with 12 weeks of OBV/PTV/r + SOF ± RBV, the overall SVR12 rate was 98% (50/51), with no virologic failures. Patients with genotype 2 infection treated with OBV/PTV/r + SOF + RBV had SVR12 rates of 90% (9/10) and 44% (4/9) following 8- and 6-week treatment durations, respectively; failure to achieve SVR12 for these patients was due to relapse without baseline or treatment-emergent resistance-associated substitutions. Thus, the investigational combination of OBV/PTV/r with SOF ± RBV was well tolerated and achieved high SVR rates with no virologic failures in patients with genotype 3 infection. Combining direct-acting antivirals with complementary mechanisms of action and different viral targets may be an effective treatment strategy that may allow for shorter durations of therapy.

Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis B who are not currently on antiviral treatment.

Vesatolimod is an oral agonist of toll-like receptor 7 designed to minimize systemic exposure and side effects. We assessed the safety and efficacy of vesatolimod in viremic chronic hepatitis B (CHB) patients not currently on oral antiviral treatment (OAV) in a phase 2, multicentre, double-blind, randomized, placebo-controlled study. A total of 192 patients stratified by HBeAg status and alanine aminotransferase level were randomized 2:2:2:1 to receive oral vesatolimod (1-, 2- or 4-mg) or placebo once weekly for 12 weeks; tenofovir disoproxil fumarate (300-mg daily) was administered daily for 48 weeks. Efficacy was assessed by quantitative serum HBsAg decline at Week 24 from baseline. In addition to safety assessments, changes in whole-blood interferon-stimulated gene (ISG) transcripts and serum cytokines were explored. Most patients were male (64.1%) and HBeAg-negative (60.9%) at baseline. Among vesatolimod-treated patients, most (60.4%-69.1%) experienced ≥1 treatment-emergent adverse event; the majority were mild or moderate in severity. No clinically meaningful differences in HBsAg changes from baseline were observed between treatment groups. No patients experienced HBsAg loss, while 3 patients experienced HBeAg loss and hepatitis B e-antibody seroconversion at week 48. HBV DNA suppression rates were similar across all treatment arms at Week 24. ISG15 induction was dose-dependent and did not correlate with HBsAg changes. A small proportion of patients exhibited dose-dependent interferon-α induction that correlated with grade of influenza-like adverse events. Overall, vesatolimod is safe and well tolerated in CHB patients. Although consistent dose-dependent pharmacodynamic induction of ISGs was demonstrated, it did not result in clinically significant HBsAg decline.

Diagnosing liver fibrosis: a narrative review of current literature for dermatologists.

Chronic liver disease is a growing problem worldwide due to obesity, alcohol-related liver disease and viral hepatitis. Liver fibrosis is generally asymptomatic and patients may not present until they have advanced cirrhosis, when the scope for reversibility is limited. Identification of asymptomatic individuals at an early stage is fundamental to reversing the rising toll of liver-related morbidity and mortality. Awareness of liver disease and the techniques for diagnosis is important for dermatologists, not only due to the burden of disease in the general population but also because some dermatology cohorts may have an elevated risk. For example, there is an increased prevalence of metabolic syndrome and excess alcohol use in those with psoriasis and hidradenitis suppurativa. In isolation, standard liver function tests lack sensitivity to detect advanced fibrosis and cirrhosis and are of limited value. Traditionally diagnosis has relied on liver biopsy, which remains the gold standard but is both costly and invasive. There have been several recent advances in the development of noninvasive alternatives. These include scoring systems combining clinical and conventional laboratory parameters for use as screening tools, direct serum biomarkers of fibrogenesis and tissue elastography using both ultrasound (Fibroscan) and magnetic resonance. This review summarizes current and future noninvasive diagnostic techniques for evaluation of liver fibrosis.

Liver Retransplantation in Patients With HIV-1 Infection: An International Multicenter Cohort Study.

Liver retransplantation is performed in HIV-infected patients, although its outcome is not well known. In an international cohort study (eight countries), 37 (6%; 32 coinfected with hepatitis C virus [HCV] and five with hepatitis B virus [HBV]) of 600 HIV-infected patients who had undergone liver transplant were retransplanted. The main indications for retransplantation were vascular complications (35%), primary graft nonfunction (22%), rejection (19%), and HCV recurrence (13%). Overall, 19 patients (51%) died after retransplantation. Survival at 1, 3, and 5 years was 56%, 51%, and 51%, respectively. Among patients with HCV coinfection, HCV RNA replication status at retransplantation was the only significant prognostic factor. Patients with undetectable versus detectable HCV RNA had a survival probability of 80% versus 39% at 1 year and 80% versus 30% at 3 and 5 years (p = 0.025). Recurrence of hepatitis C was the main cause of death in the latter. Patients with HBV coinfection had survival of 80% at 1, 3, and 5 years after retransplantation. HIV infection was adequately controlled with antiretroviral therapy. In conclusion, liver retransplantation is an acceptable option for HIV-infected patients with HBV or HCV coinfection but undetectable HCV RNA. Retransplantation in patients with HCV replication should be reassessed prospectively in the era of new direct antiviral agents.

Analysis of exosome release as a cellular response to MAPK pathway inhibition.

Exosome size distributions and numbers of exosomes released per cell are measured by asymmetric flow-field flow fractionation/multi-angle light scattering (A4F/MALS) for three thyroid cancer cell lines as a function of a treatment that inhibits MAPK signaling pathways in the cells. We show that these cell lines release exosomes with well-defined morphological features and size distributions that reflect a common biological process for their formation and release into the extracellular environment. We find that those cell lines with constitutive activation of the MAPK signaling pathway display MEK-dependent exosome release characterized by increased numbers of exosomes released per cell. Analysis of the measured exosome size distributions based on a generalized extreme value distribution model for exosome formation in intracellular multivesicular bodies highlights the importance of this experimental observable for delineating different mechanisms of vesicle formation and predicting how changes in exosome release can be modified by pathway inhibitors in a cell context-dependent manner.

Directly acting antivirals (DAAs) for the treatment of chronic hepatitis C virus infection in liver transplant patients: "a flood of opportunity".

Chronic hepatitis C virus (HCV) is the leading cause of liver transplantation (LT) in adults. However, infection of the allograft is universal and associated with reduced graft and patient survival. Although successful eradication improves posttransplant outcome, current antiviral therapies have poor efficacy and tolerability. Direct acting antiviral agents (DAAs) provide new opportunities for treatment of HCV recurrence. The addition of a first-generation NS3/4A protease inhibitor (PI) has increased the efficacy of pegylated interferon and ribavirin in patients with chronic HCV genotype 1 infection. Preliminary efficacy results from open-labeled studies of PI-based triple therapy in LT recipients are encouraging. However, the tolerability of triple therapy is reduced following LT, because of increased anemia and drug-drug interactions. The use of PI-based triple therapy in LT recipients seems best suited to larger centers, experienced with management of PI toxicity. Fortunately, other classes of DAAs targeting different steps of HCV replication are in clinical trials, including nucleotide polymerase (NUC-NS5B) inhibitors, nonnucleotide polymerase (non-NUC-NS5B) inhibitors and NS5A inhibitors. Several dual and triple DAA regimens are in clinical development. Phase II studies conducted in patients before and after LT suggest that these regimens will dramatically reduce the impact of recurrent HCV. There is a tide in the affairs of men. Which, taken at the flood, leads on to fortune (Shakespeare: J Caesar Act 4, scene 3).

Multidrug-resistant endemic clonal strain of Candida auris in India.

Candida auris is a recently described rare agent of fungemia. It is notable for its antifungal resistance. A total of 15 C. auris isolates, originating from seven cases of fungemia, three cases of diabetic gangrenous foot, and one case of bronchopneumonia from a tertiary care hospital in south India, were investigated. All of the 15 isolates were identified by sequencing and 14 of these along with 12 C. auris isolates previously reported from two hospitals in Delhi, north India, two each from Japan and Korea were genotyped by amplified fragment length polymorphism (AFLP). In vitro antifungal susceptibility testing (AFST) was done by the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method. Candida auris isolates were misidentified as Candida haemulonii by VITEK. All were resistant to fluconazole [geometric mean minimum inhibitory concentration (MIC) 64 µg/ml] and 11 isolates were resistant to voriconazole (MIC ≥1 µg/ml). Forty-seven percent of the C. auris isolates were resistant to flucytosine (MIC ≥64 µg/ml) and 40% had high MIC (≥1 µg/ml) of caspofungin. Breakthrough fungemia developed in 28.6% of patients and therapeutic failure in 4 (66.7%) patients. Interestingly, the 26 Indian C. auris isolates from north and south India were clonal and phenotypically and genotypically distinct from Korean and Japanese isolates. The present study demonstrates that C. auris is a potential emerging pathogen that can cause a wide spectrum of human mycotic infections. The prevalence of a C. auris endemic clonal strain resistant to azoles and other antifungals in Indian hospitals with high rates of therapeutic failure in cases of fungemia is worrisome.

Patient perception of skin-cancer prevention and risk after liver transplantation.

INTRODUCTION: Sun exposure is a major risk factor for the development of skin cancer. This is particularly relevant in immunosuppressed liver-transplant recipients (LTRs). Preventative strategies may help minimize the skin-cancer risk in this patient group. METHODS: We assessed 670 patients in our post-transplant clinic, using questionnaires. Patient data were collected, and we assessed whether patients had received education (such as formal talks or information from transplant coordinators or from hepatologists) on skin, sun exposure and skin cancer. In a subset of 280 of the LTRs who responded, we recorded their recall of sun-protection advice and assessed the level of patient adherence to such advice. RESULTS: The response rate was 57.5% (349/607), with a mean responder age of 51.1 years (range 19-84) and an average post-transplant time of 7.1 years (range 0-27). In the recall assessment, 37.2% reported that they were given advice about their skin, while 18.1% were seen by a dermatologist, and education on sun exposure and the risks of skin cancer was given to 65.6% and 47.9%, respectively. Over three-quarters (78%; 185/280) of the patients used mechanical sun protection (i.e. hats/clothing), while 66% reported using sunscreen; 31.8% of these used a sunscreen of the recommended sun protection factor (SPF) of > 30. Twelve patients had developed squamous cell carcinoma after a mean of 10.9 years (1-23) post-transplant; half of these had used either no sunscreen or one with an SPF of < 15. CONCLUSIONS: Despite the fact that LTRs are given information on sun-exposure and SC before and after transplantation, recall of such advice and use of sun-protection methods was only moderate, indicating that regular reinforcement of SC education is needed.

Schizophyllum commune as an emerging fungal pathogen: a review and report of two cases.

We report Schizophyllum commune as the aetiological agent of one case each of allergic broncho-pulmonary mycosis (ABPM) and pulmonary fungal ball, and present a literature review. The fungus was characterised by clamp connections, hyphal spicules, and formation of basidiocarps with basidiospores. The phenotypic identification was confirmed by sequencing of the ITS region. To-date, ABPM and pulmonary fungal ball to S. commune have been reported exclusively from Japan and North America respectively. Of the 71 globally reported cases due to S. commune, 45 (63%) were bronchopulmonary, 22 (31%) sinusitis and 4 extrapulmonary. Taken together, cases of bronchopulmonary disease and sinusitis numbered 67 (94%), indicating the respiratory tract as the primary target of disease. Concerning the country-wise distribution, Japan topped the list with 33 cases (46%), followed by Iran - 7 cases (10%), U.S.A. - 6 cases (9%), and a lower prevalence of 1.4-6% for the remaining 12 countries. The preponderance of the disease in Japan may be attributed to its greater awareness vis-à-vis that in other countries rather than to any geographical/climatic factors. We believe that the burden of S. commune-incited disease is currently underestimated, warranting comprehensive prospective studies to determine its prevalence.

Predictors of recurrence following laparoscopic minor hepatectomy for hepatocellular carcinoma in the UK.

AIMS: Minor hepatectomy, which is increasingly carried out laparoscopically (LLR), is a cornerstone of curative treatment for hepatocellular carcinoma (HCC). The majority of relevant publications however originate from regions with endemic viral hepatitis. Although the incidence of HCC in the UK is increasing, little is known about outcomes following LLR. METHODS: Consecutive patients undergoing minor (involving ≤2 segments) LLR or open resection (OLR) at our institute between 2014 and 2021 were compared. Selection from a plethora of factors potentially impacting on overall (OS) and disease free survival (DFS) was optimised with Lasso regression. To enable analysis of patients having repeat resection, multivariate frailty modelling was utilised to calculate hazard ratios (HR). RESULTS: The analysis of 111 liver resections included 55 LLR and 56 OLR. LLR was associated with a shorter hospital stay (5 ± 2 vs. 7 ± 2 days; p < 0.001) and a lower comprehensive complication index (4.43 vs. 9.96; p = 0.006). Mean OS (52.3 ± 2.3 vs. 49.9 ± 3.0 months) and DFS (33.9 ± 3.4 vs. 36.5 ± 3.6 months; p = 0.59) were comparable between LLR and OLR, respectively (median not reached). Presence of mixed cholangiocarcinoma/HCC, satellite lesions and AFP level predicted OS and DFS. In addition tumour size was predictive of DFS. CONCLUSIONS: In the studied population minor LLR was associated with shorter hospital stay and fewer complications while offering non-inferior long-term outcomes. A number of predictors for disease free survival have been elucidated that may aid in identifying patients with a high risk of disease recurrence and need for further treatment.

Pregnancy loss after chorionic villus sampling and genetic amniocentesis in twin pregnancies: a systematic review.

OBJECTIVE: To review the available evidence regarding pregnancy loss following first-trimester chorionic villus sampling (CVS) and mid-trimester genetic amniocentesis in twins. METHODS: We searched the MEDLINE database from January 1990 to May 2011 for randomized and cohort studies reporting on the risk of pregnancy loss after first-trimester CVS performed between 9 and 14 weeks and after genetic amniocentesis performed between 14 and 22 weeks. Where appropriate, we calculated pooled proportions and relative risks with 95% CI. RESULTS: No randomized studies were found. For CVS, nine studies fulfilled the inclusion criteria. The overall pregnancy-loss rate was 3.84% (95% CI, 2.48-5.47; n = 4). The rate of pregnancy loss before 20 weeks was 2.75% (95% CI, 1.28-4.75; n = 3) and before 28 weeks was 3.44% (95% CI, 1.67-5.81; n = 3). For amniocentesis, the overall pregnancy-loss rate was 3.07% (95% CI, 1.83-4.61; n = 4). The rate of pregnancy loss before 20 weeks was 2.25% (95% CI, 1.23-3.57; n = 2), before 24 weeks was 2.54% (95% CI, 1.43-3.96; n = 9) and before 28 weeks was 1.70% (95% CI, 0.37-3.97; n = 5). Pooled data from four case-control studies showed a higher risk (2.59% vs. 1.53%) of pregnancy loss before 24 weeks following amniocentesis (relative risk = 1.81; 95% CI, 1.02-3.19). There were no statistically significant differences in reported pregnancy loss between transabdominal and transcervical approaches, use of a single-needle system vs. a double-needle system and single uterine entry vs. double uterine entry in the CVS group. Similarly, in the amniocentesis group, there was no statistically significant difference in fetal loss between the single uterine entry vs. the double uterine entry. CONCLUSION: In the absence of randomized studies, it is not possible to estimate accurately the excess risk following invasive procedures in twins. Currently available data show similar overall pregnancy-loss rates for both amniocentesis and CVS with the excess risk of around 1% above the background risk.

Fetomaternal outcome in pregnancy with severe thrombocytopenia.

OBJECTIVES: STo study the feto-maternal outcome in pregnancy with severe thrombocytopenia. MATERIALS AND METHODS: It was an observational study involving 1150 pregnant women with term gestation in labour, who were screened for thrombocytopenia. Ninety-four subjects (8.17%) were found to have thrombocytopenia i.e. platelet count < 1,50,/000/mm3, out of which 47 subjects (group A) had platelet count of less than 50.000/mm3 Simultaneously, 47 term pregnant women (group B) having a normal platelet count i.e. > 1.5 lac/mm3 formed the control group. All the subjects were followed during labour and postpartum period for any feto-maternal outcome. RESULTS: Significant history of bleeding tendencies like prolonged bleeding from wound site, easy bruisability and menorrhagia (p = 0.023) was evident in the study population. Abruptio placentae and early onset pregnancy induced hypertension (PIH) in previous gestations was more commonly found in the study population. Anemia and PIH were significantly more in group A. Incision site oozing during cesarean section was significantly more in group A. Moderate thrombocytopenia was more in neonates of study group (p = 0.014), but without any bleeding complications in neonates. CONCLUSIONS: Careful surveillance is required in these high risk patients for earlier detection and treatment of complications so as to decrease the fetomaternal morbidities.

Empirical Explorations of SYNCHEM.

During the past several years, a substantial body of experience has accumulated in the use of SYNCHEM, a large-scale program which is able to discover synthesis routes for relatively complex organic structures without on-line guidance on the part of its chemist user. These results indicate that the approach to computer-directed organic synthesis route discovery embodied in the program has been valid and reasonable, and that SYNCHEM is likely to be fruitful from the point of view of its intended users as well as for our research objectives in artificial intelligence. The experiments have revealed a number of insufficiencies in the program as well. Most of these are rectified in SYNCHEM2, a revised version of the program which includes, among other improvements, a more highly developed synthesis search algorithm and the routine consideration of stereochemistry.

Design and synthesis of novel substituted quinazoline derivatives as antileishmanial agents.

4-(Substituted-benzylidine)-2-substituted-5,6-dihydrobenzo[h]quinazoline (5a-p) and 4-(substituted-benzylidine)-2-substituted-3, 4, 5, 6-tetrahydrobenzo[h]quinazoline (6a-p) have been synthesized from 2-(substituted-benzylidine)tetralone-1(3a-d) and several substituted guanidine sulfates(4a-d).These compounds were tested for their in vitro antileishmanial activity. The compounds 6i, 6f, 6g show promising antileishmanial activity against Leishmania donovani.