Danon Cardiomyopathy: Specific Imaging Signs.

Danon disease (DD) is a rare, X-linked genetic disorder caused by LAMP2 deficiency. Clinical phenotype involves early cardiomyopathy development along with pre-excitation, skeletal myopathy, retinopathy, and cognitive impairment. We highlight how a noninvasive diagnostic approach based on clinical and imaging red flags for DD can be employed to raise high clinical suspicion for DD, which was confirmed by genetic testing results. (Level of Difficulty: Intermediate.).

Saroglitazar for Nonalcoholic Fatty Liver Disease: A Single Centre Experience in 91 Patients.

Background: Saroglitazar is a novel, dual peroxisome proliferator-activated receptors-α/γ agonist and is being investigated for the treatment of nonalcoholic fatty liver disease (NAFLD). Patients and methods: Consecutive overweight (body mass index [BMI] >23 kg/m2) patients of NAFLD, diagnosed based on controlled attenuation parameter (CAP) >248 dB/m, and attending the outpatient department of a tertiary care centre in New Delhi, were enrolled. Patients with cirrhosis (liver stiffness measurement [LSM] >13.5 kPa) and those with concomitant liver disease due to other aetiologies (alcohol, viral, etc.) were excluded. All patients received saroglitazar 4 mg/day; in addition, they were advised to reduce weight and were counselled regarding diet and exercise. At 3-month follow-up, patients were categorized into those who were able to reduce ≥5% body weight and those who could n'ot, and both these groups were compared. Results: A total of 91 patients (median age 45 years [range 18-66 years]; 81% men) were included in the study. The median BMI was 29.3 kg/m2 (range 23.6-42.2 kg/m2). The baseline median (range) aspartate transaminase, alanine transaminase, gamma glutamyl transferase, LSM and CAP values were 40 IU/dL (range 22-144 IU/dL), 48 IU/dL (range 13-164 IU/dL), 42 IU/dL (range 4-171 IU/dL), 6.7 kPa (range 3.6-13.1 kPa), and 308 dB/m (range 249-400 dB/m). All patients tolerated saroglitazar well. At 3-month, 57 patients (63%) were able to reduce ≥5% weight, whereas in the remaining 34 patients (37%), the weight reduction was <5% from baseline. Transaminases values improved in both the groups; however, LSM and CAP values improved only in patients who reduced weight. Conclusion: In overweight patients with NAFLD, a 3-month therapy with saroglitazar is able to improve transaminases but not LSM and CAP values unless accompanied by weight reduction of at least 5%. Larger randomized controlled trials are needed to document the independent effect of saroglitazar in these patients.

Therapeutic vaccine BRII-179 restores HBV-specific immune responses in patients with chronic HBV in a phase Ib/IIa study.

BACKGROUND & AIMS: Functional cure of chronic HBV infection (CHB) without life-long treatment requires the restoration of defective HBV-specific humoral and cellular immunity. Therapeutic vaccines based on the major structural and non-structural proteins have been tested in patients with CHB but have shown scarce immunogenicity. BRII-179, also known as VBI-2601, is a novel formulation comprised of all 3 HBV surface envelope proteins (Pre-S1, Pre-S2, and S). Safety, antiviral activity, and immunogenicity of BRII-179 admixed with co-adjuvant interferon (IFN)-α were assessed in patients with CHB. METHOD: This randomized, open-label, controlled phase Ib/IIa study included 2 dose levels, 20 µg BRII-179 (Part 1, n = 25) and 40 µg BRII-179 (Part 2, n = 24). Patients, virally suppressed under nucleos(t)ide analogue (NA) therapy were randomized 1:2:2 into 3 cohorts in Part 1 and 1:1 into 2 cohorts in Part 2 to receive 4 monthly intramuscular injections of BRII-179 admixed with/without 3 MIU IFN-α. Antibody and cellular responses to HBsAg, as well as evolution of circulating HBsAg were monitored. RESULTS: Both 20 µg and 40 µg BRII-179 with/without IFN-α were well tolerated with no severe adverse events. BRII-179 induced anti-HBs responses in >30% patients in all treatment cohorts, however, moderate anti-Pre-S1 or anti-Pre-S2 antibody responses were only observed in patients receiving BRII-179 with IFN-α. BRII-179 also restored S-, Pre-S1-, Pre-S2-specific IFN-γ-producing T-cells in the majority of treated patients. Overall, no notable reduction of HBsAg was observed after BRII-179 treatment. CONCLUSION: In patients with CHB under NA therapy, BRII-179 with/without IFN-α exhibited a good safety profile and induced HBV-specific B- and T-cell immune responses. These data support further clinical evaluation of BRII-179 in combination with other therapies. CLINICAL TRIAL NUMBER: ACTRN12619001210167. LAY SUMMARY: BRII-179 is a therapeutic vaccine designed to improve the immune response in patients with chronic hepatitis B. In this study, BRII-179 alone or with a low dose of interferon-α was safe, well tolerated, and induced enhanced HBV-specific antibody and T-cell responses in patients with chronic hepatitis B. However, BRII-179 treatment alone had minimal effect on patient's virological status. The potential of BRII-179 to achieve a functional cure in conjunction with other agents is being evaluated in the clinic.

Influence of human embryo cultivation in a classic CO2 incubator with 20% oxygen versus benchtop incubator with 5% oxygen on live births: the randomized prospective trial.

SummaryOur objective was to assess the effect of benchtop incubators with low oxygen concentrations on the clinical and embryological parameters of our patients. We conducted a prospective, randomized, opened controlled trial on infertile patients in stimulated cycles. In total, 738 infertile patients were assessed for eligibility and, after final exclusions, 230 patients were allocated either to a 5% O2 group (benchtop incubator) or a 20% O2 group (classic incubator). Finally, 198 patients in the 5% O2 group and 195 in the 20% O2 group were analysed. The outcomes measured were fertilization rate, clinical pregnancy rate, and live birth rate. The primary outcome - live birth rate per all transfers - did not show any improvement in the 5% oxygen group over the 20% oxygen group (25.3% versus 22.6%, P=0.531), but the number of day 5 blastocysts was significantly higher (P=0.009). Fertilization rate did not show any beneficial effect of reduced oxygen (5%) (73.4%±22.4% versus 74.6%±24.0%, P=0.606) per all transfers but there was statistically significant difference in the day 5 SET subgroup (85.3±15.1 versus 75.1±17.5; P=0.004). Clinical pregnancy rate showed results in favour of the 5% oxygen group for all subgroups (day 3: 23.7% versus 21.1%, P=0.701; day 5 SET: 35.0% versus 30.6%. P=0.569) but showed statistical significance only in the day 5 SET subgroup (51.1% versus 29.8%; P=0.038). Culturing of embryos in benchtop incubators under low oxygen produced more blastocysts and therefore was a better alternative for embryo selection, which resulted in higher pregnancy rates. To achieve higher live birth rates, embryo quality is not the only factor.

Hepatitis B Virus Infection of Normal Hepatic Stem/Progenitor Cells.

BACKGROUND/AIMS: Whether the hepatitis B virus (HBV) infects normal hepatic stem/progenitor cells (NSCs) and if so, whether such infections play a role in the pathogenesis of HBV-induced chronic liver disease (CLD) and/or hepatocellular carcinoma (HCC) remains to be determined. The objectives of this study were to determine whether HBV infects NSCs and whether such infections alter NSC activity in a manner likely to contribute to the development of CLD and/or HCC. METHODS: Liver biopsies from five hepatitis B surface antigen (HBsAg) positive patients were co-stained for HBcAg and HBx and the stem cell markers EpCAM, Oct-4 and Nanog. In addition, primary NSCs derived from healthy human livers were exposed to HBV contaminated serum in vitro. Supernatant and/or cellular HBsAg, HBcAg and HBV-DNA expression were documented over the subsequent 30 days of culture. Pro- and anti-inflammatory cytokine expression, membrane potential differences (PDs), proliferative and telomerase activities of HBV-infected NSCs were also documented. RESULTS: Markers of HBV infection were present within the NSC population of all five biopsy specimens. In vitro, HBV markers appeared within three days of exposure, peaked in expression after 10-15 days and remained positive thereafter for the duration of cell viability. There were no consistent changes in HBV-infected NSC pro- or anti-inflammatory cytokine expression, membrane PDs, proliferative or telomerase activities. CONCLUSIONS: Although the results of this study need to be confirmed, they suggest that HBV infects human NSCs but in the short term, do not alter those NSC features or activities associated with CLD and/or HCC.

Vitamin D3 supplementation in obese, African-American, vitamin D deficient adolescents.

OBJECTIVES: Obese, African-American (AA) adolescents are at increased risk for vitamin D deficiency. The primary objective of this pilot study was to examine the effect of vitamin D supplementation upon 25-hydroxy vitamin D (25OHD) levels in obese, AA adolescents. METHODS: A randomized, double-blinded, controlled pilot study included 26 obese (BMI ≥ 95%ile), vitamin D deficient (25OHD < 20 ng/mL), pubertal AA adolescents (ages 12-17). Subjects received cholecalciferol 1000 IU or 5000 IU daily for 3 months. Serum 25OHD, vitamin D binding protein, parathyroid hormone, and cardiometabolic risk markers were obtained at baseline and post-treatment. RESULTS: Of 39 subjects enrolled, 26 (67%) were vitamin D deficient (mean 25OHD 12.0 ±â€¯3.8 ng/mL) at baseline and were randomized, with 22 completing the study. Sex, age, season, pubertal stage, BMI, insulin resistance (HOMA-IR) and 25OHD were similar at baseline between the 1000 IU and 5000 IU groups. Post-treatment, 25OHD increased less in the 1000 IU group (5.6 ng/mL, p = 0.03) vs. the 5000 IU group (15.6 ng/mL, p = 0.002). 83% of the 5000 IU group and 30% of the 1000 IU group reached post-treatment 25OHD ≥ 20 ng/mL (p = 0.01); 50% of the 5000 IU group, but no subject from the 1000 IU group, achieved 25OHD ≥ 30 ng/mL (p = 0.009). We detected no group differences in mineral metabolites or cardiometabolic risk markers following supplementation. CONCLUSIONS: Cholecalciferol dosing in excess of the current Institute of Medicine dietary reference intakes was required to achieve 25OHD levels ≥20 ng/mL in obese, AA adolescents. Supplementation of 5000 IU may be required to achieve the desired goal.

Potential Liver Transplant Recipients with Hepatitis C: Should They Be Treated Before or After Transplantation?

Treatment of hepatitis C virus (HCV) with newer directly acting antivirals (DAAs) and lead to sustained viral response (SVR) in majority of patients and SVR has been documented to be associated with reversal of liver cirrhosis. The improved SVR rates and safety profiles of DAAs have led to the treatment of patients with decompensated cirrhosis awaiting liver transplantation (LT). Several clinical trials of DAAs in decompensated HCV patients have recently demonstrated SVR rates above 80%, which have been associated with significant improvements, in the Child-Pugh-Turcotte scores/or model for end-stage liver disease scores in a proportion of patients. Moreover, it has been shown that HCV RNA becomes negative after 2-4 weeks of treatment, and those who are transplanted after becoming HCV RNA negative will be have very low the risk of HCV recurrence after transplantation. Some of the patients may have reached the "point of no return" and may proceed to worsening of decomposition over time. To avoid the risk of worsening, there is an additional option of treating these patients after LT should they develop recurrent HCV infection. Currently there are no guidelines as to select patients who would benefit from treatment prior to LT as opposed to those who will be better off being treated after the transplant surgery. The article discusses a possible approach for such selection.

Transmission of hepatitis D virus between spouses: A longitudinal study of the first reported Canadian case.

In chronic hepatitis B (CHB), hepatitis D virus (HDV) superinfection can lead to acute liver failure. The incidence of HDV superinfection is unknown, but is often detected in immigrants from HDV endemic countries. In this report, we characterize long-term clinical and virological outcomes in a hepatitis B virus (HBV) infected carrier before and after HDV superinfection, acquired from their spouse having HBV/HDV co-infection. A 38 year-old Mongolian male with CHB on anti-HBV therapy developed acute liver failure following HDV superinfection. Although he recovered, avoiding the need for liver transplant, HDV serological and molecular markers of infection persisted for the subsequent 16-month follow-up period, suggesting the development of CHB/HDV co-infection. The source of his HDV was from his wife of 10 years, a 34-year old Mongolian female known to have inactive CHB/HDV co-infection but who was not on anti-HBV therapy. Phylogenetic analysis of the complete HDV genome from the couple showed >99% similarity, with post-transmission longitudinal sequence revealing specific nucleotide substitutions between both spouse's HDV genome sequences. This study highlights the ongoing risk of HDV superinfection due to long-term co-habitation or sexual transmission in CHB patients. The fact that transmission occurred after almost a decade of marriage may be due to host immune or environmental factors that created a more favorable condition for transmission.

Snake bite in third trimester of pregnancy with systemic envenomation and delivery of a live baby in a low resource setting: A case report.

BACKGROUND: Snake bite in the third trimester of pregnancy with late presentation, systemic envenomation; disseminated intravascular coagulopathy and delivery of a live neonate is uncommon in a low resource setting. CASE: We present a 22 year old unbooked Gravida 3 Para 1+ 1 1alive lentiviral positive woman at 32 weeks gestation with snake bite, leg swelling, vaginal bleeding and labour pains. At presentation, there were anemia, tachycardia, hypotension; a gravid uterus with a single fetus in longitudinal lie, cephalic presentation, regular fetal heart rate and cervical dilatation of 3 cm. Preterm labour with antepartum hemorrhage due to venomous snake bite was diagnosed. Multidisciplinary management instituted led to the survival of both mother and baby. CONCLUSION: In resource constrained setting, disseminated intravascular coagulopathy arising from systemic envenomation due to snake bite in pregnancy could be challenging. Obstetric outcome depends on the degree of envenomation, gestational age at presentation, timing, duration and quality of treatment.

Delayed Severe Hemobilia Due to Bilio-venous Fistula After Percutaneous Transhepatic Biliary Drainage: Treatment With Covered Stent Placement.

Biliovenous fistula occurs due to development of a communication between hepatic duct and portal vein branches and is a rare complication of percutaneous transhepatic biliary drainage (PTBD). Most of them are self-limiting and only occasionally they need interventional management. Placement of biliary stent graft is a viable option. We present here a case of a 56-year-old male with carcinoma of gall bladder presenting with hemodynamic shock due to severe hemobilia after PTBD and treated successfully by biliary covered stent placement.

Indian National Association for Study of the Liver (INASL) Guidance for Antiviral Therapy Against HCV Infection: Update 2016.

India contributes significantly to the global burden of HCV. While the nucleoside NS5B inhibitor sofosbuvir became available in the Indian market in March 2015, the other directly acting agents (DAAs), Ledipasvir and Daclatasvir, have only recently become available in the India. The introduction of these DAA in India at a relatively affordable price has led to great optimism about prospects of cure for these patients as not only will they provide higher efficacy, but combination DAAs as all-oral regimen will result in lower side effects than were seen with pegylated interferon alfa and ribavirin therapy. Availability of these newer DAAs has necessitated revision of INASL guidelines for the treatment of HCV published in 2015. Current considerations for the treatment of HCV in India include the poorer response of genotype 3, nonavailability of many of the DAAs recommended by other guidelines and the cost of therapy. The availability of combination DAA therapy has simplified therapy of HCV with decreased reliance of evaluation for monitoring viral kinetics or drug related side effects.

Evaluation of a new syringe presentation of reduced-antigen content diphtheria, tetanus, and acellular pertussis vaccine in healthy adolescents--A single blind randomized trial.

Reduced-antigen-content diphtheria-tetanus-acellular pertussis (dTpa) vaccine, Boostrix™, is indicated for booster vaccination of children, adolescents and adults. The original prefilled disposable dTpa syringe presentation was recently replaced by another prefilled-syringe presentation with latex-free tip-caps and plunger-stoppers. 671 healthy adolescents aged 10-15 years who had previously received 5 or 6 previous DT(P)/dT(pa) vaccine doses, were randomized (1:1) to receive dTpa booster, injected using the new (dTpa-new) or previous syringe (dTpa-previous) presentations. Immunogenicity was assessed before and 1-month post-booster vaccination; safety/reactogenicity were assessed during 31-days post-vaccination. Non-inferiority of dTpa-new versus dTpa-previous was demonstrated for all antigens (ULs 95% CIs for GMC ratios ranged between 1.03-1.13). 1-month post-booster, immune responses were in similar ranges for all antigens with both syringe presentations. dTpa delivered using either syringe presentation was well-tolerated. These clinical results complement the technical data and support the use of the new syringe presentation to deliver the dTpa vaccine.

Intrahepatic cholangiocarcinoma masquerading as liver abscess.

Malignancy masquerading as liver abscess, and presenting with fever, is mainly described in patients with colorectal cancers with liver metastasis. Primary liver tumors such as hepatocellular carcinoma or intrahepatic cholangiocarcinoma presenting as non-resolving liver abscess is extremely uncommon and carries a dismal prognosis. We present a rare case of non-resolving liver abscess as a presenting manifestation of intrahepatic cholangiocarcinoma.