BL-02: a versatile X-ray scattering and diffraction beamline for engineering applications at Indus-2 synchrotron source.

A hard X-ray engineering applications beamline (BL-02) was commissioned recently and started operation in March 2019 at the Indian synchrotron source, Indus-2. This bending-magnet-based beamline is capable of operating in various beam modes, viz. white, pink and monochromatic beam. The beamline utilizes the X-ray diffraction technique in energy-dispersive and angle-dispersive modes to carry out experiments mainly focused on engineering problems, viz. stress measurement, texture measurement and determination of elastic constants in a variety of bulk as well as thin-film samples. An open-cradle six-circle diffractometer with ∼12 kg load capacity allows accommodation of a wide variety of engineering samples and qualifies the beamline as a unique facility at Indus-2. The high-resolution mode of this beamline is suitably designed so as to carry out line profile analysis for characterization of micro- and nano-structures. In the present article the beamline is described starting from the beamline design, layout, optics involved, various operational modes and experimental stations. Experiments executed to validate the beamline design parameters and to demonstrate the capabilities of the beamline are also described. The future facilities to be incorporated to enhance the capabilities of the beamline are also discussed.

Minimal Hepatic Encephalopathy in Patients with Alcohol Related and Non-alcoholic Steatohepatitis Related Cirrhosis by Psychometric Hepatic Cephalopathy Score and Critical Flicker Frequency.

BACKGROUND: alcohol may have additional neurotoxic ill-effects in patients with alcohol related cirrhosis apart from hepatic encephalopathy. We aimed to evaluate minimal hepatic encephalopathy (MHE) with Psychometric Hepatic Encephalopathy (PHES) score and Critical Flicker Frequency (CFF) in alcohol (ALD) and non-alcoholic steatohepatitis related (NASH) related cirrhosis. METHODS: 398 patients were screened between March 2016 and December 2018; of which 71 patients were included in ALD group and 69 in NASH group. All included patients underwent psychometric tests which included number connection test A and B (NCT-A and NCT-B), serial dot test (SDT), digit symbol test (DST), line tracing test (LTT) and CFF. MHE was diagnosed when their PHES was <-4. RESULTS: the prevalence of MHE was significantly higher in ALD group compared to NASH (69.01% vs 40.58%; P=0.007). The performance of individual psychometric tests was significantly poorer in ALD (P<0.05). Overall sensitivity and specificity of CFF was 76.62% (95%CI 65.59 - 85.52) and 46.03% (95%CI 33.39 - 59.06) respectively. Mean CFF was significantly lower in ALD than NASH (37.07 (SD 2.37) vs 39.05 (SD 2.40), P=0.001); also in presence of MHE (36.95 (SD 2.04) vs 37.96 (SD 1.87), P=0.033) and absence of MHE (37.34 (SD 3.01) vs 39.79 (SD 2.46), P=0.001). CONCLUSION: MHE is significantly more common in patients with ALD cirrhosis than NASH counterparts. Overall CFF values are less in alcohol related cirrhosis than NASH related cirrhosis, even in presence or absence of MHE. We recommend additional caution in managing MHE in ALD cirrhosis.

Predictors of length of hospital stay among preterm infants admitted to neonatal intensive care unit: Data from a multicentre collaborative network from India (INNC: Indian National Neonatal Collaborative).

AIM: Prediction of length of stay (LOS) among preterm neonates is important for counselling of parents and for assessing neonatal intensive care unit (NICU) census and economic burden. The aim of this study is to evaluate perinatal and postnatal factors that influence LOS in preterm infants (25-33 weeks of gestation) admitted to participating NICUs of Indian National Neonatal Collaborative (INNC). METHODS: From the INNC database, the data which were prospectively entered using uniformed pre-defined criteria were analysed. RESULTS: A total of 3095 infants were included from 12 centres. Every week decrease in gestation increased LOS by 9 days. The median LOS for infants with gestational age of 25, 26, 27, 28, 29, 30, 31, 32 and 33 weeks were 86, 70, 62, 52, 40, 30, 23, 16 and 10 days, respectively. On multivariate analysis, abnormal antenatal umbilical artery doppler, severe small for gestational age (SGA), requirement of resuscitation, respiratory distress syndrome (RDS), seizures, sepsis, necrotising enterocolitis (NEC), major malformations and bronchopulmonary dysplasia (BPD) increased LOS by 5.4 (3.5-7.4), 21.6 (19-23.9), 4.7 (3.3-6.1), 3 (1.7-4.3), 15.2 (8.5-22.1), 11.2 (9.1-13.2), 9.8 (5.2-14.4), 8.8 (4.4-13.3) and 5.6 (0.5-10.7) days, respectively. CONCLUSIONS: Apart from lower gestation and birth weight, abnormal antenatal umbilical artery doppler, severe SGA, resuscitation need, major malformations, RDS, seizures, sepsis, NEC and BPD influenced LOS in preterm infants. In comparison with other networks or data from developed countries, LOS in our network was comparatively less for similar gestational age infants.

Depth-resolved compositional analysis of W/B4C multilayers using resonant soft X-ray reflectivity.

W/B4C multilayers (MLs) consisting of ten layer pairs with varying boron carbide layer thicknesses have been investigated. The ML structures were characterized using grazing-incidence hard X-ray reflectivity (GIXR), resonant soft X-ray reflectivity (RSXR), hard X-ray photoelectron spectroscopy (HAXPES) and X-ray absorption near-edge spectroscopy (XANES). Depth-resolved spectroscopic information on the boron carbide layer in W/B4C MLs was extracted with sub-nanometre resolution using reflectivity performed in the vicinity of the B K-edge. Interestingly, these results show that the composition of boron carbide films is strongly dependent on layer thicknesses. HAXPES measurements suggest that most of the boron is in the chemical state of B4C in the multilayer structures. XANES measurements suggest an increase in boron content and C-B-C bonding with increase in boron carbide layer thickness.

Onsite mentoring of special newborn care unit to improve the quality of newborn care.

BACKGROUND: It has been possible to set up special newborn care units (SNCUs) and to improve the survival of newborns in India. However, several challenges remain affecting their effective functioning. Different approaches have been attempted and several policies have also been implemented to address this issue. OBJECTIVES: To evaluate the feasibility of implementing best practices in neonatal care by onsite mentoring in an SNCU over 4 months. METHODS: The mentoring team was from a tertiary care hospital in Karnataka. The SNCU was functioning at the district hospital, catering to approximately 3500 live births per year. Onsite mentoring was carried out from August 2016 to November 2016. This was a prospective implementation research. Framework focused on infection control, preterm care, care at birth, advocacy for infrastructure and resources, and facility-based refresher training. RESULTS: A total of 16 visits were done by the mentoring team and 2 weeks of in-house residency. There were improvements in hand hygiene compliance from 0% to 87.5%, in cleaner IV site (from 50% to 100%), decreased unnecessary oxygen administration (from 75% to 33.3%), decreased antibiotic usage (from 70.5% to 35.5%), decrease in the number of babies receiving >5 days of antibiotics (from 41.6% to 0%), and increased kangaroo mother care initiation rate from 0% to 41.6%. The facility got level IIA accreditation by the end of the intervention period. CONCLUSIONS: Onsite mentorship program of SNCU is feasible and planning should be contextual. With the problems being uniform across most facilities, the model could be replicated across the country.

Barriers and enablers to skin-to-skin contact at birth in healthy neonates - a qualitative study.

BACKGROUND: Skin to skin contact (SSC) at birth is the standard of care for newborns without risk factors. However, implementation of SSC at birth has been far from optimal. A qualitative study was undertaken to determine the barriers, enablers and potential solutions to implementation of SSC at birth in healthy newborn infants in a level III neonatal-care facility in Bangalore, India. METHODS: Consultants and residents/postgraduates (PG) from the departments of Obstetrics (n = 19) and Pediatrics (n = 14) and nurses (n = 8) in the labor room (LR) participated in the study. In depth interviews (IDI) and focus group discussions (FGD) were carried out with an interview guide and a moderators' guide containing inbuilt probes. Subjects of FGD were homogenous. All IDI and FGD were audio-taped, transcribed and analyzed using N VIVO version 9 (using free and tree nodes). Two authors separately coded the transcripts. Major and minor themes were identified. Rigor was ensured by triangulation and theoretical saturation. Informed consent and ethical approval was obtained. RESULTS: All subjects were aware of SSC at birth, some of its benefits and had practiced SSC. The major barriers identified were lack of personnel (nurses), time constraint, difficulty in deciding on eligibility for SSC, safety concerns, interference with clinical routines, and interdepartmental issues. Recall of an adverse event during SSC was also a major barrier. Furthermore, we found that most participants considered 1 h as impractical; and promoted 5-15 min SSC. Minor themes were gender bias of the newborn and cultural practices. The participants offered solutions such as assigning a helper exclusively for SSC, allowing a family member into the LR, continuing SSC after initial routines, antenatal counselling, constant reminders in the form of periodic sessions with audiovisual aids or posters in the obstetrics ward, training of new nurses and PG, and inclusion of SSC in medical and nursing curriculum. CONCLUSIONS: The major barriers to SSC at birth are lack of personnel, time constraint and safety concerns. Training, designated health personnel for SSC and teamwork are the key interventions likely to improve SSC at birth.

Aquifer wise seasonal variations and spatial distribution of major ions with focus on fluoride contamination-Pandharkawada block, Yavatmal district, Maharashtra, India.

Seasonal variations in groundwater reveal lesser concentrations of major ions except NO3(-) during post-monsoon seasons in shallow aquifers as compared to deeper aquifers. The F(-) concentration from deeper aquifers is high in both seasons and shows a moderate positive relationship with weathering depth and is >5 mg/L in compound lava flow. Groundwater is mainly a Ca-HCO3 type in shallow aquifers and mixed type in deeper aquifers. Fluoride shows a positive correlation with pH, Na(+), HCO3(-) in shallow aquifers and an inverse correlation with Ca(2+) and HCO3(-) from deeper aquifers in both seasons. Approximately 45% of the samples are not suitable for drinking from both aquifers but suitable for irrigation purposes. Rock-water interaction, moderate alkalinity, sluggish movement, and higher residence time are the main causes for high F(-) in deeper aquifers as compared to shallow aquifers. As recommendations, drinking water requirement may be met from shallow aquifers/surface water and fluoride rich groundwater for other purposes. Most effective defluoridation techniques like ion exchange and reverse osmosis may be adopted along with integrated fluorosis mitigation measures and rooftop rainwater harvesting. Supplementary calcium and phosphorous rich food should be provided to children and creating awareness about safe drinking water habits, side effects of high F(-), and NO3(-) rich groundwater, improving oral hygiene conditions are other measures.

Downstaging with Atezolizumab-Bevacizumab: A Case Series.

Background/aims: Hepatocellular carcinoma (HCC) is generally diagnosed at an advanced stage, which limits curative treatment options for these patients. Locoregional therapy (LRT) is the standard approach to bridge and downstage unresectable HCC (uHCC) for liver transplantation (LT). Atezolizumab-bevacizumab (atezo-bev) can induce objective responses in nearly one-third of patients; however, the role and outcomes of downstaging using atezobev remains unknown. Methods: In this retrospective single-center study, we included consecutive patients between November 2020 and August 2023, who received atezo-bev with or without LRT and were subsequently considered for resection/LT after downstaging. Results: Of the 115 patients who received atezo-bev, 12 patients (10.4%) achieved complete or partial response and were willing to undergo LT; they (age: 58.5 years; women-17%; Barcelona Clinic Liver Cancer Stage System B/C:5/7) had received 3-12 cycles of atezo-bev, and 4 of them had received prior LRT. Three patients died before LT, while three were awaiting LT. Six patients underwent curative therapies: four underwent living donor LT after a median of 79.5 (54-114) days following the last atezo-bev dose, one underwent deceased donor LT 38 days after the last dose, and one underwent resection. All but one patient had complete pathologic response with no viable HCC. Three patients experienced wound healing complications, and one required re-exploration and succumbed to sepsis. After a median follow-up of 10 (4-30) months, none of the alive patients developed HCC recurrence or graft rejection. Conclusions: Surgical therapy, including LT, is possible after atezo-bev therapy in wellselected patients after downstaging.

APASL clinical practice guidelines on the management of acute kidney injury in acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a syndrome that is characterized by the rapid development of organ failures predisposing these patients to a high risk of short-term early death. The main causes of organ failure in these patients are bacterial infections and systemic inflammation, both of which can be severe. For the majority of these patients, a prompt liver transplant is still the only effective course of treatment. Kidneys are one of the most frequent extrahepatic organs that are affected in patients with ACLF, since acute kidney injury (AKI) is reported in 22.8-34% of patients with ACLF. Approach and management of kidney injury could improve overall outcomes in these patients. Importantly, patients with ACLF more frequently have stage 3 AKI with a low rate of response to the current treatment modalities. The objective of the present position paper is to critically review and analyze the published data on AKI in ACLF, evolve a consensus, and provide recommendations for early diagnosis, pathophysiology, prevention, and management of AKI in patients with ACLF. In the absence of direct evidence, we propose expert opinions for guidance in managing AKI in this very challenging group of patients and focus on areas of future research. This consensus will be of major importance to all hepatologists, liver transplant surgeons, and intensivists across the globe.

Stability and normal incidence reflectivity of W/B4C multilayer mirror near the boron K absorption edge.

A multilayer structure consisting of alternate layers of W and B4C has been deposited using a magnetron sputtering system. The structure of the as-deposited and vacuum-annealed W/B4C multilayer sample has been characterized using grazing incidence x-ray reflectivity, grazing incidence diffraction, and the normal incidence reflectivity has been measured using synchrotron radiation. A two-layer model consisting of tungsten and boron carbide is presented. The multilayer structure was found to be stable after 800°C annealing. Grazing incidence x-ray diffraction measurements suggested that W is polycrystalline with small grain size. No signature of tungsten carbide or tungsten boride formation could be observed during the annealing treatments. A near normal incidence soft x-ray reflectivity (SXRR) of ~8.3% was obtained at 6.8 nm wavelength. A little drop (~1%) in SXRR after 800°C annealing suggested that there were no compositional changes within the layers during the annealing treatments.

Human albumin infusion is safe and effective even in patients without acute kidney injury and spontaneous bacterial peritonitis.

BACKGROUND AND OBJECTIVES: Human albumin (HA) solution is currently recommended only for patients with spontaneous bacterial peritonitis (SBP) and acute kidney injury (AKI). However, its use in hospitalized patients is quite frequent. The objective was to compare the outcomes of patients receiving HA in recommended (Gr. A) vs. non-recommended (Gr. B) indications. METHODS: In this prospective study, consecutive hospitalized patients who received HA were included. Apart from comparing the proportion of patients achieving resolution of hyponatremia, infection and hepatic encephalopathy among Gr. A and Gr. B, we also compared the in-hospital survival and performed a sub-group analysis of patients with the European Association for the Study of the Liver (EASL) acute-on-chronic liver failure (ACLF) and decompensated cirrhosis (DC). RESULTS: Of the 396 hospitalized patients who received HA, 180 had AKI and/or SBP (Gr. A), and 216 received albumin for non-recommended indications (Gr. B). The mean age, sex and etiology distribution were similar. The total dose of HA was higher (88 ± 61.62 g vs. 71.31 ± 488.17 g; p = 0.003) and the duration longer (4 ± 2.37 vs. 3.4 ± 1.82 days; p = 0.005) in Gr. A than B. The resolution of infection and HE was similar among both groups, while hyponatremia resolution was significantly higher in Gr. B (94.7%) than Gr. A (75.6%; p < 0.001). On Kaplan-Meier analysis, survival was significantly higher in Gr. B (94%) than Gr. A (78.9%; p < 0.001). The incidence of albumin-induced fluid overload was comparable (2.8% vs. 1.4%; p = 0.32). Patients with ACLF were sicker with a higher incidence of microbiologically proven infection, hepatic encephalopathy (HE) and hyponatremia than in the DC group. Resolution of infection and hyponatremia and in-hospital survival was significantly lower in the ACLF group (72.5%) than in the DC group (92.7%; p < 0.001). Eighty-six per cent of patients achieved resolution of ACLF. CONCLUSIONS: HA infusion is safe and effective even in patients without AKI and SBP and leads to the resolution of infection, hyponatremia, HE and ACLF.

INASL-SAASL Consensus Statements on NAFLD Name Change to MAFLD.

There is an ongoing debate on the change of terminology of non-alcoholic fatty liver disease (NAFLD) to metabolic associated fatty liver disease (MAFLD). Experts from the Indian National Association for Study of the Liver (INASL) and the South Asian Association for Study of the Liver (SAASL) involved in diagnosing, managing, and preventing NAFLD met in March 2022 to deliberate if the name change from NAFLD to MAFLD is appropriate, as proposed by a group of experts who published a "consensus" statement in 2020. Proponents of name change to MAFLD opined that NAFLD does not reflect current knowledge, and the term MAFLD was suggested as a more appropriate overarching term. However, this "consensus" group which proposed the name change to MAFLD did not represent the views and opinions of gastroenterologists and hepatologists, as well as perceptions of patients across the globe, given the fact that change of nomenclature for any disease entity is bound to have multidimensional impact on all aspects of patient care. This statement is the culmination of the participants' combined efforts who presented recommendations on specific issues concerning the proposed name change. The recommendations were then circulated to all the core group members and updated based on a systematic literature search. Finally, all the members voted on them using the nominal voting technique as per the standard guidelines. The quality of evidence was adapted from the Grades of Recommendation, Assessment, Development and Evaluation system.

AARC score determines outcomes in patients with alcohol-associated hepatitis: a multinational study.

BACKGROUND AND AIM: Acute-on-chronic liver failure (ACLF) is a severe form of alcoholic hepatitis (SAH). We aimed to study the natural course, response to corticosteroids (CS), and the role of the Asian Pacific Association for the Study of Liver (APASL) research consortium (AARC) score in determining clinical outcomes in AH patients. METHODS: Prospectively collected data from the AARC database were analyzed. RESULTS: Of the 1249 AH patients, (aged 43.8 ± 10.6 years, 96.9% male, AARC score 9.2 ± 1.9), 38.8% died on a 90 day follow-up. Of these, 150 (12.0%) had mild-moderate AH (MAH), 65 (5.2%) had SAH and 1034 (82.8%) had ACLF. Two hundred and eleven (16.9%) patients received CS, of which 101 (47.87%) were steroid responders by day 7 of Lille's model, which was associated with improved survival [Hazard ratio (HR) 0.15, 95% CI 0.12-0.19]. AARC-ACLF grade 3 [OR 0.28, 0.14-0.55] was an independent predictor of steroid non-response and mortality [HR 3.29, 2.63-4.11]. Complications increased with degree of liver failure [AARC grade III vs. II vs I], bacterial infections [48.6% vs. 37% vs. 34.7%; p < 0.001); extrahepatic organ failure [66.9% vs. 41.8% vs. 35.4%; p < 0.001] respectively. The AARC score better discriminated 90-day mortality. Harrell's C-index was 0.72 compared to other scores. CONCLUSION: Nearly 4 of 5 patients with AH present with ACLF. Such patients have a higher risk of infections, organ failures, lower response to CS, and higher mortality. Patients with AH and ACLF with AARC grade 3 should be considered for an early liver transplant.

Identifying the early predictors of non-response to steroids in patients with flare of autoimmune hepatitis causing acute-on-chronic liver failure.

BACKGROUND AND AIMS: Early identification of non-response to steroids is critical in patients with autoimmune hepatitis (AIH) causing acute-on-chronic liver failure (ACLF). We assessed if this non-response can be accurately identified within first few days of treatment. METHODS: Patients with AIH-ACLF without baseline infection/hepatic encephalopathy were identified from APASL ACLF research consortium (AARC) database. Diagnosis of AIH-ACLF was based mainly on histology. Those treated with steroids were assessed for non-response (defined as death or liver transplant at 90 days for present study). Laboratory parameters, AARC, and model for end-stage liver disease (MELD) scores were assessed at baseline and day 3 to identify early non-response. Utility of dynamic SURFASA score [- 6.80 + 1.92*(D0-INR) + 1.94*(∆%3-INR) + 1.64*(∆%3-bilirubin)] was also evaluated. The performance of early predictors was compared with changes in MELD score at 2 weeks. RESULTS: Fifty-five out of one hundred and sixty-five patients (age-38.2 ± 15.0 years, 67.2% females) with AIH-ACLF [median MELD 24 (IQR: 22-27); median AARC score 7 (6-9)] given oral prednisolone 40 (20-40) mg per day were analyzed. The 90 day transplant-free survival in this cohort was 45.7% with worse outcomes in those with incident infections (56% vs 28.0%, p = 0.03). The AUROC of pre-therapy AARC score [0.842 (95% CI 0.754-0.93)], MELD [0.837 (95% CI 0.733-0.94)] score and SURFASA score [0.795 (95% CI 0.678-0.911)] were as accurate as ∆MELD at 2 weeks [0.770 (95% CI 0.687-0.845), p = 0.526] and better than ∆MELD at 3 days [0.541 (95% CI 0.395, 0.687), p < 0.001] to predict non-response. Combination of AARC score > 6, MELD score > 24 with SURFASA score ≥ - 1.2, could identify non-responders at day 3 (concomitant- 75% vs either - 42%, p < 0.001). CONCLUSION: Baseline AARC score, MELD score, and the dynamic SURFASA score on day 3 can accurately identify early non-response to steroids in AIH-ACLF.

Low cost calibrated mechanical noisemaker for hearing screening of neonates in resource constrained settings.

BACKGROUND & OBJECTIVES: There is a need to develop an affordable and reliable tool for hearing screening of neonates in resource constrained, medically underserved areas of developing nations. This study valuates a strategy of health worker based screening of neonates using a low cost mechanical calibrated noisemaker followed up with parental monitoring of age appropriate auditory milestones for detecting severe-profound hearing impairment in infants by 6 months of age. METHODS: A trained health worker under the supervision of a qualified audiologist screened 425 neonates of whom 20 had confirmed severe-profound hearing impairment. Mechanical calibrated noisemakers of 50, 60, 70 and 80 dB (A) were used to elicit the behavioural responses. The parents of screened neonates were instructed to monitor the normal language and auditory milestones till 6 months of age. This strategy was validated against the reference standard consisting of a battery of tests - namely, auditory brain stem response (ABR), otoacoustic emissions (OAE) and behavioural assessment at 2 years of age. Bayesian prevalence weighted measures of screening were calculated. RESULTS: The sensitivity and specificity was high with least false positive referrals for 70 and 80 dB (A) noisemakers. All the noisemakers had 100 per cent negative predictive value. 70 and 80 dB (A) noisemakers had high positive likelihood ratios of 19 and 34, respectively. The probability differences for pre- and post- test positive was 43 and 58 for 70 and 80 dB (A) noisemakers, respectively. INTERPRETATION & CONCLUSIONS: In a controlled setting, health workers with primary education can be trained to use a mechanical calibrated noisemaker made of locally available material to reliably screen for severe-profound hearing loss in neonates. The monitoring of auditory responses could be done by informed parents. Multi-centre field trials of this strategy need to be carried out to examine the feasibility of community health care workers using it in resource constrained settings of developing nations to implement an effective national neonatal hearing screening programme.

Fetal vascular malperfusion (FVM): diagnostic implications and clinical associations.

INTRODUCTION: Fetal vascular malperfusion (FVM) is diagnosed by the presence of vascular lesions in the muscularized fetal vessels in the placenta and the resultant changes in the downstream villi. The Amsterdam Placental Working Group recognizes two patterns of FVM namely segmental and global. The aim of this study was to estimate the frequency of FVM lesion in our population and to understand its neonatal associations. METHODS: Fifty-four placentas with FVM and 56 controls collected over 34 months. The maternal and neonatal details were collected from the case charts. The patterns and grades of FVM lesions were related to the clinical factors and significance analyzed statistically using the Chi-square test and t-test and p < .05 was considered significant. RESULTS: The frequency of FVM was 8.7%. The FVM group showed lower mean gestational age, birth weight, and placental weight with a higher frequency of IUGR. Poor neonatal survival, non-reassuring fetal status, neurological abnormalities, neonatal sepsis, asphyxia, low Apgar, and respiratory support requirement were significantly higher in the FVM group. A similar frequency of segmental and global lesions was seen. High grade lesions (n = 35) were common than low grade (n = 19). Neonatal associations were more often seen in segmental and high-grade lesions. DISCUSSION: In the absence of antenatal diagnostic tools to identify FVM, placental examination is critical and the only definitive method to diagnose FVM, which alerts the clinician to monitor for several neonatal morbidities. Identification and typing the lesion as per the new guidelines proves significant risk associations with specific types of FVM.

Pathological and genetic markers improve recurrence prognostication with the University of California Los Angeles Integrated Staging System for patients with clear cell renal cell carcinoma.

PURPOSE: To elucidate which patients with clear cell renal cell carcinoma have the highest risk for disease relapse after curative nephrectomy is challenging but is acutely relevant in the era of approved adjuvant therapies. Pathological and genetic markers were used to improve the University of California Los Angeles Integrated Staging System (UISS) for the risk stratification and prognostication of recurrence free survival (RFS). PATIENTS AND METHODS: Necrosis, sarcomatoid features, Rhabdoid features, chromosomal loss 9p, combined chromosomal loss 3p14q and microvascular invasion (MVI) were tested in univariable and multivariable analyses for their ability to improve the discriminatory ability of the UISS. RESULTS: In the development cohort, during the median follow-up time of 43.4 months (±SD 54.1 months), 50/240 (21%) patients developed disease recurrence. MVI (HR: 2.22; p = 0.013) and the combined loss of chromosome 3p/14q (HR: 2.89; p = 0.004) demonstrated independent association with RFS and were used to improve the assignment to the UISS risk category. In the current UISS high-risk group, only 7/50 (14%) recurrence cases were correctly identified; while in the improved system, 23/50 (45%) were correctly prognosticated. The concordance index meaningfully improved from 0.55 to 0.68 to distinguish patients at intermediate risk versus high risk. Internal validation demonstrated a robust prognostication of RFS. In the external validation cohort, there was no case with disease recurrence in the low-risk group, and the mean RFS times were 13.2 (±1.8) and 8.2 (±0.8) years in the intermediate and high-risk groups, respectively. CONCLUSIONS: Adding MVI and combined chromosomal loss3p/14q to the UISS improves the ability to define the patient group with clear cell renal cell carcinomawho are at the highest risk for disease relapse after surgical treatment.

Acute variceal bleeding portends poor outcomes in patients with acute-on-chronic liver failure: a propensity score matched study from the APASL ACLF Research Consortium (AARC).

BACKGROUND AND AIMS: Limited data exist regarding outcomes of acute variceal bleeding (AVB) in patients with acute-on-chronic liver failure (ACLF), especially in those with hepatic failure. We evaluated the outcomes of AVB in patients with ACLF in a multinational cohort of APASL ACLF Research Consortium (AARC). METHODS: Prospectively maintained data from AARC database on patients with ACLF who developed AVB (ACLF-AVB) was analysed. This data included demographic profile, severity of liver disease, and rebleeding and mortality in 6 weeks. These outcomes were compared with a propensity score matched (PSM) cohort of ACLF matched for severity of liver disease (MELD, AARC score) without AVB (ACLF without AVB). RESULTS: Of the 4434 ACLF patients, the outcomes in ACLF-AVB (n = 72) [mean age-46 ± 10.4 years, 93% males, 66% with alcoholic liver disease, 65% with alcoholic hepatitis, AARC score: 10.1 ± 2.2, MELD score: 34 (IQR: 27-40)] were compared with a PSM cohort selected in a ratio of 1:2 (n = 143) [mean age-44.9 ± 12.5 years, 82.5% males, 48% alcoholic liver disease, 55.7% alcoholic hepatitis, AARC score: 9.4 ± 1.5, MELD score: 32 (IQR: 24-40)] of ACLF-without AVB. Despite PSM, ACLF patients with AVB had a higher baseline HVPG than without AVB (25.00 [IQR: 23.00-28.00] vs. 17.00 [15.00-21.75] mmHg; p = 0.045). The 6-week mortality in ACLF patients with or without AVB was 70.8% and 53.8%, respectively (p = 0.025). The 6-week rebleeding rate was 23% in ACLF-AVB. Presence of ascites [hazard ratio (HR) 2.2 (95% CI 1.03-9.8), p = 0.026], AVB [HR 1.9 (95% CI 1.2-2.5, p = 0.03)], and MELD score [HR 1.7 (95% CI 1.1-2.1), p = 0.001] independently predicted mortality in the overall ACLF cohort. CONCLUSION: Development of AVB confers poor outcomes in patients with ACLF with a high 6-week mortality. Elevated HVPG at baseline represents a potential risk factor for future AVB in ACLF.

A low frequency of pancreatic islet insulin-expressing cells derived from cord blood stem cell allografts in humans.

AIMS/HYPOTHESIS: We sought to establish if stem cells contained in cord blood cell allografts have the capacity to differentiate into insulin-expressing beta cells in humans. METHODS: We studied pancreases obtained at autopsy from individuals (n = 11) who had prior opposite-sex cord blood transplants to reconstitute haematopoiesis. Pancreatic tissue sections were stained first by XY-fluorescence in situ hybridisation and then insulin immunohistochemistry. Pancreases obtained at autopsy from participants without cord blood cell infusions served as controls (n = 11). RESULTS: In the men with prior transplant of female cord blood, there were 3.4 ± 0.3% XX-positive insulin-expressing islet cells compared with 0.32 ± 0.05% (p < 0.01) in male controls. In women with prior transplant of male cord blood cells we detected 1.03 ± 0.20% XY insulin-expressing islet cells compared with 0.03 ± 0.03 in female controls (p < 0. 001). CONCLUSIONS/INTERPRETATION: Cord blood stem cells have the capacity to differentiate into insulin-expressing cells in non-diabetic humans. It remains to be established whether these cells have the properties of beta cells.