Aga Khan University Hospital

There is great geographical variation in the distribution of hepatocellular carcinoma (HCC), with the majority of all cases worldwide found in the Asia-Pacific region, where HCC is one of the leading public health problems. Since the "Toward Revision of the Asian Pacific Association for the Study of the Liver (APASL) HCC Guidelines" meeting held at the 25th annual conference of the APASL in Tokyo, the newest guidelines for the treatment of HCC published by the APASL has been discussed. This latest guidelines recommend evidence-based management of HCC and are considered suitable for universal use in the Asia-Pacific region, which has a diversity of medical environments.

OBJECTIVE: Behçet's disease (BD) is a chronic, relapsing, inflammatory vascular disease with no pathognomonic test. Low sensitivity of the currently applied International Study Group (ISG) clinical diagnostic criteria led to their reassessment. METHODS: An International Team for the Revision of the International Criteria for BD (from 27 countries) submitted data from 2556 clinically diagnosed BD patients and 1163 controls with BD-mimicking diseases or presenting at least one major BD sign. These were randomly divided into training and validation sets. Logistic regression, 'leave-one-country-out' cross-validation and clinical judgement were employed to develop new International Criteria for BD (ICBD) with the training data. Existing and new criteria were tested for their performance in the validation set. RESULTS: For the ICBD, ocular lesions, oral aphthosis and genital aphthosis are each assigned 2 points, while skin lesions, central nervous system involvement and vascular manifestations 1 point each. The pathergy test, when used, was assigned 1 point. A patient scoring ≥4 points is classified as having BD. In the training set, 93.9% sensitivity and 92.1% specificity were assessed compared with 81.2% sensitivity and 95.9% specificity for the ISG criteria. In the validation set, ICBD demonstrated an unbiased estimate of sensitivity of 94.8% (95% CI: 93.4-95.9%), considerably higher than that of the ISG criteria (85.0%). Specificity (90.5%, 95% CI: 87.9-92.8%) was lower than that of the ISG-criteria (96.0%), yet still reasonably high. For countries with at least 90%-of-cases and controls having a pathergy test, adding 1 point for pathergy test increased the estimate of sensitivity from 95.5% to 98.5%, while barely reducing specificity from 92.1% to 91.6%. CONCLUSION: The new proposed criteria derived from multinational data exhibits much improved sensitivity over the ISG criteria while maintaining reasonable specificity. It is proposed that the ICBD criteria to be adopted both as a guide for diagnosis and classification of BD.

Importance: Detailed information about the association of COVID-19 with outcomes in pregnant individuals compared with not-infected pregnant individuals is much needed. Objective: To evaluate the risks associated with COVID-19 in pregnancy on maternal and neonatal outcomes compared with not-infected, concomitant pregnant individuals. Design, Setting, and Participants: In this cohort study that took place from March to October 2020, involving 43 institutions in 18 countries, 2 unmatched, consecutive, not-infected women were concomitantly enrolled immediately after each infected woman was identified, at any stage of pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed up until hospital discharge. Exposures: COVID-19 in pregnancy determined by laboratory confirmation of COVID-19 and/or radiological pulmonary findings or 2 or more predefined COVID-19 symptoms. Main Outcomes and Measures: The primary outcome measures were indices of (maternal and severe neonatal/perinatal) morbidity and mortality; the individual components of these indices were secondary outcomes. Models for these outcomes were adjusted for country, month entering study, maternal age, and history of morbidity. Results: A total of 706 pregnant women with COVID-19 diagnosis and 1424 pregnant women without COVID-19 diagnosis were enrolled, all with broadly similar demographic characteristics (mean [SD] age, 30.2 [6.1] years). Overweight early in pregnancy occurred in 323 women (48.6%) with COVID-19 diagnosis and 554 women (40.2%) without. Women with COVID-19 diagnosis were at higher risk for preeclampsia/eclampsia (relative risk [RR], 1.76; 95% CI, 1.27-2.43), severe infections (RR, 3.38; 95% CI, 1.63-7.01), intensive care unit admission (RR, 5.04; 95% CI, 3.13-8.10), maternal mortality (RR, 22.3; 95% CI, 2.88-172), preterm birth (RR, 1.59; 95% CI, 1.30-1.94), medically indicated preterm birth (RR, 1.97; 95% CI, 1.56-2.51), severe neonatal morbidity index (RR, 2.66; 95% CI, 1.69-4.18), and severe perinatal morbidity and mortality index (RR, 2.14; 95% CI, 1.66-2.75). Fever and shortness of breath for any duration was associated with increased risk of severe maternal complications (RR, 2.56; 95% CI, 1.92-3.40) and neonatal complications (RR, 4.97; 95% CI, 2.11-11.69). Asymptomatic women with COVID-19 diagnosis remained at higher risk only for maternal morbidity (RR, 1.24; 95% CI, 1.00-1.54) and preeclampsia (RR, 1.63; 95% CI, 1.01-2.63). Among women who tested positive (98.1% by real-time polymerase chain reaction), 54 (13%) of their neonates tested positive. Cesarean delivery (RR, 2.15; 95% CI, 1.18-3.91) but not breastfeeding (RR, 1.10; 95% CI, 0.66-1.85) was associated with increased risk for neonatal test positivity. Conclusions and Relevance: In this multinational cohort study, COVID-19 in pregnancy was associated with consistent and substantial increases in severe maternal morbidity and mortality and neonatal complications when pregnant women with and without COVID-19 diagnosis were compared. The findings should alert pregnant individuals and clinicians to implement strictly all the recommended COVID-19 preventive measures.

Background: The COVID‑19 pandemic and associated public health measures have disrupted the lives of people around the world. It is already evident that the direct and indirect psychological and social effects of the COVID‑19 pandemic are insidious and affect the mental health of young children and adolescents now and will in the future. The aim and objectives of this knowledge-synthesis study were to identify the impact of the pandemic on children’s and adolescent’s mental health and to evaluate the effectiveness of different interventions employed during previous and the current pandemic to promote children’s and adolescents’ mental health. Methodology: We conducted the systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and included experimental randomized and nonrandomized controlled trials, observational studies, and qualitative studies. Results: Of the 5828 articles that we retrieved, 18 articles met the inclusion criteria. We thematically analyzed them and put the major findings under the thematic areas of impact of the pandemic on children’s and adolescents’ mental health. These studies reported that pandemics cause stress, worry, helplessness, and social and risky behavioral problems among children and adolescents (e.g., substance abuse, suicide, relationship problems, academic issues, and absenteeism from work). Interventions such as art-based programs, support services, and clinician-led mental health and psychosocial services effectively decrease mental health issues among children and adolescents. Conclusion: Children and adolescents are more likely to experience high rates of depression and anxiety during and after a pandemic. It is critical that future researchers explore effective mental health strategies that are tailored to the needs of children and adolescents. Explorations of effective channels regarding the development and delivery of evidenced-based, age-appropriate services are vital to lessen the effects and improve long-term capacities for mental health services for children and adolescents. Key Practitioner Message: The COVID-19 pandemic’s physical restrictions and social distancing measures have affected each and every domain of life. Although the number of children and adolescents affected by the disease is small, the disease and the containment measures such as social distancing, school closure, and isolation have negatively impacted the mental health and well-being of children and adolescents. The impact of COVID-19 on the mental health of children and adolescents is of great concern. Anxiety, depression, disturbances in sleep and appetite, as well as impairment in social interactions are the most common presentations. It has been indicated that compared to adults, this pandemic may continue to have increased long term adverse consequences on children’s and adolescents’ mental health. As the pandemic continues, it is important to monitor the impact on children’s and adolescents’ mental health status and how to help them to improve their mental health outcomes in the time of the current or future pandemics.

The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set up in 2004 on acute-on-chronic liver failure (ACLF) was published in 2009. With international groups volunteering to join, the “APASL ACLF Research Consortium (AARC)” was formed in 2012, which continued to collect prospective ACLF patient data. Based on the prospective data analysis of nearly 1400 patients, the AARC consensus was published in 2014. In the past nearly four-and-a-half years, the AARC database has been enriched to about 5200 cases by major hepatology centers across Asia. The data published during the interim period were carefully analyzed and areas of contention and new developments in the field of ACLF were prioritized in a systematic manner. The AARC database was also approached for answering some of the issues where published data were limited, such as liver failure grading, its impact on the ‘Golden Therapeutic Window’, extrahepatic organ dysfunction and failure, development of sepsis, distinctive features of acute decompensation from ACLF and pediatric ACLF and the issues were analyzed. These initiatives concluded in a two-day meeting in October 2018 at New Delhi with finalization of the new AARC consensus. Only those statements, which were based on evidence using the Grade System and were unanimously recommended, were accepted. Finalized statements were again circulated to all the experts and subsequently presented at the AARC investigators meeting at the AASLD in November 2018. The suggestions from the experts were used to revise and finalize the consensus. After detailed deliberations and data analysis, the original definition of ACLF was found to withstand the test of time and be able to identify a homogenous group of patients presenting with liver failure. New management options including the algorithms for the management of coagulation disorders, renal replacement therapy, sepsis, variceal bleed, antivirals and criteria for liver transplantation for ACLF patients were proposed. The final consensus statements along with the relevant background information and areas requiring future studies are presented here.

OBJECTIVE: The aim of this study was to assess the characteristics and care of patients with diabetes in countries with a sizable Muslim population and to study diabetes features during Ramadan and the effect of fasting. RESEARCH DESIGN AND METHODS: This was a population-based, retrospective, transversal survey conducted in 13 countries. A total of 12,914 patients with diabetes were recruited using a stratified sampling method, and 12,243 were considered for the analysis. RESULTS: Investigators recruited 1,070 (8.7%) patients with type 1 diabetes and 11,173 (91.3%) patients with type 2 diabetes. During Ramadan, 42.8% of patients with type 1 diabetes and 78.7% with type 2 diabetes fasted for at least 15 days. Less than 50% of the whole population changed their treatment dose (approximately one-fourth of patients treated with oral antidiabetic drugs [OADs] and one-third of patients using insulin). Severe hypoglycemic episodes were significantly more frequent during Ramadan compared with other months (type 1 diabetes, 0.14 vs. 0.03 episode/month, P = 0.0174; type 2 diabetes, 0.03 vs. 0.004 episode/month, P < 0.0001). Severe hypoglycemia was more frequent in subjects who changed their dose of OADs or insulin or modified their level of physical activity. CONCLUSIONS: The large proportion of both type 1 and type 2 diabetic subjects who fast during Ramadan represent a challenge to their physicians. There is a need to provide more intensive education before fasting, to disseminate guidelines, and to propose further studies assessing the impact of fasting on morbidity and mortality.

BACKGROUND: While maternal, infant and under-five child mortality rates in developing countries have declined significantly in the past two to three decades, newborn mortality rates have reduced much more slowly. While it is recognised that almost half of the newborn deaths can be prevented by scaling up evidence-based available interventions (such as tetanus toxoid immunisation to mothers, clean and skilled care at delivery, newborn resuscitation, exclusive breastfeeding, clean umbilical cord care, and/or management of infections in newborns), many require facility-based and outreach services. It has also been stated that a significant proportion of these mortalities and morbidities could also be potentially addressed by developing community-based packaged interventions which should also be supplemented by developing and strengthening linkages with the local health systems. Some of the recent community-based studies of interventions targeting women of reproductive age have shown variable impacts on maternal outcomes and hence it is uncertain if these strategies have consistent benefit across the continuum of maternal and newborn care. OBJECTIVES: To assess the effectiveness of community-based intervention packages in reducing maternal and neonatal morbidity and mortality; and improving neonatal outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2014), World Bank's JOLIS (25 May 2014), BLDS at IDS and IDEAS database of unpublished working papers (25 May 2014), Google and Google Scholar (25 May 2014). SELECTION CRITERIA: All prospective randomised, cluster-randomised and quasi-randomised trials evaluating the effectiveness of community-based intervention packages in reducing maternal and neonatal mortality and morbidities, and improving neonatal outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, assessed trial quality and extracted the data. Data were checked for accuracy. MAIN RESULTS: The review included 26 cluster-randomised/quasi-randomised trials, covering a wide range of interventional packages, including two subsets from three trials. Assessment of risk of bias in these studies suggests concerns regarding insufficient information on sequence generation and regarding failure to adequately address incomplete outcome data, particularly from randomised controlled trials. We incorporated data from these trials using generic inverse variance method in which logarithms of risk ratio (RR) estimates were used along with the standard error of the logarithms of RR estimates.Our review showed a possible effect in terms of a reduction in maternal mortality (RR 0.80; 95% confidence interval (CI) 0.64 to 1.00, random-effects (11 studies, n = 167,311; random-effects, Tau² = 0.03, I² 20%). However, significant reduction was observed in maternal morbidity (average RR 0.75; 95% CI 0.61 to 0.92; four studies, n = 138,290; random-effects, Tau² = 0.02, I² = 28%); neonatal mortality (average RR 0.75; 95% CI 0.67 to 0.83; 21 studies, n = 302,646; random-effects, Tau² = 0.06, I² = 85%) including both early and late mortality; stillbirths (average RR 0.81; 95% CI 0.73 to 0.91; 15 studies, n = 201,181; random-effects, Tau² = 0.03, I² = 66%); and perinatal mortality (average RR 0.78; 95% CI 0.70 to 0.86; 17 studies, n = 282,327; random-effects Tau² = 0.04, I² = 88%) as a consequence of implementation of community-based interventional care packages.Community-based intervention packages also increased the uptake of tetanus immunisation by 5% (average RR 1.05; 95% CI 1.02 to 1.09; seven studies, n = 71,622; random-effects Tau² = 0.00, I² = 52%); use of clean delivery kits by 82% (average RR 1.82; 95% CI 1.10 to 3.02; four studies, n = 54,254; random-effects, Tau² = 0.23, I² = 90%); rates of institutional deliveries by 20% (average RR 1.20; 95% CI 1.04 to 1.39; 14 studies, n = 147,890; random-effects, Tau² = 0.05, I² = 80%); rates of early breastfeeding by 93% (average RR 1.93; 95% CI 1.55 to 2.39; 11 studies, n = 72,464; random-effects, Tau² = 0.14, I² = 98%), and healthcare seeking for neonatal morbidities by 42% (average RR 1.42; 95% CI 1.14 to 1.77, nine studies, n = 66,935, random-effects, Tau² = 0.09, I² = 92%). The review also showed a possible effect on increasing the uptake of iron/folic acid supplementation during pregnancy (average RR 1.47; 95% CI 0.99 to 2.17; six studies, n = 71,622; random-effects, Tau² = 0.26; I² = 99%).It has no impact on improving referrals for maternal morbidities, healthcare seeking for maternal morbidities, iron/folate supplementation, attendance of skilled birth attendance on delivery, and other neonatal care-related outcomes. We did not find studies that reported the impact of community-based intervention package on improving exclusive breastfeeding rates at six months of age. We assessed our primary outcomes for publication bias and observed slight asymmetry on the funnel plot for maternal mortality. AUTHORS' CONCLUSIONS: Our review offers encouraging evidence that community-based intervention packages reduce morbidity for women, mortality and morbidity for babies, and improves care-related outcomes particularly in low- and middle-income countries. It has highlighted the value of integrating maternal and newborn care in community settings through a range of interventions, which can be packaged effectively for delivery through a range of community health workers and health promotion groups. While the importance of skilled delivery and facility-based services for maternal and newborn care cannot be denied, there is sufficient evidence to scale up community-based care through packages which can be delivered by a range of community-based workers.

Inappropriate mechanical debridement, persistence of bacteria in the canals and apex, poor obturation quality, over and under extension of the root canal filling, and coronal leakage are some of the commonly attributable causes of failure. Despite the high success rate of endodontic treatment, failures do occur in a large number of cases and most of the times can be attributed to the already stated causes. With an ever increasing number of endodontic treatments being done each day, it has become imperative to avoid or minimize the most fundamental of reasons leading to endodontic failure. This paper reviews the most common causes of endodontic failure along with radiographic examples.

Mycobacterium tuberculosis drug resistance (DR) challenges effective tuberculosis disease control. Current molecular tests examine limited numbers of mutations, and although whole genome sequencing approaches could fully characterise DR, data complexity has restricted their clinical application. A library (1,325 mutations) predictive of DR for 15 anti-tuberculosis drugs was compiled and validated for 11 of them using genomic-phenotypic data from 792 strains. A rapid online 'TB-Profiler' tool was developed to report DR and strain-type profiles directly from raw sequences. Using our DR mutation library, in silico diagnostic accuracy was superior to some commercial diagnostics and alternative databases. The library will facilitate sequence-based drug-susceptibility testing.

OBJECTIVE: To determine if vitamin A supplementation is associated with reductions in mortality and morbidity in children aged 6 months to 5 years. DESIGN: Systematic review and meta-analysis. Two reviewers independently assessed studies for inclusion. Data were double extracted; discrepancies were resolved by discussion. Meta-analyses were performed for mortality, illness, vision, and side effects. DATA SOURCES: Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Medline, Embase, Global Health, Latin American and Caribbean Health Sciences, metaRegister of Controlled Trials, and African Index Medicus. Databases were searched to April 2010 without restriction by language or publication status. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised trials of synthetic oral vitamin A supplements in children aged 6 months to 5 years. Studies of children with current illness (such as diarrhoea, measles, and HIV), studies of children in hospital, and studies of food fortification or β carotene were excluded. RESULTS: 43 trials with about 215,633 children were included. Seventeen trials including 194,483 participants reported a 24% reduction in all cause mortality (rate ratio=0.76, 95% confidence interval 0.69 to 0.83). Seven trials reported a 28% reduction in mortality associated with diarrhoea (0.72, 0.57 to 0.91). Vitamin A supplementation was associated with a reduced incidence of diarrhoea (0.85, 0.82 to 0.87) and measles (0.50, 0.37 to 0.67) and a reduced prevalence of vision problems, including night blindness (0.32, 0.21 to 0.50) and xerophthalmia (0.31, 0.22 to 0.45). Three trials reported an increased risk of vomiting within the first 48 hours of supplementation (2.75, 1.81 to 4.19). CONCLUSIONS: Vitamin A supplementation is associated with large reductions in mortality, morbidity, and vision problems in a range of settings, and these results cannot be explained by bias. Further placebo controlled trials of vitamin A supplementation in children between 6 and 59 months of age are not required. However, there is a need for further studies comparing different doses and delivery mechanisms (for example, fortification). Until other sources are available, vitamin A supplements should be given to all children at risk of deficiency, particularly in low and middle income countries.

BACKGROUND: Most ischaemic strokes are caused by blood clots blocking an artery in the brain. Clot prevention with anticoagulants might improve outcome if bleeding risks were low. This is an update of a Cochrane review first published in 1995, and previously updated in 2004. OBJECTIVES: To assess the effect of anticoagulant therapy versus control in the early treatment (less than 14 days) of patients with acute ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched 2 October 2007), and two Internet clinical trials registries for relevant ongoing studies (last searched October 2007). SELECTION CRITERIA: Randomised trials comparing early anticoagulant therapy (started within two weeks of stroke onset) with control in patients with acute presumed or confirmed ischaemic stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed trial quality, and extracted the data. MAIN RESULTS: Twenty-four trials involving 23,748 participants were included. The quality of the trials varied considerably. The anticoagulants tested were standard unfractionated heparin, low-molecular-weight heparins, heparinoids, oral anticoagulants, and thrombin inhibitors. Based on 11 trials (22,776 participants) there was no evidence that anticoagulant therapy reduced the odds of death from all causes (odds ratio (OR) 1.05; 95% confidence interval (CI) 0.98 to 1.12) at the end of follow up. Similarly, based on eight trials (22,125 participants), there was no evidence that anticoagulants reduced the odds of being dead or dependent at the end of follow up (OR 0.99; 95% CI 0.93 to 1.04). Although anticoagulant therapy was associated with fewer recurrent ischaemic strokes (OR 0.76; 95% CI 0.65 to 0.88), it was also associated with an increase in symptomatic intracranial haemorrhages (OR 2.55; 95% CI 1.95 to 3.33). Similarly, anticoagulants reduced the frequency of pulmonary emboli (OR 0.60; 95% CI 0.44 to 0.81), but this benefit was offset by an increase in extracranial haemorrhages (OR 2.99; 95% CI 2.24 to 3.99). AUTHORS' CONCLUSIONS: Since the last version of the review, neither of the two new relevant studies have provided additional information to change the conclusions. In patients with acute ischaemic stroke, immediate anticoagulant therapy is not associated with net short or long-term benefit. Treatment with anticoagulants reduced recurrent stroke, deep vein thrombosis and pulmonary embolism, but increased bleeding risk. The data do not support the routine use of any the currently available anticoagulants in acute ischaemic stroke.

INTRODUCTION More than 600,000 people die of hepatocellular carcinoma (HCC) each year. Worldwide research on the disease needs to be intensified in both the medical and pharmaceutical fields, especially with a focus on providing help to areas where resources are limited. Treatment approaches depend on the stage of the disease at diagnosis and on access to complex treatment regimens. However, advanced disease is not curable, and management of advanced disease is expensive and only marginally effective in increasing quality-adjusted life years. The delivery of healthcare services for HCC can be improved by developing centers of excellence. Concentrating medical care in this way can lead to an increased level of expertise, so that resections are performed by surgeons who understand liver disease and the limitations of resection and other relevant procedures. Promising new agents are beyond the reach of those who would benefit most: in low-resource countries, sorafenib is out of the question for general use. For example, “snapshot” cost indications of monthly pharmacy prices for sorafenib are: $7300 in China, $5400 in the United States, $5000 in Brazil, €3562 in France, and $1400 in Korea (source: N Engl J Med. 2008;359:378–390; PMID 18650519). From a global perspective, therefore, the most urgent task is to prevent the occurrence of HCC. The only effective strategy is primary prevention of viral hepatitis, and in most countries this is already in place in the form of hepatitis B vaccination of newborns. Prevention of alcohol abuse and preventing the spread of hepatitis C virus (HCV) and metabolic syndrome are also relevant. Another important task is to prevent aflatoxin formation through proper care of crops and food storage. The next best approach is to increase awareness among the healthcare community to promote surveillance of patients who are at risk and achieve earlier diagnosis and resection or ablation of small lesions. Global Prevalence and Incidence HCC is the sixth most common malignancy worldwide. It is the fifth most common malignant disease in men and the eighth most common in women. It is the third most common cause of death from cancer, after lung and stomach cancer. HCC is the most common malignant disease in several regions of Africa and Asia. At least 300,000 of the 600,000 deaths worldwide occur in China alone, and the majority of the other 300,000 deaths occur in resource-challenged countries in sub-Saharan Africa. These devastating figures are most likely due to: Failure to recognize those at risk (with hepatitis B and/or C) High prevalence of risk factors in the population Lack of medical expertise and facilities for early diagnosis Lack of effective treatment after diagnosis Other important factors include poor compliance, with inadequate attendance or absent in surveillance programs and thus late presentation of patients with large tumors; low awareness of the benefits of HCC treatment and ways of preventing underlying liver disease; and a negative opinion among some physicians about screening. In Japan, the United States, Latin America, and Europe, hepatitis C is the major cause of HCC. The incidence of HCC is 2% to 8% per year in patients with chronic hepatitis C and established cirrhosis. In Japan, the mortality from HCC has more than tripled since the mid-1970s. HCV infection is responsible for 75% to 80% of cases and hepatitis B virus (HBV) for 10% to 15% of cases. HCV-related HCC has been linked to blood transfusions in the 1950s and 1960s, intravenous drug use, and the reuse of syringes and needles. In many (but not all) countries, the spread of HCV is declining, but due to migration the disease burden has not changed. In Asia, Africa, and in some eastern European countries, chronic hepatitis B is the prime cause of HCC, far outweighing the impact of chronic hepatitis C (Fig. 1). There are 300 million people infected with HBV, 120 million of whom are Chinese. In China and Africa, hepatitis B is the major cause of HCC; approximately 75% of the HCC patients have hepatitis B.FIGURE 1.: The worldwide geographic distribution of chronic hepatitis B virus infection (source: Centers for Disease Control, 2006).HCC Risk Factors HCC is associated with liver disease independently of the specific cause of the disease: Infectious: chronic hepatitis B or C. Nutritional and toxic: alcohol, obesity (nonalcoholic fatty liver disease), aflatoxin (cofactor with HBV), tobacco. Genetic: tyrosinosis, hemochromatosis (iron overload). However, iron overload as a cause per se and as a result of dietary intake (due to cooking in iron pots) is a subject of controversy. α1-antitrypsin deficiency. Immunologic: autoimmune chronic active hepatitis, primary biliary cirrhosis. The major risk factors for HCC are: Chronic HBV or HCV infection. Alcoholic cirrhosis. Nonalcoholic steatohepatitis. Diabetes (metabolic syndrome is the likely risk process). Cirrhosis by itself, of whatever cause. In Europe, North America, and Japan, HCC occurs mainly in patients with established cirrhosis. The risk of developing HCC in patients infected with HBV increases with: The viral load Male sex Older age The presence of cirrhosis Exposure to aflatoxins Location in sub-Saharan Africa, where patients develop HCC at a younger age The risk of developing HCC in patients infected with HCV and cirrhosis increases in combination with: Concurrent alcohol abuse Obesity/insulin resistance Previous or concurrent infection with HBV. Primary Care Physical findings: If the tumor is small: often without symptoms Physical signs may not be found at all Signs related to the chronic liver disease and/or underlying cirrhosis In more advanced cases: Palpable mass in the upper abdomen, or a hard, irregular liver surface Tenderness in the upper right abdominal quadrant Splenomegaly, ascites, jaundice (also symptoms of cirrhosis) Hepatic arterial bruit (heard over the tumor) Signs that should raise a suspicion of HCC in patients with previously compensated cirrhosis: Rapid deterioration of liver function New-onset (or refractory) ascites Acute intra-abdominal bleeding Increased jaundice Weight loss and fever New-onset encephalopathy Variceal bleeding Patients with late-stage HCC may present with: Right upper quadrant abdominal pain Symptoms and signs of underlying cirrhosis Weakness Abdominal swelling Nonspecific gastrointestinal symptoms Jaundice Loss of appetite Weight loss Anorexia Laboratory findings: Usually nonspecific Signs of cirrhosis: Thrombocytopenia Hypoalbuminemia Hyperbilirubinemia Coagulopathy Electrolyte disturbances Liver enzymes abnormal, but nonspecific Elevated α-fetoprotein (AFP; requires definitionsof levels and appropriate setting) Elevated alkaline phosphatase Follow-up to assess the patient after therapy—to be performed every 3 to 6 months: Physical examination Laboratory blood tests Computed tomography (CT), magnetic resonance imaging, and ultrasonography Referring to a specialist may help in: Confirming the diagnosis (and excluding possible alternatives—eg, liver diseases). Determining the extent of hepatic involvement and (remaining) liver function. Excluding extrahepatic disease. Choosing the best therapeutic option, including palliative care. If expert centers are within reach, it is generally recommended that HCC patients should be referred there, where care and options are optimally applied with all the expertise required from different areas of knowledge. Diagnosis Initial patient evaluation: Complete history Full physical examination Initial laboratory tests: Complete blood count Serum glucose Renal function and serum electrolytes AFP Albumin Prothrombin time Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin Hepatitis B surface antigen and anti-HCV (if not already known) Chest x-ray and/or CT scan Ascitic fluid cytology may also be considered, despite its low sensitivity—it is simple and practicable in Africa. Diagnostic Tests (Table 1) Sufficient to establish a diagnosis of HCC is a combined finding of: the classic appearance on one of the imaging modalities—that is, a large and/or multifocal hepatic mass with arterial hypervascularity; and elevated serum AFP, against a background of chronic (generally asymptomatic), generally cirrhotic-stage liver disease.TABLE 1: Tests Used to Diagnose Hepatocellular CarcinomaUltrasound Imaging, CT, or Magnetic Resonance Imaging Radiology and/or biopsy are the definitive diagnostic tools. Contrast-enhanced ultrasound may produce false-positive findings for HCC in patients with intrahepatic cholangiocarcinoma. AFP is an adjunctive diagnostic tool. A persistent AFP level of more than 400 ng/mL or a rapid increase in the AFP level may be a useful diagnostic criterion. In patients with lower AFP levels when radiology is not available, the diagnosis of HCC can only be made by clinical judgment. Even if options for treating HCC are absent or very limited, AFP testing and ultrasound imaging may be available. Cautionary Notes It is important to distinguish the use of AFP testing as a screening tool from its use as a diagnostic tool. Although it is considered to be a useful and feasible screening tool in China, others disagree. Its performance as a diagnostic tool is better. A positive AFP test (above 400 ng/mL, for example, can be considered diagnostic, but an AFP that is negative or below the predetermined cut-off point does not exclude HCC, as up to 40% of HCCs will never produce AFP. However, 90% of black African patients have raised AFP levels that are above the diagnostic level of 500 ng/mL in 70% of patients. However, this in turn may reflect the late presentation of these patients. In Western patients, AFP testing is less useful. Increased AFP and a mass are the diagnostic criteria of malignancy, but it is not possible to distinguish between HCC and cholangiocarcinoma. The incidence of cholangiocarcinoma is increasing, and cirrhosis is a risk factor. If the radiographic findings are conclusive, the diagnosis is certain; but if radiology is not conclusive, a biopsy is recommended to confirm the diagnosis. Cascades—A Resource-sensitive Approach A “cascade” is a hierarchical set of diagnostic, therapeutic, and management options for dealing with risk and disease, ranked by the resources locally available. A gold-standard approach is feasible in regions and countries where liver transplantation is available for the treatment of HCC. Elsewhere, resection and/or local ablation are available, but not liver transplantation. What is it still possible to do in the various settings in which transplantation or resection and/or local ablation are available? To answer this question, this guideline is structured on the basis of resource-sensitive cascades: for minimal-resource and medium-resource areas, the guideline discusses primary and secondary prevention, patient evaluation, and treatment options. For high-resource regions and countries, the guideline published by the American Association for the Study of Liver Diseases (AASLD) should be consulted. MINIMAL RESOURCES Minimal-resource regions are defined as those in which hardly any treatment options are available. The focus is on prevention and symptomatic treatment. At best, resection or local ablation may be available in some areas. Defining the criteria for referral to a specialist is a complex matter. As patients with advanced cases (and these are the majority of cases in resource-challenged countries) have no treatment options except supportive care, referral is generally futile. Only patients with early cases can benefit (imaging technology is required to identify early cases) and should be referred to specialists. All recommendations should focus on primary prevention and on the treatment of viral hepatitis and cirrhosis. Primary HCC Prevention Particularly when potentially curative treatment is unavailable, primary prevention is very important in reducing the risk of HCC (Table 2).TABLE 2: Options for Primary Prevention of Hepatocellular Carcinoma The vaccination prevention strategy against viral hepatitis (HBV) should be carried out worldwide; so far, it has been implemented in 152 countries. It is supported by nongovernmental organizations such as the Gates Foundation and the Global Alliance for Vaccines and Immunization. In Nigeria, vaccination costs less than a dollar; vaccines are also administered free for babies in public hospitals and immunization centers through the National Program on Immunization. Pakistan runs the World Health Organization's “Expanded Program of Immunization,” with free immunization for all newborns. Antiviral therapy should be recommended if needed: In many countries, the problem with antiviral therapy is management (drug resistance), compliance, and education. Costs may also be a problem, although several medications are reported to be relatively inexpensive. One year of lamivudine treatment costs $165 in Sudan; adefovir is inexpensive in India and China; and entecavir in China costs $5/d compared with $22/d in developed countries. Health education on viral hepatitis should emphasize the ways in which it is possible for the disease to spread in relation to local practices involving blood-blood contact, such as circumcision, scarification, tribal marks, and tattoos; in relation to the care of open sores and marks after multiple-use tooth extraction equipment; and in connection to the reuse of needles (or multiple-dose vials). Secondary HCC Prevention—Surveillance Screening should be encouraged in regions in which it is possible to offer curative treatment for HCC. There is little point in carrying out mass screening of a population if the resources for further investigation and treatment are lacking. Screening should only be undertaken if at least one of these management options is available: liver transplantation, resection, transarterial chemoembolization (TACE), or ablation techniques. Treatment with acetic acid (vinegar) is used in some places. One of the starting points for screening is to identify asymptomatic patients with HCC. If patients have cancer symptoms at diagnosis, the outcome is not good and treatment is not likely to be cost-effective. Treatment Options Appropriate treatment options that may or may not be beyond the scope of local medical facilities include: Partial liver resection Percutaneous ethanol injection (PEI) or radiofrequency ablation (RFA) TACE Traditional chemotherapy has no place in the management of HCC. Patients should be offered symptomatic treatment when it is needed and possible. MEDIUM RESOURCES Medium-resource regions are defined as those in which both resection and ablation are available for the treatment of HCC, but transplantation is not an option. In addition to primary HCC prevention (as discussed under “Minimal Resources” above), detailed recommendations can be provided on surveillance, diagnosis, and treatment. The delivery of healthcare services for HCC can be improved by developing centers of excellence—concentrating medical care can lead to an increased level of expertise, so that resections are performed by surgeons who understand liver disease and the limitations of each treatment modality. Secondary HCC Prevention—Surveillance When resection and/or local ablation are available for the treatment of HCC, there should be an emphasis on surveillance. Primary prevention—that is, hepatitis B vaccination of youngsters—is optimal in reducing the risk of HCC. Early diagnosis and treatment are essential for improving survival, but preventing recurrent HCC is still a major challenge. HCC surveillance may improve early detection of the disease. Generally, treatment options are broader when HCC is detected at an earlier stage. Finding early-stage disease is a prerequisite for improved prognosis. Screening should be encouraged in regions in which it is possible to offer curative treatment for HCC. The risk factors for HCC are well known, and this allows cost-effective surveillance. Screening for early detection of HCC is recommended for the groups of high-risk patients listed in Table 3.TABLE 3: Criteria for Hepatocellular Carcinoma ScreeningSurveillance involves establishing screening tests, screening intervals, diagnostic criteria, and recall procedures (Table 4).TABLE 4: Surveillance Techniques Depending on the clinical condition and the available resources, an ultrasound screening interval of 6 to 12 months is recommended. In advanced cases and in patients with cirrhosis, ultrasound screening should be performed every 4 to 6 months. Patient education is an essential prerequisite. Tertiary HCC Prevention—Recurrence Recurrent HCC may result from multicentric carcinogenesis or inadequate initial treatment. Prevention of HCC recurrence requires early diagnosis and complete removal of primary HCC lesions. Currently, there is no proof of the efficacy of tertiary prevention of HCC with any agent, including chemotherapy, HBV and HCV therapy, or interferon. There are no safe and effective chemotherapeutic agents available yet to prevent the recurrence of HCC. Molecular-targeted drugs seem to show promising clinical activity, but the median survival is not satisfactory and these agents are very costly. Anti-HBV oral nucleoside/nucleotide analogs are required for patients with ongoing active chronic hepatitis B with HCC as a complication and who are in Child-Pugh class A or B. Evaluation The management of HCC is changing. In the developed countries, HCC patients are increasingly being evaluated and managed at specialized centers by multidisciplinary teams consisting of hepatologists, oncologists, radiologists, surgeons, and pathologists. The Barcelona Clinic Liver Cancer (BCLC) staging system takes into account variables related to tumor stage, liver function, physical status, and cancer-related symptoms, and links these with treatment options and life expectancy. On the basis of the BCLC staging system, patients may be classified as having: Early HCC: single nodule or three nodules ≤3 cm. These patients may benefit from curative therapies. Intermediate HCC: multinodular. These patients may benefit from chemoembolization. Advanced HCC: multinodular with portal These patients may benefit from palliative new agents may be HCC: very poor life symptomatic treatment. a diagnosis of HCC has been liver function is one of the factors in the treatment performance and to be in liver function are: Child-Pugh Serum Prothrombin Hepatic encephalopathy hepatic A test result would confirm relevant portal which is important when resection is Treatment Options Treatment options depend on liver function, tumor and the presence or of or In most curative such as resection, or liver transplantation are not the options to Screening of is the only way of at a stage at which are of being of the treatment options are expensive and/or specialized and local ablation are the treatment options most likely to be used in patients with HCC surveillance in developing countries. resection and ablation can a in small Partial liver a curative approach for HCC. Only a of the patients for this option, due to advanced disease stage and/or liver function. can be due to tumor that the time or a is, a tumor in a liver that is to develop or These are safe and effective when resection is not an option, or when the patient is transplantation. is available, but requires at least and are effective for cm. is more effective than alcohol injection in cm. The of is more in all tumor is the of care for patients with good liver function and disease that is not to or but who have no extrahepatic no and no cancer Table a of benefits in HCC, and levels of developed by an expert American Association for the Study of Liver Diseases (AASLD) of and of in Hepatocellular Care Patients with Child-Pugh class C cirrhosis should be offered symptomatic treatment More such as and therapy, are available at specialized RESOURCES regions are defined as those in which liver transplantation is available for the treatment of HCC. For detailed of diagnostic and therapeutic options and of the of chemotherapy, the should be of hepatocellular

Recent data for the global burden of disease reflect major demographic and lifestyle changes, leading to a rise in non-communicable diseases. Most countries with high levels of tuberculosis face a large comorbidity burden from both non-communicable and communicable diseases. Traditional disease-specific approaches typically fail to recognise common features and potential synergies in integration of care, management, and control of non-communicable and communicable diseases. In resource-limited countries, the need to tackle a broader range of overlapping comorbid diseases is growing. Tuberculosis and HIV/AIDS persist as global emergencies. The lethal interaction between tuberculosis and HIV coinfection in adults, children, and pregnant women in sub-Saharan Africa exemplifies the need for well integrated approaches to disease management and control. Furthermore, links between diabetes mellitus, smoking, alcoholism, chronic lung diseases, cancer, immunosuppressive treatment, malnutrition, and tuberculosis are well recognised. Here, we focus on interactions, synergies, and challenges of integration of tuberculosis care with management strategies for non-communicable and communicable diseases without eroding the functionality of existing national programmes for tuberculosis. The need for sustained and increased funding for these initiatives is greater than ever and requires increased political and funder commitment.

BACKGROUND: The preferred timing of umbilical-cord clamping in preterm infants is unclear. METHODS: We randomly assigned fetuses from women who were expected to deliver before 30 weeks of gestation to either immediate clamping of the umbilical cord (≤10 seconds after delivery) or delayed clamping (≥60 seconds after delivery). The primary composite outcome was death or major morbidity (defined as severe brain injury on postnatal ultrasonography, severe retinopathy of prematurity, necrotizing enterocolitis, or late-onset sepsis) by 36 weeks of postmenstrual age. Analyses were performed on an intention-to-treat basis, accounting for multiple births. RESULTS: Of 1634 fetuses that underwent randomization, 1566 were born alive before 30 weeks of gestation; of these, 782 were assigned to immediate cord clamping and 784 to delayed cord clamping. The median time between delivery and cord clamping was 5 seconds and 60 seconds in the respective groups. Complete data on the primary outcome were available for 1497 infants (95.6%). There was no significant difference in the incidence of the primary outcome between infants assigned to delayed clamping (37.0%) and those assigned to immediate clamping (37.2%) (relative risk, 1.00; 95% confidence interval, 0.88 to 1.13; P=0.96). The mortality was 6.4% in the delayed-clamping group and 9.0% in the immediate-clamping group (P=0.03 in unadjusted analyses; P=0.39 after post hoc adjustment for multiple secondary outcomes). There were no significant differences between the two groups in the incidences of chronic lung disease or other major morbidities. CONCLUSIONS: Among preterm infants, delayed cord clamping did not result in a lower incidence of the combined outcome of death or major morbidity at 36 weeks of gestation than immediate cord clamping. (Funded by the Australian National Health and Medical Research Council [NHMRC] and the NHMRC Clinical Trials Centre; APTS Australian and New Zealand Clinical Trials Registry number, ACTRN12610000633088 .).

Penetrating brain injury (PBI), though less prevalent than closed head trauma, carries a worse prognosis. The publication of Guidelines for the Management of Penetrating Brain Injury in 2001, attempted to standardize the management of PBI. This paper provides a precise and updated account of the medical and surgical management of these unique injuries which still present a significant challenge to practicing neurosurgeons worldwide. The management algorithms presented in this document are based on Guidelines for the Management of Penetrating Brain Injury and the recommendations are from literature published after 2001. Optimum management of PBI requires adequate comprehension of mechanism and pathophysiology of injury. Based on current evidence, we recommend computed tomography scanning as the neuroradiologic modality of choice for PBI patients. Cerebral angiography is recommended in patients with PBI, where there is a high suspicion of vascular injury. It is still debatable whether craniectomy or craniotomy is the best approach in PBI patients. The recent trend is toward a less aggressive debridement of deep-seated bone and missile fragments and a more aggressive antibiotic prophylaxis in an effort to improve outcomes. Cerebrospinal fluid (CSF) leaks are common in PBI patients and surgical correction is recommended for those which do not close spontaneously or are refractory to CSF diversion through a ventricular or lumbar drain. The risk of post-traumatic epilepsy after PBI is high, and therefore, the use of prophylactic anticonvulsants is recommended. Advanced age, suicide attempts, associated coagulopathy, Glasgow coma scale score of 3 with bilaterally fixed and dilated pupils, and high initial intracranial pressure have been correlated with worse outcomes in PBI patients.

Healthcare workers involved in aerosol-generating procedures, such as tracheal intubation, may be at elevated risk of acquiring COVID-19. However, the magnitude of this risk is unknown. We conducted a prospective international multicentre cohort study recruiting healthcare workers participating in tracheal intubation of patients with suspected or confirmed COVID-19. Information on tracheal intubation episodes, personal protective equipment use and subsequent provider health status was collected via self-reporting. The primary endpoint was the incidence of laboratory-confirmed COVID-19 diagnosis or new symptoms requiring self-isolation or hospitalisation after a tracheal intubation episode. Cox regression analysis examined associations between the primary endpoint and healthcare worker characteristics, procedure-related factors and personal protective equipment use. Between 23 March and 2 June 2020, 1718 healthcare workers from 503 hospitals in 17 countries reported 5148 tracheal intubation episodes. The overall incidence of the primary endpoint was 10.7% over a median (IQR [range]) follow-up of 32 (18-48 [0-116]) days. The cumulative incidence within 7, 14 and 21 days of the first tracheal intubation episode was 3.6%, 6.1% and 8.5%, respectively. The risk of the primary endpoint varied by country and was higher in women, but was not associated with other factors. Around 1 in 10 healthcare workers involved in tracheal intubation of patients with suspected or confirmed COVID-19 subsequently reported a COVID-19 outcome. This has human resource implications for institutional capacity to deliver essential healthcare services, and wider societal implications for COVID-19 transmission.

BACKGROUND: The role of Artificial intelligence (AI) which is defined as the ability of computers to perform tasks that normally require human intelligence is constantly expanding. Medicine was slow to embrace AI. However, the role of AI in medicine is rapidly expanding and promises to revolutionize patient care in the coming years. In addition, it has the ability to democratize high level medical care and make it accessible to all parts of the world. MAIN TEXT: Among specialties of medicine, some like radiology were relatively quick to adopt AI whereas others especially pathology (and surgical pathology in particular) are only just beginning to utilize AI. AI promises to play a major role in accurate diagnosis, prognosis and treatment of cancers. In this paper, the general principles of AI are defined first followed by a detailed discussion of its current role in medicine. In the second half of this comprehensive review, the current and future role of AI in surgical pathology is discussed in detail including an account of the practical difficulties involved and the fear of pathologists of being replaced by computer algorithms. A number of recent studies which demonstrate the usefulness of AI in the practice of surgical pathology are highlighted. CONCLUSION: AI has the potential to transform the practice of surgical pathology by ensuring rapid and accurate results and enabling pathologists to focus on higher level diagnostic and consultative tasks such as integrating molecular, morphologic and clinical information to make accurate diagnosis in difficult cases, determine prognosis objectively and in this way contribute to personalized care.

OBJECTIVES: To assess the compliance of Asian intensive care units and hospitals to the Surviving Sepsis Campaign's resuscitation and management bundles. Secondary objectives were to evaluate the impact of compliance on mortality and the organisational characteristics of hospitals that were associated with higher compliance. DESIGN: Prospective cohort study. SETTING: 150 intensive care units in 16 Asian countries. PARTICIPANTS: 1285 adult patients with severe sepsis admitted to these intensive care units in July 2009. The organisational characteristics of participating centres, the patients' baseline characteristics, the achievement of targets within the resuscitation and management bundles, and outcome data were recorded. MAIN OUTCOME MEASURE: Compliance with the Surviving Sepsis Campaign's resuscitation (six hours) and management (24 hours) bundles. RESULTS: Hospital mortality was 44.5% (572/1285). Compliance rates for the resuscitation and management bundles were 7.6% (98/1285) and 3.5% (45/1285), respectively. On logistic regression analysis, compliance with the following bundle targets independently predicted decreased mortality: blood cultures (achieved in 803/1285; 62.5%, 95% confidence interval 59.8% to 65.1%), broad spectrum antibiotics (achieved in 821/1285; 63.9%, 61.3% to 66.5%), and central venous pressure (achieved in 345/870; 39.7%, 36.4% to 42.9%). High income countries, university hospitals, intensive care units with an accredited fellowship programme, and surgical intensive care units were more likely to be compliant with the resuscitation bundle. CONCLUSIONS: While mortality from severe sepsis is high, compliance with resuscitation and management bundles is generally poor in much of Asia. As the centres included in this study might not be fully representative, achievement rates reported might overestimate the true degree of compliance with recommended care and should be interpreted with caution. Achievement of targets for blood cultures, antibiotics, and central venous pressure was independently associated with improved survival.

Abstract AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca 2+ -impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.

Currently Covid-19 pandemic is a leading challenge across the globe. It is mandatory to attain and maintain good nutritional status to fight against virus. Nutritional status of individual is affected by several factors such as age, sex, health status, life style and medications. Nutritional status of individuals has been used as resilience towards destabilization during this COVID-19 pandemic. Optimal nutrition and dietary nutrient intake impact the immune system, therefore the only sustainable way to survive in current context is to strengthen the immune system. There is no evidence found that supplement can cure the immune system except Vit C, which is one of the best way to improve immune system. A proper diet can ensure that the body is in proper state to defeat the virus. However along with the dietary management guidelines the food safety management and good food practices is compulsory. This article explores the importance of nutrition to boost immunity and gives some professional and authentic dietary guidelines about nutrition and food safety to withstand COVID-19. doi: https://doi.org/10.12669/pjms.36.COVID19-S4.2776 How to cite this:Aman F, Masood S. How Nutrition can help to fight against COVID-19 Pandemic. Pak J Med Sci. 2020;36(COVID19-S4):COVID19-S121-S123. doi: https://doi.org/10.12669/pjms.36.COVID19-S4.2776 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.