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Proposed short titleY90-Resin Microspheres Radioembolization Followed by Nivolumab in Advanced Hepatocellular CarcinomaBackground : Nivolumab (N) and Y90-resin microspheres radioembolization (Y90-RE) aretherapeutic options in advanced hepatocellular carcinoma (aHCC). Emerging evidence suggests synergy between radiotherapy and immune checkpoint inhibitors. Methods : Eligible Child-Pugh A aHCC patients were treated with Y90-RE followed by N 240mg, 21 days after Y90-RE and every 2 weeks thereafter. Pre- and on-treatment tumor biopsies were obtained. Primary end-point was overall response rate (ORR) (RECIST v1·1), defined as the composite overall response observed for lesions both within and outside Y90-RE field. Secondary end points included progression free survival (PFS), overall survival (OS), and safety. This study is registered with ClinicalTrials.gov, NCT03033446 .Findings : Forty patients were enrolled, 36 received Y90-RE followed by N. At baseline: 61·1% had hepatitis B; 66·7% BCLC stage C; 50·0% had AFP > 400ng/mL; median number of liver lesions was 5 (range 1- >20); median size of largest liver lesion was 78·5 mm (range 14-177mm); 38·9% had prior TACE/RFA/MWA; and 12·5% had prior systemic therapy. ORR was 30·6% (16·4% to 48·1%). ORR was 43·5% in patients with no extra-hepatic spread (EHS) (n=23). 81% of target lesions within Y90-RE field regressed. Median PFS and OS were 5·6 months (95% CI 2·1 to 8·8 months) and 16.9 months (95% CI 8·1 to 27·6 months). Treatment was well tolerated with only 13·8% experiencing grade (G) 3/4 treatment related adverse events (TRAEs). Immune activation predicted response to Y90-RE followed by N. Interpretation : Y90-RE followed by N resulted in an encouraging ORR of 30·6% in aHCC and of 43·5% in subjects with no EHS. 81% of target lesions within Y90-RE field regressed suggesting synergy. Importantly, this combination is safe and tolerable with low G 3/4 TRAEs of 13·8%. Trial Registration: NCT number: NCT03033446 Funding: Funding for this study was acquired from National Medical Research Council Singapore (NMRC/CIRG/1454/2016), Bristol-Myers Squibb (BMS), and SIRTEX Declaration of Interest: David Tai All support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.): BMS, SIRTEX, NMRC Singapore (CIRG/1470/2017) Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: IPSEN, Eisai, BMS Consulting fees: Novartis, BMS, MSD Choo Su Pin Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Roche, BMS, Ipsen, Lilly, AZ, Roche. Consulting fees: BMS, Roche, Ipsen, Servier, Eisai, AstraZeneca. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: MOH Medishield Life Cancer Drug committee Stock or stock options: BMS David Ng All support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.): SIRTEX Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: SIRTEX Joycelyn Lee Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS, IPSEN, Bayer Research Funding: Bayer Pierce K.H. Chow Grants or contracts from any entity: Sirtex Medical, Ipsen, IQVIA, New B Innovation, Perspectum, AMiLi, MiRXES, Genentech, Engine Biosciences. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Sirtex Medical, Ipsen, Oncosil, Bayer, Roche, New B Innovation, MSD, BTG PLC, Eisai, Abbott, AZ, IQVIA, Genentech, Worrell Guerbet, LEK Consulting, COR2ED. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: AVATAMED Stock or stock options: AVATAMED Too Chow Wei Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: SIRTEX Consulting fees: SIRTEX Ethical Approval: All patients provided written informed consent and the institutional review board committee approved the protocol (Singhealth IRB Ref No. 2016/2613). The study was done in accordance with the Declaration of Helsinki and Good Clinical Practice.

Background: Mobility is defined as the ability to independently move around the environment and is a key contributor to quality of life. The aim of this study was to evaluate the use of mobility as a decisive outcome for the marketing authorisation of drugs by the European Medicines Agency (EMA). Methods: Fifteen therapeutic areas which commonly lead to mobility impairments and alter the quantity and/or the quality of walking were selected: two systemic neurological diseases, four conditions primarily affecting exercise capacity, seven musculoskeletal diseases, and two conditions representing sensory impairments. European Public Assessment Reports (EPARs) published by the EMA up to September 2020 were examined for mobility endpoints included in their ‘main studies’, defined as those which were decisive for EU approval. Clinical study registries and primary scientific publications for these studies were also reviewed. Findings: 484 EPARs yielded 186 relevant documents with 402 ‘main studies’. The EPARs reported 153 primary and 584 secondary endpoints which considered mobility; 70 different assessment tools (38 patient-reported outcomes, 13 clinician-reported outcomes, 8 performance outcomes, and 13 composite endpoints) were used. Importantly, only 15·7% of those tools distinctly informed on patients’ mobility status. 105/402 (26·1%) of the ‘main studies’ did not have any mobility assessment and none of these studies included a digital mobility outcome. The supplementary review of study registries and primary publications revealed only five uses of mobility assessments not reported by EPARs. Interpretation: For conditions with a high impact on mobility, distinct mobility assessment was given little consideration in the marketing authorisation of drugs by the EMA. Where mobility impairment was considered to be a relevant outcome, questionnaires or composite scores were predominantly used. Reporting biases for such outcomes presents challenges for the interpretation of study results. Funding: Mobilise-D (Innovative Medicines Initiative) and Robert Bosch Stiftung, Germany. Declaration of Interest: SJ is partly supported by the Robert Bosch Stiftung Stuttgart. MW reports grants from HORIZON2020 IMI No. 820820, during the conduct of the study. DS reports grants from HORIZON2020 IMI No. 820820, during the conduct of the study. MC reports personal fees from Takeda Pharmaceuticals, during the conduct of the study; personal fees from Takeda Pharmaceuticals, outside the submitted work. JK reports grants from HORIZON2020 IMI No. 820820, during the conduct of the study. JGA reports grants from HORIZON2020 IMI No. 820820, and from AstraZeneca, Chiesi, Esteve, outside the submitted work. WM receives or received funding from the European Union, the German Federal Ministry of Education of Research, Michael J. Fox Foundation, Robert Bosch Foundation, Neuroalliance, Lundbeck and Janssen. He received speaker honoraria from Abbvie, Bayer, GlaxoSmithKline, Licher MT, Rolke Pharma and UCB, was invited to Advisory Boards of Abbvie, Biogen, Lundbeck and Market Access & Pricing Strategy GmbH, and is an advisory board member of the Critical Path for Parkinson's Consortium. He serves as the co-chair of the MDS Technology Task Force. MP reports grants from HORIZON2020 IMI No. 820820, outside the submitted work. MS is supported by the Robert Bosch Stiftung Stuttgart and reports grants from HORIZON2020 IMI 2 Mobilise D, during the conduct of the study, and grants and non-financial support from Green Cross WellBeing Co. Ltd., Gilead Sciences Inc., Robert Bosch GmbH, and CORAT Therapeutics GmbH , as well as other from Agena Bioscience GmbH, outside the submitted work. CB disclosed consultation from E. Lilly and speaker fees from Amgen, Nutricia and Pfizer reports grants from HORIZON2020 IMI No. 820820, during the conduct of the study. RT, BS, LL, LR, SCR declare no competing interests.

Background: We explored parents’ experiences of using a hybrid closed-loop system when caring for a very young child with type 1 diabetes. Our objectives were to understand the impact of using this technology on users’ quality of life and inform its use in routine clinical care. Methods: Interviews were conducted with parents of 30 children (aged 1-7 years) who participated in a randomised controlled trial comparing closed-loop insulin delivery with sensor-augmented pump therapy. Findings: Parents reported major clinical benefits to using the closed-loop system, including more time being spent in range. Parents welcomed opportunities to collaborate with the system (using Ease-off and Boost functions) when their own knowledge could enhance its efficacy. Parents also reported a lessened need for health professional input after the initial transition onto the system had been made. Parents described wide-ranging quality-of-life benefits to using a system that automatically regulated blood glucose. Parents reported sleeping better, worrying less about their child and feeling more confident entrusting their child’s care to others, and how these individuals were more willing to assume caregiving responsibilities. Parents also described how their child felt more normal and experienced better sleep, mood and concentration, and lessened distress. Siblings also benefitted from parents’ time and attention being less focused on diabetes management. While parents highlighted multiple benefits to being able to administer insulin using a smartphone, difficulties were experienced stowing this device on the child’s body. Interpretation: Using a hybrid closed-loop system in very young children can have potentially life-changing consequences and may result in a lessened demand for health professionals’ input. Systems may need to be customised for use in very young children. Funding Information: The European Commission within the Horizon 2020 Framework Programme under the grant agreement number 731560 funded this work. Declaration of Interests: RH reports having received speaker honoraria from Eli Lilly and Novo Nordisk, serving on advisory panels for Eli Lilly and Novo Nordisk, receiving licence fees from BBraun and Medtronic. RH reports patent patents, patent applications, shareholding and directorship at CamDiab. FC has attended Advisory Boards and obtained speaking fees for Abbott, Medtronic, Lilly, and NovoNordisk. EFR reports having received speaker honoraria from Eli Lilly and Novo Nordisk, and serving on advisory boards for Eli Lilly and Sanofi. SH declares having received speakers honoraria from Eli Lilly, Sanofi and Pfizer. TMK has received speaking honoraria from Eli Lilly and MerckSerono, and consulted Sanofi for a transition brochure. BRM has received speaker honoraria from Abbott Diabetes Care, Eli Lilly, Medtronic, Novo Nordisk, Roche Diabetes Care, Sanofi and Menarini, and has been on the advisory boards of Roche Diabetes Care and Abbott Diabetes Care. The Authors JL, DR, RIH, CKB, JF, JMA, AT, US and BK declare that there is no conflict of interest. Ethics Approval Statement: Participants were consented into the interview study when they were consented into the trial. Approval was received from relevant Ethics Committees in participating sites/countries and relevant national regulatory authorities.

Background: Coronavirus disease 2019 (COVID-19) associated pulmonary aspergillosis (CAPA) has emerged as a complication in critically ill COVID-19 patients. To determine the prevalence of CAPA in patients with COVID-19 in intensive care units (ICU) and to investigate risk factors for CAPA as well as outcome. Methods: The European Confederation of Medical Mycology (ECMM) conducted a multinational study including 20 centers from nine different countries to assess epidemiology, risk factors, treatment and outcome of CAPA. CAPA was defined according to ECMM/ISHAM consensus definitions. Findings: A total of 592 patients were included in this study, including 11 (1.9%) patients with histologically proven CAPA, 80 (13.5%) patients with probable CAPA, 18 (3%) with possible CAPA and 483 (81.6%) without CAPA. CAPA was diagnosed a median of 8 days (range 0-31) after ICU admission predominantly in older patients [adjusted hazard ratio (aHR) 1.04 per year] with any form of invasive respiratory support (HR 3.4) and receiving tocilizumab (HR 2.45). Median prevalence of CAPA per center was 10.7% (range 1.7% - 26.8%). CAPA was associated with significantly lower 90-day ICU survival rate (29% in patients with CAPA versus 57% in patients without CAPA; Mantel-Byar p

Coronavirus disease 2019 (COVID-19)–associated mucormycosis (CAM) has recently been increasingly reported, particularly among patients with uncontrolled diabetes. Patients with diabetes and hyperglycemia often display an inflammatory state that may be potentiated by the activation of antiviral immunity to SARS-CoV-2, and thus may favor secondary infections. We analyze 80 published and unpublished cases of CAM, with a predominance (42/80) of cases from India. Uncontrolled diabetes mellitus as well as systemic corticosteroid treatment represented major comorbid predisposing factors and rhino-orbital cerebral mucormycosis was the most frequent presentation of disease. Mortality was high at 49%, driven particularly by those with pulmonary or disseminated mucormycosis and those with cerebral involvement. Furthermore, a significant proportion of surviving patients suffered life-changing morbidities (loss of vision in 46% of survivors). Our review indicates that CAM may be a relevant complication of severe COVID-19, particularly in those with uncontrolled diabetes. Funding: Martin Hoenigl received funding from Astellas for two investigator initiated studies (ISR005824 and ISR005838), and was supported by the National Institutes of Health, Grant UL1TR001442. Agostinho Carvalho was supported by the Fundacao para a Ciencia e a Tecnologia (FCT) (UIDB/50026/2020 and UIDP/50026/2020), the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) (NORTE-01-0145-FEDER-000039), the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 847507, and the “la Caixa” Foundation (ID 100010434) and FCT under the agreement LCF/PR/HR17/52190003. Declaration of Interest: MH received research funding from Gilead, Pfizer, Astellas, Scynexis and NIH. JPG received speaker and expert advice fees from Pfizer and Gilead. NK has received research grants or honoraria as a speaker or advisor from Astellas, Gilead, MSD, and Pfizer, outside the submitted work. KL received consultancy fees from SMB Laboratoires Brussels, MSD and Gilead, travel support from Pfizer, speaker fees from FUJIFILM WAKO, Pfizer and Gilead, a service fee from Thermo fisher Scientific. OAC is supported by the German Federal Ministry of Research and Education, is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy – CECAD, EXC 2030 – 390661388 and has received research grants from, is an advisor to, or received lecture honoraria from Actelion, Allecra Therapeutics, Al-Jazeera Pharmaceuticals, Amplyx, Astellas, Basilea, Biosys, Cidara, Da Volterra, Entasis, F2G, Gilead, Grupo Biotoscana, Immunic, IQVIA, Janssen, Matinas, Medicines Company, MedPace, Melinta Therapeutics, Menarini, Merck/MSD, Mylan, Nabriva, Noxxon, Octapharma, Paratek, Pfizer, PSI, Roche Diagnostics, Scynexis, and Shionogi. PLW performed diagnostic evaluations and received meeting sponsorship from Bruker, Dynamiker, and Launch Diagnostics; Speakers fees, expert advice fees and meeting sponsorship from Gilead; and speaker and expert advice fees 489 from F2G and speaker fees MSD and Pfizer. Is a founding member of the European Aspergillus PCR Initiative. ACh received funding support from educational grant of Pfizer, MSD Pharmaceutical Ltd, and Gilead. All other authors no conflicts. Ethical Approval: MISSING

Background: Prolonged symptoms after SARS-CoV-2 infection are well-documented. However, which factors influence development of long-term symptoms, how symptoms vary across ethnic groups, and whether long-term symptoms correlate with serologic biomarkers remain elusive. Methods: Adult inpatient and outpatient SARS-CoV-2 RT-PCR positive patients were recruited at Stanford from March 2020 to February 2021. Study participants were seen for in-person visits at diagnosis and every 1-3 months for up to one year after diagnosis; they completed symptom surveys and underwent sampling procedures (blood draw and nasal swab) at each visit. Findings: Our cohort (n=617) ranged from asymptomatic to critical COVID-19 infections. 40% of participants reported at least one symptom associated with COVID-19 six months after diagnosis. Median time from diagnosis to first resolution of all symptoms was 44 days, median time from diagnosis to sustained symptom resolution with no recurring symptoms for one month or longer was 214 days. Serum anti-nucleocapsid IgG level in the first week of infection was predictive of time to symptom resolution. A prior diagnosis of lung disease was associated with longer time to symptom resolution. COVID-19 disease severity, ethnicity, sex, cytomegalovirus (CMV) seropositivity, and remdesivir use did not affect time to sustained symptom resolution. More than 90% of participants had SARS-CoV-2-specific antibody>1000 AU/mL nine months after diagnosis. Interpretation: Our findings showed that all disease severities had a similar risk of developing post-COVID-19 syndrome in an ethnically diverse population. Comorbid lung disease and lower levels of initial IgG response to SARS-CoV-2 nucleocapsid antigen were associated with longer symptom duration. Trial Registration: National clinical trial database NCT04664309. Funding: NIH CTSA grant, U54 NIH Grant, R21 NIEHS, Sean N Parker Center for Allergy and Asthma Research at Stanford University, the Sunshine Foundation, the Crown Foundation, and the Parker Foundation. Declaration of Interest: Dr. Boyd received support for the current manuscript from Meso Scale Discovery and NIH; 418 received consulting fees by Regeneron for expert testimony, has stocks or stock options in 419 AbCellera Biologics; Dr. Chinthrajah reports grants from NIAID, CoFAR, Aimmune, DBV 420 Technologies, Astellas, Regeneron, Stanford Maternal and Child Health Research Institute 421 (MCHRI), and FARE. She is an Advisory Board Member at Alladapt Therapeutics, Novartis, 422 Genentech, Sanofi, Allergenis, and Nutricia; Dr. Manisha Desai received support from Chan 423 Zuckerberg Foundation; Dr. Maecker received grants or contracts from NIH, Bill & Melinda 424 Gates Foundation, Ionis Corporation, Amgen Corporation; Consulting fees from Magarray Corp; 425 payment or honoraria from UCLA, UC Davis; leadership or fiduciary role at Cytek SAB; stocks 426 or stock options at BD Biosciences; Dr. Nadeau reports grants from National Institute of Allergy and Infectious Diseases (NIAID), National Heart, Lung, and Blood Institute (NHLBI), National Institute of Environmental Health Sciences (NIEHS), and Food Allergy Research & Education (FARE); Director of World Allergy Organization (WAO) , Advisor at Cour Pharma, Consultant for Excellergy, Red tree ventures, and Phylaxis, Co-founder of Before Brands, Alladapt, Latitude, and IgGenix; and National Scientific Committee member at Immune Tolerance Network (ITN), and National Institutes of Health (NIH) clinical research centers, outside the submitted work; patents include, “Mixed allergen composition and methods for using the same”, “Granulocyte-based methods for detecting and monitoring immune system disorders”, “Methods and Assays for Detecting and Quantifying Pure Subpopulations of White Blood Cells in Immune System Disorders,” and “Methods of isolating allergen-specific antibodies from humans and uses thereof”; Dr. Benjamin Pinsky received grants or contracts for the present manuscript from MesoScale Diagnostics; Dr. Angele Rogers was a Clinical Trials Advisory Board Member for Merck; Dr. Sindher reports support for the present manuscript from the NIH, Regeneron, DBV Technologies, Aimmune, Novartis, CoFAR, FARE, participated on a DSMB for Astra Zeneca, DBV, and received payment or honorarium from FARE; Neera Ahuja, Maja Artandi, Linda Barman, Catherine Blish, Andra Blomkalns, William Collins, MacKenzie Cox, Linda Geng, Xiaolin Jia, Megan Mahoney, Monali Manohar, Ruth O’hara, Rajan Puri, Katharina Roltgen, Laura Vaughan, Samuel Yang, Shu Cao, Iris Chang, Hena Din, Evan Do, Andrea Fernandez, Alexandra Lee, Natasha Purington, Yael Rosenberg-Hasson, Theo Snow, Daniel Solis, Michelle Verghese, and Yingjie Weng have no conflict of interest. Ethical Approval: This study was reviewed and approved by the Stanford Administrative Panel on Human Subjects in Medical Research.

Background: There are limited data on the frequency of myelin oligodendrocyte glycoprotein (MOG)-IgG and aquaporin-4 (AQP4)-IgG among pediatric-onset MS (POMS) patients and healthy controls. Using a prospective cohort of POMS patients and healthy controls, we aimed to determine the frequency of MOG-IgG and AQP4-IgG in both groups, compare clinical characteristics and outcomes in seronegative vs seropositive children, and identify predictors of final diagnosis. Methods: POMS patients and controls were enrolled at 14 US sites through a case-control study on POMS risk factors. Follow-up data were prospectively collected. Serum AQP4-IgG and MOG-IgG were assessed using live cell-based assays. Medical records were re-reviewed in seropositive cases to confirm final diagnosis. Findings: We included 1196 participants, 493 POMS and 703 controls. AQP4-IgG was negative in all participants. MOG-IgG was positive in 30/493 cases (6%) and 0/703 (0%) controls. Twenty-five of 30 MOG-IgG positives (83%) were determined to have MOG-IgG-associated disease (MOGAD) while 5/30 (17%) maintained a diagnosis of MS. The MOG-IgG false-positive rate was 1%. MOGAD cases, compared with MS, were more commonly female (84% vs 64%; p=0.044), presented at younger age (mean 8∙2±4∙2 vs 14∙7±2∙6 years; p

Background: Automated insulin delivery (AID) systems have been shown to be safe and effective in reducing hyper- and hypoglycaemia, but are not universally available, accessible, and affordable. Therefore, user-driven open-source AID systems are becoming increasingly popular. Methods: This study investigated motivations why people with diabetes or their caregivers decide to build and use a personalised open-source AID. A cross-sectional online survey was conducted to assess personal motivations and associated self-reported clinical outcomes. Findings: Of 897 participants from 35 countries, 80·4% were adults with diabetes and 19·6% were caregivers of children with diabetes. Primary motivations to commence open-source AID included: improving glycaemic outcomes (94% of adults, 95% of caregivers), reducing acute (87%/96%) and long-term (83%/91%) complication risk, interacting less frequently with diabetes technology (81%/76%), improving their/child’s sleep quality (72%/80%), increasing their/child’s life expectancy (72%/85%), lack of commercially available AID systems (71%/70%), and unachieved therapy goals with available therapy options (68%/69%). Improving their own sleep quality was an almost universal motivator for caregivers (94%). Significant improvements, independent of age and gender, were observed in self-reported HbA1C, 7·14±1·13% (54·5±12·4 mmol/mol) to 6·24±0·64% (44·7±7·0 mmol/mol; p

Integrated Child Development Service (ICDS) scheme is the most important nutritional programme in the field of child welfare. Its effectiveness depends upon the efficiency of its functionaries at grass root level i.e., Anganwadi workers (AWW). AWW assumes a pivotal role due to her close and continuous contact with the beneficiaries children grow and develop amazingly. AWWs play the most dominant role in providing basic education, nutrition and ensuring health in rural and urban areas. AWWs was not able to work as per the activities specified in the recommended time as records maintenance consumed a lot of time i.e. three times more than the recommended time. Low honorarium, register work, meeting out of duty hours, short attendance of children and adolescent girls, not adequate space in Anganwadi centre (AWC), no government building for AWC were some of the problems reported by AWW. AWWs were unable to render services as per the recommended time because considerable time was spent in maintaining records and other activities. The study analyzes the trends and problems faced by AWWs of Warangal Rural District of Telangana State and suggests overcoming their problems. It is quite regrettable and sad to note that despite their social commitment and diligence they are very poorly paid and treated worse than the class fourth employers. That is an urgent need that the Telangana Government should look in the matter with all sympathy and concern.

Background: Immunosuppressive and immunomodulatory therapies are a major issue during the current coronavirus disease 2019 (Covid-19) pandemic, and in anticipation of possible next waves. Methods: In a nationwide study we retrospectively collected data of persons with Multiple Sclerosis (PwMS) with suspected or confirmed Covid-19. We assessed the association of therapies for MS with Covid-19 by comparing their observed frequency with the one expected in non-pandemic conditions (expressing the association by Odds Ratios [OR]). We evaluated baseline characteristics and MS therapies associated to a severe Covid-19 course by multivariate logistic models. Findings: Of 784 PwMS with suspected (n=593) or confirmed (n=191) Covid-19 and a median follow-up of 84 days (range=30-135), 13 (1·66%) died: 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-three (4·2%) were admitted to an Intensive Care Unit; 90 (11·5%) had a radiologically documented pneumonia; 88 (11·2%) were hospitalized. We found an excess of patients treated with Ocrelizumab (OR=1·84,95%CI=1·31-2·56, p

Background: Since March 6, 2020, the FDA has continued to monitor, inspect and enforce the promotion of products by companies that claim to mitigate, prevent, treat, diagnose; or cure COVID-19. Herein, we provide a descriptive review of the violative companies and their products in question. Methods: We examined the warning and notice of violation letters to companies posted on the FDA webpage over a 6-month period from March 6-August 31. Of all letters, we identified the product in violation, the venue of promotion, violation type, and country of the violating firm. Findings: A total of 93 letters were reported. Across all letters, USA-based companies had the leading number of warning and violation letters. The most common product category was CBD-containing products, followed by essential oils, and approved drug products for off-label use. While all letters reported the promotion of unapproved product(s) (93/93; 100%), the majority of letters reported misbranding (90/93; 97%), and/or had claims that lacked scientific substantiation (83/93; 89%). Finally, all promotional violations were linked to websites, along with other mainstream venue(s): Facebook, Instagram, YouTube, Twitter, LinkedIn, and/or email. Interpretation: Despite the desperate need of COVID-19 treatments, it remains mandatory for the promotion of products by companies to comply to standard regulatory requirements. As the pandemic persists, the FDA must continue their efforts to monitor, inspect, and enforce violative companies. Improving awareness among the public, healthcare providers, and stakeholders could increase the value of the drug approval process and protect patients and consumers from risks posed by these products. Funding Statement: No funding was received for this study. Declaration of Interests: We declare we have no conflicts of interest. Dr. Witek declares being a member of the Board of Directors of Trudell Medical International and Molecular Sciences Corporation. Dr. Nowak declares receiving consulting fees from TELUS Corporation, Akira by TELUS Health, and the Dalla Lana School of Public Health. Honoraria from the Ontario Medical Association, Ontario College of Family Physicians, Centre for Effective Practice, Canada Health Infoway, University of Toronto, and McMaster University.

Hospital and health care administrators have often named prescription drug costs as one of their largest cost problems. Relatedly, a significant body of research demonstrates that meals and honoraria from pharmaceutical firms to physicians leads to higher prescribing of expensive, brand name drugs. Some administrators and scholars have advocated for mandatory disclosure of these payments in order to reduce this conflict of interest, but many practitioners believe disclosure has little effect on prescribing. This paper uses a quasi-experiment of a 2009 payment disclosure policy in Massachusetts to estimate the causal impact of public disclosure on prescribing. The comprehensive dataset includes all retail prescriptions for 262 drugs in 9 drug classes written by 5730 physicians in five states over 48 months. We show a significant post-disclosure reduction in brand name drug prescriptions by Massachusetts physicians, relative to control doctors in other states. These effects are driven by heavy prescribers of brand name drugs in the pre-policy period, particularly for drugs with large pre-policy sales forces. Effects are also detected before the first data were released, implying that the effects are not because patients or administrators responded to the disclosed payments. Instead, some physicians may have reduced payments after disclosure is mandated, leading to changes in their prescriptions. Taken in tandem with the many studies showing that industry payments influence prescribing, this study suggests a strong role for mandatory public disclosure in reducing conflicts of interest in medicine and costly prescribing of brand name drugs.

The study is envisaged as a tool as it permits perspective building on the purview of legal aid provision as well as suggest directions for a change. It has aided to understand the current structure and necessary changes and roles that are mandated to be adopted. The study reveals many common and active trends – honorarium paid to Legal Aid Counsels at high courts, set criteria of income limit for incurring such legal aid services. The aim is to analyze such fixed data and expose necessary gaps in it, and to come up with essentials changes and recommendations that need to be adopted.

Background: Sleep interruptions and nocturnal hypokinesia are common in Parkinson's disease (PD). Pilot work using wearable technologies showed fewer nocturnal movements in patients with advanced PD compared to controls. However, the prevalence of these impairments in early stage of the disease and the influence of non-motor symptoms, and dopaminergic medication are unknown. Methods: This study evaluated wearable sensor data collected in 305 patients with PD at different Hohen and Yahr disease stages (HY HY H&Y3=77) and 205 healthy controls (HC). Subjects wore a tri-axial accelerometer continuously (24/7) on the lower back for at least 2 days. Percent upright-time and nighttime walking were defined based on the vertical axis of the acceleration signal and were classified as sleep interruptions. The number, velocity, time, side, and degree of rotations in bed during the night evaluated nocturnal movements. Findings: Nocturnal lying-time was similar between PD and controls (p=0.501), however, the number of turns and the turn velocity significantly decreased (p

Background: Breast cancer (BC) with a low hormone receptor (HR) expression (1-9%), although qualifying for endocrine therapy, very often have a molecular phenotype similar to triple-negative BC. In this study we evaluated the clinical behavior of low HR-expressing tumors in a multiparametric cohort of 9027 patients. Methods: We analyzed neoadjuvant clinical trial cohorts (n=4366) and a cancer registry cohort (n=5138). We compared patients with negative [oestrogen (ER) and progesterone receptor (PR)

Background: The WAKE-UP trial recently revealed the efficacy of magnetic resonance imaging (MRI)-based intravenous thrombolysis with alteplase at 0·9 mg/kg in acute ischemic stroke patients with unknown time of onset. We assessed whether lower-dose alteplase at 0·6 mg/kg is efficacious and safe in patients under the same conditions. Methods: This was an investigator-initiated, multicenter, randomized, open-label, blinded-endpoint trial. Patients met the standard indication criteria for intravenous thrombolysis other than a time last-known-well >4·5 h (e.g., wake-up stroke). Patients were randomly assigned (1:1) to receive alteplase at 0·6 mg/kg or standard medical treatment if MRI showed acute ischemic lesion on diffusion-weighted imaging and no marked corresponding hyperintensity on FLAIR. The primary outcome was a favorable outcome (90-day modified Rankin Scale score of 0-1). Findings: Following the early stop and positive results of the WAKE-UP trial, this trial was prematurely terminated with 131 of the anticipated 300 patients (55 women; mean age: 74·4±12·2 years; median National Institutes of Health Stroke Scale score: 7; interquartile range: 4-13). Favorable outcome was comparable between the alteplase group (32/68, 47·1%) and the control group (28/58, 48·3%) (relative risk (RR), 0·97; 95% confidence interval (CI), 0·68 to 1·41; p=0·892). Symptomatic intracranial hemorrhage within 22-36 h occurred in 1/71 (1·4%) and 0/60 (RR, infinity; 95%CI, 0·06 to infinity; p=1·0), respectively. Death at 90 days occurred in 2/71 (2·8%) and 2/60 (3·3%) (RR, 0·85; 95%CI, 0·06 to 12·58; p=1·0), respectively. Interpretation: No difference in favorable outcome was seen between alteplase and control groups among ischemic stroke patients with unknown time of onset. The safety of alteplase at 0·6 mg/kg was comparable to that of standard treatment. Early study termination precludes any definitive conclusions, and additional research may be warranted. Trial Registration: This trial was registered with ClinicalTrials.gov NCT02002325 and UMIN 000011630. Funding Statement: This trial was funded mainly by the Japan Agency for Medical Research and Development (AMED) (JP16ek0210025h and JP18ek0210091h), and the Ministry of Health, Labour, and Welfare, and partly by the Intramural Research Fund for Cardiovascular Diseases of National Cerebral and Cardiovascular Center (H23-4-3; maintenance of the administration infrastructure for international multicenter studies of clinical stroke; P. I., K. Toyoda), and the Mihara Cerebrovascular Disorder Research Promotion Fund. Declaration of Interests: MK reports honoraria from Bayer, BMS/Pfizer, Daiichi-Sankyo and Nippon Boehringer Ingelheim, scientific advisory board from Ono, and research supports from Takeda, Daiichi-Sankyo, Nippon Boehringer Ingelheim, Astellas, Pfizer and Shionogi, outside the submitted work. RI reports personal fees from Bayer, personal fees from Bristol-Myers Squibb, personal fees from Daiichi-Sankyo, personal fees from Boehringer Ingelheim, personal fees from Pfizer, personal fees from Stryker, personal fees from Medtronic, personal fees from Otsuka Pharmaceutical, personal fees from GE, grants from Tohoku Fukushi University, personal fees from Tanabe Mitsubishi , personal fees from Johnson and Johnson, outside the submitted work. TI reports grants from Ogaki Tokusyukai Hospital, grants from GlaxoSmithKline K.K., outside the submitted work. YN reports personal fees from Bayer, Bristol-Myers Squibb, Eisai, Daiichi Sankyo, Mochida, Ono, and Takeda, outside the submitted work. YO reports personal fees from Boehringer Ingelheim, personal fees from Bayer, personal fees from Pfizer, personal fees from Daiichi-Sankyo, personal fees from Bristol Myer Squibb, personal fees from Otsuka, outside the submitted work. NS reports personal fees from Otsuka, outside the submitted work. SY reports personal fees from Medtronic, personal fees from Stryker, personal fees from Kaneka Medics, personal fees from Otsuka Pharmaceutical, during the conduct of the study; personal fees from Boehringer-Ingelheim, personal fees from Daiichi Sankyo, personal fees from Pfizer, personal fees from Bayer, personal fees from Sanofi, personal fees from Bristol-Meyers, outside the submitted work. TU reports personal fees from Boehringer Ingelheim, personal fees from Bristol-Myers Squibb, personal fees from AstraZeneca K.K., personal fees from Bayer Pharmaceutical Co., Ltd., personal fees from Otsuka Pharmaceutical Co., Ltd., personal fees from Takeda Pharmaceutical Co., Ltd., personal fees from Mitsubishi-Tanabe Pharma Co., Ltd, personal fees from UCB Japan Co., Ltd., personal fees from Kowa Shinyaku Co., Ltd., personal fees from Sumitomo Dainippon Pharma Co., Ltd., personal fees from Astellas Pharma Inc., personal fees from AbbVie GK, personal fees from Medtronic Japan Co., Ltd., personal fees from Eisai Co., Ltd., personal fees from Daiichi Sankyo Co., Ltd., personal fees from CSL Behring, personal fees from Japanese Physical Therapy Association, outside the submitted work. MI reports grants from Shimadzu Corporation, grants and personal fees from Otsuka Pharmaceutical Company Ltd., personal fees from Daiichi Sankyo Company Ltd., personal fees from Pfizer Inc., personal fees from Eisai, outside the submitted work. TK reports personal fees from Bayer Yakuhin Ltd, grants and personal fees from Daiichi Sankyo Co Ltd, grants and personal fees from Chugai Pharmaceutical Co Ltd, grants from Takeda Pharmaceutical Co Ltd, grants from Eisai Co Ltd, grants from Astellas Pharma Inc, grants from MSD KK, grants from Mitsubishi Tanabe Pharma Co, outside the submitted work. Dr. Sasaki reports personal fees from Mitsubishi Tanabe, personal fees from Bayer, personal fees from Astellas, personal fees from Ono Pharma, personal fees from Mediphysics, personal fees from Actelion, personal fees from Ezai, personal fees from FujiFilm, personal fees from Daiichi Sankyo, personal fees from Nippon Boehlinger Ingelheim, personal fees from Otsuka, personal fees from Chugai, grants and personal fees from Hitachi, grants from Actelion, grants from GE Healthcare, outside the submitted work. KK reports personal fees（honoraria for lecture presentations） from Bayer Yakuhin. KM reports personal fees and other from Bayer Yakuhin, personal fees from Otsuka Pharmaceutical, personal fees from Boehringer-Ingelhaem, personal fees from Mitsubishi Tanabe Pharma Cooperation, outside the submitted work; and personal fees (honoraria for seminar presentation) and other (Advisory Board) from AstraZeneca; personal fees (honoraria for seminar presentation) from Pfizer, Japan Stryker, Dai-ichi Sankyo, Astellas Pharma, Nippon Chemiphar and Fuji Film RI Pharma; and other (Advisory Board) from CSL Behring, Medico's Hirata, EPS Corporation, HEALIOS K.K. and T-PEC Corporation. KT reports personal fees from Daiichi-Sankyo, personal fees from Bayer Yakuhin, personal fees from Brystol-Meyers-Squibb, personal fees from Nippon Behringer Ingerheim, outside the submitted work. None of the other authors have any conflicts of interest to declare. Ethics Approval Statement: The trial protocol was approved by the Ministry of Health, Labour, and Welfare, Japan to perform a treatment not covered by the national health insurance system. The trial was approved by the local ethics committee or institutional review board at each participating center. Patients or their relatives provided written informed consent according to ethical regulations.

Background: Postoperative adjuvant chemotherapy with S-1 for 1 year (corresponding to 8 courses) is a standard care for pathological stage II gastric cancer. It remains unclear whether duration of S-1 for 1 year could be shortened to 6 months (corresponding to 4 courses) without worsening the survival. Methods: We conducted a phase 3, open-label, randomized controlled non-inferiority trial at 59 hospitals in Japan. Patients with pathological stage II adenocarcinoma of the stomach were randomly assigned (1:1) to 4 courses S-1 or 8 courses S-1. 80 mg/m2/day of S-1 was administered for 4 weeks with a rest for 2 weeks as one course. Primary endpoint was relapse-free survival (RFS), analyzed by intension to treat. Total sample size was determined to be 1,000, expecting 3-year RFS of 85% with non-inferiority margin of hazard ratio (HR) of 1·37, one-sided alpha of 5% and 80% power. Findings: Between Feb 2012 and Mar 2017, 590 patients were enrolled (8-courses, 295; 4-courses, 295). Among them, 528 patients were analyzed at the first planned interim analysis in Mar 2017. The point estimate of HR of the 4- courses group compared with the 8-courses group was 2·52 (95% CI: 1·11- 5·77), which was greater than 1·37 and met the prespecified criteria for early termination, associated with predictive probability of 2·9% for showing non-inferiority at the final analysis. Updated 3-year RFS analyzed in May 2017 were 93·1% (95% CI 87·8%-96·1%) for the 8-courses group and 89·8% (95% CI 84·2%-93·5%) for the 4-courses group (HR 1·84, 95% CI 0·93-3·63). Interpretation: Postoperative S-1 adjuvant chemotherapy for p-stage II gastric cancer should be continued for 1 year. Clinical Trial Number: This study is registered at UMIN-CTR, number UMIN000007306. Funding Statement: Japan Agency for Medical Research and Development; the Ministry of Health, Labour and Welfare of Japan; the National Cancer Center Research and Development Fund. Declaration of Interests: TYo had received reports grants from Japan Agency for Medical Research and Development (AMED) during the conduct of the study, lecture fees from Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol, MSD, Daiichi Sankyo, Yakult Honsha, Takeda Pharmaceutical, Nippon Kayaku, Kaken Pharmaceutical, Abbott Japan, Medtronic, Johnson & Johnson, and Olympus, and grant supports from Taiho Pharmaceutical, Chugai Pharmaceutical, and Yakult Honsha outside the submitted work. JM had received grants from Ministry of Health, Labour and Welfare, Japan, grants from Japan Agency for Medical Research andÝevelopment (AMED) during the conduct of the study. KY had received grants, personal fees, and non-financial support from Taiho Pharm. Co. during the conduct of the study, grants, personal fees, and non-financial support from Sanofi, grants, personal fees, and non-financial support from Chugai Pharm. Co., Ltd., grants, personal fees, and non-financial support from Yakult Honsha Co., Ltd., grants, personal fees, and non-financial support from Eli Lilly Japan K.K., grants, personal fees, and non-financial support from Daiichi Sankyo Co., Ltd., grants, personal fees, and non-financial support from Merck Serono Co., Ltd., grants, personal fees, and non-financial support from Novartis Pharma, grants, personal fees, and non-financial support from EA Pharma Co., Ltd., grants, personal fees, and non-financial support from Johnson & Johnson K.K., grants, personal fees, and non-financial support from Covidien Japan, grants, personal fees, and non-financial support from Takeda Pharmaceutical Co., Ltd., grants, personal fees, and non-financial support from Ono Pharm. Co.,Ltd, grants and personal fees from Nippon Kayaku Co.,Ltd., grants and personal fees from Otsuka Pharma Co., Ltd., grants from Sumitomo Dainippon Pharma, grants from Bristol Myers Japan, grants from Tsumura, grants from Kyowa Hakko Kirin, grants from Astellas, grants from Toyama Chemical, grants from KCI, grants from Abbott Japan, grants from Asahi Kasei, personal fees from Olympus, personal fees from Terumo, personal fees from Denka, personal fees from MSD K.K., personal fees from Bayer Yakuhin, Ltd, outside the submitted work. SI had received grants from MSD, grants from Ono Pharmaceutical, personal fees from Chugai Pharmaceutical, personal fees from Otsuka Pharmaceutical Factory outside the submitted work. HK had received grants from Ministry of Health, Labour and Welfare, Japan, grants from Japan Agency for Medical Research and Ýevelopment (AMED) during the conduct of the study and personal fees from Johnson & Johnson outside the submitted work. HF had received grants from Ministry of Health, Labour and Welfare, Japan, grants from National Cancer Center, Japan during the conduct of the study, personal fees from Taiho Pharma, and personal fees from Chugai Pharmaceutical outside the submitted work. NB had received honorarium from Taiho, Ono, Chugai, Shionogi, Yakult, Bristol Myers Squibb, Eli Lilly, Merck Serono, and study grant from Taiho, Ono and Bristol Myers Squibb outside of the submitted work. TS had received personal fees from Taiho Pharma outside the submitted work. MS had received personal fees from Taiho Pharmaceutical during the conduct of the study. Ethics Approval Statement: This study was done in accordance with the international ethical recommendations stated in the Declaration of Helsinki, Japanese Ethical Guidelines for Clinical Research. All patients were required to provide written informed consent prior to enrollment.

Background: Preclinical data indicates that stereotactic body radiotherapy (SBRT) works synergistically with pembrolizumab, but the effect and potential toxicity might depend on the timing of SBRT. The current study assessed the safety of two different SBRT schedules in combination with pembrolizumab for metastatic urothelial carcinoma (mUC), and explored correlative biomarkers including circulating tumor DNA (ctDNA). Methods: An open-label phase 1 trial was conducted at Ghent University Hospital in patients with mUC to assess the dose-limiting toxicity (DLT) of the combination of pembrolizumab (200mg intravenously, 3-weekly) and SBRT (3x8Gy to the largest lesion). Patients were randomized (1:1) to receive SBRT either prior to the first (arm A) or the third (arm B) cycle of pembrolizumab. Blood was collected throughout the trial for biomarker analysis. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events version 4.0. Secondary endpoints included best overall response measured per Response Evaluation Criteria in Solid Tumors v1.1 (RECISTv1.1). Findings: Between November 14, 2016 and January 2, 2018, eighteen patients were randomized (nine to each arm) and started trial treatment. No DLT occurred. Treatment-related AEs grade 1-2 occurred in 6/9 and 9/9 patients in arm A and B respectively. One patient in arm B experienced lymphopenia grade 3, unrelated to SBRT. No treatment-related AEs grade 4- 5 occurred. An objective response rate as per RECISTv1.1 of 0% and 44·4% was noted in arm A and B respectively. Targeted sequencing of tissue DNA and ctDNA revealed high genomic concordance. A decline in ctDNA was observed in responding patients. Interpretation Neo-adjuvant and concomitant SBRT combined with pembrolizumab is safe, with potentially superior responses in the latter. ctDNA monitoring is feasible during disease evolution. Clinical Trial Number: The trial is registered on ClinicalTrials.gov (NCT02826564), and is complete. Funding Statement: This trial was supported in part by a research grant from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp. Declaration of Interests: NS reports travel grants from Merck Sharpe & Dohme, Astellas, Bayer and Bristol-Myers Squibb. KD reports travel grants from Ipsen, Astellas, and Ferring; and honorarium from Ipsen, Astellas, Intuitive Surgical, and Medtronic Belgium. VF report travel grants and honorarium from Ipsen and Astellas. DDM reports a research grant from Roche; travel grants from Roche, Pfizer, and Astellas; and honorarium from Bristol-Myers Squibb, Pfizer, Janssen, and Bayer. LB reports a travel grant and honorarium from Incyte Biosciences. AWW reports honorarium from Sanofi and Janssen and research grants from Janssen. SR reports a research grant from Roche; travel grants from Merck Sharpe & Dohme, Roche, Pfizer, Bristol-Myers Squibb; and honorarium from Merck Sharpe & Dohme, Bristol-Myers Squibb, Roche, and Pfizer. PO reports research grants from Merck Sharpe & Dohme, Astellas and Janssen; travel grants from Ipsen and Ferring Pharmaceuticals; and honorarium from Ferring and Bayer. All other authors declare no competing interests. Merck Sharpe & Dohme provided financial support and pembrolizumab for the present study. Ethics Approval Statement: The study protocol was approved by the Ethics Committee of Ghent University Hospital (EC2016/0661).

By every account, Justice Antonin Scalia was an extraordinarily gifted, insightful, entertaining, charismatic, and combative (usually engagingly so) judge and individual. But in the area of a judicial code of conduct, Justice Scalia simply did not follow the standard in effect since 1974 under the Judicial Code of Conduct and 28 U.S.C. §455(a) that a judge “shall disqualify” himself in any case where his “impartiality might reasonably be questioned.” Instead, Justice Scalia followed the standard in effect for the 50 years before under which his own “opinion” of his impartiality was dispositive without any objective review. To do this, Justice Scalia used a loophole of viewing the Judicial Code of Conduct, which technically covers every Federal judge except a Supreme Court justice, as just “a key source of guidance.” He then evidently treated the identical recusal standard under 28 U.S.C. §455(a), which expressly applies to Supreme Court “justices,” as infirm because the application of the Congressionally-legislated standard to “Article III” Supreme Court justices has not been tested in court. While in a limited sense Justice Scalia may thus been treating the Code of Conduct and the recusal statute as “a key source of guidance,” his actions, including the 21-page March 2004 memorandum against his recusal in the Cheney v. United States District Court case, are only explainable on the basis that he was following the pre-1974 standard for recusal under which his subjective “opinion” of his own impartiality controlled without any review under an objective, reasonable-person standard. Justice Scalia’s partiality in cases before the Court was most explosively revealed in a nearly unnoticed radio interview on Armed American Radio given on February 14, 2016, the day after Justice Scalia’s death, by Alan Gottlieb, the founder of the Second Amendment Foundation, about the litigation that culminated in Justice Scalia’s groundbreaking 2008 opinion in Heller v. District of Columbia:“I ... had the pleasure to spend a day with [Justice Scalia] in Nuremberg, Germany when he came to accept an award from the World Forum for the Future of Sports Shooting Activities [in March 2007].... I guess this is something that I probably haven’t shared with anyone on the air, I’ve talked to some people about it privately. But that was the day in fact that the appeals court in Washington, DC ruled against the city in DC and knocked down the DC gun ban and both Scalia and I knew that it was going to be headed to the Supreme Court and that the city of DC was going to appeal it. So we didn’t talk directly about the case itself because it would have been like sort of a conflict, but he did say something to me that was very encouraging to me at the time. And that was, he said, “You know, Alan, it takes four votes on the Supreme Court to hear a case, and it takes five to win it. If I don’t think we have the five to win it, there won’t be four to hear it.” And that just made me feel like I knew at that point in time that if the Supreme Court took the Heller case, that we were going to win it.”Justice Scalia’s conversation with Mr. Gottlieb, whose gun rights foundation was an amicus in the case (and which filed another gun rights case against the City of Chicago the next day) was clearly improper, and it shows that Justice Scalia had made up his mind about Heller before the Supreme Court had even received the first papers. Another interview reveals that Justice Scalia held a “real roundtable discussion” with “half a dozen” gun rights lawyers the day before.Compounding the issue of not following the modern standard on impartiality, Justice Scalia regularly failed to disclose honoraria, outside income, and gifts that he received primarily in the form of high-end hunting trips over the last two decades of his service. Without information about the honoraria, outside income, and gifts, potential conflicts could not be identified and considered. The undisclosed hunting trips included not only the infamous 2004 trip on Air Force Two for duck-hunting in Louisiana with Vice President Cheney while Vice President Cheney’s case was pending before the Court, but also completely unnoticed trips with relatives and friends to such locations as the 8,000 acre Galena Plantation in North Mississippi, which may be a top quail hunting lodge but also celebrates the relocated and restored log cabin of the first Grand Wizard of the Ku Klux Klan. On another November 2015 hunting trip to Louisiana, an internationally-renowned chef was brought into prepare three-star meals for Justice Scalia along with Vice President Dick Cheney, former Secretary of State James A. Baker, III, and lobbyist and former Republican National Committee Chair Haley Barbour as if it was a White House State Dinner. Other undisclosed hunting trips were with the leaderships of national hunting organizations like Safari Club International, the National Wild Turkey Federation, Ducks Unlimited, and the Order of St. Hubertus. The extravagant February 2016 weekend at the Cibolo Creek resort with the leadership of the Order of St. Hubertus where Justice Scalia passed away would be valued conservatively at $10,000 for the justice and a guest, including a chartered jet from Houston International Airport and guided hunting of pen-raised birds. Former federal district judge Charles Pickering, whose son’s Congressional district was redrawn in a case the Supreme Court decided in 2003, estimates that he personally took Justice Scalia on 40 hunting trips. According to Mississippi Governor Phil Bryant, Justice Scalia stayed at the Governor’s mansion and went duck hunting with him while cases involving the Affordable Care Act, which Governor Bryant sought to block with executive and legal actions, were before the Supreme Court. Similar to the Mississippi governors who preceded him in resisting school integration, Governor Bryant has resisted the benefits of the Affordable Care Act for over 300,000 Mississippians as”a socialist takeover of health care forced down the throats of the American people” and has said that the decisions of “a majority” of the Supreme Court justices, “including, again, the Chief Justice” are “incredibly troubling to me.” More recently, in the Western North Carolina mountains, Justice Scalia hunted with a State elections board chair who is a named defendant in two cases over voter suppression measures and Congressional redistricting that are now before the Supreme Court. Many important decisions, including the 2008 anti-gun-control decision in Heller, which Justice Scalia called his “proudest” achievement, must be asterisked because Justice Scalia did not disqualify himself under the Code of Conduct or 28 U.S.C. §455(a) as in effect since 1974. On the occasions when a litigant or the press raised the issue of his failure to recuse, Justice Scalia expressed disbelief that anyone rationally believes a Supreme Court justice “can be bought so cheap” and diminished the seriousness of the questions with an analogy to calling a tennis player for “foot-faults.” Because the Supreme Court historically has only taken action on ethical matters with unanimity, Justice Scalia’s force of personality and ability to withhold a unanimous vote appears to have held the Chief Justice and other members of the Supreme Court at bay and kept them from enforcing or revisiting the ethical standards needed “to maintain the public’s trust” in the judiciary. As Justice Scalia himself often expressed it, we need to “get over it” and move on with improving the administration of justice. The 5-4 Heller decision must definitely be asterisked because the deciding justice’s “impartiality might reasonably be questioned.” But that does not mean it is likely to be overturned. We can, however, learn from this and other cases where “impartiality might reasonably be questioned” that the Judicial Code of Conduct and 28 U.S.C. §455(a) must apply to Supreme Court justices without allowing a “duty to sit” to cause the Code to revert to the subjective standard that applied before 1974. And meaningful and enforceable disclosure standards can be adopted to ensure full disclosure of honoraria and gifts, including “personal hospitality” at properties or facilities owned by a host, as well as consideration of the identities of the hosts and intermediaries who arrange such trips in deciding whether to recuse in cases before the Supreme Court. And, lastly, in light of this extensive record of gifted trips, the pay of Supreme Court justices should be raised so there is less temptation for any justice to accept honoraria or gifts from persons with business that may come before the Court.

The study was conducted in Sukkur city. The data for ongoing study was collected through convenience sampling method. It is an exploratory research with quantitative analysis. Samples were consisted on 150 female child domestic workers. The age of respondents is between 10-14 years. 45% respondents are Sindhi, 39% Urdu, 9% Saraiki, 5% Balouchi and 2% are Punjabi speaking. Per month family income of 56% respondents is Pak Rs. 9,000 to 12,000. Fathers of 83% respondents while mothers of 89% respondents are illiterate. 53% female child domestic workers were never enrolled. 33% respondents have 09 family members. 56% respondents live in ranted homes and 53% respondents get honorarium of Pk Rs. 11,00-15,00 per month and they work 08 hours daily.

The study was conducted in Union Council (UC) Ali WAhan, District Sukkur and the data was collected through purposive sampling. 50 respondents all working girls in carpet weaving industry were interviewed. Carpet weaving is hazardous work and children are prohibited to do. The result of study shows that 58% respondents were never enrolled to school. 84% respondents initiated work due to poverty, 44% respondents honorarium is Pak Rs. 2,001-2,500 per month (26 working days) and 56% respondents working hours are 48 hours in a week (06 days). 60% respondents father are illiterate. 74% respondents have not their own homes. 78% respondents faced physical injuries during work. 80% respondents feel backache due to long working hours or wrong posture during work. 66% respondents know that carpet weaving is hazardous work and not suitable them. 46% respondents believe that child labour in carpet weaving industry is decreasing. 80% respondents want to study instead of work. The study recommends that governmet as well as NGOs should introduce women empowerment/poverty uplifting programmes on grass root level. These programmes may consist on business management skills trainings and micro finance for mothers. Therefore they generate income instead of their children through child labour.

Current research is unique in nature due to 1st hand information and participation of 30 female children (10-14 years old) through convenience sampling technique in commercial domestic work (CDW) in Rohri City. CDW is a form of most exploitative child labour due to stay of children at working sites (3rd party homes). All the respondents (100% girls) were never enrolled in any educational institution due to multiple reasons for example poverty (47%), restricted girls’ education (13%) and parents of respondents (43% fathers and 63% mothers) were illiterate. 50% respondents work minimum 6 hours a day. All the domestic workers were working without direct supervision of their siblings or parents. Honorarium of 50% respondents was ranging between 500-1000 PKR (US$ 5 to 10 per month).

The Mid-Day Meal (MDM) scheme is the world's largest school-based feeding program aimed at improving the nutritional status of students and promoting the universalization of elementary education. Using government data, this brief reports on MDM performance along the following parameters: a) Overall trends in allocation and expenditures across states b) Expenditure performance on key MDM components such as cooking costs, foodgrains and honorarium to cookcum-helper (CCH) c) Progress on construction of kitchen-cum-stores, and d) Coverage as indicated through the provision of meals to students.

On 1 November 2007 the Minister of Finance and the Minister of Revenue asked for submissions on ways to simply the current law on the taxation of reimbursement and honoraria paid volunteers in the non-profit sector. A number of proposals were outlined in a Inland Revenue Department issues paper released on 1 November. This working paper presents the results of a survey of 1537 individuals and 224 organisations who replied to a web based questionnaire that was conducted in August and September 2007. The results have been used to support a number of recommendations towards simplification and clarification of current tax law.