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Background: Androgenetic alopecia (AGA) is the most common hair loss disorder seen in men. It can have an early onset but has also been associated with ageing and senescence. It often induces pronounced psychological impact. ALRV5XR, a new hair loss treatment herein evaluated, was designed to target multiple molecular pathways involved in hair growth and hair follicle stem cell biology. The main objectives of the study were the assessment of safety and efficacy profiles of ALRV5XR in men.Methods: This 24-week, parallel randomised, placebo-controlled, double-blinded clinical trial was performed in a USA community clinic. Healthy men (age 22-65) with AGA and belonging to the Hamilton-Norwood (HN) classification I-VII and Fitzpatrick skin type (FST) I-VI, were randomly allocated in a 1:1 ratio into ALRV5XR or placebo treatment groups. Dermatologist assessment, phototrichograms, and blood samples were obtained in a blinded fashion at baseline, 12 and 24 weeks. Subjects were given a masked treatment consisting of oral capsules, shampoo, conditioner, and follicle serum, which was intended for daily use. Efficacy was assessed via absolute and per cent changes in terminal hair (TH) density, and response rates. The trial was registered with clinicaltrials.gov (NCT04450589) and is completed.Findings: Forty-six subjects were enroled in the study, 23 allocated to the ALRV5XR treatment and 23 to the placebo group. Enrolment occurred from April 11 to October 23, 2018. Thirty-six subjects completed the trial (17 ALRV5XR, 19 placebo) and 11 subjects in each group were evaluable for TH outcomes. At 24 weeks, the absolute change in TH density improved by 21.0 THs/cm(2) (95% CI: 9.2-32.8; p = 0.0014), and the relative density increased by 16.4% (95% CI: 7.4%-25.5%; p = 0.0012). The odds ratio for being a responder ( >= 0 change) was 87.4. TH density increased linearly and was not affected by HN, FST, ethnicity, age, or body mass index. All subjects in the ALRV5XR group responded to treatment while 81.8% of the placebo group decreased TH density. ALRV5XR induced statistically significant changes in both decrease in vellus hair (VH) density as well as in concomitant increase of the TH/VH ratio when compared to placebo. ALRV5XR was well tolerated, and no adverse events were observed.Interpretation: ALRV5XR treatment resulted in clinically significant TH regrowth in men with AGA. Furthermore, it appeared to reverse the characteristic hair miniaturisation seen in this condition. When compared to results of published trials of standard therapy, ALRV5XR showed a multi-fold increase both in efficacy and in response rates. In addition, the continuance of TH regrowth from 12 to 24 weeks suggests that the normal structure and function of non-productive telogen follicles is restored and that a normal hair phenotype may be attained by extended ALRV5XR treatment. (C) 2021 The Author(s). Published by Elsevier Ltd.

Background Because of their direct patient contact, healthcare workers (HCW) face an unprecedented risk of exposure to COVID-19. The aim of this study was to examine incidence of COVID-19 disease among asymptomatic HCW and community participants in Northern Virginia during 6 months of follow-up. Methods This is a prospective cohort study that enrolled healthy HCW and residents who never had a symptomatic COVID-19 infection prior to enrolment from the community in Northern Virginia from April to November 2020. All participants were invited to enrol in study, and they were followed at 2-, and 6-months intervals. Participants were evaluated by commercial chemiluminescence SARS-CoV-2 serology assays as part of regional health system and public health surveillance program to monitor the spread of COVID-19 disease. Findings Of a total of 1,819 asymptomatic HCW enrolled, 1,473 (96%) had data at two-months interval, and 1,323 (73%) participants had data at 6-months interval. At baseline, 21 (1.15%) were found to have prior COVID-19 exposure. At two-months interval, COVID-19 rate was 2.8% and at six months follow-up, the overall incidence rate increased to 4.8%, but was as high as 7.9% among those who belong to the youngest age group (20–29 years). Seroconversion rates in HCW were comparable to the seropositive rates in the Northern Virginia community. The overall incidence of COVID-19 in the community was 4.5%, but the estimate was higher among Hispanic ethnicity (incidence rate = 15.3%) potentially reflecting different socio-economic factors among the community participants and the HCW group. Using cross-sectional logistic regression and spatio-temporal mixed effects models, significant factors that influence the transmission rate among HCW include age, race/ethnicity, resident ZIP-code, and household exposure, but not direct patient contact. Interpretation In Northern Virginia, the seropositive rate of COVID-19 disease among HCW was comparable to that in the community.

Arginase 1 (ARG1) deficiency is a rare urea cycle disorder (UCD), with an estimated frequency of 1 per 2,200,000 births in Japan. Patients with ARG1 deficiency develop symptoms in late infancy or pre-school age with progressive neurological manifestations and sometimes present with severe hepatic disease. We previously investigated the status of UCDs in Japan; however, only one patient was identified as having ARG1 deficiency. Therefore, we aimed to investigate the current status of patients with ARG1 deficiency in 2018–2021 because almost 10 years have passed since the previous study. We present the disease history, clinical outcome, and treatment of five surviving patients with ARG1 deficiency and discuss the features of ARG1 deficiency in Japan. We found that clinicians often face difficulty in diagnosing ARG1 deficiency at the early stage of onset because of interpatient variability in onset time and clinical manifestations. Blood L-arginine and guanidino compounds were considered to be the major factors causing adverse neurodevelopmental outcomes. Therefore, early detection and intervention of ARG1 deficiency is essential for improved neurodevelopmental outcomes. Liver transplantation has been considered an effective treatment option that can dramatically improve the quality of life of patients, prior to the neurological manifestation of symptoms caused by ARG1 deficiency.

Background: Management and control of the COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus SARS-CoV-2 is critically dependent on quick and reliable identification of the virus in clinical specimens. Detection of viral RNA by a colorimetric reverse transcription loop-mediated isothermal amplification (RT-LAMP) is a simple, reliable and cost-effective assay, deployable in resource-limited settings (RLS). Our objective was to evaluate the intrinsic and extrinsic performances of RT-LAMP in RLS. Methods: This is a multicenter prospective observational study of diagnostic accuracy, conducted from October 2020 to February 2021 in four African Countries: Cameroon, Ethiopia, Kenya and Nigeria; and in Italy. We enroled 1657 individuals who were either COVID-19 suspect cases, or asymptomatic and presented for screening. RNA extracted from pharyngeal swabs was tested in parallel by a colorimetric RT-LAMP and by a standard real time polymerase chain reaction (RT-PCR). Findings: The sensitivity and specificity of index RT LAMP compared to standard RT-PCR on 1657 prospective specimens from infected individuals was determined. For a subset of 1292 specimens, which underwent exactly the same procedures in different countries, we obtained very high specificity (98%) and positive predictive value (PPV = 99%), while the sensitivity was 87%, with a negative predictive value NPV = 70%, Stratification of RT-PCR data showed superior sensitivity achieved with an RT-PCR cycle threshold (Ct) below 35 (97%), which decreased to 60% above 35. Interpretation: In this field trial, RT-LAMP appears to be a reliable assay, comparable to RT-PCR, particularly with medium-high viral loads (Ct

Background: Within Ulaanbaatar, Mongolia, risk factors for pneumonia are concentrated among children living in informal settlements comprised of temporary shelters (gers). We used pneumococcal carriage surveillance among children from formal and informal settlements hospitalised with pneumonia to evaluate the direct and indirect effects of 13-valent pneumococcal conjugate vaccine (PCV13) against vaccine-type (VT) pneumococcal carriage following a phased introduction of PCV13. Methods: We enrolled and collected nasopharyngeal swabs from children 2-59 months of age presenting to hospital. Pneumococci were detected using lytA qPCR and serotyped using microarray on a random monthly selection of swabs between November 2015 and March 2019 from two districts in Ulaanbaatar. PCV13 status was determined using written records. We quantified the associations between individual PCV13 status (direct effects) and district-level PCV13 coverage (indirect effects) and VT carriage using generalised estimating equations and explored interactions by settlement type. Findings: A total of 1 292 swabs from 6 046 participants were tested for pneumococci. Receipt of PCV13 and increasing PCV13 coverage independently reduced the risk of VT carriage. For each percent increase in PCV13 coverage, the adjusted odds of VT carriage decreased by 1•0% (OR 95% CI 0•983-0•996; p=0•001), with a predicted decrease in VT carriage rate from 29•1% to 13•1% as coverage reached 100%. There was a trend towards a slower decline within informal settlements (p=0•100). Adjusted PCV13 vaccine effectiveness against VT carriage was 39•1% (95% CI 11•4-58•1%, p=0•009). Interpretation: Substantial indirect effects were observed following PCV13 introduction, including among children living within informal settlements. Funding: Bill & Melinda Gates Foundation; Gavi, the Vaccine Alliance.

Highlights • GPC3 mutation in primary osteosarcoma becomes abundant in its metastasis. • Mutant GPC3 is over-produced in metastatic spheroids with multidrug resistance. • Anti-GPC3 antibody effectively commits metastatic spheroids to apoptosis. • GPC3 would be a promising therapeutic target of osteosarcomas., Background Drug resistance and the lack of molecular therapeutic target are the main challenges in the management of osteosarcomas (OSs). Identification of novel genetic alteration(s) related with OS recurrence and chemotherapeutic resistance would be of scientific and clinical significance. Methods To identify potential genetic alterations related with OS recurrence and chemotherapeutic resistance, the biopsies of a 20-year-old male osteosarcoma patient were collected at primary site (p-OS) and from its metastatic tumor (m-OS) formed after 5 months of adjuvant chemotherapy. Both OS specimens were subjected to cancer-targeted next generation sequencing (NGS) and their cell suspensions were cultured under three-dimensional condition to establish spheroid therapeutic model. Transcript-oriented Sanger sequencing for GPC3, the detected mutated gene, was performed on RNA samples of p-OS and m-OS tissues and spheroids. The effects of anti-GPC3 antibody and its combination with cisplatin on m-OS spheroids were elucidated. Results NGS revealed 4 mutations (GPC3, SOX10, MDM4 and MAPK8) and 6 amplifications (MDM2, CDK4, CCND3, RUNX2, GLI1 and FRS2) in p-OS, and 3 mutations (GPC3, SOX10 and EGF) and 10 amplifications (CDK4, CCND3, MDM2, RUNX2, GLI1, FRS2, CARD11, RAC1, SLC16A7 and PMS2) in m-OS. Among those alterations, the mutation abundance of GPC3 was the highest (56.49%) in p-OS and showed 1.54 times increase in m-OS. GPC3 transcript-oriented Sanger sequencing confirmed the mutation at 1046 in Exon 4, and immunohistochemical staining showed increased GPC3 production in m-OS tissues and its spheroids. EdU cell proliferation and Calcein/PI cell viability assays revealed that of the anti-OS first line drugs (doxorubicin, cisplatin, methotrexate, ifosfamide and carboplatin), 10 μM carboplatin exerted the best inhibitory effects on the p-OS but not the m-OS spheroids. 2 μg/mL anti-GPC3 antibody effectively committed m-OS spheroids to death by itself (76.43%) or in combination with cisplatin (92.93%). Conclusion This study demonstrates increased abundance and up-regulated expression of mutant GPC3 in metastatic osteosarcoma and its spheroids with multidrug resistance. As GPC3-targeting therapy has been used to treat hepatocellular carcinomas and it is also effective to OS PDSs, GPC3 would be a novel prognostic parameter and therapeutic target of osteosarcomas.

The World Health Organization (WHO) has been implementing antimicrobial surveillance with a “One Health” approach, known as the Global Surveillance ESBL E. coli Tricycle Project. We describe the implementation of the Tricycle Project (pilot) in Indonesia, focusing on its results, challenges and recommendations. The samples were 116 patients with bloodstream infections caused by ESBL E. coli, 100 rectal swabs collected from pregnant women, 240 cecums of broiler, and 119 environmental samples, using the standardized method according to the guidelines. ESBL-producing E. coli was found in 40 (40%) of the 100 pregnant women, while the proportion of ESBL-producing E. coli was 57.7% among the total E. coli-induced bloodstream infections. ESBL-producing E. coli was isolated from 161 (67.1%) out of 240 broilers. On the other hand, the average concentration of E. coli in the water samples was 2.0 × 108 CFU/100 mL, and the ratio of ESBL-producing E. coli was 12.8% of total E. coli. Unfortunately, 56.7% of questionnaires for patients were incomplete. The Tricycle Project (pilot) identified that the proportion of ESBL-producing E. coli was very high in all types of samples, and several challenges and obstacles were encountered during the implementation of the study in Indonesia. The finding of this study have implication to health/the antimicrobial resistance (AMR) surveillance. We recommend continuing this project and extending this study to other provinces to determine the AMR burden as the baseline in planning AMR control strategies in Indonesia. We also recommend improving the protocol of this study to minimize obstacles in the field., Highlights • Tricycle project is the first antimicrobial surveillance with one health approach in Indonesia. • The burden of ESBL E.coli in Environment in Jakarta. • The ESBL E.coli as indicator for antimicrobial surveillance in One Health approach.

Background Optimal ω-6/ω-3 polyunsaturated fatty acids ratio (PUFAR) is reported to exert protective effects against chronic diseases. However, data on PUFAR and diabetic retinopathy (DR) remains scarce. We aimed to thoroughly quantify whether and how PUFAR was related to DR as well as its role in DR detection. Methods This two-centre case-control study was conducted from August 2017 to June 2018 in China, participants were matched using a propensity score matching algorithm. We adopted multivariable logistic regression models and restricted cubic spline analyses to estimate the independent association of PUFAR with DR, adjusting for confounders identified using a directed acyclic graph. The value of PUFAR as a biomarker for DR identification was further evaluated by receiver operating characteristic analyses and Hosmer-Lemeshow tests. Findings An apparent negative relationship between PUFAR and DR was observed. Adjusted odds of DR decreased by 79% (OR: 0·21, 95% CI: 0·10–0·40) with an interquartile range increase in PUFAR. Similar results were also obtained in tertile analysis. As compared to those in the 1st tertile of PUFAR, the adjusted odds of DR decreased by 76% (OR: 0·24, 95% CI: 0·08–0·66) and 93% (OR: 0·07, 95% CI: 0·03–0·22) for subjects in the 2nd and 3rd tertiles, respectively. Good calibration and discrimination of the PUFAR associated predictive model were detected and PUFAR = 35 would be an ideal cut-off value for DR identification. Interpretation Our results suggest that serum PUAFR is inversely associated with DR. Although PUFAR-alteration is not observed amongst different stages of DR, it can serve as an ideal biomarker in distinguishing patients with DR from those without DR. Funding This study was funded by Natural Science Foundation of Zhejiang Province, Zhejiang Basic Public Welfare Research Project, the Major Project of the Eye Hospital of Wenzhou Medical University, and the Academician's Science and Technology Innovation Program in Zhejiang province. Part of this work was also funded by the National Nature Science Foundation of China, and Research Project for College Students in Wenzhou Medical University.

Objectives: To assess ultra-early neuroprognostic significance of GFAP, NF-L, UCH-L1, tau, and S100B concentrations, change trajectory, and combination profile after Out-of-Hospital Cardiac Arrest (OHCA). Methods: Prospective enrollment of 22 OHCA and 10 control patients at an academic tertiary care center between May 1, 2017 and January 28, 2020. Blood was collected within one hour of return of spontaneous circulation (ROSC) (H0), at hours 6 (H6), 12, 18, 24, and daily or until discharge or death. Biomarker concentrations, multifactor score, and trajectory change were assessed and compared to final neurologic status (good vs poor Cerebral Performance Category; CPC 1–2 vs CPC 3–5, respectively). Results: 10 patients had good and 12 had poor neurologic outcomes. Poor outcome patients had higher biomarker concentrations and combined biomarker scores at early time points. The earliest significant difference between good and poor outcome patients’ serum biomarkers were at H12 for GFAP (good median: 425 pg/mL [IQR:370−630] vs poor: 5954[1712–65,055] pg/mL; p

Background HIV infection promotes the expansion of immunosuppressive regulatory T-cells (Tregs), contributing to immune dysfunction, tissue fibrosis and disease progression. Early antiretroviral treatment (ART) upon HIV infection improves CD4 count and decreases immune activation. However, Treg dynamics and their epigenetic regulation following early ART initiation remain understudied. Methods Treg subsets were characterized by flow cytometry in 103 individuals, including untreated HIV-infected participants in acute and chronic phases, ART-treated in early infection, elite controllers (ECs), immunological controllers (ICs), and HIV-uninfected controls. The methylation status of six regulatory regions of the foxp3 gene was assessed using MiSeq technology. Findings Total Treg frequency increased overtime during HIV infection, which was normalized in early ART recipients. Tregs in untreated individuals expressed higher levels of activation and immunosuppressive markers (CD39, and LAP(TGF-β1)), which remained unchanged following early ART. Expression of gut migration markers (CCR9, Integrin-β7) by Tregs was elevated during untreated HIV infection, while they declined with the duration of ART but not upon early ART initiation. Notably, gut-homing Tregs expressing LAP(TGF-β1) and CD39 remained higher despite early treatment. Additionally, the increase in LAP(TGF-β1)+ Tregs overtime were consistent with higher demethylation of conserved non-coding sequence (CNS)-1 in the foxp3 gene. Remarkably, LAP(TGF-β1)-expressing Tregs in ECs were significantly higher than in uninfected subjects, while the markers of Treg activation and gut migration were not different. Interpretation Early ART initiation was unable to control the levels of immunosuppressive Treg subsets and their gut migration potential, which could ultimately contribute to gut tissue fibrosis and HIV disease progression. Funding This study was funded by the Canadian Institutes of Health Research (CIHR, grant MOP 142294) and in part by the AIDS and Infectious Diseases Network of the Reseau SIDA et maladies infectieuses du Fonds de recherche du Quebec-Sante (FRQ-S).

Background Cisplatin (CN) is considered as a cytotoxic agent and DNA synthesis inhibitor. D-Ribose-l-Cysteine (DRLC) is an active ingredient of riboceine, help cells to produce glutathione on body demand. Aim Current study focused on ameliorating potential and fertility enhancing activities of D-Ribose–l-Cysteine in cisplatin induced oligoasthenoteratozoospermia and seminiferous epithelium degeneration. Materials and method Sixty (60) male rats randomized into six groups of ten (n = 10) rats each. Group A (control) received 2.0 ml distilled water, group B received single dose of 8 mg/kg bwt CN, group C received 30 mg/kg bwt DRLC, group D received single dose of 8 mg/kg CN follow by 30 mg/kg bwt DRLC, group E received single dose of 8 mg/kg CN and vitamin C, group F received single dose of 8 mg/kg cisplatin follow by DRLC + Vit.C for 56 days. Parameters tested include: Sperm parameters, testosterone (TT), luteinizing hormone (LH), Follicle stimulating Hormone, (FSH), Prolactin, and testicular 17β-HSD activity, Blood hydroperoxide (BHP), Malondialdehyde (MDA), Superoxide Dismutase (SOD), Glutathione (GSH) and Catalase (CAT), testicular histology and fertility test. Results Cisplatin significantly reduced testicular volume, body weight, sperm quality, fertility indices, TT, FSH, LH, 17β-HSD, SOD, GSH, CAT, diameter and cross-sectional area of seminiferous tubules, spermatogenesis score. And elevate prolactin, testicular injury score, BHP and MDA compared with control group. Cisplatin only treated rats showed degenerated seminiferous epithelium with empty lumen. Intervention of D-Ribose-Cysteine ameliorated toxic impacts of CN on testis and improved the male fertility. Conclusion D-Ribose-l-Cysteine therefore, preserves testicular integrity and functions thereby, preventing the deleterious impact of CN., Graphical abstract Schematic illustration of experimental design and administration.Image 1

BACKGROUND: Several SARS-CoV-2 lineages with spike receptor binding domain (RBD) N501Y mutation have spread globally. We evaluated the impact of N501Y on neutralizing activity of COVID-19 convalescent sera and on anti-RBD IgG assays. METHODS: The susceptibility to neutralization by COVID-19 patients' convalescent sera from Hong Kong were compared between two SARS-CoV-2 isolates (B117-1/B117-2) from the α variant with N501Y and 4 non-N501Y isolates. The effect of N501Y on antibody binding was assessed. The performance of commercially-available IgG assays was determined for patients infected with N501Y variants. FINDINGS: The microneutralization antibody (MN) titers of convalescent sera from 9 recovered COVID-19 patients against B117-1 (geometric mean titer[GMT],80; 95% CI, 47-136) were similar to those against the non-N501Y viruses. However, MN titer of these serum against B117-2 (GMT, 20; 95% CI, 11-36) was statistically significantly reduced when compared with non-N501Y viruses (P

The impact of hematopoietic stem cell transplantation (HSCT) on growth in patients diagnosed with mucopolysaccharidosis I Hurler (MPS-IH) has been historically regarded as unsatisfactory. Nevertheless, the growth patterns recorded in transplanted patients have always been compared to those of healthy children. The objective of this study was to verify the impact of HSCT on MPS-IH long term growth achievements. The auxological data of 15 patients were assessed longitudinally and compared both to the WHO growth centiles for healthy individuals and to recently published curves of untreated MPS-IH children. Despite a progressive decrease after HSCT when estimated with reference to the WHO growth charts, median height SDS showed a progressive and statistically significant increase when comparing the stature recorded at each timepoint in our population to the curves of untreated MPS-IH individuals (from ‐0.39 SDS at t0 to +1.35 SDS 5 years after HSCT, p value < 0.001 and to +3.67 SDS at the age of 9 years, p value < 0.0001). In conclusion, though not efficient enough to restore a normal growth pattern in MPS-IH patients, we hereby demonstrate that HSCT positively affects growth and provides transplanted patients with a remarkable height gain compared to untreated gender- and age- matched individuals.

Background SARS-CoV-2 has challenged health service provision worldwide. This work evaluates safe surgical pathways and standard operating procedures implemented in the high volume, global city of London during the first wave of SARS-CoV-2 infection. We also assess the safety of minimally invasive surgery(MIS) for anatomical lung resection. Methods This multicentre cohort study was conducted across all London thoracic surgical units, covering a catchment area of approximately 14.8 Million. A Pan-London Collaborative was created for data sharing and dissemination of protocols. All patients undergoing anatomical lung resection 1st March-1st June 2020 were included. Primary outcomes were SARS-CoV-2 infection, access to minimally invasive surgery, post-operative complication, length of intensive care and hospital stay (LOS), and death during follow up. Findings 352 patients underwent anatomical lung resection with a median age of 69 (IQR: 35–86) years. Self-isolation and pre-operative screening were implemented following the UK national lockdown. Pre-operative SARS-CoV-2 swabs were performed in 63.1% and CT imaging in 54.8%. 61.7% of cases were performed minimally invasively (MIS), compared to 59.9% pre pandemic. Median LOS was 6 days with a 30-day survival of 98.3% (comparable to a median LOS of 6 days and 30-day survival of 98.4% pre-pandemic). Significant complications developed in 7.3% of patients (Clavien-Dindo Grade 3–4) and 12 there were re-admissions(3.4%). Seven patients(2.0%) were diagnosed with SARS-CoV-2 infection, two of whom died (28.5%). Interpretation SARS-CoV-2 infection significantly increases morbidity and mortality in patients undergoing elective anatomical pulmonary resection. However, surgery can be safely undertaken via open and MIS approaches at the peak of a viral pandemic if precautionary measures are implemented. High volume surgery should continue during further viral peaks to minimise health service burden and potential harm to cancer patients. Funding This work did not receive funding.

Background To inform the on-going debate about the use of universal prescriptive versus national intrauterine growth charts, we compared perinatal mortality for small and large-for-gestational-age (SGA/LGA) infants according to international and national charts in Europe. Methods We classified singleton births from 33 to 42 weeks of gestation in 2010 and 2014 from 15 countries (N = 1,475,457) as SGA (birthweight 90th percentile) using the international Intergrowth-21st newborn standards and national charts based on the customised charts methodology. We computed sex-adjusted odds ratios (aOR) for stillbirth, neonatal and extended perinatal mortality by this classification using multilevel models. Findings SGA and LGA prevalence using national charts were near 10% in all countries, but varied according to international charts with a north to south gradient (3.0% to 10.1% and 24.9% to 8.0%, respectively). Compared with appropriate for gestational age (AGA) infants by both charts, risk of perinatal mortality was increased for SGA by both charts (aOR[95% confidence interval (CI)]=6.1 [5.6–6.7]) and infants reclassified by international charts from SGA to AGA (2.7 [2.3–3.1]), but decreased for those reclassified from AGA to LGA (0.6 [0.4–0.7]). Results were similar for stillbirth and neonatal death. Interpretation Using international instead of national charts in Europe could lead to growth restricted infants being reclassified as having normal growth, while infants with low risks of mortality could be reclassified as having excessive growth. Funding InfAct Joint Action, CHAFEA Grant n°801,553 and EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking ConcePTION grant n°821,520. AH received a PhD grant from EHESP. publishedVersion

Aims/Hypothesis Hyperglycemia and hypoglycemia are associated with increased morbidity and mortality in the inpatient setting. Standard point of care capillary glucose testing (POCT) is commonly used in hospitalized patients to monitor their glucose levels. The goal of this study was to examine the relationships between the glucose readings obtained by a continuous glucose monitoring system (CGMS) (Freestyle Libre) and the capillary blood glucose results obtained by the inpatient glucose POCT meter (Accuchek Inform II) as well as between CGMS readings and the serum glucose values obtained by the hospital laboratory. Study participants had either primary or secondary diagnosis of diabetes mellitus and were admitted to non-critical units. We hypothesized that there exists an acceptable agreement between the capillary blood glucose results obtained by the inpatient glucose POCT meter (Accuchek Inform II) and the readings obtained by the CGMS (Freestyle Libre); and that there exists an acceptable agreement between the serum glucose levels and the glucose values obtained by the CGMS. Methods This was an Institutional Review Board approved prospective cohort study for the non– critical inpatient setting. Fifty-two hospitalized patients with diabetes were recruited. After informed consent was obtained, patients were instructed on the application and use of the CGMS. The data were assessed using a standard regression analysis and modified Bland Altman analysis. All analyses were conducted using SAS, release 3.8 Enterprise Edition (SAS Institute Inc., Cary, NC). Results Fifty-two subjects recruited into the study represented a sample of convenience. There were a total of 467 AccuChek-Libre pairs, The regression analysis showed a negative bias between. Libre and AccuChek, R2 = 0.83, with Libre glucose readings on average being lower than those of AccuChek. Using Bland-Altman analysis, 42% of the 467 Libre-AccuChek pairs had a difference in glucose reading more than 15%. Mean absolute relative difference (MARD) between Libre and AccuChek was 15.6%; mean relative difference (MRD) between Libre and AccuChek was −11.4%. The regression analysis showed a negative bias between Libre and serum glucose, R2 = 0.89. Using Bland Altman analysis, 36% of the 44 Libre-serum pairs had a difference in glucose reading more than 15%. Mean absolute relative difference (MARD) between Libre and serum glucose was 13.2%; mean relative difference (MRD) between Libre and serum glucose was −12.5%. A review of the data pairs showed that 71/467 Accuchek-Libre pairs had one result that was either below 70 mg/dl or above 200 mg/dl (combined American Diabetes Association-ADA-, American College of Physicians-ACP- and American College of Endocrinology-AACE- goals). Thus 85%, of these pairs would have yielded results that engendered the same intervention (e.g. treatment for hypoglycemia or hyperglycemia). Likewise 5/45 Serum-Libre pairs had one result that was either below 70 mg/dl or above 200 mg/dl; thus 89% of these pairs would have yielded results requiring the same intervention. Conclusion/Interpretation These findings confirm the existent literature and indicate acceptable agreement between the standard POCT and the CGMS as well as between serum glucose and the CGMS values. Because of the advantages of the CGMS over capillary blood glucose testing (reduced patient discomfort and reduced staff exposure to patients in isolation) CGMS use may be preferable to the current bedside capillary blood glucose testing in hospitalized patients with diabetes mellitus. As with other laboratory measures, clinical judgement needs to be exercised when the laboratory values are used to guide patient care.

Parkinson's disease (PD) is a chronic neurodegenerative disorder that is characterized by motor symptoms as a result of a loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), accompanied by chronic neuroinflammation, oxidative stress, formation of α-synuclein aggregates. Celastrol, a potent anti-inflammatory and anti-oxidative pentacyclic triterpene, has emerged as a neuroprotective agent. However, the mechanisms by which celastrol is neuroprotective in PD remain elusive. Here we show that celastrol protects against dopamine neuron loss, mitigates neuroinflammation, and relieves motor deficits in MPTP-induced PD mouse model and AAV-mediated human α-synuclein overexpression PD model. Whole-genome deep sequencing analysis revealed that Nrf2, NLRP3 and caspase-1 in SNc may be associated with the neuroprotective actions of celastrol in PD. By using multiple genetically modified mice (Nrf2-KO, NLRP3-KO and Caspase-1-KO), we identified that celastrol inhibits NLRP3 inflammasome activation, relieves motor deficits and nigrostriatal dopaminergic degeneration through Nrf2-NLRP3-caspase-1 pathway. Taken together, these findings suggest that Nrf2-NLRP3-caspase-1 axis may serve as a key target of celastrol in PD treatment, and highlight the favorable properties of celastrol for neuroprotection, making celastrol as a promising disease-modifying agent for PD.

Background The Italian Lombardy region has been the epicenter of COVID-19 since February 2020. This study analyses the epidemiology of pediatric type 1 diabetes (T1D) onset during the first two pandemic waves and three previous years. Methods All the 13 pediatric diabetes centers in Lombardy prospectively evaluated charts of children at T1D onset (0–17 years), during year 2020. After calculating the annual incidence, the data were compared with those of the 3 previous years, using generalized linear models, adjusted for age and sex. Monthly T1D new onsets and diabetic ketoacidosis (DKA) were investigated yearly from 2017 to 2020. Data were extracted from outpatients charts of the pediatric diabetes centers and from the database of the national institute of statistics. Findings The estimated incidence proportion of T1D was 16/100·000 in 2020, compared to 14, 11 and 12 in 2019, 2018 and 2017, respectively. When adjusting for age and gender, the incidence was significantly lower in 2018 and 2017 compared to 2020 (adjusted incidence ratio: 0.73 and 0.77 respectively, with 95% CI: 0.63 to 0.84, and 0.67 to 0.83; p = 0·002 and p = 0·01), but no difference was found between the years 2020 and 2019. A reduction trend in the percentage of T1D diagnosis during the first wave (March-April) over the total year diagnoses was observed compared to previous years (11·7% in 2020, 17·7% in 2019, 14·1% in 2018 and 14·4% 2017). No difference was observed during the second wave (October-December) (32·8% in 2020, 33·8% in 2019, 34% in 2018, 30·7% in 2017). The proportion of DKA over the total T1D diagnoses during the second wave had higher trend than the first one (41·7% vs 33·3%), while severe DKA over the total DKA appeared higher during the first wave (60% vs 37·1%). Interpretation The study suggests an increase in the incidence of pediatric T1D in Lombardy throughout the past five years. Pandemic waves may have affected the clinical presentation at onset. Funding None.

Background: We describe the epidemiology of COVID-19 in South Africa following importation and during implementation of stringent lockdown measures. Methods: Using national surveillance data including demographics, laboratory test data, clinical presentation, risk exposures (travel history, contacts and occupation) and outcomes of persons undergoing COVID-19 testing or hospitalised with COVID-19 at sentinel surveillance sites, we generated and interpreted descriptive statistics, epidemic curves, and initial reproductive numbers (Rt). Findings: From 4 March to 30 April 2020, 271,670 SARS-CoV-2 PCR tests were performed (462 tests/100,000 persons). Of these, 7,892 (2.9%) persons tested positive (median age 37 years (interquartile range 28-49 years), 4,568 (58%) male, cumulative incidence of 13.4 cases/100,000 persons). Hospitalization records were found for 1,271 patients (692 females (54%)) of whom 186 (14.6%) died. Amongst 2,819 cases with data, 489/2819 (17.3%) travelled internationally within 14 days prior to diagnosis, mostly during March 2020 (466 (95%)). Cases diagnosed in April compared with March were younger (median age, 37 vs. 40 years), less likely female (38% vs. 53%) and resident in a more populous province (98% vs. 91%). The national initial Rt was 2.08 (95% confidence interval (CI): 1.71-2.51). Interpretation: The first eight weeks following COVID-19 importation were characterised by early predominance of imported cases and relatively low mortality and transmission rates. Despite stringent lockdown measures, the second month following importation was characterised by community transmission and increasing disease burden in more populous provinces. Funding Statement: South African National and provincial health departments. Declaration of Interests: We declare no competing interests. Ethics Approval Statement: Surveillance activities for NMC including SARS-COV-2 infection are conducted by the NICD according to National Health Act Regulations. Publication of surveillance data in the peer-reviewed literature was approved by the University of the Witwatersrand Human Research Ethics Committee (Medical) protocol M160667.

Background: Indonesia is undergoing a nutrition transition (NT) comprised of rising rates of over- weight/obesity and consumption of high fat food/snacks but is still struck by undernutrition, causing a double burden of malnutrition. Little research pertains to the double burden of malnutrition and its associations with diet in rural Indonesia using primary village level data. Methods: We conducted a 24-hour food recall and food frequency questionnaire and assessed anthropo- metric status of rural villagers from four villages in Central Java, Indonesia. Exploratory principal compo- nent analysis was used to identify dietary patterns and multi-level modeling was performed to identify variables associated with dietary pattern indicative of the NT. Findings: 1,521 participants were included in analysis. Double burden of malnutrition was prevalent whereby 32.3% of children were stunted, 68.8% of women 35-49 years-old were overweight, and 39% of homes were classified as double burden. The NT was evident in a dietary pattern associated with soft drink, snacks, and animal products. There was small but significant correlation between undernutri- tion and stunting status among children (r = −0.139, p < 0.01). The NT was associated with young age (B = 1.696, 95% CI = 1.508-1.885) but not with overweight (B = −0.099, 95% CI = −0.184-−0.013). Interpretation: Our findings suggest that whilst the typical pattern of the double burden of malnutrition (stunted child/overweight adult) exists in rural Central Java, dietary patterns indicative of the NT are predominant among children, not adults. Overweight among adults may not be necessarily due to a diet indicative of the NT, and nutrition interventions in rural Central Java should focus on educating parents of young children about the health-risks of a diet associated with a NT. Funding: Funding was obtained from the UBS-Optimus Foundation and the National Health and Medical Research Council.

Background Dyspnea and exercise intolerance are commonly reported post-acute sequelae of SARS-CoV-2 infection (PASC), but routine diagnostic testing is often normal. Cardiopulmonary exercise testing (CPET) offers comprehensive assessment of dyspnea to characterize pulmonary PASC. Methods We performed a retrospective cohort study of CPET performed on patients reporting dyspnea and/or exercise intolerance following confirmed Covid-19 between August 1, 2020 and March 1, 2021, and compared them to age- and sex-matched patients with unexplained dyspnea referred for CPET at the same center in the pre-Covid-19 era. Findings Compared to matched unexplained dyspnea comparators, PASC patients shared similar medical comorbidities and subjective dyspnea at referral (mMRC score 1.6 ± 0.9 vs. 1.4 ± 0.9, P = 0.5). Fifteen (83.3%) PASC patients underwent high resolution computed tomography of the chest, of which half (46.7%) were normal, and 17 (94.4%) patients had pulmonary function testing, of which the majority (76.5%) were normal. All patients underwent CPET, and 12 (67%) had normal findings. Compared to matched comparators, PASC patients had similar peak oxygen consumption, oxygen consumption at ventilatory anaerobic threshold, and ventilatory efficiency measured by the minute ventilation to carbon dioxide production (VE/VCO2) slope. Interpretation Despite prominent dyspnea, physiological abnormalities on CPET were mild across a range of initial Covid-19 severity and similar to matched comparators referred for dyspnea without antecedent SARS-CoV-2. Funding The project was supported by the NHLBI (R01HL131029, R01HL151841, U10HL110337, T32HL116275) and a KL2 award (5KL2TR002542–02) from Harvard Catalyst.

Background IBI362 (LY3305677) is a novel weekly-dose glucagon-like peptide-1 and glucagon receptor dual agonist being developed for the treatment of obesity and type 2 diabetes. The aim of this randomised, placebo-controlled, multiple ascending dose phase 1b study was to evaluate the safety, tolerability, pharmacokinetics and efficacy of IBI362 in Chinese adults with overweight or obesity. Methods This study enrolled adults with overweight (body mass index [BMI]≥24 kg/m2) accompanied by hyperphagia and/or at least one comorbidity or obesity (BMI≥28 kg/m2) from six study centres in China. Eligible participants were randomised 2:1 to receive once-weekly subcutaneous injection of IBI362 or placebo in each of the three ascending dose cohorts for 12 weeks with additional 8 weeks of safety follow-up. The dose-escalation regimens were: 3.0 mg cohort (1.0 mg weeks 1–4; 2.0 mg weeks 5–8; 3.0 mg weeks 9–12); 4.5 mg cohort (1.5 mg weeks 1–4; 3.0 mg weeks 5–8; 4.5 mg weeks 9–12); 6.0 mg cohort (2.0 mg weeks 1–4; 4.0 mg weeks 5–8; 6.0 mg weeks 9–12). The participants, investigators and study site personnel involved in treating and assessing participants within each cohort were masked to treatment allocation. The primary endpoints were safety and tolerability of IBI362. This study is registered with ClinicalTrials.gov, number NCT04440345. Findings Between June 15th, 2020 and January 15th, 2021, 12 participants were enrolled and randomised in each cohort. Throughout the study, no participant discontinued the treatment due to safety reason and no serious adverse event was reported. Gastrointestinal adverse events and decreased appetite were the most common adverse events and mostly mild in severity. Three participants receiving IBI362 reported mild and asymptomatic cardiac disorders revealed by electrocardiogram. Estimated percent changes in mean body weight from baseline to week 12 were −4.81% (95%CI −6.61 to −3.02), −6.40% (−8.23 to −4.58) and −6.05% (−7.91 to −4.18) for participants receiving IBI362 in the 3.0 mg, 4.5 mg and 6.0 mg cohort, respectively, compared with 0.60% (−0.86 to 2.07) for those receiving placebo. Interpretation IBI362 was well tolerated and showed a body weight-lowering effect in Chinese adults with overweight or obesity. Funding Innovent Biologics.

Background Because Forced Vital Capacity (FVC) is reduced in Black relative to White Americans of the same age, sex, and height, standard lung function prediction equations assign a lower "normal" range for Black patients. The prognostic implications of this race correction are uncertain. Methods We analyzed 5,294 White and 3,743 Black participants age 20–80 in NHANES III, a nationally-representative US survey conducted 1988–94, which we linked to the National Death Index to assess mortality through December 31, 2015. We calculated the FVC-percent predicted among Black and White participants, first applying NHANES III White prediction equations to all persons, and then using standard race-specific prediction equations. We used Cox proportional hazard models to calculate the association between race and all-cause mortality without and with adjustment for FVC (using each FVC metric), smoking, socioeconomic factors, and comorbidities. Findings Black participants’ age- and sex-adjusted mortality was greater than White participants (HR 1.46; 95%CI:1.29, 1.65). With adjustment for FVC in liters (mean 3.7 L for Black participants, 4.3 L for White participants) or FVC percent-predicted using White equations for everyone, Black race was no longer independently predictive of higher mortality (HR∼1.0). When FVC-percent predicted was “corrected” for race, Black individuals again showed increased mortality hazard. Deaths attributed to chronic respiratory disease were infrequent for both Black and White individuals. Interpretation Lower FVC in Black people is associated with elevated risk of all-cause mortality, challenging the standard assumption about race-based normal limits. Black-White disparities in FVC may reflect deleterious social/environmental exposures, not innate differences. Funding No funding.

Background Patients with breast cancer presenting with single lymph node metastasis (from a sentinel node) experience prolonged survival compared to patients with multiple lymph node metastases (≥3). However, little information is available on the genetic and immunological characteristics of breast cancer metastases within the regional lymph nodes as they progress from the sentinel lymph node (SLN) downstream to multiple regional lymph nodes (MLNs). Methods Genomic profiling was performed using a next-generation sequencing panel covering 520 cancer-related genes in the primary tumour and metastatic lymph nodes of 157 female patients with breast cancer. We included primary tumours, metastatic lymph nodes and adjacent clinically normal lymph nodes (20 patients from the SLN group and 28 patients from the MLNs group) in the whole transcriptome analysis. Findings The downstream metastatic lymph nodes (P = 0.029) and the primary breast tumours (P = 0.011) had a higher frequency of PIK3CA mutations compared to the SLN metastasis. We identified a distinct group of 14 mutations from single sentinel node metastasis and a different group of 15 mutations from multiple nodal metastases. Only 4 distinct mutations (PIK3CA, CDK4, NFKBIA and CDKN1B) were conserved in metastases from both lymph node settings. The tumour mutational burden (TMB) was significantly lower in single nodal metastasis compared to the paired primary breast cancer (P = 0.0021), while the decline in TMB did not reach statistical significance in the MLNs group (P = 0.083). In the gene set enrichment analysis, we identified 4 upregulated signatures in both primary tumour and nodal metastases from the MLNs group, including 3 Epithelial-mesenchymal transition(EMT) signatures and 1 angiogenesis signature. Both the CD8/Treg ratio and the CD8/EMT ratio were significantly higher in adjacent normal lymph nodes from patients with a single metastasis in the SLN compared with samples from the MLNs group (P = 0.045 and P = 0.023, respectively). This suggests that the immune defence from the MLNs patients might have a less favourable microenvironment, thus permitting multiple lymph nodes metastasis. Interpretation Single lymph node metastases and multiple lymph node metastases have significant differences in their molecular profiles and immune profiles. The findings are associated with more aggressive tumour characteristics and less favourable immune charactoristics in patients with multiple nodal metastases compared to those with a single metastasis in the sentinel node. Funding This work was supported by funds from High-level Hospital Construction Project (DFJH201921), the National Natural Science Foundation of China (81902828 and 82002928), the Fundamental Research Funds for the Central Universities (y2syD2192230), and the Medical Scientific Research Foundation of Guangdong Province (B2019039).

Background: Operating schools safely under pandemic conditions is a widespread policy goal. We analyse the effectiveness of classroom cohorting, i.e., the decomposition of classrooms into smaller isolated units, in inhibiting the spread of SARS-CoV-2 in European secondary schools and compare different cohorting strategies. Methods: Using real-world network data on 12,291 adolescents collected in classrooms in England, Germany, the Netherlands, and Sweden in 2010/2011, we apply agent-based simulations to compare the effect of forming cohorts randomly to network-based cohorting. Network-based cohorting attempts to allocate out-of-school contacts to the same cohort to prevent cross-cohort infection more effectively. We consider explicitly minimizing out-of-school cross-cohort contacts, approximating this information-heavy optimization strategy by chained nominations of contacts, and dividing classrooms by gender. We also compare the effect of instructing cohorts in-person every second week to daily but separate in-person instruction of both cohorts. Findings: We find that cohorting reduces the spread of SARS-CoV-2 in classrooms. Relative to random cohorting, network-based strategies further reduce infections and quarantines when transmission dynamics are strong. In particular, network-based cohorting inhibits superspreading in classrooms. Cohorting that explicitly minimizes cross-cohort contacts is most effective, but approximation based on chained nominations and classroom division by gender also outperform random cohorting. Every-second-week instruction in-person contains outbreaks more effectively than daily in-person instruction of both cohorts. Interpretation: Cohorting of school classes can curb SARS-CoV-2 outbreaks in the school context. Factoring in out-of-school contacts can achieve a more effective separation of cohorts. Network-based cohorting reduces the risk of outbreaks in schools and can prevent superspreading events. Funding: None.

Highlights • We created a new algorism to detect a left atrial appendage (LAA) thrombus on CT. • We measured HU density at one proximal (ostium) and seven distal sites of LAA. • A distal/proximal ratio and a standard deviation of HU density were analyzed by ROC. • Combination of the two parameters demonstrated a high accuracy for LAA thrombus., Background Transesophageal echocardiography (TEE) is currently the gold standard technique for diagnosing left atrial appendage (LAA) thrombi. Cardiac computed tomography (CT) has been expected to become an alternative method to TEE; however, a reliable quantitative evaluation method has not been established. Methods and results We enrolled 177 patients with persistent atrial fibrillation who underwent both cardiac CT and TEE before catheter ablation. The patients were classified into two groups according to the TEE results: the thrombus group (13 patients) and non-thrombus group (164 patients). The Hounsfield unit (HU) density at the proximal LAA (LAAp) and distal LAA (LAAd) was measured on cardiac CT images. The LAAd/LAAp HU ratio and standard deviation of HU density (HU-SD) at the LAAd were evaluated. We created an algorithm by decision tree analysis to predict LAA thrombus formation using the HU ratio and HU-SD. Definite absence of LAA thrombus (Category-I) was diagnosed for 139 patients by combining the first and second branching of the decision tree (Category-Ia: HU ratio of ≥0.26, Category-Ib: HU ratio of

The trace element selenium is of essential importance for the synthesis of a set of redox active proteins. We investigated three complementary serum selenium status biomarkers in relation to overall survival and recurrence following diagnosis of primary invasive breast cancer in a large prospective cohort study. The Sweden Cancerome Analysis Network – Breast Initiative (SCAN-B) is a prospective population-based study including multiple participating hospitals. Main analyses included 1996 patients with a new diagnosis of primary invasive breast cancer, with blood sampling at the time of diagnosis. In sera of the patients, total serum selenium, selenoprotein P (SELENOP), and glutathione peroxidase 3 (GPx3) activity was analysed. All three biomarkers showed a positive correlation (p, Graphical abstract Image 1, Highlights • Three different serum biomarkers of selenium status are inversely associated with all-cause mortality following breast cancer diagnosis. • Lower serum glutathione peroxidase 3 activity is associated with more recurrences following breast cancer. • Patients in the lowest quintile regarding all three serum biomarkers have a particularly high all-cause mortality.

Background: Monitoring rates of severe maternal morbidity (such as eclampsia and uterine rupture) is useful to assess the quality of obstetric care, particularly in low and lower-middle-income countries (LMICs). Methods: We undertook a systematic review characterising the proportion and causes of severe maternal morbidity in the Asia Pacific region. We searched Medline, Embase, Cochrane CENTRAL library and the World Health Organization Western Pacific Index database for studies in the Asia-Pacific reporting maternal morbidity/near miss using a predefined search strategy. We included cohort, case-control and cross-sectional studies published in English before September 2020. A meta-analysis was performed calculating the overall proportion of near miss events by sub-region, country, near miss definition, economic status, setting and cause using a random-effects model. Findings: We identified 26,232 articles, screened 24,306 and retrieved 454 full text articles. Of these, 197 studies spanning 27 countries were included. 13 countries in the region were not represented. There were 30,183,608 pregnancies and 100,011 near misses included. The total proportion of near miss events was 4•4 (95% CI 4•3-4•5) per 1000 total births. The greatest proportion of near misses were found in the Western Pacific region (around Papua New Guinea) at 11•8 per 1000 births (95% CI 6•6-17•1; I2 96.05%). Low-income countries displayed the greatest proportion of near misses (13•4, 95% CI 6•0-20•7), followed by lower-middle income countries (11•1; 95% CI 10•4 - 11•9). High-income countries had the lowest proportion (2•2, 95% CI 2•1-2•3). Postpartum haemorrhage was the most common near miss event (5•9, 95% CI 4•5-7•2), followed by eclampsia (2•7, 95% CI 2•4 - 2•9). Interpretation: There is a high burden of severe maternal morbidity in the Asia-Pacific. LMICs are disproportionately affected. Most of the common causes are preventable. This provides an opportunity to implement targeted interventions which could have major clinical impact.

Background: In-hospital cardiac arrest (IHCA) carries a high mortality and significant morbidity in survivors. Gastrointestinal bleeding (GIB) can complicate cardiac arrests. We aim to study the association between GIB and the in-hospital outcomes of patients with IHCA. Methods and results: The National Inpatient Sample 2016–2018 databases were used. IHCA were identified using ICD-10-PCS code for cardiopulmonary resuscitation. Other diagnoses including GIB were identified using ICD-10-CM codes. Multivariate logistic regression was used to study the effect of GIB on in-hospital mortality. Gamma regression with log link was used to determine the effect of GIB on length of stay and cost of admission. In patients with IHCA, GIB as a secondary diagnosis is associated with an increased in hospital mortality (unadjusted 74.2% vs 68.3%, adjusted OR 1.17, 95% confidence interval [CI] 1.09–1.25, p

Background: The COVID-19 pandemic restrictions affect provision and quality of neonatal care. This global study explores parents' experiences regarding the impact of the restrictions on key characteristics of infant and family-centred developmental care (IFCDC) during the first year of the pandemic. Methods: For this cross-sectional study, a pre-tested online survey with 52 questions and translated into 23 languages was used to collect data between August and November 2020. Parents of sick or preterm infants born during the pandemic and receiving special/intensive care were eligible for participation. Data analysis included descriptive statistics and statistical testing based on different levels of restrictive measures. Findings: In total, 2103 participants from 56 countries provided interpretable data. Fifty-two percent of respondents were not allowed to have another person present during birth. Percentages increased with the extent of restrictions in the respondents' country of residence (p = 0.002). Twenty-one percent of total respondents indicated that no-one was allowed to be present with the infant receiving special/intensive care. The frequency (p < 0.001) and duration (p = 0.001) of permitted presence largely depended on the extent of restrictions. The more restrictive the policy measures were, the more the respondents worried about the pandemic situation during pregnancy and after birth. Interpretation: COVID-19 related restrictions severely challenged evidence-based cornerstones of IFCDC, such as separating parents/ legal guardians and their newborns. Our findings must therefore be considered by public health experts and policy makers alike to reduce unnecessary suffering, calling for a zero separation policy. Funding: EFCNI received an earmarked donation by Novartis Pharma AG in support of this study. (c) 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Introduction A reliable biomarker is urgently needed in the diagnosis and management of acid sphingomyelinase deficiency (ASMD, also known as Niemann Pick A, A/B, and B). Lyso-sphingomyelin (LSM) has previously been proposed as a biomarker for this disease. However, existing studies have not investigated the relationship between LSM levels and clinical subtype or severity. The purpose of this study is to address this gap in knowledge. Material and methods We present a cross-sectional study of 28 patients with ASMD, enrolled in an ongoing natural history study at the Icahn School of Medicine at Mount Sinai and The Children's Hospital at Montefiore. Plasma LSM levels from 28 patients were analyzed, including 7 patients with the infantile neurovisceral phenotype (ASMD type A), 3 patients with chronic neurovisceral disease (ASMD type A/B) and 18 patients with chronic visceral ASMD (ASMD type B). The association between LSM levels and clinical subtype, dichotomized as infantile (type A) or chronic (type A/B and B), was analyzed using the Wilcoxon rank sum test. In secondary analysis, the association between LSM levels and clinical severity among the chronic ASMD patients was analyzed using the Kruskal-Wallis test. Results LSM levels were elevated in all patients with ASMD when compared to a reference range of (0.04–3.8 (ng/mL)). Median LSM levels were higher in patients with infantile ASMD (386 ng/mL [314, 605]) compared to chronic ASMD (133 ng/mL [90, 209]), p, Highlights • Lyso-sphingomyelin (LSM) has previously been proposed as a biomarker for acid sphingomyelinase deficiency (ASMD). • Existing studies have not investigated the relationship between degree of LSM elevation and clinical subtype or severity. • We present a cross-sectional study of 28 patients with ASMD enrolled in an ongoing natural history study. • LSM levels were elevated in all patients with ASMD compared to reference ranges. • Median LSM levels were higher in patients with infantile ASMD compared to chronic ASMD. • Among individuals with chronic ASMD, there was a positive association between LSM level and clinical severity.

The removal/recovery of cadmium from wastewaters by conventional technologies is proving expensive due to the non-renewability of the materials used and the high costs of both operation and materials. Biosorption using agricultural wastes is emerging as a method that offers economical alternate biological materials to save the purpose. Functional groups like carboxyl, hydroxyl, sulphydryl, and amido present in these Agricultural waste-based biosorbents (AWB) make it possible for them to attach Cd2+ from waters. This review article discusses the potential use of different AWBs for the removal of cadmium in terms of their adsorption efficiencies, variable influencing factors, and pre-treatment methods. The literature studies consulted signpost that AWBs have equal and even greater adsorption capabilities in some cases compared to conventional adsorbents. Initial concentration, pH, ionic strength, co-ions, biosorbent dosage, temperature, and particle size of AWBs significantly determine the biosorption potential for Cd2+ removal. Furthermore, physical and chemical pre-treatments of AWBs bring remarkable improvement in Cd2+ uptake capacity, but some chemical additives have been found to have negative impacts on aquatic life. Nevertheless, there are some gaps observed, which require further study, such as (i) searching for pre-treatment chemicals with maximum adsorption potential enhancement with minimal impact on aquatic lives, (ii) developing the most cost-effective modification methods, and (iii) assessing AWBs under real wastewater systems. The study moreover recommends that the extensive use of AWBs should not jeopardize food security.

Background: COVID-19 symptomatology in Africa appears significantly less serious than in the industrialized world. We and others previously postulated a partial explanation for this phenomenon, being a different, more activated immune system due to parasite infections. We investigated this hypothesis in an endemic area in Africa. Methods: Ethiopian COVID-19 patients were enrolled and screened for intestinal parasites. The primary outcome was the proportion of patients with severe COVID-19. Logistic regression models were used to estimate the association between parasite infection, and COVID-19 severity. Models were adjusted for sex, age, residence, and comorbidities. Findings: 751 SARS-CoV-2 infected patients were enrolled, of whom 284 (37·8%) had intestinal parasitic infection. Only 27/255 (10·6%) severe COVID-19 patients were co-infected with intestinal parasites, while 257/496 (51·8%) non-severe COVID-19 patients appeared parasite positive (p

Background: Although an elevated systolic blood pressure (SBP) is associated with cognitive dysfunction, BP may decrease with advanced cognitive dysfunction; therefore, we attempted to identify the turning point in the relationship between cognitive function and SBP in elderly subjects. Methods: In pooled datasets of general populations and outpatient clinics (age>65 years), in which the risk of frailty or cognitive dysfunction was assessed (N = 4076), the relationship between SBP and the Mini Mental State Examination (MMSE) score was examined. Results: Mean age was 72.5 ± 6.2 years (male 45.1%), and SBP was 133.0 ± 19.5 mmHg. In an analysis of locally weighted scatter plot smoothing, the relationship between SBP and MMSE scores changed at an MMSE score of 24 points. In subjects with preserved cognitive function (MMSE ≥24 points), MMSE scores decreased with increases in SBP (B = −0.047 per 10 mmHg increase, P = 0.002) after adjustments for age, sex, body mass index, alcohol habit, smoking status, diabetes, a history of stroke, and the geriatric nutritional index; however, in subjects with reduced cognitive function (MMSE

Background Plasma ferritin is a widely used indicator to detect iron deficiency, but the threshold ferritin that defines iron deficiency remains uncertain. Our aim was to define the ferritin concentration at which the body begins to upregulate iron absorption from the diet; this could provide a functionally-defined threshold of incipient iron deficiency. We hypothesized this threshold ferritin concentration would correspond to the threshold hepcidin concentration at which iron absorption begins to increase. Methods We performed a pooled analysis of our stable iron isotope studies (n = 1058) conducted from 2006 to 2019 in healthy women (age 18–50 years; mean±SD ferritin 33.7 ± 27.1 μg/L) that measured iron absorption from labeled test meals providing physiological amounts of iron. To fit relationships between iron absorption, ferritin and hepcidin, we used generalized additive modeling, and to identify thresholds, we estimated the first derivatives of the fitted trend to assess inflection points in these relationships. Findings Hepcidin increased linearly with increasing ferritin over the entire range of ferritin values. Iron absorption began to increase below a threshold hepcidin value of 3.09 (95%CI: 2.80, 3.38) nmol/l, above which iron absorption remained stable. Iron absorption began to increase below a threshold ferritin value of 51.1 (95%CI: 49.1, 53.1) µg/l, above which iron absorption remained stable. The latter two findings were internally consistent in that, in the relationship between hepcidin and ferritin, a hepcidin of ~3 nmol/l corresponded to a ferritin of ~51 µg/l. Interpretation Based on physiological upregulation of iron absorption, a threshold ferritin of, EClinicalMedicine, 39

Funding Information: Outside the submitted work, the authors disclose the following. Bausell H received personal fees from BioMarin, Ultragenyx, Horizon and Vitaflo. Bélanger-Quintana A reports personal fees from BioMarin, Nutricia, Vitaflo, Orphan Europe, Takeda and Genzyme. Rocha JC received research grants from BioMarin, Glutamine and Cambrooke, as well as personal fees from BioMarin, Applied Pharma Research, Nutricia, Merck Serono, Vitaflo, Cambrooke, PIAM and Lifediet. MacDonald A reports research funding from BioMarin, Nutricia, Applied Pharma Research, Vitaflo, Galen, Metax, Mevalia and Arla, as well as lecture fees from BioMarin, Applied Pharma Research, Nutricia and Vitaflo, and consultancy fees from BioMarin, Applied Pharma Research, Arla, Nutricia and Vitaflo. Met Ed reports grant funding from BioMarin, Nutricia, Vitaflo and Horizon Pharmaceuticals. Bernstein L and Rohr F report lecture fees from Vitaflo. Publisher Copyright: © 2021 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved. Background: The metabolic dietitian/nutritionist (hereafter ‘dietitian’) plays an essential role in the nutritional management of patients with phenylketonuria (PKU), including those on pegvaliase. Currently, more educational support and clinical experience is needed to ensure that dietitians are prepared to provide optimal nutritional management and counselling of pegvaliase-treated patients. Methods: Via a face-to-face data-review meeting, followed by a virtual consolidation meeting, a group of expert dietitians and one paediatrician discussed and developed a series of recommendations on the nutritional evaluation and management of patients receiving pegvaliase. The consensus group consisted of 10 PKU experts: six dietitians and one paediatrician from Europe and three dietitians from the US. One European and three US dietitians had experience with pegvaliase-treated patients. Results: The consensus group recommended that a physician, dietitian and nurse are part of the pegvaliase treatment team. Additionally, a psychologist/counsellor should be included if available. Practical proposals for the nutritional evaluation of pegvaliase-treated patients at baseline, during the induction and titration phases and for long-term maintenance were developed. The consensus group suggested assessment of blood Phe at least monthly or every 2 weeks in the event of low blood Phe (i.e., blood Phe

The use of botulinum neurotoxin-A (BoNT-A) is an alternative for the management of orofacial pain disorders. Although only Botox has labeled, there are other commercial brands available for use, among them: Dysport, Botulift, Prosigne, and Xeomin. The objective of the present study was to evaluate the possible differences in the antinociceptive effect evoked by different commercially available formulations of BoNT-A in an animal model of inflammatory orofacial pain induced by formalin injection. Male C57/BL6 mice (20–25 g) were submitted to the pre-treatment with five different commercial brands of BoNT-A (Botox, Botulift, Xeomin, Dysport, or Prosigne; with doses between 0.02 and 0.2 Units of Botulinum Toxin, in 20 μL of 0.9% saline) three days prior the 2% formalin injection. All injections were made subcutaneously into the right perinasal area. After formalin injections, nociceptive behaviors like rubbing the place of injection were quantified during the neurogenic (0–5 min) and inflammatory (15–30 min) phases. The treatment using Botox, Botulift, and Xeomin were able to induce antinociceptive effects in both phases of the formalin-induced pain animal model, however, Dysport and Prosigne reduced the response in neither of them. Our data suggest that the treatment using different formulations of BoNT-A is not similar in efficacy as analgesics when evaluated in formalin-induced orofacial pain in mice., Graphical abstract Image 1, Highlights • Botulinum neurotoxin-a reduced formalin-induced orofacial pain in mice. • There are differences in the analgesic potential of different available commercial brands of botulinum neurotoxin-A. • Botox, Botulift, Xeomin demonstrated analgesic effect when evaluated in formalin-induced orofacial pain in mice.

Background: Prolonged QT intervals are reported in patients with COVID-19. Additionally, virus particles in heart tissue and abnormal troponin levels have been reported. Consequently, we hypothesize that cardiac electrophysiologic abnormalities may be associated with COVID-19. Methods: This is a retrospective study between March 15th, 2020 and May 30th, 2020 of 828 patients with COVID-19 and baseline ECG. Corrected QT (QTc) and QRS intervals were measured from ECGs performed prior to intervention or administration of QT prolonging drugs. QTc and QRS intervals were evaluated as a function of disease severity (patients admitted versus discharged; inpatients admitted to medical unit vs ICU) and cardiac involvement (troponin elevation >0.03 ng/ml, elevated B-natriuretic peptide (BNP) or NT pro-BNP >500 pg/ml). Multivariable analysis was used to test for significance. Odds ratios for predictors of disease severity and mortality were generated. Findings: Baseline QTc of inpatients was prolonged compared to patients discharged (450.1±30.2 versus 423.4±21.7 msec, p

BackgroundThe importance of the maternal-infant dyad in the genesis of nonalcoholic fatty liver disease (NAFLD) is of increasing interest. The Avon Longitudinal Study of Parents and Children (ALSPAC) showed that at age 24, 1 in 5 had NAFLD measured by transient elastography and controlled attenuation parameter (CAP). Our aim was to investigate the association between breastfeeding duration and maternal pre-pregnancy BMI on offspring NAFLD in young adulthood.Methods4021 participants attended clinic for FibroScan and CAP measurement using Echosens 502 Touch®. 440 participants with Alcohol Use Disorders were excluded. Offspring of 100 non-singleton pregnancies were excluded. 2961 valid CAP measurements for NAFLD were analysed. Exposures of interest were breastfeeding of any duration, ≥6months exclusive breastfeeding, and maternal pre-pregnancy BMI. Multivariable regression models estimated the odds of NAFLD at 24 years. We performed a paternal negative control test to explore residual confounding in the analyses of pre-pregnancy BMI.FindingsThere was a modest inverse association of exclusive and non-exclusive breastfeeding ≥6 months having a protective effect on NAFLD in offspring (OR 0·92 [95%CI 0·66-1·27] and OR 0·90 [0·67-1·21] respectively).The odds of offspring NAFLD in overweight pre-pregnancy maternal BMI and paternal BMI was OR 2·09 [1·62-2·68] and OR 1·33 [95%CI 1·07-1·65] respectively, with the ratio of effect sizes OR 1·57 [1·11-2·22]. Similarly, odds of offspring NAFLD with obese pre-pregnancy maternal BMI and paternal BMI was OR 2·66 [1·71-4·14] and OR 1·35 [0·91-2·00] respectively, with the ratio of effect sizes OR 1·98 [1·05-3·74].InterpretationHigher maternal pre-pregnancy BMI was associated with offspring NAFLD, having accounted for shared parental confounding. We did not replicate previous work that found a strong association between breastfeeding and NAFLD.FundingMedical Research Council UK, Alcohol Research UK, David Telling Charitable TrustKeywordsALSPACNon-alcoholic fatty liver diseaseYoung adultsTransient elastographyControlled attenuation parameterBreastfeedingMaternal pre-pregnancy BMI

Background Research priority setting in health care has historically been done by expert health care providers and researchers and has not involved patients, family or the public. Survivors & family members have been particularly absent from this process in the field of resuscitation research and specifically adult out of hospital cardiac arrest (OHCA). As such, we sought to conduct a priority setting exercise in partnership with survivors, lay responders and their families in order to ensure that their priorities were visible. We partnered with the James Lind Alliance (UK) and used their commonly used consensus methodology for Public Priority Setting Partnerships (PSPs) to identify research priorities that reflected the perspectives of all stakeholders. Methods We used two rounds of public and health care professional surveys to create the initial priority lists. The initial survey collected open-ended questions while the second round consolidated the list of initial questions into a refined list for prioritization. This was done by reviewing existing evidence and thematic categorization by the multi-disciplinary steering committee. An in-person consensus workshop was conducted to come to consensus on the top ten priorities from all perspectives. The McMaster PPEET tool was used to measure engagement. Results The initial survey yielded more than 425 responses and 1450 “questions” from survivors and family members (18%), lay responders, health care providers and others. The second survey asked participants to rank a short list of 125 questions. The final top 25 questions were brought to the in-person meeting, and a top ten were selected through the JLA consensus process. The final list of top ten questions included how to improve the rate of lay responder CPR, what interventions used at the scene of an arrest can improve resuscitation and survival, how survival can be improved in rural areas of Canada, what resuscitation medications are most effective, what care patient’s family members need, what post-discharge support is needed for survivors, how communication should work for everyone involved with a cardiac arrest, what factors best predict neurologically intact survival, whether biomarkers/genetic tests are effective in predicting OHCA and more research on the short and long-term psycho-social impacts of OHCA on survivors. The PPEET showed overwhelmingly positive results for the patient and family engagement experience during the final workshop. Conclusions This inclusive research priority setting provides essential information for those doing resuscitation research internationally. The results provide a guide for priority areas of research and should drive our community to focus on questions that matter to survivors and their families in our work. In particular the Canadian Resuscitation Outcomes Consortium will be incorporating the top ten list into its strategic plan for the future.

Background Electroencephalography (EEG) is commonly used after cardiac arrest. Burst suppression with identical bursts (BSIB) has been reported as a perfectly specific predictor of poor outcome but published case series are small. We describe two patients with BSIB who awakened from coma after cardiac arrest. Methods We identified two out-of-hospital cardiac arrest (OHCA) patients with coma and BSIB. We determined the etiology of arrest, presenting neurological examination, potential confounders to neurological assessment, neurodiagnostics and time to awakening. We reviewed and interpreted EEGs using 2021 American Clinical Neurophysiology Society guidelines. We quantified identicality of bursts by calculating pairwise correlation coefficients between the first 500 ms of each aligned burst. Results In case one we present a 62-year-old man with OHCA secondary to septic shock. EEG showed burst suppression pattern, with bursts consisted of high amplitude generalized spike waves in lock-step with myoclonus (inter-burst correlation = 0.86). He followed commands 3 days after arrest, when repeat EEG showed a continuous, variable and reactive background without epileptiform activity. Case two was a 49-year-old woman with OHCA secondary to polysubstance overdose. Initial EEG revealed burst suppression with high amplitude generalized polyspike-wave bursts with associated myoclonus. She followed commands on post-arrest day 4, when repeat EEG showed a continuous, variable and reactive background with frequent runs of bifrontal predominant sharply contoured rhythmic delta activity. Conclusion These cases highlight the perils of prognosticating with a single modality in comatose cardiac arrest patients.

Measles-containing vaccines (MCV), specifically vaccines against measles and rubella (MR), are extremely effective and critical for the eradication of measles and rubella diseases. In developed countries, vaccination rates are high and vaccines are readily available, but continued high prevalence of both diseases in developing countries and surges in measles deaths in recent years have highlighted the need to expand vaccination efforts. To meet demand for additional vaccines at a globally affordable price, it is highly desirable to streamline vaccine production thereby reducing cost and speeding up time to delivery. MR vaccine characterization currently relies on the 50% cell culture infectious dose (CCID50) assay, an endpoint assay with low reproducibility that requires 10-14 days to complete. For streamlining bioprocess analysis and improving measurement precision relative to CCID50, we developed the VaxArray Measles and Rubella assay kit, which is based on a multiplexed microarray immunoassay with a 5-hour time to result. Here we demonstrate vaccine-relevant sensitivity ranging from 345 – 800 IFU/mL up to 100,000 IFU/mL and specificity that allows simultaneous analysis in bivalent vaccine samples. The assay is sensitive to antigen stability and has minimal interference from common vaccine additives. The assay exhibits high reproducibility and repeatability, with 15% CV, much lower than the typical 0.3 log10 error (~65%) observed for the CCID50 assay. The intact protein concentration measured by VaxArray is reasonably correlated to, but not equivalent to, CCID50 infectivity measurements for harvest samples. However, the measured protein concentration exhibits equivalency to CCID50 for more purified samples, including concentrated virus pools and monovalent bulks, making the assay a useful new tool for same-day analysis of vaccine samples for bioprocess development, optimization, and monitoring.

Background Malignant gliomas are deadly tumours with few therapeutic options. Although immunotherapy may be a promising therapeutic strategy for treating gliomas, a significant barrier is the CD11b+ tumour-associated myeloid cells (TAMCs), a heterogeneous glioma infiltrate comprising up to 40% of a glioma's cellular mass that inhibits anti-tumour T-cell function and promotes tumour progression. A theranostic approach uses a single molecule for targeted radiopharmaceutical therapy (TRT) and diagnostic imaging; however, there are few reports of theranostics targeting the tumour microenvironment. Methods Utilizing a newly developed bifunctional chelator, Lumi804, an anti-CD11b antibody (αCD11b) was readily labelled with either Zr-89 or Lu-177, yielding functional radiolabelled conjugates for PET, SPECT, and TRT. Findings 89Zr/177Lu-labeled Lumi804-αCD11b enabled non-invasive imaging of TAMCs in murine gliomas. Additionally, 177Lu-Lumi804-αCD11b treatment reduced TAMC populations in the spleen and tumour and improved the efficacy of checkpoint immunotherapy. Interpretation 89Zr- and 177Lu-labeled Lumi804-αCD11b may be a promising theranostic pair for monitoring and reducing TAMCs in gliomas to improve immunotherapy responses. Funding A full list of funding bodies that contributed to this study can be found in the Acknowledgements section., Graphical abstract Image, graphical abstract

Background Machine learning techniques can explore low prevalence data to offer insight into identification of factors associated with non-marital sexual violence (NMSV). NMSV in India is a health and human rights concern that disproportionately affects adolescents, is under-reported, and not well understood or addressed in the country. Methods We applied machine learning methods to retrospective cross-sectional data from India's nationally-representative National Family Health Survey 4, a demographic and health study conducted in 2015–16, which offers 4000+ variables as potential independent variables. We used Least Absolute Shrinkage and Selection Operator (lasso) or L-1 regularized logistic regression models as well as L-2 regularized logistic regression or ridge models; we conducted an iterative thematic analysis (ITA) of variables generated from a series of regularized models. Findings Thematic analysis of regularized models highlight that past exposure to violence was most predictive of NMSV, followed by geography, sexual behavior, and poor sexual and reproductive health knowledge. After these, indicators largely related to resources and autonomy (e.g., access to health services, and income generating) were associated with NMSV. Exploratory analysis with the subsample of never married adolescents 15–19 years old, a population with higher representation of recent NMSV, further emphasized the role of wealth and mobility as key correlates of NMSV, along with poor HIV knowledge, tobacco use, higher fertility preferences, and attitudes accepting of marital violence. Interpretation Findings indicate the validity of machine learning with iterative theme analysis (ITA) to identify factors associated with violence. Findings were consistent with prior work demonstrating associations between NMSV and other violence experiences, but also showed novel correlates such as lower SRH knowledge and service utilization and, for girls, norms and preferences suggesting more restrictive gender norms. Sexual and reproductive health, gender equity and safety focused interventions are important for addressing NMSV in India, particularly for adolescents. Funding This work was funded by the Bill and Melinda Gates Foundation, Grant OPP1179208 (PI: Raj).

Huge quantities of harvest wastes that are generated from agricultural practices at every farming season in Nigeria are not put into significant use. As an attempt towards adopting these abundant by-products as bioenergy resources for electricity generation, yearly quantities of both cocoa and kolanut harvest residues were estimated in this study. Hygroscopic natures and moisture contents of the two, and their blends, were also analyzed and compared. It was estimated that approximately 681,000 tons and 90,000 tons of cocoa and kolanut husks respectively, are produced in the country annually. While the proximate analyses showed that the sample made of 100% cocoa waste had the least volatile matter and moisture contents in addition to having highest fixed ash and fixed carbon contents, the reverse was the case with the sample made of 100% kolanut waste composition. From the ultimate analyses, however, the latter appears to possess the best characteristic (highest hydrogen and least oxygen contents), but its highest nitrogen content is a pointer to its exhibition of poor thermal property. The gross calorific contents of the samples were, therefore employed for definitive determination of their thermoelectric potentials and these gave higher heating values of 15.19 MJ/kg and 13.87 MJ/kg respectively, with the blends having their values within this range in proportionality to the mass percentage of kolanut husk in the blends. In addition to the two wastes exhibiting good energy characteristics, the study concludes that their blending offers benefit of reduction in ash content. At the optimal blend of equal composition of the two materials (50%CPH/50%KPH), it was estimated that 29,000 MW of electricity is accruable from the wastes., Highlights • Cocoa and kolanut harvest wastes of 681,000 and 90,000 tons respectively, are generated in Nigeria annually. • HHVs of the two agro-residues are 15.19 and 13.87 MJ/kg respectively, with their blends having values within this range. • The optimal blend composition of the two agro-residues has electric power generation potential estimated at 29,000 MW., Agro-wastes, biofuel materials, cocoa pod husk, kolanut pod husk, biomass blends, electrification.

Background New-onset atrial fibrillation (AF) in critically ill patients is associated with adverse outcomes. In non-critical settings, the circadian variation in paroxysmal AF is of significant interest; however, circadian variation in critically ill patients with new-onset AF has not been thoroughly studied. This study aimed to examine the association between AF onset time and in-hospital mortality. Methods This was a secondary analysis of a prospective multicenter observational study enrolling adult critically ill patients. According to AF onset time, patients were divided into nighttime (0:00–7:59), daytime (8:00–15:59), and evening (16:00–23:59). We conducted a multiple logistic regression analysis to assess the potential association between AF onset time and in-hospital mortality. We also assessed the distribution of AF onset, crude in-hospital mortality, and adjusted in-hospital mortality according to bihourly intervals. Results Of 423 patients, in-hospital mortality was 26%. During nighttime, 135 patients (32%) developed new-onset AF. AF emerged during daytime for 141 (33%) and during evening for 147 (35%). Daytime AF was significantly associated with an increased risk of in-hospital mortality (adjusted OR: 1.92; 95% CI: 1.07–3.44; p = 0.030). Bihourly interval analysis showed that adjusted in-hospital mortality was unevenly distributed and bimodal with troughs between 6:00 and 7:59 and between 18:00 and 19:59. A similar trend was seen in the distribution of the number of new-onset AF. Conclusions We found that the bihourly adjusted in-hospital mortality was distributed in a bimodal fashion. Further research is needed to determine the causes of the diurnal variation and its impact on patient outcomes.

Background Survival following liver transplant (LT) is influenced by a variety of factors, including donor risk factors and recipient disease burden and co-morbidities. It is difficult to separate these effects from those of socioeconomic factors, such as income or insurance. The United Network for Organ Sharing (UNOS) created equitable access policies, such as Share 35, to ensure that organs are distributed to individuals with greatest medical need; however, the effect of Share 35 on disparities in post-LT survival is not clear. This study aimed to (1) characterize associations between post-transplant survival and race and ethnicity, income, insurance, and citizenship status, when adjusted for other clinical and demographic factors that may influence survival, and (2) determine if the direction of associations changed after Share 35. Methods A retrospective, cohort study of adult LT recipients (n = 83,254) from the UNOS database from 2005 to 2019 was conducted. Kaplan-Meier survival graphs and stepwise multivariate cox-regression analyses were performed to characterize the effects of socioeconomic status on post-LT survival, adjusted for recipient and donor characteristics, across the time period and after Share 35. Findings Male sex (HR: 0.93 (95% CI: 0.90-0.96)), private insurance (0.91 (0.88-0.94)), income (0.82 (0.79-0.85)), U.S. citizenship, and Asian (0.81 (0.75-0.88)) or Hispanic (0.82 (0.79-0.86)) race and ethnicity were associated with higher post-transplant survival, after adjustment for clinical and demographic factors (Table 3). These associations were found across the entire time period studied and many persisted after the implementation of Share 35 in 2013 (Table 3; male sex (0.84 (0.79-0.90)), private insurance (0.94 (0.89-1.00)), income (0.82 (0.77-0.89)), and Asian (0.87 (0.73-1.02)) or Hispanic (0.88 (0.81-0.96)) race and ethnicity). Interpretation Recipients' socioeconomic factors at time of transplant may impact long-term post-transplant survival, and a single policy may not significantly alter these structural health inequalities. Funding None.

VBM acknowledges the national grant PI16/01770 from the Instituto de Salud Carlos III, ISCIII (The PROBILIFE study). EV thanks the support of the Spanish Ministry of Science and Innovation (PI15/00283, PI18/00805) integrated into the Plan Nacional de I+D+I and co-financed by the ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER); the Instituto de Salud Carlos III; the CIBER of Mental Health (CIBERSAM) (...), Cervera-Martínez, J., Atienza-Carbonell, B., Mota, J.C., Bobes-Bascarán, T., Crespo-Facorro, B., Esteban, C., García-Portilla, M.P., Gomes-da-Costa, S., González-Pinto, A., Jaén-Moreno, M.J., Sarramea, F., Vieta, E., Zorrilla, I., Tabarés-Seisdedos, R., Kapczinski, F., De Boni, R.B., Balanzá-Martínez, V.

Background Ciliary dysfunction underlies a range of genetic disorders collectively termed ciliopathies, for which there are no treatments available. Bardet-Biedl syndrome (BBS) is characterised by multisystemic involvement, including rod-cone dystrophy and renal abnormalities. Together with Alstrom syndrome (AS), they are known as the ‘obesity ciliopathies’ due to their common phenotype. Nonsense mutations are responsible for approximately 11% and 40% of BBS and AS cases, respectively. Translational readthrough inducing drugs (TRIDs) can restore full-length protein bypassing in-frame premature termination codons, and are a potential therapeutic approach for nonsense-mediated ciliopathies. Methods Patient fibroblasts harbouring nonsense mutations from two different ciliopathies (Bardet-Biedl Syndrome and Alstrom Syndrome) were treated with PTC124 (ataluren) or amlexanox. Following treatment, gene expression, protein levels and ciliogenesis were evaluated. The expression of intraflagellar transport protein IFT88 and G-protein coupled receptor SSTR3 was investigated as a readout of ciliary function. Findings mRNA expression was significantly increased in amlexanox-treated patient fibroblasts, and full-length BBS2 or ALMS1 protein expression was restored in PTC124- and amlexanox-treated fibroblasts. Treatment with TRIDs significantly improved ciliogenesis defects in BBS2Y24*/R275* fibroblasts. Treatment recovered IFT88 expression and corrected SSTR3 mislocalisation in BBS2Y24*/R275* and ALMS1S1645*/S1645* fibroblasts, suggesting rescue of ciliary function. Interpretation The recovery of full-length BBS2 and ALMS1 expression and correction of anatomical and functional ciliary defects in BBS2Y24*/R275* and ALMS1S1645*/S1645* fibroblasts suggest TRIDs are a potential therapeutic option for the treatment of nonsense-mediated ciliopathies. Funding Wellcome Trust 205174/Z/16/Z, National Centre for the Replacement, Refinement & Reduction of Animals in Research. Deutsche Forschungsgemeinschaft SPP2127 (DFG Grant MA 6139/3-1).

An integrated model, based on a One Health approach, was implemented to estimate the epidemiological and economic outcomes of cystic echinococcosis (CE) in Veneto region, an hypo-endemic area of Northern Italy, and the costs for its prevention. Data and information needed to populate the model were retrieved from published literature, official statistics, expert opinions, or actively searched through data mining (i.e., Hospital and slaughterhouse data), when fundamental data were not available. Human-health and animal-health costs, both public and private, were considered. The overall impact of CE in the study area was estimated in an yearly cost of about 0.5 million €, due to an average of 19.5 human hospitalized cases and about 200 infected animals among cattle and sheep, per year. The human:animal costs ratio was about 8:1. Most of the infected animals were autochthonous, while the identification of an autochthonous source of the infection for the human cases was extremely difficult, and unlikely in most cases. No specific action resulted to be in place for human surveillance, while veterinary surveillance accounted for a yearly cost of about 22,000 €. Sheepherders were found to pay privately an overall amount of around 2000 € for the preventive treatment of their dogs every year, but the applied protocol proved to be sub-optimal. The source of most of the human cases was likely external to the study area, and their economic impact accounts for a cost that is far exceeding that of surveillance and preventive actions in place in the veterinary sector. Although autochthonous human cases appeared to be very rare, the strengthening of preventive actions and surveillance systems can reduce the risk of their increment., Highlights • The study integrated epidemiology and economic aspects in a One Health perspective. • The research estimates in detail the overall impact of CE in a hypo-endemic region in Italy. • The study provided data for evidence-based actions to control CE in the study area. • The investigated case study represents a reproducible model for zoonotic diseases evaluation.