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Background: Influenza viruses evolve rapidly and cause regular seasonal epidemics in humans challenging effective vaccination. The virus surface HA glycoprotein is the primary target for the host immune response. Here, we investigated the vaccine efficacy and evolution patterns of human influenza A/H3N2 viruses that circulated in Kenyan in the period before and after the 2009 A/H1N1 pandemic, targeting the HA1 domain. Materials and methods: A hundred and fifteen HA sequences of Kenyan virus viruses were analyzed relative to the corresponding WHO vaccine reference strains using bioinformatics approaches. Results: Our analyses revealed varied amino acid substitutions at all the five antigenic sites (A–E) of the HA1 domain, with a majority the changes occurring at sites A and B. The Kenyan A/H3N2 viruses isolated during 2007/2008 seasons belonged to A/Brisbane/10/2007-like viruses lineage, while those circulating in 2009–2012 belonged to the lineage of A/Victoria/361/2011-like viruses. The 2013 viruses clustered in clade 3C.3 of the A/Samara/73/2013-like viruses. The mean evolutionary rate of the A/H3N2 viruses analyzed in the study was at 4.17 × 10−3 (95% HPD = 3.09 × 10−3–5.31 × 10−3) nucleotide substitutions per site per year, whereas the TMRCA was estimated at 11.18 (95% HPD = 9.00–14.12) years ago from 2013. The prediction of vaccine efficacy revealed modest vaccine efficaciousness during 2008, and 2010 influenza seasons, whilst sub-optimal effectiveness was registered in 2007, 2009, 2012 and 2013. Further, the overall selective pressure acting on the HA1 domain was estimated at 0.56 (ω

A major challenge in analyses of molecular spectra from biological samples has been the detection of trace biomarkers, which are subtle biochemical alterations (in parts per million (ppm)) caused by disease, buried in pronounced background fluorescence. We report a quantitative chemometrics-assisted Raman study of subtle biochemical alterations associated with breast cancer malignancy using whole blood samples, based on a 785 nm laser excitation. To understand biochemical differences between healthy (control) and diseased samples, spectral analysis was undertaken in the 500–1800 cm−1 region using principal components analysis (PCA), linear discriminant analysis (LDA), and partial least squares discriminant analysis (PLS-DA). The subtle spectral markers at 589, 594, 630, 858, 868, 1005, 1160, 1250, 1347, 1358, 1626, 1630, and 1638 cm−1 differentiated controls from diseased patients and were assigned to proteins, lipids, and nucleic acids. Out of the above, six spectral regions were determined: 589, 594, 630, 1626, 1630 and 1638 cm−1, which can be regarded as new spectral markers for breast cancer. Various pure basic biochemical components were used to develop a partial least squares regression calibration model for quantitative analysis. The relative concentrations of biochemical alterations in healthy and diseased samples were estimated by applying the developed least squares fitting model to the determined trace spectral markers’ measured blood spectrum. The fitting model revealed that the relative concentrations of proteins, lipids, and nucleic acids increased with disease status (p 80%, and overall diagnostic accuracies between 90 and 100%. Considering the limited number of samples involved in this study, preliminary results from this approach are promising, encouraging further investigations.

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

Objectives: To assess SARS-CoV-2 prevalence and health outcomes among inmates over 60 years during a COVID-19 outbreak in a major penitentiary complex in the Federal District, Brazil. Methods: A mass test campaign was performed on May 13, 2020, using antibody-detection rapid tests for asymptomatic inmates and reverse transcriptase-polymerase chain reaction testing for those who were symptomatic. Those with negative results were retested on June 16. Inmates were interviewed to characterise background health conditions and the presence of symptoms. Results: A total of 159 inmates were evaluated. In the first mass testing, 79.9% (127/159) of inmates had been infected, of whom 53.5% (68/127) reported symptoms. In the second testing round, 17 new cases were identified, increasing the total to 90.6% (144/159) of inmates with a positive result. Comorbidities were present in 67.3% of inmates; 2 hospitalisations and no COVID-related deaths were recorded. Conclusion: More than 90% of inmates aged >60 years were infected with SARS-CoV-2 during the outbreak. Periodic health monitoring, active case finding and early care for symptomatic patients contributed to positive post-infection outcomes. Such measures must be considered essential for the surveillance of COVID-19 in environments with limited capacity to promote social distance, such as penitentiary institutions.

Background: Non-alcoholic steatohepatitis (NASH)-associated hepatocellular carcinoma (HCC) is a rising indication for liver transplantation. This unique population, with multiple comorbidities, has potential for worse post-transplant outcomes. We compared post-transplant survival of NASH and non-NASH HCC patients using a large cohort., Methods: Adults transplanted for HCC between 2008 and 2018, from United Network for Organ Sharing (UNOS) and University Health Network (UHN) databases were divided into two populations: NASH and non-NASH. Recipient characteristics and post-transplant survival were compared. Subgroup analyses were performed within and beyond Milan criteria., Results: 2071 of 20,672 (10.0%) patients underwent transplantation for NASH HCC, with annual proportional increase of 1.2%UHN (p = 0.02) and 1.3%UNOS (p < 0.001). The 1-,3-,5-year post-transplant survival were 90.8%, 83.9%, 76.3% NASH HCC versus 91.9%, 82.1%, 74.9% non-NASH HCC (p = 0.94). No survival differences were observed in populations within or beyond Milan. Competing-risk analysis demonstrated no differences in risk for cardiovascular-related death (HR1.24, 95%CI 0.87-1.55, p = 0.16), or HCC recurrence-related death (HR1.21, 95%CI 0.89-1.65, p = 0.23). NASH HCC patients had lower risk of liver-related deaths (HR0.57, 95%CI 0.34-0.98, p = 0.04)., Discussion: NASH HCC is a rising indication for liver transplantation. Despite demographic differences, no post-transplantation survival differences were observed between NASH and non-NASH HCC. This justifies equivalent organ allocation, irrespective of NASH status., Competing Interests: Conflicts of interest None declared., (Copyright © 2023 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Many countries curate national registries of liver transplant (LT) data. These registries are often used to generate predictive models; however, potential performance and transferability of these models remain unclear. We used data from 3 national registries and developed machine learning algorithm (MLA)-based models to predict 90-day post-LT mortality within and across countries. Predictive performance and external validity of each model were assessed. Prospectively collected data of adult patients (aged ≥18 years) who underwent primary LTs between January 2008 and December 2018 from the Canadian Organ Replacement Registry (Canada), National Health Service Blood and Transplantation (United Kingdom), and United Network for Organ Sharing (United States) were used to develop MLA models to predict 90-day post-LT mortality. Models were developed using each registry individually (based on variables inherent to the individual databases) and using all 3 registries combined (variables in common between the registries [harmonized]). The model performance was evaluated using area under the receiver operating characteristic (AUROC) curve. The number of patients included was as follows: Canada, n = 1214; the United Kingdom, n = 5287; and the United States, n = 59,558. The best performing MLA-based model was ridge regression across both individual registries and harmonized data sets. Model performance diminished from individualized to the harmonized registries, especially in Canada (individualized ridge: AUROC, 0.74; range, 0.73-0.74; harmonized: AUROC, 0.68; range, 0.50-0.73) and US (individualized ridge: AUROC, 0.71; range, 0.70-0.71; harmonized: AUROC, 0.66; range, 0.66-0.66) data sets. External model performance across countries was poor overall. MLA-based models yield a fair discriminatory potential when used within individual databases. However, the external validity of these models is poor when applied across countries. Standardization of registry-based variables could facilitate the added value of MLA-based models in informing decision making in future LTs., (Copyright © 2022 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Adult-to-adult living donor liver transplantation (LDLT) offers an opportunity to decrease the liver transplant waitlist and reduce waitlist mortality. We sought to compare donor and recipient characteristics and post-transplant outcomes after LDLT in the US, the UK, and Canada., Methods: This is a retrospective multicenter cohort-study of adults (≥18-years) who underwent primary LDLT between Jan-2008 and Dec-2018 from three national liver transplantation registries: United Network for Organ Sharing (US), National Health Service Blood and Transplantation (UK), and the Canadian Organ Replacement Registry (Canada). Patients undergoing retransplantation or multi-organ transplantation were excluded. Post-transplant survival was evaluated using the Kaplan-Meier method, and multivariable adjustments were performed using Cox proportional-hazards models with mixed-effect modeling., Results: A total of 2,954 living donor liver transplants were performed (US: n = 2,328; Canada: n = 529; UK: n = 97). Canada has maintained the highest proportion of LDLT utilization over time (proportion of LDLT in 2008 - US: 3.3%; Canada: 19.5%; UK: 1.7%; p <0.001 - in 2018 - US: 5.0%; Canada: 13.6%; UK: 0.4%; p <0.001). The 1-, 5-, and 10-year patient survival was 92.6%, 82.8%, and 70.0% in the US vs. 96.1%, 89.9%, and 82.2% in Canada vs. 91.4%, 85.4%, and 66.7% in the UK. After adjustment for characteristics of donors, recipients, transplant year, and treating transplant center as a random effect, all countries had a non-statistically significantly different mortality hazard post-LDLT (Ref US: Canada hazard ratio 0.53, 95% CI 0.28-1.01, p = 0.05; UK hazard ratio 1.09, 95% CI 0.59-2.02, p = 0.78)., Conclusions: The use of LDLT has remained low in the US, the UK and Canada. Despite this, long-term survival is excellent. Continued efforts to increase LDLT utilization in these countries may be warranted due to the growing waitlist and differences in allocation that may disadvantage patients currently awaiting liver transplantation., Lay Summary: This multicenter international comparative analysis of living donor liver transplantation in the United States, the United Kingdom, and Canada demonstrates that despite low use of the procedure, the long-term outcomes are excellent. In addition, the mortality risk is not statistically significantly different between the evaluated countries. However, the incidence and risk of retransplantation differs between the countries, being the highest in the United Kingdom and lowest in the United States., Competing Interests: Conflict of interest Gonzalo Sapisochin discloses consultancy for Astra-Zeneca, Roche, Novartis, and Integra. Gonzalo Sapisochin has received financial compensation for talks for Roche, Astra-Zeneca, Chiesi, and Integra. Gonzalo Sapisochin has received a grant from Roche. None of the other authors have any conflicts of interest to declare. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: The Choosing Wisely Campaign was launched in 2012 and has been applied to a broad spectrum of disciplines in almost thirty countries, with the objective of reducing unnecessary or potentially harmful investigations and procedures, thus limiting costs and improving outcomes. In Canada, patients with burn injuries are usually initially assessed by primary care and emergency providers, while plastic or general surgeons provide ongoing management. We sought to develop a series of Choosing Wisely statements for burn care to guide these practitioners and inform suitable, cost-effective investigations and treatment choices., Methods: The Choosing Wisely Canada list for Burns was developed by members of the Canadian Special Interest Group of the American Burn Association. Eleven recommendations were generated from an initial list of 29 statements using a modified Delphi process and SurveyMonkey™., Results: Recommendations included statements on avoidance of prophylactic antibiotics, restriction of blood products, use of adjunctive analgesic medications, monitoring and titration of opioid analgesics, and minimizing 'routine' bloodwork, microbiology or radiological investigations., Conclusions: The Choosing Wisely recommendations aim to encourage greater discussion between those involved in burn care, other health care professionals, and their patients, with a view to reduce the cost and adverse effects associated with unnecessary therapeutic and diagnostic procedures, while still maintaining high standards of evidence-based burn care., (Copyright © 2021 Elsevier Ltd and ISBI. All rights reserved.)

Introduction: Using a skills-based learning environment as a launch pad for developing empathy for patients with substance use disorder or at high risk for opioid overdose allows for learning continuity and early intervention. Empathy for this patient population may reduce bias and stigma associated with negative health outcomes. Previous studies have assessed empathy in pharmacy students, but not in the context of substance use disorder and opioid overdose harm reduction among first professional year pharmacy students in skills-based education. This cohort study aimed to measure the change in empathy and opioid overdose-related attitudes before and after a two-part skills-based learning activity that focused on drug diversion and opioid overdose treatment., Methods: First professional year pharmacy students were given a pre- and post-survey consisting of empathy and attitudes sections. The Kiersma-Chen Empathy Scale (KCES) and the Opioid Overdose Attitudes Scale (OOAS) were used. The intervention was a skills-based learning activity with two segments, one that focused on naloxone counseling and the other focused on drug diversion., Results: The aggregate mean change in KCES and OOAS scores of the cohort increased by 1.837 (P = .014) and 2.349 (P = .008), respectively. Of note, students with lower baseline empathy and attitudes scores showed more improvement in both KCES and OOAS scores., Conclusions: Students showed improvement in empathy and attitudes regarding opioid overdose and substance use disorder. A larger magnitude of improvement was noted with lower baseline scores., (Published by Elsevier Inc.)

Background: Necrotising soft tissue infections (NSTI) are destructive and often life-threatening infections of the skin and soft tissue, necessitating prompt recognition and aggressive medical and surgical treatment. After debridement, the aim of surgical closure and reconstruction is to minimize disability and optimize appearance. Although skin grafting may fulfil this role, techniques higher on the reconstructive ladder, including local, regional and free flaps, are sometimes undertaken. This systematic review sought to determine the circumstances when this is true, which flaps were most commonly employed, and for which anatomical areas., Methods: A systematic review of the literature was conducted utilising electronic databases (Medline, Embase, Cochrane Library). Full text studies of flaps used for the management of NSTI's (including Necrotising Fasciitis and Fournier Gangrene) were included. The web-based program 'Covidence' facilitated storage of references and data management. Data obtained in the search included reference details (journal, date and title), the study design, the purpose of the study, the study findings, number of patients with NSTI included, the anatomical areas of NSTI involved, the types of flaps used, and the complication rate., Results: After screening 4555 references, 501 full text manuscripts were assessed for eligibility after duplicates and irrelevant studies were excluded. 230 full text manuscripts discussed the use of 888 flap closures in the context of NSTI in 733 patients; the majority of these were case series published in the last 20 years in a large variety of journals. Reconstruction of the perineum following Fournier's gangrene accounted for the majority of the reported flaps (58.6%). Free flaps were used infrequently (8%), whereas loco-regional muscle flaps (18%) and loco-regional fasciocutaneous flaps (71%) were employed more often. The reported rate of partial or complete flap loss was 3.3%., Conclusion: Complex skin and soft tissue defects from NSTIs, not amenable to skin grafting, can be more effectively and durably covered using a spectrum of flaps. This systematic review highlights the important contribution that the plastic surgeon makes as an integral member of multidisciplinary teams managing these patients., (Copyright © 2021 Elsevier Ltd and ISBI. All rights reserved.)

Background: The mechanisms underlying the role of T-type calcium channels (T-channels) in thalamocortical excitability and oscillations in vivo during neurosteroid-induced hypnosis are largely unknown., Methods: We used patch-clamp electrophysiological recordings from acute brain slices ex vivo, recordings of local field potentials (LFPs) from the central medial thalamic nucleus in vivo, and wild-type (WT) and Ca v 3.1 knock-out mice to investigate the molecular mechanisms of hypnosis induced by the neurosteroid analogue (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH)., Results: Patch-clamp recordings showed that 3β-OH inhibited isolated T-currents but had no effect on phasic or tonic γ-aminobutyric acid A currents. Also in acute brain slices, 3β-OH inhibited the spike firing mode more profoundly in WT than in Ca v 3.1 knockout mice. Furthermore, 3β-OH significantly hyperpolarised neurones, reduced the amplitudes of low threshold spikes, and diminished rebound burst firing only in WT mice. We found that 80 mg kg -1 i.p. injections of 3β-OH induced hypnosis in >60% of WT mice but failed to induce hypnosis in the majority of mutant mice. A subhypnotic dose of 3β-OH (20 mg kg -1 i.p.) accelerated induction of hypnosis by isoflurane only in WT mice, but had similar effects on the maintenance of isoflurane-induced hypnosis in both WT and Ca v 3.1 knockout mice. In vivo recordings of LFPs showed that a hypnotic dose of 3β-OH increased δ, θ, α, and β oscillations in WT mice in comparison with Ca v 3.1 knock-out mice., Conclusions: The Ca v 3.1 T-channel isoform is critical for diminished thalamocortical excitability and oscillations that underlie neurosteroid-induced hypnosis., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Debate still exists regarding whether preventive surgical decompression should be offered to high-risk patients experiencing cerebellar stroke. This study aimed to predict neurologic decline based on risk factors, volumetric analysis, and imaging characteristics., Methods: This retrospective cohort study comprised patients ≥18 years who presented with acute cerebellar ischemic stroke (CIS) between January 2011 and December 2016. Diagnostic imaging was used to calculate metrics based on individual stroke, cerebellar, and posterior fossa volumes. Head computed tomography scans on presentation and day of peak swelling were used to tabulate a CIS score., Results: The study included 86 patients; most were male and African American. Posterior inferior communicating artery stroke was most common (50%). On initial presentation imaging, 18.6% had documented hydrocephalus, 20.9% had brainstem compression, 22.1% had brainstem stroke, and 39.5% had stroke in another vascular territory. Cardioembolic stroke was the most common etiology, followed by cryptogenic stroke. Overall, patients who underwent surgical intervention had larger stroke volumes on presentation. Patients undergoing surgical intervention also experienced faster cerebellar swelling compared with patients without intervention. Total CIS scores were statistically significant and remained significant on the peak day of swelling. CIS score was independently associated with neurosurgical intervention; patients in this group with delayed interventions (median CIS score, 6; range, 4-8) later deteriorated and required emergent surgical decompression. Eleven patients without intervention had CIS score >6; 4 patients died of stroke complications., Conclusions: Volumetric studies and CIS score are objective measures that may help predict decline on imaging before clinical deterioration., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: National Comprehensive Cancer Network guidelines for the treatment of locally advanced rectal cancer advocate neoadjuvant chemoradiotherapy followed by total mesorectal excision and adjuvant chemotherapy (AC). The aim of this retrospective study was to determine our local patterns of AC use and to examine factors that influenced initiation and completion of AC among patients with stage II/III rectal cancer., Patients and Methods: The study population consisted of stage II/III rectal cancer patients who were treated at the University of Rochester from 2011 to 2014. Chart reviews were conducted to determine rates of AC initiation and completion. The documented reasons for failure to initiate or complete AC were examined. A multivariate analysis was also completed to evaluate factors that may have influenced the initiation and use of AC., Results: Eighty-one patients were included in the analysis. Median age was 62 years, and 53 (65.4%) were male. Median time from surgery to initiation of AC in those who received AC was 8.0 weeks. Forty-seven patients (58.0%) completed their prescribed AC course. Twenty-four patients (29.6%) did not start AC and 9 patients (11.1%) were unable to complete their course of AC. Primary reasons for not undergoing AC were patient preference (37.5%) and prolonged surgical recovery (33.3%). Primary reasons for not completing AC were treatment toxicities (55.5%) and patient preference (22.2%). Multivariate analysis identified a positive association between clinical stage III disease at diagnosis and initiation of AC. There was no independent association between pathologic response to neoadjuvant therapy at time of surgery and receipt of AC., Conclusion: A large proportion of patients at a single academic center did not start or complete their prescribed postoperative AC for locally advanced rectal cancer. Ongoing studies are investigating a total neoadjuvant approach, which may result in better chemotherapy adherence and further improve the pathologic downstaging rate., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Influenza viruses evolve rapidly and cause regular seasonal epidemics in humans challenging effective vaccination. The virus surface HA glycoprotein is the primary target for the host immune response. Here, we investigated the vaccine efficacy and evolution patterns of human influenza A/H3N2 viruses that circulated in Kenyan in the period before and after the 2009 A/H1N1 pandemic, targeting the HA1 domain., Materials and Methods: A hundred and fifteen HA sequences of Kenyan virus viruses were analyzed relative to the corresponding WHO vaccine reference strains using bioinformatics approaches., Results: Our analyses revealed varied amino acid substitutions at all the five antigenic sites (A-E) of the HA1 domain, with a majority the changes occurring at sites A and B. The Kenyan A/H3N2 viruses isolated during 2007/2008 seasons belonged to A/Brisbane/10/2007-like viruses lineage, while those circulating in 2009-2012 belonged to the lineage of A/Victoria/361/2011-like viruses. The 2013 viruses clustered in clade 3C.3 of the A/Samara/73/2013-like viruses. The mean evolutionary rate of the A/H3N2 viruses analyzed in the study was at 4.17×10 -3 (95% HPD=3.09×10 -3 -5.31×10 -3 ) nucleotide substitutions per site per year, whereas the TMRCA was estimated at 11.18 (95% HPD=9.00-14.12) years ago from 2013. The prediction of vaccine efficacy revealed modest vaccine efficaciousness during 2008, and 2010 influenza seasons, whilst sub-optimal effectiveness was registered in 2007, 2009, 2012 and 2013. Further, the overall selective pressure acting on the HA1 domain was estimated at 0.56 (ω<1), suggesting that a majority of codon sites in the HA1 epitopes were evolving under purifying selection., Conclusions: Generally, our results highlight the genetic plasticity of A/H3N2 viruses and reveal considerable disparity in vaccine efficaciousness against the A/H3N2 viruses that circulated in Kenya, specifically during 2007, 2009, 2012, and 2013 influenza seasons. Our findings underscore the importance and need for consistent surveillance and molecular characterization of influenza viruses, to inform decision making and enhance early of detection of strains with epidemic/pandemic potential as well as benefit in guiding decisions regarding the appropriate annual influenza vaccine formulations., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: A substantial unmet need remains for safe and effective vaccines against dengue virus disease, particularly for individuals who are dengue-naive and those younger than 9 years. We aimed to assess the efficacy, safety, and immunogenicity of a live attenuated tetravalent dengue vaccine (TAK-003) in healthy children aged 4-16 years., Methods: We present data up to 18 months post-vaccination from an ongoing phase 3, randomised, double-blind trial of TAK-003 in endemic regions of Asia and Latin America (26 medical and research centres across Brazil, Colombia, Dominican Republic, Nicaragua, Panama, Philippines, Sri Lanka, and Thailand). Healthy children aged 4-16 years were randomly assigned 2:1 (stratified by age and region) to receive two doses of TAK-003 or two doses of placebo, 3 months apart. Investigators, participants and their parents or guardians, and sponsor representatives advising on trial conduct were masked to trial group assignments. Participants presenting with febrile illness were tested for virologically confirmed dengue (VCD) by serotype-specific RT-PCR. In timeframes beginning 30 days post-second dose, the primary endpoint (overall vaccine efficacy) was assessed in the first 11 months, and the secondary endpoints (efficacy by baseline serostatus, serotype, hospitalised dengue, and severe dengue) in the first 17 months. This study is registered with ClinicalTrials.gov, NCT02747927., Findings: 20 099 participants were randomly assigned and vaccinated between Sept 7, 2016, and Aug 18, 2017; 19 021 (94·6%) were included in the per protocol analysis, and 20 071 (99·9%) in the safety set. The primary endpoint was achieved with an overall vaccine efficacy of 80·2% (95% CI 73·3 to 85·3; 61 cases of VCD in the TAK-003 group vs 149 cases of VCD in the placebo group). In the secondary endpoint assessment timeframe, an overall vaccine efficacy of 73·3% (95% CI 66·5 to 78·8) was observed. Analysis of secondary endpoints showed efficacies of 76·1% (95% CI 68·5 to 81·9) in individuals who were seropositive at baseline, 66·2% (49·1 to 77·5) in individuals who were seronegative at baseline, 90·4% (82·6 to 94·7) against hospitalised dengue, and 85·9% (31·9 to 97·1) against dengue haemorrhagic fever. Efficacy varied by individual serotypes (DENV 1, 69·8% [95% CI 54·8 to 79·9]; DENV 2, 95·1% [89·9 to 97·6]; DENV 3, 48·9% [27·2 to 64·1]; DENV 4, 51·0% [-69·4 to 85·8]). Cumulative rates of serious adverse events were similar in TAK-003 (4·0%) and placebo (4·8%) recipients, and were consistent with expected medical disorders in the study population. Infection was the most frequent reason leading to serious adverse events. 20 participants (<0·1% of the safety set) were withdrawn from the trial due to 21 adverse events by the end of part two; 14 of these participants received TAK-003 and six received placebo., Interpretation: TAK-003 was well tolerated and efficacious against symptomatic dengue in children regardless of serostatus before immunisation. Vaccine efficacy varied by serotype, warranting continued follow-up to assess longer-term vaccine performance., Funding: Takeda Vaccines., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: An unmet clinical need remains for an effective tetravalent dengue vaccine suitable for all age groups, regardless of serostatus. We assessed the immunogenicity and safety of three different dose schedules of a tetravalent dengue vaccine (TAK-003) over a 48-month period in children living in dengue-endemic countries., Methods: We did a large, phase 2, double-blind, placebo-controlled trial at three sites in the Dominican Republic, Panama, and the Philippines. Healthy participants aged 2-17 years were randomly assigned 1:2:5:1 using an interactive web response system with stratification by age to receive either a two-dose primary series (days 1 and 91), one primary dose (day 1), one primary dose plus booster (days 1 and 365), or placebo. Participants and relevant study personnel were masked to the random assignment until completion of the study at month 48. To maintain masking, TAK-003 recipients were administered placebo doses when appropriate. The primary objective was assessment of neutralising geometric mean titres for each serotype to month 48 assessed in the per-protocol immunogenicity subset. Secondary safety endpoints included proportions of participants with serious adverse events and symptomatic virologically confirmed dengue. This study is registered with ClinicalTrials.gov, NCT02302066., Findings: Between Dec 5, 2014, and Feb 13, 2015, 1800 children were randomly assigned to the following groups: two-dose primary series (n=201), one primary dose (n=398), one primary dose plus 1-year booster (n=1002), and placebo (n=199). Of them, 1479 (82%) participants completed the 48-month study. Immunogenicity endpoints were assessed in 562 participants enrolled in the immunogenicity subset, of whom 509 were included in the per-protocol subset. At month 48, antibody titres remained elevated in all TAK-003 groups compared with placebo, irrespective of baseline serostatus. At month 48, geometric mean titres were 378 (95% CI 226-632) in two-dose, 421 (285-622) in one-dose, 719 (538-960) in one-dose plus 1-year booster, and 100 (50-201) in placebo recipients against DENV 1; 1052 (732-1511), 1319 (970-1794), 1200 (927-1553), and 208 (99-437) against DENV 2; 183 (113-298), 201 (135-298), 288 (211-392), and 71 (37-139) against DENV 3; and 152 (97-239), 164 (114-236), 219 (165-290), and 46 (26-82) against DENV 4; and tetravalent seropositivity rate was 89% (79-96), 86% (80-92), 97% (93-99), and 60% (47-72), respectively. Virologically confirmed dengue was recorded in 37 (2%) TAK-003 and 13 (7%) placebo participants, with a relative risk of 0·35 (0·19-0·65). No vaccine-related serious adverse events or severe dengue virus disease were reported., Interpretation: TAK-003 elicited antibody responses against all four serotypes, which persisted to 48 months post-vaccination, regardless of baseline serostatus. No important safety risks were identified. We observed a long-term reduction in risk of symptomatic dengue virus disease in vaccinees. Results from this study provide a long-term safety database and support assessment of the vaccine in the ongoing phase 3 efficacy study., Funding: Takeda Vaccines., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Historically, practicing neurosurgeons have been key drivers of neurosurgical innovation. We sought to describe the patents held by U.S. academic neurosurgeons and to explore the relationship between patents and royalties received., Methods: The Centers for Medicare and Medicaid CMS Open Payments Data was used to identify academic neurosurgeons who had received royalties and royalty amounts during a 5-year period (2013-2017). Online patent databases were used to gather patent details. Patent citations and 5-year individual and departmental patent Hirsch (h)-indexes were calculated. Royalties were correlated with the number of patents, patent citations, and patent h-index., Results: We found that 119 academic neurosurgeons (7.8%) from 57 U.S. teaching programs (48.3%) had received royalty payments; 72 (60.5%) had published 648 patents. All surgeons were men, with approximately one half in the "late" stages of their career (45.3%) and subspecializing in spinal surgery (50.4%). The patented products or devices were most commonly used for spinal surgery (72.1%), with 2010-2019 the most productive period (n = 455; 70.2%). The median number of citations per patent was 32 (range, 0-620), with 33% having ≥100 citations. The highest individual and institutional patent h-index was 95; 25 (34.7%) neurosurgeons had a patent h-index of ≥5. The median total royalty payment per individual neurosurgeon was $111,011 (range, $58.05-$76,715,750.34). Royalties were correlated with the number of patents (Spearman r = 0.37; P ≤ 0.001), citations (Spearman r, 0.38; P ≤ 0.001), and inventor h-index (Spearman r = 0.38; P ≤ 0.001)., Conclusions: Few U.S. academic neurosurgeons (7.8%) receive royalties and hold patents (4.7%), with an even smaller select group having a patent h-index of ≥5 (1.6%)., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: It is not unusual to find neurosurgeons in the news and entertainment. The present study examined the portrayal of neurosurgeons by major print and online media sources., Methods: Two search strategies identified articles from October 1, 2012 to October 1, 2017 containing the keyword "neurosurgeon." The top 25 newspapers in the United States, determined by their circulation, were searched using the LexisNexis Academic or NewsBank databases; a layman's Google News search was used to collect online stories. Each identified article was evaluated to confirm the relevance and then examined for content. Relevant characteristics for each article and neurosurgeon were determined and analyzed., Results: Our searches returned 1005 articles comprising 561 unique stories about 203 different neurosurgeons. One particular neurosurgeon had 459 reports (45.7%). More articles were reported in 2015 (405; 40.3%) than any other single year. Most articles featured male neurosurgeons (879; 87.1%) and neurosurgeons who had been practicing for >20 years (636; 63.0%), with just 10 institutions accounting for the training of most of them (733; 72.6%). The articles were classified as positive (270; 26.9%), negative (356; 35.4%), or neutral (379; 37.7%) in terms of their reflection on the field of neurosurgery. The odds of a negative story were greater for male neurosurgeons, within 10 years of residency completion, and in a nonacademic position., Conclusions: Neurosurgeons are naturally subject to media coverage, and we must be cognizant that this predilection can serve as both an occupational advantage and an occupational hazard., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) is diagnosed in up to 126,000 patients worldwide annually. Ceritinib is a next-generation ALK-targeted tyrosine kinase inhibitor that is approved for the treatment of patients with metastatic ALK+ NSCLC. In December 2017, the US Food and Drug Administration-approved dose of ceritinib was changed from 750 mg/day under fasting conditions to 450 mg/day taken with food for the treatment of patients with ALK+ NSCLC. This change was implemented on the basis of data from studies designed to investigate ways to reduce the frequency of gastrointestinal adverse events noted in patients enrolled in several ASCEND clinical trials that evaluated a ceritinib 750-mg fasted dose as either first- or second/third-line treatment. This review highlights and discusses published findings from the ASCEND-8 food-effect trial and includes commentary from physicians regarding their own clinical cases of patients who were enrolled in the trial and treated with either the 750-mg fasted or 450-mg fed dose of ceritinib. The review also discusses the implications of using the recently approved ceritinib 450-mg dose in the clinical setting., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Women with refractory urgency urinary incontinence (ie, unresponsive to behavioral and pharmacological interventions) are treated with onabotulinumtoxinA or sacral neuromodulation., Objective: The objective of the study was to compare treatment efficacy and adverse events in women <65 and ≥65 years old treated with onabotulinumtoxinA or sacral neuromodulation., Study Design: This study was a planned secondary analysis of a multicenter, randomized trial that enrolled community-dwelling women with refractory urgency urinary incontinence to onabotulinumtoxinA or sacral neuromodulation treatments. The primary outcome was a change in mean daily urgency urinary incontinence episodes on a bladder diary over 6 months. Secondary outcomes included ≥75% urgency urinary incontinence episode reduction, change in symptom severity/quality of life, treatment satisfaction, and treatment-related adverse events., Results: Both age groups experienced improvement in mean urgency urinary incontinence episodes per day following each treatment. There was no evidence that mean daily urgency urinary incontinence episode reduction differed between age groups for onabotulinumtoxinA (adjusted coefficient, -0.127, 95% confidence interval, -1.233 to 0.979; P = .821) or sacral neuromodulation (adjusted coefficient, -0.698, 95% confidence interval, -1.832 to 0.437; P = .227). Among those treated with onabotulinumtoxinA, women <65 years had 3.3-fold greater odds of ≥75% resolution than women ≥65 years (95% confidence interval, 1.56 -7.02). Women <65 years had a greater reduction in Overactive Bladder Questionnaire Short Form symptom bother scores compared with women ≥65 years by 7.49 points (95% confidence interval, -3.23 to -11.74), regardless of treatment group. There was no difference between quality of life improvement by age. Women ≥65 years had more urinary tract infections following onabotulinumtoxinA and sacral neuromodulation (odds ratio, 1.9, 95% confidence interval, 1.2-3.3). There was no evidence of age differences in sacral neuromodulation revision/removal or catheterization following onabotulinumtoxinA treatment., Conclusion: Younger women experienced greater absolute continence, symptom improvement, and fewer urinary tract infections; both older and younger women had beneficial urgency urinary incontinence episode reduction, similar rates of other treatment adverse events, and improved quality of life., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Completion lymph node dissection (CLND) following a positive sentinel lymph node biopsy (SLNB) has been reported to be less morbid than lymphadenectomy for palpable disease (therapeutic lymph node dissection; TLND). The reporting of morbidity data can be heterogeneous, and hence no 'average' surgical complication rates of these procedures has been reported. This review aims to determine complications rates to inform patients undergoing surgery for metastatic melanoma., Methods: A systematic review of English-language literature from 2000 to 2017, reporting morbidity information about CLND and TLND for melanoma, was performed. The methodological quality of the included studies was performed using the methodological index for non-randomised studies (MINORS) instrument and Detsky score. Pooled proportions of post-operative complications were constructed using a random effects statistical model., Results: After application of inclusion and exclusion criteria, 18 articles progressed to the final analysis. In relation to TLND (1627 patients), the overall incidence of surgical complications was 39.3% (95% CI 32.6-46.2); including wound infection/breakdown 25.4% (95% CI: 20.9-30.3); lymphoedema 20.9% (95% CI: 13.8-29.1); and seroma 20.4% (95% CI: 15.9-25.2). For CLND (1929 patients), the overall incidence of surgical complications was 37.2% (95% CI 27.6-47.4); including wound infection/breakdown 21.6% (95% CI: 13.8-30.6); lymphoedema 18% (95% CI: 12.5-24.2); and seroma 17.9% (95% CI: 10.3-27). The complication rate was marginally lower for CLND but not to statistical significance., Discussion: This study provides information about the incidence of complications after CLND and TLND. It can be used to counsel patients about the procedures and it sets a benchmark against which surgeons can audit their practice., (Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.)

Background: Low health literacy increases the risk for hospital readmissions. Despite this, the measurement and use of health literacy to guide discharge counseling and planning in heart failure patients is not commonly performed. A short 3-Question Brief Health Literacy Screen (BHLS) is available and takes less than three minutes to complete, but has never been evaluated to help determine whether health literacy affects healthcare use after discharge in patients with heart failure., Objective: The purpose of this study was to assess 30-day readmissions and emergency department visits based on health literacy evaluated by the BHLS in an acute care heart failure population., Methods: This was a prospective observational cohort study conducted at a large quaternary health system. Hospitalized patients with a diagnosis of heart failure were assessed for health literacy using the BHLS. Unplanned healthcare use after discharge including 30-day, all-cause ED visits and hospital readmissions was assessed using univariate and logistic regression models., Results: Two hundred and sixty four patients aged 66.6 ± 14.3 (mean ± SD) years met inclusion/exclusion criteria of whom 175 (66.3%) had a BHLS score >9 (adequate health literacy) and 89 (33.7%) had a BHLS score ≤9 (low health literacy). Predictors of low health literacy included older age (p = 0.019), lower education level (p < 0.001) and unemployed (p = 0.048). After controlling for potential confounders, low health literacy was independently associated with 30-day healthcare use after hospital discharge (OR:1.80; 95% CI: 1.04-3.11; p = 0.035)., Conclusion: Using a short, 3-question validated survey instrument, it was demonstrated that low health literacy was associated with increased 30-day unplanned healthcare use after discharge in this heart failure population. These results provide a clinically useful, easily incorporated tool that could identify high-risk patients at need for clinical interventions., (Copyright © 2016 Elsevier Inc. All rights reserved.)