What Aimed Movement Models Fit Distal Pointing With Varying Depth?

OBJECTIVE: With the rapid improvements in drone technology, there is an increasing interest in distal pointing to diffuse drones. This study investigated the effect of depth on distal pointing when the hand does not traverse the entire distance from start to target so that the most suitable mathematical model can be assessed. BACKGROUND: Starting from the Fitts paradigm, researchers have proposed different models to predict movement time when the distance to the target is variable. They do consider distance, but they are based on statistical modeling rather than the underlying control mechanisms. METHODS: Twenty-four participants volunteered for an experiment in a full-factorial Fitts' paradigm task (3 levels of movement amplitude *7 levels of target width *3 levels of distance from participant to screen). Movement time and the number of errors were the dependent variables. RESULTS: Depth has a significant effect when the target width is small, but depth has no effect when the target width is large. The angular version of the two-part model is superior to the one-part Fitts' model at larger distances. Besides, Index of difficulty for distal pointing, IDDP with adjustable k achieves the best fit even though the model is very sensitive to the value of k and the complexity of the model could be resulting in an overfitting. The result implies that the effects of movement amplitude and target width are not comparable and grouping them to form a dependent index of difficulty can be misleading especially when distance is an added variable. CONCLUSION: The angular version of the two-part model is a viable and meaningful description for distal pointing. Even though the IDDP with adjustable k is the best predictor for movement time when depth is an added variable, there is no physical interpretation for it. APPLICATION: A reasonable predictive model for performance assessments and predictions in distal pointing.

Identification of Healthy Tissue from Malignant Tissue in Surgical Margin Using Raman Spectroscopy in Oral Cancer Surgeries.

Accurate identification of tissue types in surgical margins is essential for ensuring the complete removal of cancerous cells and minimizing the risk of recurrence. The objective of this study was to explore the clinical utility of Raman spectroscopy for the detection of oral squamous cell carcinoma (OSCC) in both tumor and healthy tissues obtained from surgical resection specimens during surgery. This study enrolled a total of 64 patients diagnosed with OSCC. Among the participants, approximately 50% of the cases were classified as the most advanced stage, referred to as T4. Raman experiments were conducted on cryopreserved tissue samples collected from patients diagnosed with OSCC. Prominent spectral regions containing key oral biomarkers were analyzed using the partial least squares-support vector machine (PLS-SVM) method, which is a powerful multivariate analysis technique for discriminant analysis. This approach effectively differentiated OSCC tissue from non-OSCC tissue, achieving a sensitivity of 95.7% and a specificity of 93.3% with 94.7% accuracy. In the current study, Raman analysis of fresh tissue samples showed that OSCC tissues contained significantly higher levels of nucleic acids, proteins, and several amino acids compared to the adjacent healthy tissues. In addition to differentiating between OSCC and non-OSCC tissues, we have also explored the potential of Raman spectroscopy in classifying different stages of OSCC. Specifically, we have investigated the classification of T1, T2, T3, and T4 stages based on their Raman spectra. These findings emphasize the importance of considering both stage and subsite factors in the application of Raman spectroscopy for OSCC analysis. Future work will focus on expanding our tissue sample collection to better comprehend how different subsites influence the Raman spectra of OSCC at various stages, aiming to improve diagnostic accuracy and aid in identifying tumor-free margins during surgical interventions.

A frequentist approach to dynamic borrowing.

There has been growing interest in leveraging external control data to augment a randomized control group data in clinical trials and enable more informative decision making. In recent years, the quality and availability of real-world data have improved steadily as external controls. However, information borrowing by directly pooling such external controls with randomized controls may lead to biased estimates of the treatment effect. Dynamic borrowing methods under the Bayesian framework have been proposed to better control the false positive error. However, the numerical computation and, especially, parameter tuning, of those Bayesian dynamic borrowing methods remain a challenge in practice. In this paper, we present a frequentist interpretation of a Bayesian commensurate prior borrowing approach and describe intrinsic challenges associated with this method from the perspective of optimization. Motivated by this observation, we propose a new dynamic borrowing approach using adaptive lasso. The treatment effect estimate derived from this method follows a known asymptotic distribution, which can be used to construct confidence intervals and conduct hypothesis tests. The finite sample performance of the method is evaluated through extensive Monte Carlo simulations under different settings. We observed highly competitive performance of adaptive lasso compared to Bayesian approaches. Methods for selecting tuning parameters are also thoroughly discussed based on results from numerical studies and an illustration example.

Neoadjuvant chemotherapy and radiotherapy outcomes in borderline-resectable and locally-advanced pancreatic cancer patients.

BACKGROUND: There is no agreed upon standard of care for borderline-resectable pancreatic cancer (BRPC) or locally-advanced pancreatic cancer (LAPC) patients regarding the benefit of chemotherapy or radiation alone or in combination. PATIENTS AND METHODS: We completed a retrospective cohort analysis of BRPC and LAPC patients at a cancer center with expertise in multi-disciplinary pancreatic ductal adenocarcinoma (PDAC) treatment over a 5-year period from 03/01/2014 to 03/01/2019 (cut-off date). The total evaluable newly diagnosed, treatment naïve, BRPC, and LAPC patients with adequate organ function and ability to obtain treatment after multidisciplinary review was 52 patients. After analysis, patients were evaluated for rates of resection, extent of resection (R0 or R1), median progression-free survival (mPFS), and median overall survival (mOS). RESULTS: Patients were treated with chemotherapy alone (gemcitabine and nab-paclitaxel = 77% (20/26); FOLFIRINOX = 19% (5/26); single agent gemcitabine 3.8% (1/26)), or chemotherapy followed by chemoradiation (gemcitabine +5 Gy × 5 weeks), or chemoradiation alone prior to re-staging and potential resection. Of the 29% (15/52) of patients who went on to surgical resection, 73% (11/15) achieved R0 resection. An R0 resection was achieved in 35% (9/26) of patients treated with chemotherapy alone, 7.6% (1/13) in a patient treated with chemotherapy followed by radiation, and 7.6% (1/13) with concurrent chemoradiotherapy alone. Chemotherapy alone achieved a mPFS of 16.4 months (p < 0.0025) and mOS of 26.2 months (p < 0.0001), chemotherapy followed by chemoradiation was 13.0 months and 14.9 months respectively, while concurrent chemoradiotherapy was 6.9 months and 7.3 months. CONCLUSIONS AND RELEVANCE: BRPC and LAPC patients capable of surgery after only receiving neoadjuvant treatment with chemotherapy had higher rates of R0 resection with prolonged median PFS and OS compared with any patient needing combination chemotherapy with radiotherapy.

A meta-analytic framework to adjust for bias in external control studies.

While randomized controlled trials (RCTs) are the gold standard for estimating treatment effects in medical research, there is increasing use of and interest in using real-world data for drug development. One such use case is the construction of external control arms for evaluation of efficacy in single-arm trials, particularly in cases where randomization is either infeasible or unethical. However, it is well known that treated patients in non-randomized studies may not be comparable to control patients-on either measured or unmeasured variables-and that the underlying population differences between the two groups may result in biased treatment effect estimates as well as increased variability in estimation. To address these challenges for analyses of time-to-event outcomes, we developed a meta-analytic framework that uses historical reference studies to adjust a log hazard ratio estimate in a new external control study for its additional bias and variability. The set of historical studies is formed by constructing external control arms for historical RCTs, and a meta-analysis compares the trial controls to the external control arms. Importantly, a prospective external control study can be performed independently of the meta-analysis using standard causal inference techniques for observational data. We illustrate our approach with a simulation study and an empirical example based on reference studies for advanced non-small cell lung cancer. In our empirical analysis, external control patients had lower survival than trial controls (hazard ratio: 0.907), but our methodology is able to correct for this bias. An implementation of our approach is available in the R package ecmeta.

Efficient recall of SARS-CoV-2 variant-reactive B cells and T responses in the elderly upon heterologous mRNA vaccines as boosters.

Waning antibody levels against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the emergence of variants of concern highlight the need for booster vaccinations. This is particularly important for the elderly population, who are at a higher risk of developing severe coronavirus disease 2019 (COVID-19) disease. While studies have shown increased antibody responses following booster vaccination, understanding the changes in T and B cell compartments induced by a third vaccine dose remains limited. We analyzed the humoral and cellular responses in subjects who received either a homologous messenger RNA(mRNA) booster vaccine (BNT162b2 + BNT162b2 + BNT162b2; ''BBB") or a heterologous mRNA booster vaccine (BNT162b2 + BNT162b2 + mRNA-1273; ''BBM") at Day 0 (prebooster), Day 7, and Day 28 (postbooster). Compared with BBB, elderly individuals (≥60 years old) who received the BBM vaccination regimen display higher levels of neutralizing antibodies against the Wuhan and Delta strains along with a higher boost in immunoglobulin G memory B cells, particularly against the Omicron variant. Circulating T helper type 1(Th1), Th2, Th17, and T follicular helper responses were also increased in elderly individuals given the BBM regimen. While mRNA vaccines increase antibody, T cell, and B cell responses against SARS-CoV-2 1 month after receiving the third dose booster, the efficacy of the booster vaccine strategies may vary depending on age group and regimen combination.

Very Low-Efficiency Droop in 293 nm AlGaN-Based Light-Emitting Diodes Featuring a Subtly Designed p-Type Layer.

This paper reports an AlGaN-based ultraviolet-B light-emitting diode (UVB-LED) with a peak wavelength at 293 nm that was almost free of efficiency droop in the temperature range from 298 to 358 K. Its maximum external quantum efficiencies (EQEs), which were measured at a current density of 88.6 A cm-2, when operated at 298, 318, and 338 K were 2.93, 2.84, and 2.76%, respectively; notably, however, the current droop (J-droop) in each of these cases was less than 1%. When the temperature was 358 K, the maximum EQE of 2.61% occurred at a current density of 63.3 A cm-2, and the J-droop was 1.52%. We believe that the main mechanism responsible for overcoming the J-droop was the uniform distribution of the concentrations of injected electrons and holes within the multiple quantum wells. Through the subtle design of the p-type AlGaN layer, with the optimization of the composition and doping level, the hole injection efficiency was enhanced, and the Auger recombination mechanism was inhibited in an experimental setting.

Raman Spectral Characterization of Urine for Rapid Diagnosis of Acute Kidney Injury.

Acute kidney injury (AKI) is a common syndrome characterized by various etiologies and pathophysiologic processes that deteriorate kidney function. The aim of this study is to identify potential biomarkers in the urine of non-acute kidney injury (non-AKI) and AKI patients through Raman spectroscopy (RS) to predict the advancement in complications and kidney failure. Selected spectral regions containing prominent peaks of renal biomarkers were subjected to partial least squares linear discriminant analysis (PLS-LDA). This discriminant analysis classified the AKI patients from non-AKI subjects with a sensitivity and specificity of 97% and 100%, respectively. In this study, the RS measurements of urine specimens demonstrated that AKI had significantly higher nitrogenous compounds, porphyrin, tryptophan and neopterin when compared with non-AKI. This study's specific spectral information can be used to design an in vivo RS approach for the detection of AKI diseases.

Evaluating the Effectiveness of Complexity Features of Eye Movement on Computer Activities Detection.

Recently, tools developed for detecting human activities have been quite prominent in contributing to health issue prevention and long-term healthcare. For this occasion, the current study aimed to evaluate the performance of eye-movement complexity features (from multi-scale entropy analysis) compared to eye-movement conventional features (from basic statistical measurements) on detecting daily computer activities, comprising reading an English scientific paper, watching an English movie-trailer video, and typing English sentences. A total of 150 students participated in these computer activities. The participants' eye movements were captured using a desktop eye-tracker (GP3 HD Gazepoint™ Canada) while performing the experimental tasks. The collected eye-movement data were then processed to obtain 56 conventional and 550 complexity features of eye movement. A statistic test, analysis of variance (ANOVA), was performed to screen these features, which resulted in 45 conventional and 379 complexity features. These eye-movement features with four combinations were used to build 12 AI models using Support Vector Machine, Decision Tree, and Random Forest (RF). The comparisons of the models showed the superiority of complexity features (85.34% of accuracy) compared to conventional features (66.98% of accuracy). Furthermore, screening eye-movement features using ANOVA enhances 2.29% of recognition accuracy. This study proves the superiority of eye-movement complexity features.

Evaluation of the safety and immunogenicity of different COVID-19 vaccine combinations in healthy individuals: study protocol for a randomized, subject-blinded, controlled phase 3 trial [PRIBIVAC].

BACKGROUND: Over 2021, COVID-19 vaccination programs worldwide focused on raising population immunity through the primary COVID-19 vaccine series. In Singapore, two mRNA vaccines (BNT162b2 and mRNA-1273) and the inactivated vaccine CoronaVac are currently authorized under the National Vaccination Programme for use as the primary vaccination series. More than 90% of the Singapore population has received at least one dose of a COVID-19 vaccine as of December 2021. With the demonstration that vaccine effectiveness wanes in the months after vaccination, and the emergence of Omicron which evades host immunity from prior infection and/or vaccination, attention in many countries has shifted to how best to maintain immunity through booster vaccinations. METHODS: The objectives of this phase 3, randomized, subject-blinded, controlled clinical trial are to assess the safety and immunogenicity of heterologous boost COVID-19 vaccine regimens (intervention groups 1-4) compared with a homologous boost regimen (control arm) in up to 600 adult volunteers. As non-mRNA vaccine candidates may enter the study at different time points depending on vaccine availability and local regulatory approval, participants will be randomized at equal probability to the available intervention arms at the time of randomization. Eligible participants will have received two doses of a homologous mRNA vaccine series with BNT162b2 or mRNA-1273 at least 6 months prior to enrolment. Participants will be excluded if they have a history of confirmed SARS or SARS-CoV-2 infection, are immunocompromised, or are pregnant. Participants will be monitored for adverse events and serious adverse events by physical examinations, laboratory tests and self-reporting. Blood samples will be collected at serial time points [pre-vaccination/screening (day - 14 to day 0), day 7, day 28, day 180, day 360 post-vaccination] for assessment of antibody and cellular immune parameters. Primary endpoint is the level of anti-SARS-CoV-2 spike immunoglobulins at day 28 post-booster and will be measured against wildtype SARS-CoV-2 and variants of concern. Comprehensive immune profiling of the humoral and cellular immune response to vaccination will be performed. DISCUSSION: This study will provide necessary data to understand the quantity, quality, and persistence of the immune response to a homologous and heterologous third booster dose of COVID-19 vaccines. This is an important step in developing COVID-19 vaccination programs beyond the primary series. TRIAL REGISTRATION: ClinicalTrials.gov NCT05142319 . Registered on 2 Dec 2021.

Disclosing Critical Voice Features for Discriminating between Depression and Insomnia-A Preliminary Study for Developing a Quantitative Method.

Background: Depression and insomnia are highly related-insomnia is a common symptom among depression patients, and insomnia can result in depression. Although depression patients and insomnia patients should be treated with different approaches, the lack of practical biological markers makes it difficult to discriminate between depression and insomnia effectively. Purpose: This study aimed to disclose critical vocal features for discriminating between depression and insomnia. Methods: Four groups of patients, comprising six severe-depression patients, four moderate-depression patients, ten insomnia patients, and four patients with chronic pain disorder (CPD) participated in this preliminary study, which aimed to record their speaking voices. An open-source software, openSMILE, was applied to extract 384 voice features. Analysis of variance was used to analyze the effects of the four patient statuses on these voice features. Results: statistical analyses showed significant relationships between patient status and voice features. Patients with severe depression, moderate depression, insomnia, and CPD reacted differently to certain voice features. Critical voice features were reported based on these statistical relationships. Conclusions: This preliminary study shows the potential in developing discriminating models of depression and insomnia using voice features. Future studies should recruit an adequate number of patients to confirm these voice features and increase the number of data for developing a quantitative method.

Antibody Response of Heterologous vs Homologous Messenger RNA Vaccine Boosters Against the Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Variant: Interim Results from the PRIBIVAC Study, a Randomized Clinical Trial.

BACKGROUND: Waning antibody levels post-vaccination and the emergence of variants of concern (VOCs) capable of evading protective immunity have raised the need for booster vaccinations. However, which combination of coronavirus disease 2019 (COVID-19) vaccines offers the strongest immune response against the Omicron variant is unknown. METHODS: This randomized, participant-blinded, controlled trial assessed the reactogenicity and immunogenicity of different COVID-19 vaccine booster combinations. A total of 100 BNT162b2-vaccinated individuals were enrolled and randomized 1:1 to either homologous (BNT162b2 + BNT162b2 + BNT162b2; "BBB") or heterologous messenger RNA (mRNA) (BNT162b2 + BNT162b2 + mRNA-1273; "BBM") booster vaccine. The primary end point was the level of neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wild-type and VOCs at day 28. RESULTS: A total of 51 participants were allocated to BBB and 49 to BBM; 50 and 48, respectively, were analyzed for safety and immunogenicity outcomes. At day 28 post-boost, mean SARS-CoV-2 spike antibody titers were lower with BBB (22 382 IU/mL; 95% confidence interval [CI], 18 210 to 27 517) vs BBM (29 751 IU/mL; 95% CI, 25 281 to 35 011; P = .034) as was the median level of neutralizing antibodies: BBB 99.0% (interquartile range [IQR], 97.9% to 99.3%) vs BBM 99.3% (IQR, 98.8% to 99.5%; P = .021). On subgroup analysis, significant higher mean spike antibody titer, median surrogate neutralizing antibody level against all VOCs, and live Omicron neutralization titer were observed only in older adults receiving BBM. Both vaccines were well tolerated. CONCLUSIONS: Heterologous mRNA-1273 booster vaccination compared with homologous BNT123b2 induced a stronger neutralizing response against the Omicron variant in older individuals. CLINICAL TRIALS REGISTRATION: NCT05142319.

Sustaining Antimicrobial Stewardship in a High-Antibiotic Resistance Setting.

Importance: There is a lack of studies comparing the intended and unintended consequences of prospective review and feedback (PRF) with computerized decision support systems (CDSS), especially in the longer term in antimicrobial stewardship. Objective: To examine the outcomes associated with the sequential implementation of PRF and CDSS and changes to these interventions with long-term use of antibiotics for and incidence of multidrug resistant organisms (MDROs) and other unintended outcomes. Design, Setting, and Participants: This cohort study used an interrupted time series with segmented regression analysis of data from January 2007 to December 2018. Data were extracted from the electronic medical records of patients admitted at a large university teaching hospital with high rates of antibiotic resistance in Singapore. Data were analyzed from June 2019 to June 2020. Exposures: PRF of piperacillin-tazobactam and carbapenems (intervention 1, April 2009), with the addition of hospital-wide CDSS (intervention 2, April 2011), and lifting of CDSS for half of the hospital wards for 6 months (intervention 3, March 2017). Main Outcomes and Measures: Monthly antimicrobial use was measured in defined daily doses (DDDs) per 1000 patient-days. The monthly incidence of MDROs was calculated as number of clinical isolates detected per 1000 inpatient-days over a 6-month period. Unintended outcomes examined included in-hospital mortality and age-adjusted length of stay (LOS). Results: The number of inpatients increased from 56 263 in 2007 to 63 572 in 2018. During the same period, the mean monthly patient days increased from 33 929 in 2007 to 45 603 in 2018, and the proportion of patients older than 65 years increased from 45.5% in 2007 to 56.6% in 2018. After intervention 1, there were 0.33 (95% CI, 0.18 to 0.48) more DDDs per 1000 patient-days per month of piperacillin-tazobactam and carbapenems and -11.05 (95% CI, -15.55 to -6.55) fewer DDDs per 1000 patient-days per month for other broad-spectrum antibiotics. After intervention 2, there were -0.22 (95% CI, -0.33 to -0.10) fewer DDDs per 1000 patient-days per month of piperacillin-tazobactam and carbapenems and -2.10 (95% CI, -3.13 to -1.07) fewer DDDs per 1000 patient-days per month for other broad-spectrum antibiotics. After intervention 3, use of piperacillin-tazobactam and carbapenem increased by 0.28 (95% CI, 0.02 to 0.55) DDDs per 1000 patient-days per month. After intervention 2, incidence of Clostridioides difficile decreased (estimate, -0.02 [95% CI, -0.03 to -0.01] cases per 1000 patient-days per month). Conclusions and Relevance: In this cohort study, concurrent PRF and CDSS were associated with limiting the use of piperacillin-tazobactam and carbapenems while reducing use of other antibiotics.

Accuracy of a Rapid Multiplex Polymerase Chain Reaction Plus a Chromogenic Phenotypic Test Algorithm for Detection of Extended-Spectrum ß-Lactamase and Carbapenemase-Producing Gram-Negative Bacilli in Positive Blood Culture Bottles.

We studied the performance of an algorithm combining multiplex polymerase chain reaction with phenotypic detection of extended-spectrum ß-lactamases and carbapenemases directly from positive blood culture bottles in patients with gram-negative bacteremia and found good concordance with routine cultures. Such an algorithm may be a tool to improve time to optimal therapy in patients with gram-negative bacteremia.

Strain Compensation and Trade-Off Design Result in Exciton Emission at 306 nm from AlGaN LEDs at Temperatures up to 368 K.

In this study, we suppressed the parasitic emission caused by electron overflow found in typical ultraviolet B (UVB) and ultraviolet C (UVC) light-emitting diodes (LEDs). The modulation of the p-layer structure and aluminum composition as well as a trade-off in the structure to ensure strain compensation allowed us to increase the p-AlGaN doping efficiency and hole numbers in the p-neutral region. This approach led to greater matching of the electron and hole numbers in the UVB and UVC emission quantum wells. Our UVB LED (sample A) exhibited clear exciton emission, with its peak near 306 nm, and a band-to-band emission at 303 nm. The relative intensity of the exciton emission of sample A decreased as a result of the thermal energy effect of the temperature increase. Nevertheless, sample A displayed its exciton emission at temperatures of up to 368 K. In contrast, our corresponding UVC LED (sample B) only exhibited a Gaussian peak emission at a wavelength of approximately 272 nm.

Predicting Emotional Valence of People Living with the Human Immunodeficiency Virus Using Daily Voice Clips: A Preliminary Study.

To detect depression in people living with the human immunodeficiency virus (PLHIV), this preliminary study developed an artificial intelligence (AI) model aimed at discriminating the emotional valence of PLHIV. Sixteen PLHIV recruited from the Taoyuan General Hospital, Ministry of Health and Welfare, participated in this study from 2019 to 2020. A self-developed mobile application (app) was installed on sixteen participants' mobile phones and recorded their daily voice clips and emotional valence values. After data preprocessing of the collected voice clips was conducted, an open-source software, openSMILE, was applied to extract 384 voice features. These features were then tested with statistical methods to screen critical modeling features. Several decision-tree models were built based on various data combinations to test the effectiveness of feature selection methods. The developed model performed very well for individuals who reported an adequate amount of data with widely distributed valence values. The effectiveness of feature selection methods, limitations of collected data, and future research were discussed.

Tri-modal management of primary small cell carcinoma of the pancreas (SCCP): a rare neuroendocrine carcinoma (NEC).

BACKGROUND: Primary small cell carcinoma of the pancreas (SCCP) is a rare malignant neuroendocrine carcinoma (NEC). Typically, it presents with lymphovascular invasion as well as metastasis at the time of diagnosis which portends a dismal prognosis. Treatment is typically based on therapy used for other aggressive NECs such as small cell lung cancer. Although multimodal surgery, radiation and chemotherapy may improve prognosis, the outcome generally remains poor. CASE PRESENTATION: Here we present a primary SCCP managed with neoadjuvant multi-agent chemotherapy combined with radiotherapy and surgery CONCLUSIONS: Multi-disciplinary therapy resulted in an ongoing 28 + month radiographic complete response and overall survival.

The Impact of Clinical Presentation on Survival in Patients Requiring Hemodialysis Catheters for Acute and Unplanned Dialysis: A Prospective Observational Study.

BACKGROUND: Most studies addressing hemodialysis initiation with a dialysis catheter focus on patients entering maintenance dialysis programs and exclude other patients, such as those with acute kidney injury (AKI), making interpretation and application of the results difficult for clinicians managing patients at the time of dialysis commencement. OBJECTIVE: To compare the survival of all patients requiring a catheter for hemodialysis access according to the nature of clinical presentation. DESIGN: Prospective observational. SETTING: An Australian tertiary renal unit. PATIENTS: All patients requiring a central venous catheter (CVC) for hemodialysis access between 2005 and 2015. MEASUREMENTS: Baseline comorbidities, demographics, and nature of clinical presentation. Data regarding each episode of dialysis access insufficiency and each CVC were collected. The primary outcome was all-cause mortality. METHODS: Patients were classified into 1 of 3 groups based on physician assessment at the time of presentation: patients believed to have AKI with expected renal recovery (AKI), patients considered to be entering the maintenance dialysis program without a functioning dialysis access (Maintenance Dialysis), patients unable to perform peritoneal dialysis, or use their existing hemodialysis access (Access Failure). Time-split multivariable Cox regression analyses were used to compare survival between groups. RESULTS: A total of 557 eligible patients had complete prospective data regarding CVC use and were included in the analyses. The majority of patients were in the AKI (246/557, 44%) and Maintenance Dialysis groups (182/557, 33%) compared with the Access Failure group (129/557, 23%). During a median follow-up of 3 years, 302 (54%) of the 557 patients died. Following adjustment, risk of all-cause mortality was higher in the AKI group (hazard ratio [HR]: 2.01, 95% confidence interval [CI]: 1.31-3.60, P = .001) during the first 2 years after catheter insertion and lower in years 2 to 4 (HR: 0.42, 95% CI: 0.20-0.88, P = .02) than in the reference Maintenance Dialysis group. No difference in mortality risk between the Access Failure and reference group was found. LIMITATIONS: Single-center study. Possible residual confounding owing to the observational study design. CONCLUSIONS: Patients requiring acute or unplanned hemodialysis experience high mortality, and the nature of clinical presentation does influence outcomes. Most notable is the greater early mortality experienced by patients with AKI compared to other patient groups. Prospective definition of the nature of unplanned dialysis initiation is important to accurately measure and improve outcomes in this high-risk patient population. HUMAN RESEARCH ETHICS COMMITTEE APPROVAL NUMBER: CH62/6/2017-042.

CONTEXTE: La plupart des études traitant de l'initiation d'un traitement d'hémodialyse avec cathéter portent sur des patients qui s'engagent dans un program de dialyze d'entretien et excluent les autres patients, notamment ceux atteints d'insuffisance rénale aiguë (IRA). Ceci rend difficiles l'interprétation et l'application des résultats pour les cliniciens qui traitent les patients à l'amorce de la dialyze. OBJECTIF: Comparer la survie de tous les patients nécessitant un cathéter pour l'accès à l'hémodialyse selon la nature du tableau clinique. TYPE D'ÉTUDE: Étude observationnelle prospective. CADRE: L'unité de néphrologie d'un center de soins tertiaires australien. SUJETS: Tous les patients qui, entre 2005 et 2015, ont eu besoin d'un cathéter veineux central (CVC) pour l'hémodialyse. MESURES: Les maladies concomitantes existantes et les données démographiques des patients, ainsi que la nature du tableau clinique. Les données concernant chaque CVC et épisode d'accès déficient ont été recueillies. Le principal critère de jugement était la mortalité toutes causes confondues. MÉTHODOLOGIE: Les patients ont été répartis dans trois groupes selon l'évaluation du médecin au moment de la présentation : patients soupçonnés d'IRA avec récupération rénale prévue (groupe « IRA ¼), patients sans accès fonctionnel pour la dialyze considérés comme entrant dans le program de dialyze d'entretien (groupe « dialyze d'entretien ¼), et les patients incapables de pratiquer la dialyze péritonéale ou d'utiliser leur accès vasculaire existant (groupe « échec de l'accès ¼). Des régressions de Cox multivariées à temps partagé ont été utilisées pour comparer la survie entre les groupes. RÉSULTATS: Ont été inclus dans les analyses les 557 patients admissibles pour lesquels on disposait de données prospectives complètes sur l'utilization d'un CVC. La majorité des patients se trouvaient dans les groupes « IRA ¼ (246/557; 44 %) et « dialyze d'entretien ¼ (182/557; 33 %); le groupe « échec de l'accès ¼ ne représentant que 23 % des patients inclus (129/557). Au cours d'un suivi médian de trois ans, 302 patients (54 %) sont décédés. Après correction, le risque de mortalité toutes causes confondues dans les deux premières années suivant l'insertion du cathéter était plus élevé dans le groupe IRA (RR : 2,01; IC à 95 % : 1,31-3,60; P = .001) que dans le groupe référence (dialyze d'entretien); mais moins élevé après 2 à 4 ans (RR : 0.42; IC 95 % : 0.20-0.88; P = .02). Aucune différence n'a été observée entre le groupe « échec de l'accès ¼ et le groupe de référence. LIMITES: L'étude est monocentrique et la nature observationnelle de l'étude sous-tend de possibles facteurs de confusion résiduels. CONCLUSION: Les patients nécessitant une hémodialyse aiguë ou non planifiée connaissent un taux de mortalité élevé, et la nature du tableau clinique influence les résultats. Le plus remarquable étant la mortalité précoce plus élevée des patients atteints d'IRA comparativement aux autres patients. Il est important de définir la nature prospective de l'amorce non planifiée de la dialyze afin de mesurer précisément les résultats dans cette population à haut risque, et de les améliorer.

Checkpoint Inhibition in the Treatment of Unresectable, Advanced Lymphoepithelioma-like Hepatocellular Carcinoma.

Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is a very rare neoplasm, with distinct epidemiologic, morphologic and clinical characteristics. Molecular mechanistic insight into the pathogenesis of this carcinoma suggests a pivotal role for the host immune system in the proliferation and progression of this tumor. However, while detailed genomic profiling of these hepatic tumors have revealed an intra-tumoral inflammatory mutational signature that may predispose to immune checkpoint inhibitor efficacy, no published report has described their use in this tumor type. Unfortunately, with near 100 cases of LEL-HCC reported in the literature to date and the majority of cases confined to localized and resectable disease, current evidence-based practices in the unresectable setting are lacking, with unknown benefit of chemotherapy or immunotherapy. We report on the case of a 68 year-old man with unresectable, advanced LEL-HCC who had evidence of disease stability after starting on the immune checkpoint inhibitor nivolumab. His disease response persisted off therapy for over a year and was potentially augmented by radiotherapy at the site of local progression. For this extremely rare tumor subtype, this case highlights the potential efficacy and safety of immune checkpoint blockade in LEL-HCC and reinforces the need for more robust, large-scale analysis of patients with these rare tumors to better evaluate treatment strategies and outcomes.

SARS-CoV-2 seroprevalence and transmission risk factors among high-risk close contacts: a retrospective cohort study.

BACKGROUND: The proportion of asymptomatic carriers and transmission risk factors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among household and non-household contacts remains unclear. In Singapore, extensive contact tracing by the Ministry of Health for every diagnosed COVID-19 case, and legally enforced quarantine and intensive health surveillance of close contacts provided a rare opportunity to determine asymptomatic attack rates and SARS-CoV-2 transmission risk factors among community close contacts of patients with COVID-19. METHODS: This retrospective cohort study involved all close contacts of confirmed COVID-19 cases in Singapore, identified between Jan 23 and April 3, 2020. Household contacts were defined as individuals who shared a residence with the index COVID-19 case. Non-household close contacts were defined as those who had contact for at least 30 min within 2 m of the index case. All patients with COVID-19 in Singapore received inpatient treatment, with access restricted to health-care staff. All close contacts were quarantined for 14 days with thrice-daily symptom monitoring via telephone. Symptomatic contacts underwent PCR testing for SARS-CoV-2. Secondary clinical attack rates were derived from the prevalence of PCR-confirmed SARS-CoV-2 among close contacts. Consenting contacts underwent serology testing and detailed exposure risk assessment. Bayesian modelling was used to estimate the prevalence of missed diagnoses and asymptomatic SARS-CoV-2-positive cases. Univariable and multivariable logistic regression models were used to determine SARS-CoV-2 transmission risk factors. FINDINGS: Between Jan 23 and April 3, 2020, 7770 close contacts (1863 household contacts, 2319 work contacts, and 3588 social contacts) linked to 1114 PCR-confirmed index cases were identified. Symptom-based PCR testing detected 188 COVID-19 cases, and 7582 close contacts completed quarantine without a positive SARS-CoV-2 PCR test. Among 7518 (96·8%) of the 7770 close contacts with complete data, the secondary clinical attack rate was 5·9% (95% CI 4·9-7·1) for 1779 household contacts, 1·3% (0·9-1·9) for 2231 work contacts, and 1·3% (1·0-1·7) for 3508 social contacts. Bayesian analysis of serology and symptom data obtained from 1150 close contacts (524 household contacts, 207 work contacts, and 419 social contacts) estimated that a symptom-based PCR-testing strategy missed 62% (95% credible interval 55-69) of COVID-19 diagnoses, and 36% (27-45) of individuals with SARS-CoV-2 infection were asymptomatic. Sharing a bedroom (multivariable odds ratio [OR] 5·38 [95% CI 1·82-15·84]; p=0·0023) and being spoken to by an index case for 30 min or longer (7·86 [3·86-16·02]; p<0·0001) were associated with SARS-CoV-2 transmission among household contacts. Among non-household contacts, exposure to more than one case (multivariable OR 3·92 [95% CI 2·07-7·40], p<0·0001), being spoken to by an index case for 30 min or longer (2·67 [1·21-5·88]; p=0·015), and sharing a vehicle with an index case (3·07 [1·55-6·08]; p=0·0013) were associated with SARS-CoV-2 transmission. Among both household and non-household contacts, indirect contact, meal sharing, and lavatory co-usage were not independently associated with SARS-CoV-2 transmission. INTERPRETATION: Targeted community measures should include physical distancing and minimising verbal interactions. Testing of all household contacts, including asymptomatic individuals, is warranted. FUNDING: Ministry of Health of Singapore, National Research Foundation of Singapore, and National Natural Science Foundation of China.