Clinicopathologic and Genomic Characterization of PD-L1 Positive Urothelial Carcinomas.

INTRODUCTION: Pembrolizumab was approved with an accompanying companion diagnostic (CDx) assay (PD-L1 DAKO 22C3) for urothelial carcinoma (UC). In this study, we further characterize the clinicopathologic and genomic features of UC that are programmed death-ligand 1 (PD-L1) positive. MATERIALS AND METHODS: The cohort of this study consisted of a total of 528 consecutive UC patients with PD-L1 immunohistochemistry (IHC) and comprehensive genomic profiling (CGP). All PD-L1 IHC testing was performed using the DAKO 22C3 CDx assay for UC. PD-L1 positivity was determined at a combined positive score ≥ 10. RESULTS: A total of 44.5% (235/528) patients with UC were PD-L1positive . A lower PD-L1 positivity rate was detected in primary (42.3%, 148/350) versus metastatic sites (48.9%, 87/178). PD-L1 positivity was dependent on the location of the metastatic sites. CGP revealed PD-L1positive patients had more frequent genomic alterations (GAs) in TP53 (p = .006) and RB1 (p = .003) and less frequent GAs in FGFR3 (p = .001) and MTAP (p = .028). The APOBEC mutational signature and tumor mutational burden (TMB)-high were more common in PD-L1positive patients. By testing patients with UC with CGP, in addition to PD-L1 IHC, an additional 97 patients (18.4%) in the total cohort were eligible for immunotherapy based on TMB status. CONCLUSION: PD-L1positive and PD-L1negative urothelial carcinomas are genomically different. Also, our study provides the framework for future clinical investigation with regard to specimen site selection for PD-L1 testing as well as candidate biomarker genomic alterations that may predict for better response or lack of response to immune checkpoint inhibitors. IMPLICATIONS FOR PRACTICE: In this study, a higher prevalence of TP53 and RB1 alterations and APOBEC mutational signatures in the PD-L1positive urothelial carcinoma disease subset and enrichment of FGFR3 alterations in the PD-L1negative disease subset were found. These data provide the basis for future investigation into the role of these genomic changes as positive and negative predictors of immunotherapy response. Also, differences wer seen in PD-L1 positivity based on the collection site of the sample, which can provide a framework for future clinical trial design and could influence sample selection for PD-L1 testing in patients with urothelial carcinoma when multiple samples are available.

Diabetes insipidus after discontinuation of vasopressin infusion for septic shock.

WHAT IS KNOWN AND OBJECTIVE: Despite widespread use of vasopressin for the treatment of septic shock, few cases of diabetes insipidus (DI) following its discontinuation have been reported. CASE SUMMARY: A 54-year-old man presented with pneumonia progressing to septic shock, requiring norepinephrine and vasopressin for refractory hypotension. After clinical improvement, the patient on 3 separate occasions developed polyuria and severe hypernatremia upon discontinuation of vasopressin, with prompt recovery upon its resumption. WHAT IS NEW AND CONCLUSION: Occurrence of DI upon discontinuation of vasopressin infusion appears to be rare, but incidence may be underestimated due to a paucity of published reports. Actual incidence and underlying mechanism of this phenomenon remain to be elucidated.

Towards a methodology to formulate sustainable diets for livestock: accounting for environmental impact in diet formulation.

The objective of this study was to develop a novel methodology that enables pig diets to be formulated explicitly for environmental impact objectives using a Life Cycle Assessment (LCA) approach. To achieve this, the following methodological issues had to be addressed: (1) account for environmental impacts caused by both ingredient choice and nutrient excretion, (2) formulate diets for multiple environmental impact objectives and (3) allow flexibility to identify the optimal nutritional composition for each environmental impact objective. An LCA model based on Canadian pig farms was integrated into a diet formulation tool to compare the use of different ingredients in Eastern and Western Canada. By allowing the feed energy content to vary, it was possible to identify the optimum energy density for different environmental impact objectives, while accounting for the expected effect of energy density on feed intake. A least-cost diet was compared with diets formulated to minimise the following objectives: non-renewable resource use, acidification potential, eutrophication potential, global warming potential and a combined environmental impact score (using these four categories). The resulting environmental impacts were compared using parallel Monte Carlo simulations to account for shared uncertainty. When optimising diets to minimise a single environmental impact category, reductions in the said category were observed in all cases. However, this was at the expense of increasing the impact in other categories and higher dietary costs. The methodology can identify nutritional strategies to minimise environmental impacts, such as increasing the nutritional density of the diets, compared with the least-cost formulation.

Prognostic value of breast cancer subtypes, Ki-67 proliferation index, age, and pathologic tumor characteristics on breast cancer survival in Caucasian women.

Estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (HER2) status are well-established prognostic markers in breast cancer management. The triple negative breast carcinoma subtype (ER-/PR-/HER2-) has been associated with worse overall prognosis in comparison with other subtypes in study populations consisting of ethnic minorities and young women. We evaluated the prognostic value of breast cancer subtypes, Ki-67 proliferation index (Ki-67PI), and pathologic tumor characteristics on breast cancer survival in Caucasian women in our institution, where greater than 90% of the total patient population is white. From 628 new invasive breast cancer cases in our data base (2000-late 2004), 593 (94%) were identified in Caucasian women. ER/PR/HER2 breast cancer subtypes were classified based on St. Gallen International Expert Consensus recommendations from 2011. ER/PR/HER2 status and its effect on survival were analyzed using a Kaplan-Meier curve. ER/PR/HER2 status, grade, tumor-node-metastasis status (TNM)/anatomic stage, and age were analyzed in terms of survival in a multivariate fashion using a Cox regression. Ki-67PI was analyzed between ER/PR/HER2 groups using the Kruskal-Wallis, Mann-Whitney U-tests, and 2 × 5 ANOVA. Our results showed that patients with stage IIB through stage IV breast carcinomas were 2.1-16 times more likely to die than patients with stages IA-B and IIA disease, respectively (95% CI 1.17-3.81 through 9.68-28.03, respectively), irrespective of ER/PR/HER2 subtype. Similar effect was seen with T2, N2/N3, or M1 tumors in comparison with T1, N0/N1, and M0 tumors. Chances of dying increase approximately 5% for every year increase in age. There was a significant main effect of Ki-67PI between ER/PR/HER2 subtypes, p < .001, but Ki-67PI could not predict survival. In summary, TNM status/anatomic stage of breast carcinomas and age are predictive of survival in our patient population of Caucasian women, but breast carcinoma subtypes and Ki-67 proliferation index are not.

Transmission scenarios for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and how to tell them apart.

Detection of human cases of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection internationally is a global public health concern. Rigorous risk assessment is particularly challenging in a context where surveillance may be subject to under-ascertainment and a selection bias towards more severe cases. We would like to assess whether the virus is capable of causing widespread human epidemics, and whether self-sustaining transmission is already under way. Here we review possible transmission scenarios for MERS-CoV and their implications for risk assessment and control. We discuss how existing data, future investigations and analyses may help in reducing uncertainty and refining the public health risk assessment and present analytical approaches that allow robust assessment of epidemiological characteristics, even from partial and biased surveillance data. Finally, we urge that adequate data be collected on future cases to permit rigorous assessment of the transmission characteristics and severity of MERS-CoV, and the public health threat it may pose. Going beyond minimal case reporting, open international collaboration, under the guidance of the World Health Organization and the International Health Regulations, will impact on how this potential epidemic unfolds and prospects for control.

[Transcultural adaptation into Spanish of the nursing activities score]. / Adaptación transcultural al castellano del nursing activities score.

INTRODUCTION: Assessment of nursing workload is a common practice in the daily work of nursing care. This is usually done using scales that were not designed for Spanish-speaking countries, which may not take into account the characteristics of the environments that differ from one country to another. The Nursing Activities Score (NAS) has been described as being a useful tool for measuring nursing workload among the instruments used for this measurement in intensive care units. OBJECTIVE: It was aimed to adapt the NAS into Spanish for its use in Spanish intensive care units. MATERIAL AND METHODS: The NAS was adapted using translation-back translation method with the participation of both native English speakers who were bilingual in Spanish, and Spanish translators with a high level of English. All of the translators worked individually. A single Spanish version of the scale was obtained, after which a pilot test was made in an Intensive Care Major Burns Unit of the University Hospital of Getafe (Madrid, Spain) with 30 patients and 30 nurses during their regular work shift. We also consulted the primary author of the original description of the NAS regarding items that caused some kind of conflict. RESULTS: Between the original scale and the result of the back-translations to English, we obtained agreement ratings of good in 73%, and appropriate in the remaining 27%. No item was considered to have bad correspondence. CONCLUSION: We have developed a Spanish translation of the NAS that appears well matched to the original English version.

Fibrolipomatous hamartoma of the inferior calcaneal nerve (Baxter nerve).

Fibrolipomatous hamartoma (FLH) is a rare, benign lesion of the peripheral nerves most frequently involving the median nerve and its digital branches (80 %). Pathognomonic MR features of FLH such as coaxial-cable-like appearance on axial planes and a spaghetti-like appearance on coronal planes have been described by Marom and Helms, obviating the need for diagnostic biopsy. We present a case of fibrolipomatous hamartoma of the inferior calcaneal nerve (Baxter nerve) with associated subcutaneous fat proliferation.

Hospitalisation and mortality risk of SARS-COV-2 variant omicron sub-lineage BA.2 compared to BA.1 in England.

The Omicron variant of SARS-CoV-2 became the globally dominant variant in early 2022. A sub-lineage of the Omicron variant (BA.2) was identified in England in January 2022. Here, we investigated hospitalisation and mortality risks of COVID-19 cases with the Omicron sub-lineage BA.2 (n = 258,875) compared to BA.1 (n = 984,337) in a large cohort study in England. We estimated the risk of hospital attendance, hospital admission or death using multivariable stratified proportional hazards regression models. After adjustment for confounders, BA.2 cases had lower or similar risks of death (HR = 0.80, 95% CI 0.71-0.90), hospital admission (HR = 0.88, 95% CI 0.83-0.94) and any hospital attendance (HR = 0.98, 95% CI 0.95-1.01). These findings that the risk of severe outcomes following infection with BA.2 SARS-CoV-2 was slightly lower or equivalent to the BA.1 sub-lineage can inform public health strategies in countries where BA.2 is spreading.

Influence of body mass index on outcome of the mechanically ventilated patients.

BACKGROUND: There are limited data on the impact of body mass index on outcomes in mechanically ventilated patients. METHODS: Secondary analysis of a cohort including 4698 patients mechanically ventilated. Patients were screened daily for management of mechanical ventilation, complications (acute respiratory distress syndrome, sepsis, ventilator associated pneumonia, barotrauma), organ failure (cardiovascular, respiratory, renal, hepatic, haematological) and mortality in the intensive care unit. To estimate the impact of body mass index on acute respiratory distress syndrome and mortality, the authors constructed models using generalised estimating equations (GEE). RESULTS: Patients were evaluated based on their body mass index: 184 patients (3.7%) were underweight, 1995 patients (40%) normal weight, 1781 patients (35.8%) overweight, 792 patients (15.9%) obese and 216 patients (4.3%) severely obese. Severely obese patients were more likely to receive low tidal volume based on actual body weight but high volumes based on predicted body weight. In obese patients, the authors observed a higher incidence of acute respiratory distress syndrome and acute renal failure. After adjustment, the body mass index was significantly associated with the development of acute respiratory distress syndrome: compared with normal weight; OR 1.69 (95% CI 1.07 to 2.69) for obese and OR 2.38 (95% CI 1.15 to 4.89) for severely obese. There were no differences in outcomes (duration of mechanical ventilation, length of stay and mortality in intensive care unit and hospital) based on body mass index categories. CONCLUSIONS: In this cohort, obese patients were more likely to have significant complications but there were no associations with increased mortality.

Independent and joint contribution of inappropriate complementary feeding and poor water, sanitation and hygiene (WASH) practices to stunted child growth.

The causes of undernutrition are often linked to inappropriate complementary feeding practices and poor households' access to water, sanitation and hygiene (WASH), but limited evidence exists on the combined effect of poor WASH and inappropriate complementary feeding practices on stunted child growth. We assessed the independent and joint contribution of inappropriate complementary feeding and poor WASH practices to stunted growth among children aged 6-23 months in the Jirapa Municipality of Ghana. A community-based cross-sectional analytical study design was used with a sample of 301 mothers/caregivers having children aged 6-23 months. The results indicate that in a multivariable logistic regression model that adjusted for confounders, children receiving both unimproved water and inappropriate complementary feeding had a higher and significant odd of becoming stunted (adjusted odds ratio = 33. 92; 95 % confidence interval 3⋅04, 37⋅17; P = 0⋅004) compared to households having both improved water sources and appropriate complementary feeding practices. Except for unimproved drinking water sources, poor sanitation and hygiene, which comprised the use of unimproved household toilet facilities, washing hands without soap and improper disposal of child faeces were not associated with the risks of stunting among children aged 6-23 months. The combined effect of unimproved water and inappropriate complementary feeding on stunting was greater than either unimproved water only or inappropriate complementary feeding only.

Reduced MFAP5 expression in stroma of gallbladder adenocarcinoma and its potential diagnostic utility.

The diagnosis of invasive adenocarcinoma of the gallbladder can sometimes be challenging. The presence of true desmoplastic reaction facilitates the diagnosis of invasion. However, desmoplasia-like changes can be observed in benign gallbladder conditions, and recognition of desmoplasia may be challenging based on morphology. In this study, we tested the expression pattern of microfibril-associated protein 5 (MFAP5), a promising immunohistochemical marker for desmoplasia, in benign gallbladders with desmoplasia-like reaction and gallbladders with invasive adenocarcinoma. We also evaluated the diagnostic utility of MFAP5 in challenging cases with an interobserver agreement study. The results showed that all benign cases retained intact/positive MFAP5 staining pattern in periglandular connective tissue, whereas 79.3% (23 out of 29) of cases of adenocarcinomas demonstrated diffuse and complete loss of MFAP5 staining in the tumor stroma. Interobserver agreement was improved by 2.66 times when images of MFAP5 immunohistochemistry were provided. In conclusion, MFAP5 expression is downregulated in the desmoplastic stroma of gallbladder adenocarcinoma and may provide a useful diagnostic marker in difficult cases.

Landscape of Biomarkers in Non-small Cell Lung Cancer Using Comprehensive Genomic Profiling and PD-L1 Immunohistochemistry.

Comprehensive genomic profiling (CGP) and immunohistochemistry (IHC) are important biomarker tools used for patients with non-small cell lung cancer (NSCLC) given the expanding number of standard-of-care therapies that require companion diagnostic testing. We examined 9450 NSCLC real-world patient samples that underwent both CGP and programmed death-ligand 1 (PD-L1) IHC to understand the biomarker landscape in this patient cohort. By assessing National Comprehensive Cancer Network (NCCN)-recommended biomarkers including genomic alterations, tumor mutational burden (≥10 mutations/Mb cut-off), and PD-L1 expression (Tumor Proportion Score (TPS) ≥ 50% cut-off), we show that CGP + PD-L1 IHC yielded potentially actionable results for 70.5% of the 9,450 patients with NSCLC. Among the remaining 29.5% (2,789/9,450) of patients, 86.7% (2,419/2,789) were potentially eligible for another biomarker-associated therapy and/or clinical trial based on their genomic profile. In addition, in the PD-L1TPS≥50% disease subset, BRAF mutations, MET mutations, MET amplifications, and KRAS mutations were significantly enriched; and in the PD-L1TPS<50%, EGFR mutations, ERBB2 mutations, STK11 mutations, and KEAP1 mutations were enriched. These findings highlight the improved clinical utility of combining CGP with IHC to expand the biomarker-guided therapeutic options available for patients with NSCLC, relative to single biomarker testing alone.

Household and community variations and nested risk factors for diarrhoea prevalence in southern Malawi: a binary logistic multi-level analysis.

This paper examines household and community-level influences on diarrhoeal prevalence in southern Malawi. A Bayesian multi-level modelling technique is used in the estimation of hierarchically built data from a survey of individuals nested within households nested within communities. Households have strong unobserved influence on diarrhoeal illness (sigma(2)(u) = 4.476; 95% CI: 2.081, 6.871). A joint Wald test of significance shows that an individual's age [chi(2)(4) = 55.921, p = 0.000] and school [chi(2)(2) = 18.203, p = 0.000] have strong influence on an individual's diarrhoeal prevalence. An individual's history of malarial-like illness also has a strong positive relationship with diarrhoeal prevalence [beta = 0.606, p = 0.000]. Household factors that influence diarrhoea include employment status of head of household [beta = -0.619, p < 0.021], maternal age [beta = -0.013, p < 0.003], and size of household [beta = -0.669, p = 0.000]. The positive relationship between diarrhoea and malaria-like episodes highlights common risk factors hence the need for common approaches to combat the diseases. Significant household effects underline the importance of household considerations in policy issues.

Review: Synergy between mechanistic modelling and data-driven models for modern animal production systems in the era of big data.

Mechanistic models (MMs) have served as causal pathway analysis and 'decision-support' tools within animal production systems for decades. Such models quantitatively define how a biological system works based on causal relationships and use that cumulative biological knowledge to generate predictions and recommendations (in practice) and generate/evaluate hypotheses (in research). Their limitations revolve around obtaining sufficiently accurate inputs, user training and accuracy/precision of predictions on-farm. The new wave in digitalization technologies may negate some of these challenges. New data-driven (DD) modelling methods such as machine learning (ML) and deep learning (DL) examine patterns in data to produce accurate predictions (forecasting, classification of animals, etc.). The deluge of sensor data and new self-learning modelling techniques may address some of the limitations of traditional MM approaches - access to input data (e.g. sensors) and on-farm calibration. However, most of these new methods lack transparency in the reasoning behind predictions, in contrast to MM that have historically been used to translate knowledge into wisdom. The objective of this paper is to propose means to hybridize these two seemingly divergent methodologies to advance the models we use in animal production systems and support movement towards truly knowledge-based precision agriculture. In order to identify potential niches for models in animal production of the future, a cross-species (dairy, swine and poultry) examination of the current state of the art in MM and new DD methodologies (ML, DL analytics) is undertaken. We hypothesize that there are several ways via which synergy may be achieved to advance both our predictive capabilities and system understanding, being: (1) building and utilizing data streams (e.g. intake, rumination behaviour, rumen sensors, activity sensors, environmental sensors, cameras and near IR) to apply MM in real-time and/or with new resolution and capabilities; (2) hybridization of MM and DD approaches where, for example, a ML framework is augmented by MM-generated parameters or predicted outcomes and (3) hybridization of the MM and DD approaches, where biological bounds are placed on parameters within a MM framework, and the DD system parameterizes the MM for individual animals, farms or other such clusters of data. As animal systems modellers, we should expand our toolbox to explore new DD approaches and big data to find opportunities to increase understanding of biological systems, find new patterns in data and move the field towards intelligent, knowledge-based precision agriculture systems.

Chaos, persistence, and evolution of strain structure in antigenically diverse infectious agents.

The effects of selection by host immune responses on transmission dynamics was analyzed in a broad class of antigenically diverse pathogens. Strong selection can cause pathogen populations to stably segregate into discrete strains with nonoverlapping antigenic repertoires. However, over a wide range of intermediate levels of selection, strain structure is unstable, varying in a manner that is either cyclical or chaotic. These results have implications for the interpretation of longitudinal epidemiological data on strain or serotype abundance, design of surveillance strategies, and the assessment of multivalent vaccine trials.

The foot-and-mouth epidemic in Great Britain: pattern of spread and impact of interventions.

We present an analysis of the current foot-and-mouth disease epidemic in Great Britain over the first 2 months of the spread of the virus. The net transmission potential of the pathogen and the increasing impact of control measures are estimated over the course of the epidemic to date. These results are used to parameterize a mathematical model of disease transmission that captures the differing spatial contact patterns between farms before and after the imposition of movement restrictions. The model is used to make predictions of future incidence and to simulate the impact of additional control strategies. Hastening the slaughter of animals with suspected infection is predicted to slow the epidemic, but more drastic action, such as "ring" culling or vaccination around infection foci, is necessary for more rapid control. Culling is predicted to be more effective than vaccination.

Methods of extraction of optical properties from diffuse reflectance measurements of ex-vivo human colon tissue using thin film silicon photodetector arrays.

Spatially resolved diffuse reflectance spectroscopy (SRDRS) is a promising technique for characterization of colon tissue. Herein, two methods for extracting the reduced scattering and absorption coefficients ( µ s ' ( λ ) and µ a ( λ ) ) from SRDRS data using lookup tables of simulated diffuse reflectance are reported. Experimental measurements of liquid tissue phantoms performed with a custom multi-pixel silicon SRDRS sensor spanning the 450 - 750 nm wavelength range were used to evaluate the extraction methods, demonstrating that the combined use of spatial and spectral data reduces extraction error compared to use of spectral data alone. Additionally, SRDRS measurements of normal and tumor ex-vivo human colon tissue are presented along with µ s ' ( λ ) and µ a ( λ ) extracted from these measurements.

Cross-serotype interactions and disease outcome prediction of dengue infections in Vietnam.

Dengue pathogenesis is extremely complex. Dengue infections are thought to induce life-long immunity from homologous challenges as well as a multi-factorial heterologous risk enhancement. Here, we use the data collected from a prospective cohort study of dengue infections in schoolchildren in Vietnam to disentangle how serotype interactions modulate clinical disease risk in the year following serum collection. We use multinomial logistic regression to correlate the yearly neutralizing antibody measurements obtained with each infecting serotype in all dengue clinical cases collected over the course of 6 years (2004-2009). This allowed us to extrapolate a fully discretised matrix of serotype interactions, revealing clear signals of increased risk of clinical illness in individuals primed with a previous dengue infection. The sequences of infections which produced a higher risk of dengue fever upon secondary infection are: DEN1 followed by DEN2; DEN1 followed by DEN4; DEN2 followed by DEN3; and DEN4 followed by DEN3. We also used this longitudinal data to train a machine learning algorithm on antibody titre differences between consecutive years to unveil asymptomatic dengue infections and estimate asymptomatic infection to clinical case ratios over time, allowing for a better characterisation of the population's past exposure to different serotypes.

Analytic approximation of spatial epidemic models of foot and mouth disease.

The effect of spatial heterogeneity in epidemic models has improved with computational advances, yet far less progress has been made in developing analytical tools for understanding such systems. Here, we develop two classes of second-order moment closure methods for approximating the dynamics of a stochastic spatial model of the spread of foot and mouth disease. We consider the performance of such 'pseudo-spatial' models as a function of R(0), the locality in disease transmission, farm distribution and geographically-targeted control when an arbitrary number of spatial kernels are incorporated. One advantage of mapping complex spatial models onto simpler deterministic approximations lies in the ability to potentially obtain a better analytical understanding of disease dynamics and the effects of control. We exploit this tractability by deriving analytical results in the invasion stages of an FMD outbreak, highlighting key principles underlying epidemic spread on contact networks and the effect of spatial correlations.

Plaster cast burns: the reality.

An in vivo experimental study was performed of the temperatures produced by a setting plaster cast using hot and cold water. The results confirmed a statistical difference in the temperatures reached using hot and cold water. Forearm and below knee plasters did not represent a burn risk. Lower limb cylinder casts reached sufficient temperatures to cause burns with hot water but did not remain at these temperatures long enough to pose a clinical risk.