Immune-checkpoint gene expression and BCG response in non-muscle invasive bladder cancer.

METHODS: One-hundred-six patients diagnosed with non-muscle invasive bladder cancer and treated with intravesical BCG were included and divided into two groups, BCG-responsive (n = 47) and -unresponsive (n = 59). Immunohistochemistry was used to evaluate PD-L1 expression and MSI was assessed by a commercial multiplex PCR kit. The mRNA expression profile of 15 immune checkpoints was performed using the nCounter technology. For in silico validation, two distinct cohorts sourced from the Gene Expression Omnibus (GEO) database were used. RESULTS: Among the 106 patients, only one (<1 %) exhibited MSI instability. PD-L1 expression was present in 9.4 % of cases, and no association was found with BCG-responsive status. We found low gene expression of canonic actionable immune checkpoints PDCD1 (PD-1), CD274 (PD-L1), and CTLA4, while high expression was observed for CD276 (B7-H3), CD47, TNFRSF14, IDO1 and PVR (CD155) genes. High IDO1 expression levels was associated with worst overall survival. The PDCD1, CTLA4 and TNFRSF14 expression levels were associated with BCG responsiveness, whereas TIGIT and CD276 were associated with unresponsiveness. Finally, CD276 was validated in silico cohorts. CONCLUSION: In NMIBC, MSI is rare and PD-L1 expression is present in a small subset of cases. Expression levels of PDCD1, CTLA4, TNFRSF14, TIGIT and CD276 could constitute predictive biomarkers of BCG responsiveness.

Imaging of pancreatic ductal adenocarcinoma - An update for all stages of patient management.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a common and lethal cancer. From diagnosis to disease staging, response to neoadjuvant therapy assessment and patient surveillance after resection, imaging plays a central role, guiding the multidisciplinary team in decision-planning. Review aims and findings: This review discusses the most up-to-date imaging recommendations, typical and atypical findings, and issues related to each step of patient management. Example cases for each relevant condition are presented, and a structured report for disease staging is suggested. Conclusion: Despite current issues in PDAC imaging at different stages of patient management, the radiologist is essential in the multidisciplinary team, as the conveyor of relevant imaging findings crucial for patient care.

When the fever will not stop, stop the pills! A case report

ABSTRACT Neuroleptic malignant syndrome (NMS) is a neurologic emergency potentially fatal. This rare side effect is most commonly associated with first-generation antipsychotics and less frequently with atypical or second-generation antipsychotics. The diagnosis relies on both clinical and laboratory criteria, with other organic and psychiatric conditions being ruled out. CASE REPORT: A 39-year-old female patient, who is institutionalized and completely dependent, has a medical history of recurrent urinary infections and colonization by carbapenem-resistant Klebsiella pneumoniae. Her regular medication regimen included sertraline, valproic acid, quetiapine, risperidone, lorazepam, diazepam, haloperidol, baclofen, and fentanyl. The patient began experiencing dyspnea. Upon physical examination, she exhibited hypotension and a diminished vesicular murmur at the right base during pulmonary auscultation. Initially, after hospitalization, she developed high febrile peaks associated with hemodynamic instability, prompting the initiation of antibiotic treatment. Despite this, her fever persisted without an increase in blood inflammatory parameters, and she developed purulent sputum, necessitating antibiotherapy escalation. The seventh day of hospitalization showed no improvement in symptoms, suggesting NNMS as a differential diagnosis. All antipsychotic and sedative drugs, as well as antibiotherapy, were discontinued, after which the patient showed significant clinical improvement. CONCLUSION: Antipsychotic agents are commonly employed to manage behavioral changes linked to various disorders. However, their severe side effects necessitate a high degree of vigilance, the cessation of all medications, and the implementation of supportive care measures. A prompt and accurate diagnosis of NMS is crucial to alleviating the severe, prolonged morbidity and potential mortality associated with this syndrome.

Correction: Capturing the attentional response to clinical auditory alarms: An ERP study on priority pulses.

[This corrects the article DOI: 10.1371/journal.pone.0281680.].

When the fever will not stop, stop the pills! A case report.

BACKGROUND: Neuroleptic malignant syndrome (NMS) is a neurologic emergency potentially fatal. This rare side effect is most commonly associated with first-generation antipsychotics and less frequently with atypical or second-generation antipsychotics. The diagnosis relies on both clinical and laboratory criteria, with other organic and psychiatric conditions being ruled out. CASE REPORT: A 39-year-old female patient, who is institutionalized and completely dependent, has a medical history of recurrent urinary infections and colonization by carbapenem-resistant Klebsiella pneumoniae. Her regular medication regimen included sertraline, valproic acid, quetiapine, risperidone, lorazepam, diazepam, haloperidol, baclofen, and fentanyl. The patient began experiencing dyspnea. Upon physical examination, she exhibited hypotension and a diminished vesicular murmur at the right base during pulmonary auscultation. Initially, after hospitalization, she developed high febrile peaks associated with hemodynamic instability, prompting the initiation of antibiotic treatment. Despite this, her fever persisted without an increase in blood inflammatory parameters, and she developed purulent sputum, necessitating antibiotherapy escalation. The seventh day of hospitalization showed no improvement in symptoms, suggesting NNMS as a differential diagnosis. All antipsychotic and sedative drugs, as well as antibiotherapy, were discontinued, after which the patient showed significant clinical improvement. CONCLUSION: Antipsychotic agents are commonly employed to manage behavioral changes linked to various disorders. However, their severe side effects necessitate a high degree of vigilance, the cessation of all medications, and the implementation of supportive care measures. A prompt and accurate diagnosis of NMS is crucial to alleviating the severe, prolonged morbidity and potential mortality associated with this syndrome.

Diffusion-weighted imaging for determining response to neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis.

OBJECTIVES: To determine the role of diffusion-weighted imaging (DWI) for predicting response to neoadjuvant therapy (NAT) in pancreatic cancer. MATERIALS AND METHODS: MEDLINE, EMBASE, and Cochrane Library databases were searched for studies evaluating the performance of apparent diffusion coefficient (ADC) to assess response to NAT. Data extracted included ADC pre- and post-NAT, for predicting response as defined by imaging, histopathology, or clinical reference standards. ADC values were compared with standardized mean differences. Risk of bias was assessed using the Quality Assessment of Diagnostic Studies (QUADAS-2). RESULTS: Of 337 studies, 7 were included in the analysis (161 patients). ADC values reported for the pre- and post-NAT assessments overlapped between responders and non-responders. One study reported inability of ADC increase after NAT for distinguishing responders and non-responders. A correlation with histopathological response was reported for pre- and post-NAT ADC in 4 studies. DWI's diagnostic performance was reported to be high in three studies, with a 91.6-100% sensitivity and 62.5-94.7% specificity. Finally, heterogeneity and high risk of bias were identified across studies, affecting the domains of patient selection, index test, reference standard, and flow and timing. CONCLUSION: DWI might be useful for determining response to NAT in pancreatic cancer. However, there are still too few studies on this matter, which are also heterogeneous and at high risk for bias. Further studies with standardized procedures for data acquisition and accurate reference standards are needed. CLINICAL RELEVANCE STATEMENT: Diffusion-weighted MRI might be useful for assessing response to neoadjuvant therapy in pancreatic cancer. However, further studies with robust data are needed to provide specific recommendations for clinical practice. KEY POINTS: •The role of DWI with ADC measurements for assessing response to neoadjuvant therapy in pancreatic cancer is still unclear. •Pre- and post-neoadjuvant therapy ADC values overlap between responders and non-responders. •DWI has a reported high diagnostic performance for determining response when using histopathological or clinical reference standards; however, studies are still few and at high risk for bias.

Policies, institutions, and regulations: PIRs of a stormwater management system.

Urban services, like stormwater management, are complex tasks that depend on many actors and involve activities that fall within several fields of knowledge, but infrastructure solutions have been known for a long time. Recently, the view that urban water should be treated in an integrated way has become more pronounced, breaking the pathway dependency that treated it in isolation. Since the last decade, the perception that policies, institutions, and regulations (PIRs) condition good results has become more pronounced. The key question lies in incentives capable of mobilizing actors to produce aligned PIRs in a governance system. Better results can come from transformations in the incentives that currently exist for PIRs. The compatibility between incentives, which are not always identical for all involved, aligning them toward results, is the main objective. Based on these premises, aspects related to the necessary ideological change are analyzed here, that is, at the level of ideas and conceptions, which reflect the perception of objective, involving all actors, public and private, attracting them to solve the challenges posed, for example, the delivery of services according to sustainable development goals (SDGs). Examples of this in-progress transformation, a paradigm shift, are presented as support for reflection and experimentation.

Digital expression profile of immune checkpoint genes in medulloblastomas identifies CD24 and CD276 as putative immunotherapy targets.

Introduction: Medulloblastoma is the most common and lethal pediatric malignant brain tumor. It comprises four main molecular subgroups: WNT-activated, SHH-activated, Group 3, and Group 4. Medulloblastoma treatment is surgical resection, craniospinal radiation, and chemotherapy. However, many patients do not respond to therapy, and most suffer severe side effects. Cancer immunotherapy targeting immune checkpoints (IC) (PD-1, PD-L1, and CTLA4) has been getting disappointing outcomes in brain tumors. Nevertheless, other less explored immune checkpoints may be promising candidates for medulloblastoma therapy. Objectives: In the present study, we aimed to characterize the expression profile of 19 immune checkpoints in medulloblastoma. Methods: We analyzed 88 formalin-fixed paraffin-embedded medulloblastomas previously classified for each molecular subgroup and three non-tumoral brain tissue. mRNA levels of 19 immune checkpoint-related genes were quantified using the nCounter (PanCancer Immune Profiling Panel) assay. Further in silico analysis was performed in two larger public microarray datasets, one of which enabled comparisons between tumoral and non-tumoral tissues. Immunohistochemistry of PD-L1 was performed in a subset of cases. Microsatellite instability was also molecularly analyzed. Results: We observed an absence of expression of the canonic ICs, namely PDCD1 (PD-1), CD274 (PD-L1), and CTLA4, as well as CD80, CD86, BTLA, IDO1, CD48, TNFSF14, CD160, CEACAM1, and CD244. PD-L1 protein expression was also practically absent. We found higher mRNA levels of CD24, CD47, CD276 (B7-H3), and PVR, and lower mRNA levels of HAVCR2, LAG3, and TIGIT genes, with significant differences across the four molecular subgroups. Compared to the non-tumor tissues, the expression levels of CD276 in all subgroups and CD24 in SHH, Group 3, and Group 4 subgroups are significantly higher. The in silico analysis confirmed the expression profile found in the Brazilian cohort, including the lower/absent expression of the canonic ICs. Moreover, it confirmed the overexpression of CD24 and CD276 in medulloblastomas compared with the non-tumor tissue. Additionally, CD276 and CD24 high levels were associated with worse survival. Conclusion: These results highlight the low or absence of mRNA levels of the canonic targetable ICs in medulloblastomas. Importantly, the analysis revealed overexpression of CD24 and CD276, which can constitute prognostic biomarkers and attractive immunotherapy targets for medulloblastomas.

Capturing the attentional response to clinical auditory alarms: An ERP study on priority pulses.

Clinical auditory alarms are often found in hospital wards and operating rooms. In these environments, regular daily tasks can result in having a multitude of concurrent sounds (from staff and patients, building systems, carts, cleaning devices, and importantly, patient monitoring devices) which easily amount to a prevalent cacophony. The negative impact of this soundscape on staff and patients' health and well-being, as well as in their performance, demand for accordingly designed sound alarms. The recently updated IEC60601-1-8 standard, in guidance for medical equipment auditory alarms, proposed a set of pointers to distinctly convey medium or high levels of priority (urgency). However, conveying priority without compromising other features, such as ease of learnability and detectability, is an ongoing challenge. Electroencephalography, a non-invasive technique for measuring the brain response to a given stimulus, suggests that certain Event-Related Potentials (ERPs) components such as the Mismatch Negativity (MMN) and P3a may be the key to uncovering how sounds are processed at the pre-attentional level and how they may capture our attention. In this study, the brain dynamics in response to the priority pulses of the updated IEC60601-1-8 standard was studied via ERPs (MMN and P3a), for a soundscape characterised by the repetition of a sound (generic SpO2 "beep"), usually present in operating and recovery rooms. Additional behavioural experiments assessed the behavioural response to these priority pulses. Results showed that the Medium Priority pulse elicits a larger MMN and P3a peak amplitude when compared to the High Priority pulse. This suggests that, at least for the applied soundscape, the Medium Priority pulse is more easily detected and attended at the neural level. Behavioural data supports this indication, showing significantly shorter reaction times for the Medium Priority pulse. The results pose the possibility that priority pointers of the updated IEC60601-1-8 standard may not be successfully conveying their intended priority levels, which may not only be due to design properties but also to the soundscape in which these clinical alarms are deployed. This study highlights the need for intervention in both hospital soundscapes and auditory alarm design settings.

Institutional paradigm shift: transitions in stormwater management principles.

In most cities, stormwater systems are part of the invisible and expensive urban infrastructure that plays a vital role in the urban environment but depends on weak institutional and organizational structures. Based on the evidence that solving the issues only from a technological point of view is not sufficient for the provision of stormwater services, in several countries, sustainable drainage systems (SuDS) structures are being implemented, but a new paradigm shift involving a new socio-institutional mentality that meets not only the old but also the new demands of climate and territorial changes, migratory issues, and participatory management is required.

Spontaneous Adverse Event Reporting by COVID-19 Vaccinated Healthcare Professionals Through an Electronic Form Implemented by the Hospital Pharmacy.

Aim: Implementation of a web-form based pharmacovigilance plan for the spontaneous notification of adverse events to the Comirnaty® COVID-19 vaccine during its administration to hospital healthcare professionals. Methods: An electronic pharmacovigilance form was developed containing 8 pre-defined event options, an open answer option for the description of other events and/or symptoms, and a question about the overall intensity of symptoms. The adverse events reports were standardized according to physiological and pathological condition. Results: A total of 4119 adverse events notifications were obtained with a 45% rate of electronic notification. The most clinically relevant events reported were:tachycardia (n = 19), dyspnea (n = 7), chest pain (n = 6), facial/labial edema (n = 6), lipothymia (n = 5), bronchospasm (n = 2), herpetic infection (n = 2), vasculitis (n = 2), arrhythmia (n = 1), difficult to control arterial hypertension (n = 1), gastritis (n = 1), and spontaneous abortion (n = 1). Regarding the intensity of symptoms (n = 2928), 70.0% were reported as mild, 25.8% as moderate, and 4.27% as severe, with higher intensity in the second dose compared to first dose. The highest frequency of severe events were reported in the groups from 40 to 59 years in both vaccination periods. During the vaccination process, no hospitalizations and no deaths were notified and/or recorded. Conclusion: In this real world study, comparing with Comirnaty clinical trials program, it was observed a higher frequency of adenomegaly and gastrointestinal disorders. Noteworthy, the notification of a case of miscarriage. The use of hospital pharmacy pharmacovigilance electronic forms, seemed to be relevant to notification adherence and to obtain a greater and faster knowledge of COVID-19 vaccine safety profile.

Aedes Aegypti-Insights on the Impact of Water Services.

Epidemics in general and dengue in particular surcharge the health services and the economy. However, the fighting actions are circumscribed to the health sector despite the known positive economic impacts that the investments in water supply and sanitation services (WSS) may cause on society and public health. Besides the fact that urban WSS infrastructure is closely linked to disease prevention, in Brazil, the user's perception and demand are very few and many institutional aspects, like the integration between local WSS, health, environment, and development of city councils, need to be improved and better aligned. In this way, disease control and vector density reduction remain challenges to be overcome. This article addresses the need for greater institutionalization of urban WSS relating them to health aspects from official data. It concludes that the negative impacts of lacking universal access to WSS on dengue and other mosquito diseases are dispersed in all cities, regions, and populations regardless of their degree of development. Furthermore, contrary to what is normally emphasized, the analysis carried out shows that the lack of urban stormwater management systems may be an important component of WSS in preventing the proliferation of dengue disease.

A network Data Envelopment Analysis to estimate nations' efficiency in the fight against SARS-CoV-2.

The ongoing outbreak of SARS-CoV-2 has been deeply impacting health systems worldwide. In this context, it is pivotal to measure the efficiency of different nations' response to the pandemic, whose insights can be used by governments and health authorities worldwide to improve their national COVID-19 strategies. Hence, we propose a network Data Envelopment Analysis (DEA) to estimate the efficiencies of fifty-five countries in the current crisis, including the thirty-seven Organisation for Economic Co-operation and Development (OECD) member countries, six OECD prospective members, four OECD key partners, and eight other countries. The network DEA model is designed as a general series structure with five single-division stages - population, contagion, triage, hospitalisation, and intensive care unit admission -, and considers an output maximisation orientation, denoting a social perspective, and an input minimisation orientation, denoting a financial perspective. It includes inputs related to health costs, desirable and undesirable intermediate products related to the use of personal protective equipment and infected population, respectively, and desirable and undesirable outputs regarding COVID-19 recoveries and deaths, respectively. To the best of the authors' knowledge, this is the first study proposing a cross-country efficiency measurement using a network DEA within the context of the COVID-19 crisis. The study concludes that Estonia, Iceland, Latvia, Luxembourg, the Netherlands, and New Zealand are the countries exhibiting higher mean system efficiencies. Their national COVID-19 strategies should be studied, adapted, and used by countries exhibiting worse performances. In addition, the observation of countries with large populations presenting worse mean efficiency scores is statistically significant.

Primary adenoid cystic carcinoma of the trachea: an elusive diagnosis of chronic dyspnoea.

Primary adenoid cystic carcinoma (ACC) of the trachea is a rare entity, with a 5-year survival between 50% and 80% for resectable cases and 30% in case of unresectable disease. We report a case of a primary ACC on a woman in her 70s that presented with a drawn-out history of dyspnoea. She was diagnosed with an unresectable obstructive tumour of the trachea, which required the placement of a Y-shaped stent. The patient underwent concomitant chemoradiotherapy, with partial response, and is still in follow-up, without evidence of disease progression.

Cervical carcinosarcoma: approach of a rare tumour in a rare location.

Cervical carcinosarcoma is a very rare tumour, with less than 70 cases described in the literature. We report a case of a woman in her 60s, with an atypical presentation: a single episode of high volume serous vaginal discharge. A carcinosarcoma of the uterine cervix was diagnosed and, after exclusion of distant disease, the patient was submitted to radical surgery. Due to surgical complications adjuvant treatment was not performed.

Public policy: urban stormwater in a paradigm shift, is it the end or just the beginning?

The perception that urban stormwater policies are non-existent, incomplete, or lacking in aspects that concern the environment and quality of life in cities has become increasingly common. This is partly due to the increased frequency and magnitude of rainfall events resulting from climate change and its economic, social, and environmental consequences. Population concentration and changes in patterns of living, construction, and urbanization contribute to the pollution of water runoff and receiving waters. Thus, quantity and quality problems add up and often require costly solutions, which are then addressed as economic issues. To deal with all these aspects, many of which were previously absent, stormwater public policies require a paradigm shift to break away from institutional inertia and dependence on the previous path. Without the aim of exhausting the subject, this paper discusses the policy aspects that concern stormwater management and the current and desired paradigm shift.

Performance and its determinants in the Portuguese municipal solid waste utilities.

The unprecedented population increase brings several consequences to the environment, including the rise of urbanization levels and municipal solid waste (MSW) production - one expects that it may reach 3.4 billion tons per year by 2050. This paper contributes to the debate of efficiency measurement of MSW utilities management using the Portuguese case study. Our objectives are twofold. First, we assess the efficiency levels of municipalities in MSW collection through the Data Envelopment Analysis model, choosing total costs, staff, and vehicles as inputs, and the quantity of MSW collected (selective and refuse waste) as outputs. The efficiency results point to an average inefficiency level of about 35% and potential cost savings of over €96 million yearly. Second, by using a set of fifteen performance indicators monitored by the regulatory agency, we evaluate their relationship with the efficiency of MSW utilities, through the order-m model. Our results suggest that, in opposition to the management model, the rural/urban nature of councils helps explain part of the inefficiency. In general, the conditional-to-unconditional efficiency ratios reached values statistically different from 1, meaning that those indicators help explaining their efficiency distribution and the benchmarks profile, and need to be considered in future performance analyses. Remarkable and influential indicators include the accessibility to the service (average ratio = 0.95), the recycling rate (0.94), the monetization of the vehicle fleet (0.92), the pollution resulting from greenhouse gas emissions of waste collection vehicles (0.81), and council size measured by the population or the number of households (0.47).

Sustainable water and sanitation for all: Are we there yet?

The lack of access to water and sanitation services (WSS) of a considerable share of the world population has been challenging the international community for decades. The proposal of the Millennium Development Goals and, later on, the Sustainable Development Goals (SDGs) by the United Nations (UN) intended to act as a blueprint to achieve a more equitable future for all and, in the case of WSS, "Ensure the availability and sustainable management of water and sanitation for all" (SDG 6). However, the current global pandemic further emphasised the importance of WSS, given the increasing asymmetries faced by billions worldwide, and the gaps between high-income and low- and middle-income nations. For this reason, understanding whether low- and middle-income countries have been approximating towards or deviating from the SDG 6 is crucial to derive and communicate key information for the sake of improved public governance and political decision-making. In this paper, we extend a state-of-the-art methodology based on data envelopment analysis for assessing the convergence of the low- and middle-income UN Member States regarding the SDG 6 between 2016 and 2017. We find that, on average, not only did the Member States converge by decreasing the performance spread and the gap between the best and worst practice frontiers, but also the Level of water stress: freshwater withdrawal as a proportion of available freshwater resources was the indicator in which the majority exhibited the worst performances. In the end, we derive possible policy implications, which, as our results show, are aligned with the recent UN reports on the subject.

An Incentive-Based Framework for Analyzing the Alignment of Institutional Interventions in the Public Primary Healthcare Sector: The Portuguese Case.

Over the years, the Portuguese National Health Service has undergone several reforms to face the challenges posed by internal and external factors on the access to and quality of its health services. One of its most recent reforms addressed the primary healthcare sector, where understanding the incentives behind the actors of the inherent institutional interventions and how they are aligned with the governing health policies is paramount for reformative success. With the purpose of acknowledging the alignment of the primary healthcare sector's institutional interventions from an incentive-based perspective, we propose a framework resting on a SWOT (Strengths, Weaknesses, Opportunities, and Threats) analysis, which was built in cooperation with a panel of decision-making actors from the Portuguese Ministry of Health. In the end, we derive possible policy implications and strategies. This holistic approach highlighted the positive impact of the primary healthcare reform in the upgrade of physical resources and human capital but stressed the geosocial asymmetries and the lack of intra- and inter-sectorial coordination. The proposed framework serves also as a guideline for future primary healthcare reforms, both national- and internationally.

Investment in drinking water and sanitation infrastructure and its impact on waterborne diseases dissemination: The Brazilian case.

Investment in sanitation and drinking water infrastructure is essential for universal access to these services in developing countries. Universal coverage of water and sanitation services (WSS) can prevent the dissemination of waterborne diseases and mitigate their adverse effects. These diseases are responsible for many deaths worldwide, especially among the disadvantaged population and children. A causal effect can be established between WSS investment and hospital admissions due to waterborne diseases. Therefore, we considered an innovative network-DEA approach that models the link between serially connected subsystems (upstream investment and downstream hospitalizations). This approach allowed us: to measure the efficiency of both subsystems; estimate the amount of (efficient) investment necessary to universalize the access to proper WSS infrastructure; and mitigate hospital admissions due to waterborne diseases. We used the Brazil case study to test our model. On average, Brazilian states could increase the number of people not requiring hospitalizations due to waterborne diseases by 157 thousand per R$100 million invested in sanitation and 26 thousand per R$100 million invested in drinking water. Our results suggest that relatively small (efficient) investment in those two infrastructure types has a massive impact on hospitalizations. This impact would be more significant than the investment in WSS coverage. Therefore, if safely managed, WSS would cover all citizens, and Brazil would come closer to developed countries.