The surgical technique and protocol for dynamic sentinel node biopsy for penile cancer at a Southeast Asian regional hospital.

Lymph node status is a key prognostic factor in penile cancer. The European Association of Urology (EAU) recommends intermediate-risk (pT1a, Grade 2) or high-risk (pT1b or greater) penile cancer patients with clinically non-palpable inguinal lymph node (cN0) to undergo either an invasive bilateral modified inguinal lymph node dissection (ILND) or dynamic sentinel node biopsy (DSNB). DSNB has been reported to have acceptable false negative rates, and lower rates of long-term morbidity compared to ILND. We developed a protocol for DSNB at a regional hospital in Singapore that was adopted from St James's University Hospital, Leeds Teaching Hospitals Trust. Four patients with cN0 penile cancer underwent DSNB between November 2021 and October 2022 according to this protocol. Our surgical technique and protocol are described. The patients' oncological characteristics and their outcomes were evaluated. In this small case series, there was no complication attributable to the performance of DSNB, and there was no groin that was documented to be false negative over a median follow up of 15.5 months (range, 12 to 22 months). Using our protocol, 5 of 8 groins (62.5%) were able to avoid ILND in the cN0 setting. We recommend the adoption of DSNB for the surgical staging of inguinal lymph nodes for patients with intermediate to high-risk penile cancer and non-palpable inguinal nodes due to its significantly lower risks of long-term morbidity compared to ILND. Appropriate specialist training and a multi-disciplinary team is vital to ensure the success of the procedure.

Impact of a drug allergy education course for non-specialists: Findings from ADAPT-A randomized crossover trial.

BACKGROUND: The consequences of drug allergy remain a global health concern. Drug allergy is often a neglected topic and many non-specialists lack sufficient knowledge or confidence in evaluating or managing this common condition. Evidence-based interventions to better equip non-specialists to tackle drug allergy are needed. The aim of the study is to evaluate the effectiveness of an intensive educational course on drug allergy knowledge and practice of non-specialists. METHODS: A randomized crossover trial (NCT06399601) was conducted among practicing physicians and nurses participating in an intensive drug allergy course-Advances in Drug Allergy & Penicillin Testing (ADAPT). Participants' baseline knowledge and self-reported practices were assessed with standardized questionnaires (scored from 0 to 100, with "satisfactory" defined as ≥60/100). Participants were randomized into two cohorts and attended ADAPT at different time points. Serial responses before and after the course were compared within and between cohorts. RESULTS: Seventy participants (25 physicians, 45 nurses) randomized into two groups completed the course. Baseline drug allergy knowledge (58.0 ± 19.9) and self-reported practice (36.9 ± 24.3) were unsatisfactory among non-specialists, with significantly lower scores from nurses than physicians in both domains (knowledge: 49.0 ± 17.4 vs. 74.0 ± 12.7; practice: 32.1 ± 21.3 vs. 53.3 ± 23.1; all p < 0.001). Following completion of ADAPT, participants demonstrated significant improvements in knowledge (58.0 ± 19.9 vs. 77.7 ± 15.9, p < 0.001) and self-reported practice (36.9 ± 24.3 vs. 71.0 ± 20.2, p < 0.001). All participants (100%) and 99% of participants agreed that the course improved their clinical knowledge and practice, respectively. CONCLUSIONS: ADAPT, an intensive drug allergy educational course was effective in improving drug allergy knowledge and practice for non-specialists. Further longitudinal studies are required to evaluate long-term impact.

An analysis of the trends in the usage of Pharmaceutical Benefits Scheme-subsidised cancer drugs in Australia from 2012 to 2022.

PURPOSE: Cancer treatment remains a significant and escalating healthcare expense worldwide. Although annual reports on total cancer care costs are available, the potential impact of evolving treatment guidelines and the introduction of new drugs on future budgeting remains largely uncertain. The aim of this study was to examine the trends in the use of Pharmaceutical Benefits Scheme (PBS)-subsidised cancer drugs in Australia over the past decade. METHODS: PBS codes for all PBS-subsidised cancer drugs that were listed in government-endorsed treatment protocols were obtained and used to retrieve usage data. Their patterns of use, represented by the number of prescriptions (services) processed by Services Australia, were analysed for the period between 2012 and 2022. RESULTS: The overall prescribing of cancer drugs is outpacing Australia's population growth, primarily due to an ageing population and the accelerated rise in cancer diagnoses observed over the past decade. From 846 eviQ protocols, 141 cancer drugs were available on the PBS, of which kinase inhibitor (39 drugs) and monoclonal antibody drugs (24 drugs) had the highest increase in use during the study period; 16% and 23% respectively. Of the 8 drug classes, hormonal agents (20 drugs) were the most prescribed. CONCLUSION: The utilisation of PBS-listed cancer drugs is increasing faster than population growth, especially for high-cost monoclonal antibody and kinase inhibitor drugs, indicating continued pressure on government spending.

Association of Scholarly Impact to Industrial Contributions Among Academic Interventional Radiologists.

OBJECTIVE: The Physician Sunshine Act of 2010 aimed to increase public awareness of physician-industry relationships. Our objective was to evaluate whether there is an association between scholarly impact and industry funding among academic interventional radiologists. METHODS: A database from a prior study with our group was used in which we had investigated H-indices among US interventional radiologists; academic rank, gender, institution, and geographic location were obtained. The Scopus database was queried to determine all physicians' H-index. The CMS Open Payments database was used to determine industry payments from 2015 to 2021 for each interventional radiologist. RESULTS: H-index and professor rank positively and significantly correlated with industrial funding (H-index coefficient = $6,977, P < .001 and professor rank coefficient = $183,902, P = .003). Industry funding was found to be significantly different between all ranks. Among 830 academic interventional radiologists, the mean industrial funding of male physicians was $130,034, which was significantly higher than female physicians' $28,166 (P = .00013). By academic rank, male primary investigators of associate professor and unranked position had higher industrial funding than female primary investigators (Wilcoxon test, P = .029 and P= .039, respectively). Professor and assistant professor ranks had no significant difference in industrial funding between male and female physicians (Wilcoxon's test, P = .080 and P = .053, respectively). CONCLUSION: Scholarly activity as defined by the H-index and academic rank seem to have a positive association with industry funding of academic interventional radiologists.

Safety and Preliminary Efficacy of Once-Weekly Split-Dose Selinexor in Soft Tissue Sarcoma: Results of the Phase Ib METSSAR Clinical Trial.

BACKGROUND: The approved dose of Selinexor, 60 mg twice-weekly, is associated with several clinically relevant toxicities. Preclinical studies show that a sustained-release formulation of selinexor results in a lower toxicity profile. OBJECTIVE: The phase 1b METSSAR trial assessed the safety and tolerability of an alternative dosing schedule of selinexor (to mimic the sustained-release formulation) in advanced soft tissue sarcoma (STS) patients. PATIENTS AND METHODS: Selinexor was administered in a split-dose schedule (40 mg, 20 mg, 20 mg in the morning, afternoon, and evening, respectively) on days 1, 8, 15, and 22 of a 28-day cycle, until unacceptable toxicity or disease progression. The primary endpoint was the rate of grade ≥ 3 treatment-related adverse events (TRAEs). Secondary objectives were EORTC QLQ-C30 quality of life (QoL) assessment, and preliminary efficacy. RESULTS: Twenty patients with 12 STS subtypes were enrolled and received a median of four cycles of treatment. There were no grade ≥ 3 TRAEs. Dysgeusia, nausea, fatigue, and thrombocytopenia were the most common grade ≤ 2 TRAEs. No treatments were discontinued due to TRAE, but four patients (20%) required dose reduction. Median change in global health status (GHS) score from baseline to cycle 2 (by QLQ-C30 v3.0) was - 8.33, and only 39% of patients reported a clinically meaningful decline in GHS score (≥ 10 points). Median symptom scale scores on treatment were increased for fatigue (+12.35), nausea/vomiting (+18.52), and anorexia (+16.67), but reduced for pain (- 3.70). The median progression-free survival (PFS) was 4.0 months (95% confidence interval 1.9-7.5). CONCLUSIONS: Split-dose once-weekly selinexor was reasonably well tolerated in this heterogeneous group of advanced STS patients with a better, or at least similar, clinician- and patient-reported toxicity profile compared to the standard dosing regimen. Further clinical evaluation is warranted, as better dose delivery can lead to improved antitumor efficacy.

Depressive symptoms are not associated with clinically important levels of digital home blood pressure in the electronic Framingham Heart Study.

Background: Depressive symptoms are common and share many biopsychosocial mechanisms with hypertension. Association studies between depressive symptoms and blood pressure (BP) have been inconsistent. Home BP monitoring may provide insight. Objective: To investigate the association between depressive symptoms and digital home BP. Methods: Electronic Framingham Heart Study (eFHS) participants were invited to obtain a smartphone app and digital BP cuff at research exam 3 (2016-2019). Participants with ≥3 weeks of home BP measurements within 1 year were included. Depressive symptoms were measured using the Center for Epidemiological Studies Depression Scale (CES-D). Multivariable linear mixed models were used to test the associations of continuous CES-D score and dichotomous depressive symptoms (CES-D ≥16) (independent) with home BP (dependent), adjusting for age, sex, cohort, number of weeks since baseline, lifestyle factors, diabetes, and cardiovascular disease. Results: Among 883 participants (mean age 54 years, 59% women, 91% White), the median CES-D score was 4. Depressive symptom prevalence was 7.6%. Mean systolic and diastolic BP at exam 3 were 119 and 76 mm Hg; hypertension prevalence was 48%. A 1 SD higher CES-D score was associated with 0.9 (95% CI: 0.18-1.56, P = .01) and 0.6 (95% CI: 0.06-1.07, P = .03) mm Hg higher home systolic BP and diastolic BP, respectively. Dichotomous depressive symptoms were not significantly associated with home BP (P > .2). Conclusion: Depressive symptoms were not associated with clinically substantive levels of home BP. The association between depression and cardiovascular disease risk factors warrants more data, which may be supported by mobile health measures.

Conservation features of the terrestrial Antarctic Peninsula.

Conserving landscapes used by multiple stakeholder groups requires understanding of what each stakeholder values. Here we employed a semi-structured, participatory approach to identify features of value in the terrestrial Antarctic Peninsula related to biodiversity, science and tourism. Stakeholders identified 115 features, ranging from Adélie penguin colonies to sites suitable for snowshoeing tourists. We split the features into seven broad categories: science, tourism, historic, biodiversity, geographic, habitat, and intrinsic features, finding that the biodiversity category contained the most features of any one category, while science stakeholders identified the most features of any stakeholder group. Stakeholders have overlapping interests in some features, particularly for seals and seabirds, indicating that thoughtful consideration of their inclusion in future management is required. Acknowledging the importance of tourism and other social features in Antarctica and ensuring their integration into conservation planning and assessment will increase the likelihood of implementing successful environmental management strategies into the future.

The effects of anti-TNF-α biologics on insulin resistance and insulin sensitivity in patients with rheumatoid arthritis: An update systematic review and meta-analysis.

BACKGROUND AND AIM: Increasing evidence demonstrates a link between the chronic inflammatory state in patients with rheumatoid arthritis (RA) and the development of insulin resistance. It is thought that anti-TNF-α biologic therapy may improve insulin sensitivity and ameliorate insulin resistance by the downregulation of inflammatory cytokines, however, pre-clinical and clinical studies have yielded conflicting results. A meta-analysis on this topic is necessary to summarize current evidence and generate hypotheses for future research. METHODS: Literature search was performed in four databases, namely PubMed, EMBASE, Scopus, and The Cochrane Library, from inception till April 9, 2023, querying studies reporting peripheral insulin resistance with and without anti-TNF-α use in patients with RA. Peripheral insulin resistance or sensitivity was quantified by the Homeostasis Model Assessment of Insulin Resistance (HOMA) index or the Quantitative Insulin Sensitivity Check Index (QUICKI) respectively. The difference in insulin resistance or sensitivity between the treatment and control group was calculated using standardized mean difference (SMD) for the purposes of the meta-analysis. RESULTS: Twelve articles were reviewed, with 10 longitudinal studies with a total of 297 patients included in the meta-analysis. The pooled standardized mean difference (SMD) from baseline HOMA was -0.82 (95% CI: -1.38 to -0.25) suggesting significant beneficial effects of anti-TNF-α therapy on insulin resistance. CONCLUSION: Current evidence supports the significant clinical efficacy of anti-TNF-α biologics in alleviating insulin resistance and improving insulin sensitivity in patients with active RA.

Mental health inequalities, challenges and support needs during COVID-19: a qualitative study of 14-to-25-year-olds in London.

OBJECTIVES: The impact of the COVID-19 pandemic on adolescent's mental health and relationships has received growing attention, yet the challenges and support needs of adolescents living in existing deprivation are not well understood. The current qualitative study, part of a broader project cocreating mental health and life-skill workshops with young people, documents adolescents' lived experience and support needs 4 years on from the COVID-19 pandemic. DESIGN: 20 semi-structured interviews and 6 focus groups were transcribed and thematically analysed in NVivo V.12 to inform codesigned workshops to support adolescents' needs. SETTING: Islington borough in North London, United Kingdom. PARTICIPANTS: 20 adolescents aged 14-25 years (mean=18.3; 60% female, 60% white) from Islington with a history of difficulties (eg, mental health, deprivation, court order) were referred by Islington local authority teams to our study. RESULTS: Thematic analyses revealed eight themes on adolescents' COVID-19 experiences and five associated suggestions on 'support needs': health challenges and support; relationships and support; routines and support; educational challenges and learning support; inequality and support; distrust; loss of opportunities and grief. CONCLUSIONS: In our qualitative study, adolescents spoke of positive reflections, challenges, and need for support 4 years on from the COVID-19 pandemic. Many adolescents shared their lived experiences for the first time with someone else and wished they would have the space and time to acknowledge this period of loss. Adolescents living with existing inequality and deprivation before the pandemic have reported sustained and exacerbated impacts during the pandemic, hence coproduced support for adolescents should be a priority.

Role of innate T cells in necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a destructive gastrointestinal disease primarily affecting preterm babies. Despite advancements in neonatal care, NEC remains a significant cause of morbidity and mortality in neonatal intensive care units worldwide and the etiology of NEC is still unclear. Risk factors for NEC include prematurity, very low birth weight, feeding with formula, intestinal dysbiosis and bacterial infection. A review of the literature would suggest that supplementation of prebiotics and probiotics prevents NEC by altering the immune responses. Innate T cells, a highly conserved subpopulation of T cells that responds quickly to stimulation, develops differently from conventional T cells in neonates. This review aims to provide a succinct overview of innate T cells in neonates, encompassing their phenotypic characteristics, functional roles, likely involvement in the pathogenesis of NEC, and potential therapeutic implications.

Intralesional Injections of a TNF-α Inhibitor to Treat Orofacial Granulomatosis.

We present the first documented case of successful treatment of orofacial granulomatosis by intralesional injections of a tumor necrosis factor α inhibitor to the lip. Our patient had rapid symptomatic improvement after 3 injections, and near resolution within 4 months of anti-tumor necrosis factor α therapy.

Anatomical substrates and connectivity for bradykinesia motor features in Parkinson's disease after subthalamic nucleus deep brain stimulation.

Parkinsonian bradykinesia is rated using a composite scale incorporating the slowed frequency of repetitive movements, decrement amplitude and arrhythmicity. Differential localization of these movement components within the basal ganglia will drive the development of more personalized network-targeted symptomatic therapies. In this study, using an optical motion sensor, we evaluated the amplitude and frequency of hand movements during a grasping task with subthalamic nucleus deep brain stimulation 'on' or 'off' in 15 patients with Parkinson's disease. The severity of bradykinesia was assessed blindly using the Unified Parkinson's Disease Rating Part III scale. The volumes of activated tissue of each subject were estimated where changes in amplitude and frequency were mapped to identify distinct anatomical substrates of each component in the subthalamic nucleus. The volumes of activated tissue were used to seed a normative functional connectome to generate connectivity maps associated with amplitude and frequency changes. Deep brain stimulation-induced change in amplitude was negatively correlated with a change in Unified Parkinson's Disease Rating Part III scale for right (r = -0.65, P < 0.05) and left hand grasping scores (r = -0.63, P < 0.05). The change in frequency was negatively correlated with amplitude for both right (r = -0.63, P < 0.05) and left hands (r = -0.57, P < 0.05). The amplitude and frequency changes were represented as a spatial gradient with overlapping and non-overlapping regions spanning the anteromedial-posterolateral axis of the subthalamic nucleus. Whole-brain correlation maps between functional connectivity and motor changes were also inverted between amplitude and frequency changes. Deep brain stimulation-associated changes in frequency and amplitude were topographically and distinctly represented both locally in the subthalamic nucleus and in whole-brain functional connectivity.

Examining the Association between Coffee Intake and the Risk of Developing Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis.

Irritable bowel syndrome (IBS) is a highly prevalent disorder of brain-gut interaction with a significant impact on quality of life. Coffee is a widely consumed beverage with numerous bioactive compounds that have potential effects on human health and disease states. Current studies on the effect of regular coffee consumption on the risk of developing IBS symptoms have yielded conflicting results. This systematic review and meta-analysis aimed to determine whether coffee intake is associated with developing IBS. A systematic literature search was performed in three electronic databases, namely PubMed, EMBASE, and The Cochrane Library, from inception until 31 March 2023. All original studies reporting associations between coffee intake and IBS were considered for inclusion. Odds ratios (ORs) were calculated for each study, and estimates were pooled, and where appropriate, 95% confidence intervals (95% CI) and p-values were calculated. Eight studies comprising 432,022 patients were included in the final meta-analysis. Using a fixed-effects model, coffee drinkers (any intake) had a reduced likelihood of developing IBS compared to controls, with a pooled OR of 0.84 (95% CI: 0.80 to 0.84). Sensitivity analysis confirmed the stability of the estimates. Future research should prioritise prospective cohort studies that are robust and closely track the development of incident IBS in previously healthy individuals.

Ligand-based targeting of c-kit using engineered γδ T cells as a strategy for treating acute myeloid leukemia.

The application of immunotherapies such as chimeric antigen receptor (CAR) T therapy or bi-specific T cell engager (BiTE) therapy to manage myeloid malignancies has proven more challenging than for B-cell malignancies. This is attributed to a shortage of leukemia-specific cell-surface antigens that distinguish healthy from malignant myeloid populations, and the inability to manage myeloid depletion unlike B-cell aplasia. Therefore, the development of targeted therapeutics for myeloid malignancies, such as acute myeloid leukemia (AML), requires new approaches. Herein, we developed a ligand-based CAR and secreted bi-specific T cell engager (sBite) to target c-kit using its cognate ligand, stem cell factor (SCF). c-kit is highly expressed on AML blasts and correlates with resistance to chemotherapy and poor prognosis, making it an ideal candidate for which to develop targeted therapeutics. We utilize γδ T cells as a cytotoxic alternative to αß T cells and a transient transfection system as both a safety precaution and switch to remove alloreactive modified cells that may hinder successful transplant. Additionally, the use of γδ T cells permits its use as an allogeneic, off-the-shelf therapeutic. To this end, we show mSCF CAR- and hSCF sBite-modified γδ T cells are proficient in killing c-kit+ AML cell lines and sca-1+ murine bone marrow cells in vitro. In vivo, hSCF sBite-modified γδ T cells moderately extend survival of NSG mice engrafted with disseminated AML, but therapeutic efficacy is limited by lack of γδ T-cell homing to murine bone marrow. Together, these data demonstrate preclinical efficacy and support further investigation of SCF-based γδ T-cell therapeutics for the treatment of myeloid malignancies.

Phrase parsing in a second language as indexed by the closure positive shift: The impact of language experience and acoustic cue salience.

Despite the importance of prosodic processing in utterance parsing, a majority of studies investigating boundary localization in a second language focus on word segmentation. The goal of the present study was to investigate the parsing of phrase boundaries in first and second languages from different prosodic typologies (stress-timed vs. syllable-timed). Fifty English-French bilingual adults who varied in native language (French or English) and second language proficiency listened to English and French utterances with different prosodic structures while event-related brain potentials were recorded. The utterances were built around target words presented either in phrase-final position (bearing phrase-final lengthening) or in penultimate position. Each participant listened to both English and French stimuli, providing data in their native language (used as reference) and their second language. Target words in phrase-final position elicited closure positive shifts across listeners in both languages, regardless of the language-specific acoustic cues associated with phrase-final lengthening (shorter phrase-final lengthening in English compared to French). Interestingly, directional effects were observed, where learning to parse English as a second language in a native-like manner seemed to require a higher proficiency level than learning to parse French as a second language. This pattern of results supports the idea that L2 listeners need to learn to recognize L2-specific phrase-final lengthening regardless of the apparent similarity across languages and that some language combinations might present greater challenges than others.

Perspectives of Pediatric Nephrologists, Intensivists and Nurses Regarding AKI Management and Expected Outcomes.

Background: Acute kidney injury (AKI) in critically ill children is associated with increased risk for short- and long-term adverse outcomes. Currently, there is no systematic follow-up for children who develop AKI in intensive care unit (ICU). Objective: This study aimed to assess variation regarding management, perceived importance, and follow-up of AKI in the ICU setting within and between healthcare professional (HCP) groups. Design: Anonymous, cross-sectional, web-based surveys were administered nationally to Canadian pediatric nephrologists, pediatric intensive care unit (PICU) physicians, and PICU nurses, via professional listservs. Setting: All Canadian pediatric nephrologists, PICU physicians, and nurses treating children in the ICU were eligible for the survey. Patients: N/A. Measurements: Surveys included multiple choice and Likert scale questions on current practice related to AKI management and long-term follow-up, including institutional and personal practice approaches, and perceived importance of AKI severity with different outcomes. Methods: Descriptive statistics were performed. Categorical responses were compared using Chi-square or Fisher's exact tests; Likert scale results were compared using Mann-Whitney and Kruskal-Wallis tests. Results: Surveys were completed by 34/64 (53%) pediatric nephrologists, 46/113 (41%) PICU physicians, and 82 PICU nurses (response rate unknown). Over 65% of providers reported hemodialysis to be prescribed by nephrology; a mix of nephrology, ICU, or a shared nephrology-ICU model was reported responsible for peritoneal dialysis and continuous renal replacement therapy (CRRT). Severe hyperkalemia was the most important renal replacement therapy (RRT) indication for both nephrologists and PICU physicians (Likert scale from 0 [not important] to 10 [most important]; median = 10, 10, respectively). Nephrologists reported a lower threshold of AKI for increased mortality risk; 38% believed stage 2 AKI was the minimum compared to 17% of PICU physicians and 14% of nurses. Nephrologists were more likely than PICU physicians and nurses to recommend long-term follow-up for patients who develop any AKI during ICU stay (Likert scale from 0 [none] to 10 [all patients]; mean=6.0, 3.8, 3.7, respectively) (P < .05). Limitations: Responses from all eligible HCPs in the country could not obtained. There may be differences in opinions between HCPs that completed the survey compared to those that did not. Additionally, the cross-sectional design of our study may not adequately reflect changes in guidelines and knowledge since survey completion, although no specific guidelines have been released in Canada since survey dissemination. Conclusions: Canadian HCP groups have variable perspectives on pediatric AKI management and follow-up. Understanding practice patterns and perspectives will help optimize pediatric AKI follow-up guideline implementation.

Contexte: L'insuffisance rénale aiguë (IRA) chez les enfants gravement malades est associée à un risque accru d'issues défavorables à court et à long terme. En ce moment, il n'existe aucun suivi systématique pour les enfants qui développent une IRA pendant un séjour à l'unité des soins intensifs (USI). Objectif: Cette étude visait à évaluer les variations dans la prise en charge de l'IRA, de son importance perçue et de son suivi, tant au sein des groupes de professionnels de la santé (PS) qu'entre les différents groupes de PS. Conception: Des sondages transversaux à remplir de façon anonyme en ligne ont été menés à l'échelle nationale auprès de néphrologues pédiatriques canadiens, de médecins des unités de soins intensifs pédiatriques (USIP) et de membres du personnel infirmier des USIP ayant été répertoriés à partir de listes professionnelles. Cadre: Tous les néphrologues pédiatriques canadiens, médecins et membres du personnel infirmier qui traitent des enfants en USI étaient admissibles à répondre au sondage. Patients: S/O. Mesures: Les sondages comportaient des questions à choix multiples et des questions de type échelle de Likert qui portaient sur les pratiques actuelles de la gestion et de suivi à long terme de l'IRA, notamment sur les approches institutionnelles et personnelles de pratique et sur l'importance perçue de la gravité de l'IRA avec différents résultats. Méthodologie: Des statistiques descriptives ont été réalisées. Les réponses catégorielles ont été comparées à l'aide du chi-carré ou de tests exacts de probabilité de Fisher; les résultats des échelles de Likert ont été comparés à l'aide de tests de Mann-Whitney et de Kruskal-Wallis. Résultats: Les sondages ont été complétés par 53 % des néphrologues pédiatriques (34/64), 41 % des médecins d'USIP (46/113) et par 82 membres du personnel infirmier d'USIP (taux de réponse inconnu). Plus de 65 % des prestataires de soins ont déclaré que l'hémodialyse était prescrite par le service de néphrologie, alors que la dialyze péritonéale et la thérapie de remplacement rénal continu (TRRC) étaient confiées à la fois à la néphrologie, à l'USI ou à un modèle partagé néphrologie-USI. L'hyperkaliémie grave était l'indication la plus importante de la TRR pour les néphrologues et les médecins en USIP (échelle de Likert de 0 [pas important] à 10 [le plus important]; médiane = 10, 10, respectivement). Les néphrologues ont signalé un seuil inférieur d'IRA pour l'augmentation du risque de mortalité; 38 % d'entre eux estimaient que l'IRA de stade 2 était le seuil minimum, contre 17 % des médecins en USI et 14 % du personnel infirmier. Les néphrologues étaient plus susceptibles que les médecins et le personnel infirmier des USIP de recommander un suivi à long terme pour les patients qui développent une IRA pendant leur séjour en USI (échelle Likert de 0 [aucun] à 10 [tous les patients]; moyennes respectives = 6,0; 3,8 et 3,7 [p < 0,05]). Limites: Il n'a pas été possible d'obtenir les réponses de tous les PS admissibles au pays. Des différences d'opinions sont possibles entre les PS qui ont répondu au sondage et ceux qui ne l'ont pas fait. De plus, la conception transversale de notre étude pourrait ne pas refléter adéquatement les changements apportés aux lignes directrices et aux connaissances depuis la fin de cette enquête, bien qu'aucune ligne directrice particulière n'ait été publiée au Canada depuis la diffusion du sondage. Conclusion: Les divers groupes de professionnels de la santé canadiens ont des points de vue différents en ce qui concerne la prise en charge et le suivi de l'IRA chez les enfants. La compréhension des modèles de pratique et des perspectives permettra d'optimiser la mise en œuvre de directives de suivi de l'IRA pédiatrique.

Identification and targeting of protein tyrosine kinase 7 (PTK7) as an immunotherapy candidate for neuroblastoma.

GD2-targeting immunotherapies have improved survival in children with neuroblastoma, yet on-target, off-tumor toxicities can occur and a subset of patients cease to respond. The majority of neuroblastoma patients who receive immunotherapy have been previously treated with cytotoxic chemotherapy, making it paramount to identify neuroblastoma-specific antigens that remain stable throughout standard treatment. Cell surface glycoproteomics performed on human-derived neuroblastoma tumors in mice following chemotherapy treatment identified protein tyrosine kinase 7 (PTK7) to be abundantly expressed. Furthermore, PTK7 shows minimal expression on pediatric-specific normal tissues. We developed an anti-PTK7 chimeric antigen receptor (CAR) and find PTK7 CAR T cells specifically target and kill PTK7-expressing neuroblastoma in vitro. In vivo, human/murine binding PTK7 CAR T cells regress aggressive neuroblastoma metastatic mouse models and prolong survival with no toxicity. Together, these data demonstrate preclinical efficacy and tolerability for targeting PTK7 and support ongoing investigations to optimize PTK7-targeting CAR T cells for neuroblastoma.

A phase 1 study of simvastatin in combination with topotecan and cyclophosphamide in pediatric patients with relapsed and/or refractory solid and CNS tumors.

BACKGROUND: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) can inhibit tumor proliferation, angiogenesis, and restore apoptosis in preclinical pediatric solid tumor models. We conducted a phase 1 trial to determine the maximum tolerated dose (MTD) of simvastatin with topotecan and cyclophosphamide in children with relapsed/refractory solid and central nervous system (CNS) tumors. METHODS: Simvastatin was administered orally twice daily on days 1-21, with topotecan and cyclophosphamide intravenously on days 1-5 of a 21-day cycle. Four simvastatin dose levels (DLs) were planned, 140 (DL1), 180 (DL2), 225 (DL3), 290 (DL4) mg/m2 /dose, with a de-escalation DL of 100 mg/m2 /dose (DL0) if needed. Pharmacokinetic and pharmacodynamic analyses were performed during cycle 1. RESULTS: The median age of 14 eligible patients was 11.5 years (range: 1-23). The most common diagnoses were neuroblastoma (N = 4) and Ewing sarcoma (N = 3). Eleven dose-limiting toxicity (DLT)-evaluable patients received a median of four cycles (range: 1-6). There were three cycle 1 DLTs: one each grade 3 diarrhea and grade 4 creatine phosphokinase (CPK) elevations at DL1, and one grade 4 CPK elevation at DL0. All patients experienced at least one grade 3/4 hematologic toxicity. Best overall response was partial response in one patient with Ewing sarcoma (DL0) and stable disease for four or more cycles in four patients. Simvastatin exposure increased with higher doses and may have correlated with toxicity. Plasma interleukin 6 (IL-6) concentrations (N = 6) showed sustained IL-6 reductions with decrease to normal values by day 21 in all patients, indicating potential on-target effects. CONCLUSIONS: The MTD of simvastatin with topotecan and cyclophosphamide was determined to be 100 mg/m2 /dose.

Anatomical Substrates and Connectivity for Parkinson's Disease Bradykinesia Components after STN-DBS.

Background: Parkinsonian bradykinesia is rated using a composite scale incorporating slowed frequency of repetitive movements, decrement amplitude, and arrhythmicity. Differential localization of these movement components within basal ganglia would drive the development of more personalized network-targeted symptomatic therapies. Methods: Using an optical motion sensor, amplitude and frequency of hand movements during grasping task were evaluated with subthalamic nucleus (STN)-Deep Brain Stimulation (DBS) "on" or "off" in 15 patients with Parkinson's disease (PD). The severity of bradykinesia was assessed blindly using the MDS-UPDRS Part-III scale. Volumes of activated tissue (VAT) of each subject were estimated where changes in amplitude and frequency were mapped to identify distinct anatomical substrates of each component in the STN. VATs were used to seed a normative functional connectome to generate connectivity maps associated with amplitude and frequency changes. Results: STN-DBS-induced change in amplitude was negatively correlated with change in MDS-UPDRS-III right (r = -0.65, p < 0.05) and left hand grasping scores (r = -0.63, p < 0.05). The change in frequency was negatively correlated with amplitude for both right (r = -0.63, p < 0.05) and left hand (r = -0.57, p < 0.05). The amplitude and frequency changes were represented as a spatial gradient with overlapping and non-overlapping regions spanning the dorsolateral-ventromedial axis of the STN. Whole-brain correlation maps between functional connectivity and motor changes were also inverted between amplitude and frequency changes. Conclusion: DBS-associated changes in frequency and amplitude were topographically and distinctly represented both locally in STN and in whole-brain functional connectivity.