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Background: Standardized methods for reporting surgical quality have been described for all the major urological procedures apart from radical nephroureterectomy (RNU). Objective: To propose a tetrafecta criterion for assessing the quality of RNU based on a consensus panel within the Young Association of Urology (YAU) Urothelial Group, and to test the impact of this tetrafecta in a multicenter, large contemporary cohort of patients treated with RNU for upper tract urothelial carcinoma (UTUC). Design, setting, and participants: This was a retrospective analysis of 1765 patients with UTUC treated between 2000 and 2021. Outcome measurements and statistical analysis: We interviewed the YAU Urothelial Group to propose and score a list of items to be included in the “RNU-fecta.” A ranking was generated for the criteria with the highest sum score. These criteria were applied to a large multicenter cohort of patients. Kaplan-Meier curves were built to evaluate differences in overall survival (OS) rates between groups, and a multivariable logistic regression model was used to find the predictors of achieving the RNU tetrafecta. Results and limitations: The criteria with the highest score included three surgical items such as negative soft tissue surgical margins, bladder cuff excision, lymph node dissection according to guideline recommendations, and one oncological item defined by the absence of any recurrence in ≤12 mo. These items formed the RNU tetrafecta. Within a median follow-up of 30 mo, 52.6% of patients achieved the RNU tetrafecta. The 5-yr OS rates were significantly higher for patients achieving tetrafecta than for their counterparts (76% vs 51%). Younger age, lower body mass index, and robotic approach were found to be independent predictors of tetrafecta achievement. Conversely, a higher Eastern Cooperative Oncology Group score, higher clinical stage, and bladder cancer history were inversely associated with tetrafecta. Conclusions: Herein, we present a “tetrafecta” composite endpoint that may serve as a potential tool to assess the overall quality of the RNU procedure. Pending external validation, this tool could allow a comparison between surgical series and may be useful for assessing the learning curve of the procedure as well as for evaluating the impact of new technologies in the field. Patient summary: In this study, a tetrafecta criterion was developed for assessing the surgical quality of radical nephroureterectomy in patients with upper tract urothelial carcinoma. Patients who achieved tetrafecta had higher 5-yr overall survival rates than those who did not.

Course-based undergraduate research experiences (CUREs) are an effective method of engaging large numbers of students in authentic research but are associated with barriers to adoption. Short CURE modules may serve as a low-barrier entryway, but their effectiveness in promoting expansion has not been studied. The Prevalence of Antibiotic Resistance in the Environment (PARE) project is a modular CURE designed to be a low-barrier gateway into CURE use. In a series of interviews, we track and characterize use of PARE in 19 PARE-interested instructors throughout the Innovation-Decision Process described by Rogers' Diffusion of Innovations theory. The majority (16/19) implement PARE at least once, and a majority of these implementers (11/16) expanded use by the final interview. Three of four cases of discontinuance were due to a disruption such as moving institutions or a change in course assignment and occurred for community college faculty. Expanders expressed fewer personal challenges than nonexpanders. Overall analysis shows that perception of barriers is nuanced and impacted by the innovation itself, the institutional context, and one's own experiences. These results suggest that a short duration, low barrier CURE can serve as a catalyst for implementation of a longer duration CURE.

BACKGROUND: Current guidance on the selection of appropriate contraception for people with multiple sclerosis (PwMS) is lacking. OBJECTIVE: To address this gap, an expert-led consensus program developed recommendations to support clinicians in discussing family planning and contraception with women and men with multiple sclerosis (MS). METHODS: A multidisciplinary steering committee (SC) of 13 international clinical experts led the program, supported by an extended faculty of 32 experts representing 18 countries. A modified Delphi methodology was used for decision-making and consensus-building. The SC drafted 15 clinical questions focused on patient-centered care, selection of contraception, and timing of stopping/starting contraception and disease-modifying therapies (DMTs). Statements addressing each question were drafted based on evaluation of published evidence and the experts clinical experience. Consensus was reached if ⩾75% of respondents agreed (scoring 7-9 on a 9-point scale) with each recommendation. RESULTS: Consensus was reached on 24 of 25 proposed recommendations, including how and when to discuss contraception, types and safety of contraceptives, and how to evaluate the most appropriate contraceptive options for specific patient groups, including those with significant disability or being treated with DMTs. CONCLUSION: These expert recommendations provide the first practical, relevant, and comprehensive guidance for clinicians on the selection of contraception in PwMS.

BackgroundTraumatic brain injury (TBI) and repetitive head impacts (RHI) have been linked to increased risk for multiple types of neurodegenerative disease, higher dementia risk, and earlier age of dementia symptom onset, suggesting transdiagnostic implications for later-life brain health. Frontotemporal dementia (FTD) and primary progressive aphasia (PPA) represent a spectrum of clinical phenotypes that are neuropathologically diverse. FTD/PPA diagnoses bring unique challenges due to complex cognitive and behavioral symptoms that disproportionately present as an early-onset dementia (before age 65). We performed a detailed characterization of lifetime head trauma exposure in individuals with FTD and PPA compared to healthy controls to examine frequency of lifetime TBI and RHI and associated clinical implications.MethodsWe studied 132 FTD/PPA (age 68.9 ± 8.1, 65% male) and 132 sex-matched healthy controls (HC; age 73.4 ± 7.6). We compared rates of prior TBI and RHI (contact/collision sports) between FTD/PPA and HC (chi-square, logistic regression, analysis of variance). Within FTD/PPA, we evaluated associations with age of symptom onset (analysis of variance). Within behavioral variant FTD, we evaluated associations with cognitive function and neuropsychiatric symptoms (linear regression controlling for age, sex, and years of education).ResultsYears of participation were greater in FTD/PPA than HC for any contact/collision sport (8.5 ± 6.7yrs vs. 5.3 ± 4.5yrs, p = .008) and for American football (6.2yrs ± 4.3yrs vs. 3.1 ± 2.4yrs; p = .003). Within FTD/PPA, there were dose-dependent associations with earlier age of symptom onset for TBI (0 TBI: 62.1 ± 8.1, 1 TBI: 59.9 ± 6.9, 2 + TBI: 57.3 ± 8.4; p = .03) and years of American football (0yrs: 62.2 ± 8.7, 1-4yrs: 59.7 ± 7.0, 5 + yrs: 55.9 ± 6.3; p = .009). Within bvFTD, those who played American football had worse memory (z-score: -2.4 ± 1.2 vs. -1.4 ± 1.6, p = .02, d = 1.1).ConclusionsLifetime head trauma may represent a preventable environmental risk factor for FTD/PPA. Dose-dependent exposure to TBI or RHI influences FTD/PPA symptom onset and memory function in bvFTD. Clinico-pathological studies are needed to better understand the neuropathological correlates linking RHI or TBI to FTD/PPA onset and symptoms.

The multifaceted nature of multiple sclerosis requires quantitative biomarkers that can provide insights related to diverse physiological pathways. To this end, proteomic analysis of deeply-phenotyped serum samples, biological pathway modeling, and network analysis were performed to elucidate inflammatory and neurodegenerative processes, identifying sensitive biomarkers of multiple sclerosis disease activity. Here, we evaluated the concentrations of > 1400 serum proteins in 630 samples from three multiple sclerosis cohorts for association with clinical and radiographic new disease activity. Twenty proteins were associated with increased clinical and radiographic multiple sclerosis disease activity for inclusion in a custom assay panel. Serum neurofilament light chain showed the strongest univariate correlation with gadolinium lesion activity, clinical relapse status, and annualized relapse rate. Multivariate modeling outperformed univariate for all endpoints. A comprehensive biomarker panel including the twenty proteins identified in this study could serve to characterize disease activity for a patient with multiple sclerosis.

PURPOSE OF REVIEW: Lack of consistent data and guidance have led to variations between clinicians in the management of pregnancy in women with multiple sclerosis (MS). Pregnant and/or lactating women are often excluded from clinical trials conducted in MS, and thus, the labeling for most disease-modifying therapies (DMTs) excludes use during pregnancy. This has led to heterogeneity in interpretation and labeling regarding the safety of DMTs during pregnancy and lactation and the required preconception washout periods. This review identifies key themes where there is conflicting information surrounding family planning and pregnancy in MS, focusing on the most common discussion points between physicians and patients during preconception planning, pregnancy, postpartum, and lactation. The goal was to inform the patient-physician conversation and provide best practice recommendations based on expert clinical expertise and experience. RECENT FINDINGS: We outline the latest evidence-based data for DMT use during pregnancy and lactation, the effect of MS on fertility and fertility treatments, the risk of adverse pregnancy and delivery outcomes, the risk of postpartum relapse, and immunization and clinical imaging safety during pregnancy and breastfeeding. SUMMARY: Management of family planning and pregnancy in patients with MS requires the most current information. Health care providers should discuss family planning early and frequently with patients with MS, and partners where practicable. Because management of pregnant people with MS will often require a risk/benefit analysis of their needs, shared decision-making in family planning discussions is emphasized. Additional data are needed for specific and underrepresented populations with MS (e.g., single parents or those from the LGBTQ+ community) and those at risk of racial and socioeconomic disparities in care. Pregnancy registries and the design and conduct of clinical trials focused on pregnant and lactating patients should provide additional data to guide the ongoing management of patients with MS.

Identification of Alzheimer's disease (AD) onset risk can facilitate interventions before irreversible disease progression. We demonstrate that electronic health records from the University of California, San Francisco, followed by knowledge networks (for example, SPOKE) allow for (1) prediction of AD onset and (2) prioritization of biological hypotheses, and (3) contextualization of sex dimorphism. We trained random forest models and predicted AD onset on a cohort of 749 individuals with AD and 250,545 controls with a mean area under the receiver operating characteristic of 0.72 (7 years prior) to 0.81 (1 day prior). We further harnessed matched cohort models to identify conditions with predictive power before AD onset. Knowledge networks highlight shared genes between multiple top predictors and AD (for example, APOE, ACTB, IL6 and INS). Genetic colocalization analysis supports AD association with hyperlipidemia at the APOE locus, as well as a stronger female AD association with osteoporosis at a locus near MS4A6A. We therefore show how clinical data can be utilized for early AD prediction and identification of personalized biological hypotheses.

BackgroundPeople living with multiple sclerosis (MS) face a higher likelihood of being diagnosed with a depressive disorder than the general population. Although many low-cost screening tools and evidence-based interventions exist, depression in people living with MS is underreported, underascertained by clinicians, and undertreated.ObjectiveThis study aims to design a closed-loop tool to improve depression care for these patients. It would support regular depression screening, tie into the point of care, and support shared decision-making and comprehensive follow-up. After an initial development phase, this study involved a proof-of-concept pilot randomized controlled trial (RCT) validation phase and a detailed human-centered design (HCD) phase.MethodsDuring the initial development phase, the technological infrastructure of a clinician-facing point-of-care clinical dashboard for MS management (BRIDGE) was leveraged to incorporate features that would support depression screening and comprehensive care (Care Technology to Ascertain, Treat, and Engage the Community to Heal Depression in people living with MS [MS CATCH]). This linked a patient survey, in-basket messages, and a clinician dashboard. During the pilot RCT phase, a convenience sample of 50 adults with MS was recruited from a single MS center with 9-item Patient Health Questionnaire scores of 5-19 (mild to moderately severe depression). During the routine MS visit, their clinicians were either asked or not to use MS CATCH to review their scores and care outcomes were collected. During the HCD phase, the MS CATCH components were iteratively modified based on feedback from stakeholders: people living with MS, MS clinicians, and interprofessional experts.ResultsMS CATCH links 3 features designed to support mood reporting and ascertainment, comprehensive evidence-based management, and clinician and patient self-management behaviors likely to lead to sustained depression relief. In the pilot RCT (n=50 visits), visits in which the clinician was randomized to use MS CATCH had more notes documenting a discussion of depressive symptoms than those in which MS CATCH was not used (75% vs 34.6%; χ21=8.2; P=.004). During the HCD phase, 45 people living with MS, clinicians, and other experts participated in the design and refinement. The final testing round included 20 people living with MS and 10 clinicians including 5 not affiliated with our health system. Most scoring targets for likeability and usability, including perceived ease of use and perceived effectiveness, were met. Net Promoter Scale was 50 for patients and 40 for clinicians.ConclusionsCreated with extensive stakeholder feedback, MS CATCH is a closed-loop system aimed to increase communication about depression between people living with MS and their clinicians, and ultimately improve depression care. The pilot findings showed evidence of enhanced communication. Stakeholders also advised on trial design features of a full year long Department of Defense-funded feasibility and efficacy trial, which is now underway.Trial registrationClinicalTrials.gov NCT05865405; http://tinyurl.com/4zkvru9x.

BACKGROUND AND OBJECTIVES: Racial disparities exist in both neurologic and obstetric populations, underscoring the importance of evaluating pregnancy outcomes in diverse women with multiple sclerosis (MS). The objective of this multicenter retrospective study was to compare pregnancy care and outcomes between Black and Hispanic (underrepresented) and White women with MS. METHODS: Demographic and clinical data were extracted from medical records of 9 US MS centers for women with MS/clinically isolated syndrome who delivered live births between 2010 and 2021. Sites identified at last 15 consecutive Black/Hispanic women and a matching number of White women. Socioeconomic factors, pregnancy, and MS care/outcomes were compared between groups (underrepresented and White and then Black and Hispanic) using Wilcoxon rank sum (U statistic and effect size r reported), χ2, t tests and logistic regressions as appropriate to data type. Multiple imputation by chained equation was used to account for missing data. RESULTS: Overall, 294 pregnancies resulting in live births were analyzed ( 81 Black, 67 Hispanic, and 146 White mothers). Relative to underrepresented women, White women lived in areas of higher median (interquartile range [IQR]) Child Opportunity Index (79 [45.8] vs 22 [45.8], U = 3,824, r = 0.56, p < 0.0001) and were more often employed (84.9% vs 75%, odds ratio [OR] 2.57, CI 1.46-4.50, p = 0.0008) and privately insured (93.8% vs 56.8%, OR 11.6, CI 5.5-24.5, p < 0.0001) and more received a 14-week ultrasound (98.6% vs 93.9%, OR 4.66, CI 0.99-21.96, p = 0.027). Mode of delivery was significantly different between the three groups (X2(10,294) = 20.38, p = 0.03); notably, Black women had the highest rates of emergency cesarean deliveries, and Hispanic women highest rates of uncomplicated vaginal deliveries. Babies born to underrepresented women had lower median (IQR) birthweights than babies born to White women (3,198 g [435.3 g] vs 3,275 g [412.5 g], U = 9,255, r = 0.12, p = 0.04) and shorter median (IQR) breastfeeding duration (4.5 [3.3] vs 6.0 [4.2] months, U = 8,184, r = 0.21, p = 0.003). While underrepresented women were younger than White women (mean [SD] 30.9 [4.8] vs 33.8 [4.0], t = 1.97, CI 1.96-3.98, p < 0.0001), their median (Q1-Q3, IQR) Expanded Disability Status Scale was higher (1.5 [1-2.5, 1.5] vs 1 [0-1.5, 1.5], U = 7,260, r = 0.29, p < 0.0001) before pregnancy. Finally, medical records were missing more key data for Black women (19.7% missing vs 8.9% missing, OR 2.54, CI 1.25-5.06, p = 0.008). DISCUSSION: In this geographically diverse multicenter cohort, underrepresented women entered pregnancy with higher disability and fewer health care resources. Pregnancy represents a pivotal window where structural factors affect maternal and fetal health and neurologic trajectories; it is a critical period to optimize care and health outcomes.

INTRODUCTION: Depression occurs in over 50% of individuals living with multiple sclerosis (MS) and can be treated using many modalities. Yet, it remains: under-reported by patients, under-ascertained by clinicians and under-treated. To enhance these three behaviours likely to promote evidence-based depression care, we engaged multiple stakeholders to iteratively design a first-in-kind digital health tool. The tool, MS CATCH (Care technology to Ascertain, Treat, and engage the Community to Heal depression in patients with MS), closes the communication loop between patients and clinicians. Between clinical visits, the tool queries patients monthly about mood symptoms, supports patient self-management and alerts clinicians to worsening mood via their electronic health record in-basket. Clinicians can also access an MS CATCH dashboard displaying patients mood scores over the course of their disease, and providing comprehensive management tools (contributing factors, antidepressant pathway, resources in patients neighbourhood). The goal of the current trial is to evaluate the clinical effect and usability of MS CATCH in a real-world clinical setting. METHODS AND ANALYSIS: MS CATCH is a single-site, phase II randomised, delayed start, trial enrolling 125 adults with MS and mild to moderately severe depression. Arm 1 will receive MS CATCH for 12 months, and arm 2 will receive usual care for 6 months, then MS CATCH for 6 months. Clinicians will be randomised to avoid practice effects. The effectiveness analysis is superiority intent-to-treat comparing MS CATCH to usual care over 6 months (primary outcome: evidence of screening and treatment; secondary outcome: Hospital Anxiety Depression Scale-Depression scores). The usability of the intervention will also be evaluated (primary outcome: adoption; secondary outcomes: adherence, engagement, satisfaction). ETHICS AND DISSEMINATION: University of California, San Francisco Institutional Review Board (22-36620). The findings of the study are planned to be shared through conferences and publishments in a peer-reviewed journal. The deidentified dataset will be shared with qualified collaborators on request, provision of CITI and other certifications, and data sharing agreement. We will share the results, once the data are complete and analysed, with the scientific community and patient/clinician participants through abstracts, presentations and manuscripts. TRIAL REGISTRATION NUMBER: NCT05865405.

BACKGROUND AND OBJECTIVES: Multiple sclerosis (MS) commonly affects women in their childbearing years, necessitating discussion between patients and their MS treatment team around the issues of family planning, pregnancy, and postpartum experiences. This study assessed the impact of a diagnosis of MS on womens reproductive decision-making and on their perception of counseling received surrounding pregnancy. It also sought to evaluate trends in pregnancy and postpartum experiences and determine whether experiences differed by race, ethnicity, and zip code. METHODS: Women with an MS diagnosis seen at the University of Virginia MS Clinic or at Virginia Commonwealth University (VCU) MS Clinic were invited to participate in a survey study. MS disease and pregnancy history, and, when appropriate, reasons for pregnancy avoidance were collected. Respondents who had >1 pregnancy following MS diagnosis were asked to evaluate the counseling they received from medical professionals and to share their pregnancy experiences including complications during pregnancy, delivery outcomes, and postpartum experience including breastfeeding. RESULTS: Of the 280 respondents, 76.6% were currently receiving MS specialty care. Most of them (79.3%) had not been pregnant following MS diagnosis. Of them, 20.1% indicated that this decision was driven by MS-related concerns: MS worsening with pregnancy (47%); ability to care for child secondary to MS (35%); passing MS onto child (19%); stopping disease-modifying therapies to attempt pregnancy (14%); lack of knowledge about options for pregnancy and MS (9%). Women with a more recent estimated decade of pregnancy were more likely to report neurologist counseling regarding MS and pregnancy (pregnancy before 2000: 40%, 2000-2010: 64.7%, 2010- present: 83.3%; χ2 0.020). Breastfeeding initiation was reported in 71.4% of postdiagnosis pregnancies (median duration 6 months, interquartile range 1.75-11). DISCUSSION: Over the past few decades, women with MS have received a wide range of evolving guidance surrounding family planning, pregnancy, and postpartum care. Survey data suggest improvements in MS/pregnancy counseling and medical management in recent years, which may be driven by an increase in research in the field. There remains an important need and opportunity to improve counseling of women with MS who are considering pregnancy.

Floodlight Open was a global, open-access, digital-only study designed to understand the drivers and barriers in deployment and use of a smartphone app in a naturalistic setting and broad study population of people with and without multiple sclerosis (MS). The study utilised the Floodlight Open app: a bring-your-own-device solution that remotely measures a users mood, cognition, hand motor function, and gait and postural stability via smartphone sensor-based tests requiring active user input (active tests). Levels of mobility of study participants (life-space measurement) were passively measured. Study data from these tests were made available via an open-access platform. Data from 1350 participants with self-declared MS and 1133 participants with self-declared non-MS from 17 countries across four continents were included in this report. Overall, MS participants provided active test data for a mean duration of 5.6 weeks or a mean duration of 19 non-consecutive days. This duration increased among MS participants who persisted beyond the first week to a mean of 10.3 weeks or 36.5 non-consecutive days. Passively collected life-space measurement data were generated by MS participants for a mean duration of 9.8 weeks or 50.6 non-consecutive days. This duration increased to 16.3 weeks/85.1 non-consecutive days among MS participants who persisted beyond the first week. Older age, self-declared MS disease status, and clinical supervision as part of concomitant clinical research were all significantly associated with higher persistence of the use of the Floodlight Open app. MS participants performed significantly worse than non-MS participants on four out of seven active tests. The findings from this multinational study inform future research to improve the dynamics of persistence of use of digital monitoring tools and further highlight challenges and opportunities in applying them to support MS clinical care.

BACKGROUND: Immune checkpoint inhibitors (ICIs) represent a novel class of agents approved for the treatment of several cancers and progressive multifocal leukoencephalopathy (PML). However, due to the risk of autoimmune side effects, their use in people with autoimmune diseases such as multiple sclerosis (MS) has been limited. OBJECTIVE: To characterize outcomes in a cohort of adults with MS who received ICIs. METHODS: A single-center retrospective review of medical record data was performed for people with MS treated with ICIs. RESULTS: Seven people with MS were identified, with a mean (SD) age at ICI use of 55.4 (13.7) years and a mean MS duration of 18.2 (12.2) years. Six were treated for cancer; 1 was treated for PML. After mean (SD) follow-up of 1.76 (2.15) years after ICI, outcomes are: no evidence of disease (2), residual metastatic disease (1), death due to cancer (1), death due to PML (1), and lost to follow-up (2). Notably, 0 out of 7 patients experienced an MS relapse; two out of six had new asymptomatic demyelinating magnetic resonance imaging lesions. In the three patients with expanded disability status scale (EDSS) scores at baseline and follow-up, EDSS remained stable (mean delta 0.13). CONCLUSION: In this cohort, no people with MS experienced clinical relapses and one-third experienced asymptomatic radiological activity following ICI treatment.

OBJECTIVE: Upper extremity function reflects disease progression in multiple sclerosis (MS). This study evaluated the feasibility, validity, and sensitivity to change of remote dexterity assessments applying human pose estimation to patient-uploaded videos. METHODS: A discovery cohort of 50 adults with MS recorded selfie videos of self-care tasks at home: buttoning, brushing teeth, and eating. Kinematic data were extracted using MediaPipe Hand pose estimation software. Clinical comparison tests were grip and pinch strength, 9 hole peg test (9HPT), and vibration, and patient-reported dexterity assessments (ABILHAND). Feasibility and acceptability were evaluated (Health-ITUES framework). A validation cohort (N = 35) completed 9HPT and videos. RESULTS: The modality was feasible: 88% of the 50 enrolled participants uploaded ≥3 videos, and 74% completed the study. It was also usable: assessments easy to access (95%), platform easy to use (97%), and tasks representative of daily activities (86%). The buttoning task revealed four metrics with strong correlations with 9HPT (nondominant: r = 0.60-0.69, dominant: r = 0.51-0.57, P  0.8). Cross-sectional correlations between video metrics and 9HPT were similar at 6 months, and in the validation cohort (nondominant: r = 0.46, dominant: r = 0.45, P

OBJECTIVE: Postpartum, patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) have increased risk for disease activity. Anti-CD20 IgG1 monoclonal antibodies (mAb) are increasingly used as disease-modifying therapies (DMTs). Patients may wish to both breastfeed and resume DMT postpartum. This study aimed to determine the transfer of anti-CD20 IgG1 mAbs, ocrelizumab, and rituximab (OCR/RTX), into mature breastmilk and describe maternal and infant outcomes. METHODS: Fifty-seven cis-women receiving OCR/RTX after 59 pregnancies and their infants were enrolled and followed up to 12M postpartum or 90 days post-infusion. Breastmilk was collected pre-infusion and serially up to 90 days and assayed for mAb concentration. Medical records and patients questionnaire responses were obtained to assess neurologic, breastfeeding, and infant development outcomes. RESULTS: The median average concentration of mAb in breastmilk was low (OCR: 0.08 μg/mL, range 0.05-0.4; RTX: 0.03 μg/mL, range 0.005-0.3). Concentration peaked 1-7 days post-infusion in most (77%) and was nearly undetectable after 90 days. Median average relative infant dose was  0.05) infants; neither did the proportion with normal development (breastfed: 37/41, non-breastfed: 11/13; p > 0.05). After postpartum infusion, two mothers experienced a clinical relapse. INTERPRETATION: These confirm minimal transfer of mAb into breastmilk. Anti-CD20 mAb therapy stabilizes MS activity before conception to the postpartum period, and postpartum treatments appears to be safe and well-tolerated for both mother and infant.

Interdisciplinary marine research is pivotal for addressing ocean sustainability challenges but may exclude diverse socio-economic, cultural, or identity groups. Drawing on perspectives of marine Early Career Researchers, we highlight the importance of Diversity, Equity, and Inclusion (DEI) in advancing interdisciplinary marine science and present ten recommendations to enhance DEI. As our ocean faces increasing threats, fostering DEI within this domain is not merely an aspirational goal but an ethical imperative.

Introduction: Infections represent a significant cause of morbidity and mortality in patients with multiple myeloma (MM). In Latin America, data on infectious complications in newly diagnosed MM (NDMM) patients are limited. Methods: We conducted a multicenter, prospective cohort study of patients with NDMM in Uruguay between June 2019 and December 2020. Patients with active disease, on active therapy and who provided written informed consent were included. Elegible patients were followed for 6 months from the time of diagnosis and before proceeding to autologous stem cell transplantation or until death, whichever occurred first. Our primary endpoint was the number of infectious events that required hospitalization for ≥ 24 h. Main results: Of 124 patients with NDMM, 54 (43.5 %) had infectious complications (74 infectious events), the majority (74.3 %) within the first 3 months from diagnosis. The most common sites of infection were urinary (39.2 %) and respiratory tracts (33.8 %). The microbial agent was identified in 60.8 % of patients with Gram-negative bacteria (71.4 %) as the most common pathogen. Viral and fungal infections were infrequent. In the multivariable analysis, the Eastern Cooperative Oncology Group (ECOG) performance status was ≥ 2 (odds ratio [OR], 2.16; 95 % confidence interval [95 %CI], 1.23 - 3.79; p = 0.008) and creatinine ≥ 2 mg/dl (OR, 2.33; 95 %CI, 1.33 - 4.07; p = 0.003) were independent factors associated with bacterial infections. At 6 months, 14 patients (11.3 %) had died, 50 % related to infectious complications. Conclusion: Bacterial infections are a substantial cause of hospital admissions and early death in patients with NDMM. Antibiotic prophylaxis should be considered to reduce infectious complications in patients with MM.

Abstract Ammonium fluoride (NH₄F) exhibits a variety of crystalline phases depending on temperature and pressure. By employing Raman spectroscopy and synchrotron X-ray diffraction beyond megabar pressures (up to 140 GPa), we have here observed a novel dense solid phase of NH₄F, characterised by the tetragonal P4/nmm structure also observed in other ammonium halides under less extreme pressure conditions, typically a few GPa. Using detailed ab-initio calculations and reevaluating earlier theoretical models pertaining to other ammonium halides, we examine the microscopic mechanisms underlying the transition from the low-pressure cubic phase (P-43m) to the newly identified high-pressure tetragonal phase (P4/nmm). Notably, NH₄F exhibits distinctive properties compared to its counterparts, resulting in a significantly broader pressure range over which this transition unfolds, facilitating the identification of its various stages. Our analysis points to a synergistic interplay driving the transition to the P4/nmm phase, which we name phase VIII. At intermediate pressures (around 40 GPa), a displacive transition of fluorine ions initiates a tetragonal distortion of the cubic phase. Subsequently, at higher pressures (around 115 GPa), every second ammonium ion undergoes a rotational shift, adopting an anti-tetrahedral arrangement. This coupled effect orchestrates the transition process, leading to the formation of the tetragonal phase.

Abstract Gene expression is an intricate biological process that bridges gap between the genotype and the phenotype. Canonical and hereditable epigenetic mechanisms, such as histone and DNA modifications, regulate the release of genetic information encoded in DNA without altering the underlying sequence. Many other non-canonical players, such as chromatin regulators and noncoding RNAs, are also involved in regulating gene expression. Recently, RNA modifications (epitranscriptomics) have been shown to hold enormous potential in shaping cellular transcriptomes. However, their co-transcriptional nature and uncertain heritability mean that they fall outside the current definition of epigenetics, sparking an ongoing debate in the field. Here we will discuss the relationship between canonical and non-canonical epigenetic mechanisms that govern gene expression and offer our perspective on whether (or not) epitranscriptomic modifications can be classified as epigenetic mechanisms.

Abstract Background Risk stratification and treatment benefit prediction models are urgent to improve negative sentinel lymph node (SLN-) melanoma patient selection, thus avoiding costly and toxic treatments in patients at low risk of recurrence. To this end, the application of artificial intelligence (AI) could help clinicians to better calculate the recurrence risk and choose whether to perform adjuvant therapy. Methods We made use of AI to predict recurrence-free status (RFS) within 2-years from diagnosis in 94 SLN- melanoma patients. In detail, we detected quantitative imaging information from H&E slides of a cohort of 71 SLN- melanoma patients, who registered at Istituto Tumori “Giovanni Paolo II” in Bari, Italy (investigational cohort, IC). For each slide, two expert pathologists firstly annotated two Regions of Interest (ROIs) containing tumor cells alone (TUMOR ROI) or with infiltrating cells (TUMOR + INF ROI). In correspondence of the two kinds of ROIs, two AI-based models were developed to extract information directly from the tiles in which each ROI was automatically divided. This information was then used to predict RFS. Performances of the models were computed according to a 5-fold cross validation scheme. We further validated the prediction power of the two models on an independent external validation cohort of 23 SLN- melanoma patients (validation cohort, VC). Results The TUMOR ROIs have revealed more informative than the TUMOR + INF ROIs. An Area Under the Curve (AUC) value of 79.1% and 62.3%, a sensitivity value of 81.2% and 76.9%, a specificity value of 70.0% and 43.3%, an accuracy value of 73.2% and 53.4%, were achieved on the TUMOR and TUMOR + INF ROIs extracted for the IC cohort, respectively. An AUC value of 76.5% and 65.2%, a sensitivity value of 66.7% and 41.6%, a specificity value of 70.0% and 55.9%, an accuracy value of 70.0% and 56.5%, were achieved on the TUMOR and TUMOR + INF ROIs extracted for the VC cohort, respectively. Conclusions Our approach represents a first effort to develop a non-invasive prognostic method to better define the recurrence risk and improve the management of SLN- melanoma patients.

Abstract Background High‐intensity focused ultrasound (HIFU) is widely used in the treatment of deep tumours, but clinical trials on skin tumours are not yet available. Neurofibromatosis Type I (NF1) is among the most common single‐gene inherited conditions worldwide and predisposes to benign and malignant neoplasms of the nervous system. Multiple cutaneous neurofibromas (cNFs) often cause social and functional limitations, itching and pain. Objectives The objective of this study was to investigate the safety, local tolerability and efficacy of a novel method utilizing HIFU for the treatment of cNFs. Methods A 20 MHz HIFU‐device with an integrated dermoscopic guidance and a handpiece with a focus depth of 2.3 mm below the skin surface was used. Doses of acoustic energy with 0.7 J/dose and pulse duration of 250 ms/dose were manually positioned with 1–2 mm distance between each applied dose. Number of applied doses depended on the size of the cNF. No anaesthetic was applied. Results Twenty patients with NF1 were recruited in two centres, and 147 cNFs were treated. There were no serious adverse events. Immediate and transient wheal‐and‐flare reactions occurred at treatment sites and occasionally there was minor epidermal damage which healed in 1–2 weeks. Dyspigmentation occurred in some tumours after 3–9 months but no scarring was observed at 9‐month follow‐up. During treatment, the patient‐reported pain‐score median was 3.5 (range 1–7) on a 0–10‐point scale. Clinical rating of cNFs after 9 months showed 48.9% full or major tumour reduction. The median reduction in tumour thickness measured by ultrasound at 9 months was 0.53 mm (range: –100% to +19%). Conclusions HIFU treatment is a new noninvasive, rapid and tolerable treatment modality that with high precision targets intradermal lesions. This study demonstrates acceptable safety, local tolerance and efficacy of HIFU for the treatment of cNFs that may further be developed also for other skin tumours.

Abstract Background Traumatic brain injury (TBI) and repetitive head impacts (RHI) have been linked to increased risk for multiple types of neurodegenerative disease, higher dementia risk, and earlier age of dementia symptom onset, suggesting transdiagnostic implications for later-life brain health. Frontotemporal dementia (FTD) and primary progressive aphasia (PPA) represent a spectrum of clinical phenotypes that are neuropathologically diverse. FTD/PPA diagnoses bring unique challenges due to complex cognitive and behavioral symptoms that disproportionately present as an early-onset dementia (before age 65). We performed a detailed characterization of lifetime head trauma exposure in individuals with FTD and PPA compared to healthy controls to examine frequency of lifetime TBI and RHI and associated clinical implications. Methods We studied 132 FTD/PPA (age 68.9 ± 8.1, 65% male) and 132 sex-matched healthy controls (HC; age 73.4 ± 7.6). We compared rates of prior TBI and RHI (contact/collision sports) between FTD/PPA and HC (chi-square, logistic regression, analysis of variance). Within FTD/PPA, we evaluated associations with age of symptom onset (analysis of variance). Within behavioral variant FTD, we evaluated associations with cognitive function and neuropsychiatric symptoms (linear regression controlling for age, sex, and years of education). Results Years of participation were greater in FTD/PPA than HC for any contact/collision sport (8.5 ± 6.7yrs vs. 5.3 ± 4.5yrs, p = .008) and for American football (6.2yrs ± 4.3yrs vs. 3.1 ± 2.4yrs; p = .003). Within FTD/PPA, there were dose-dependent associations with earlier age of symptom onset for TBI (0 TBI: 62.1 ± 8.1, 1 TBI: 59.9 ± 6.9, 2 + TBI: 57.3 ± 8.4; p = .03) and years of American football (0yrs: 62.2 ± 8.7, 1-4yrs: 59.7 ± 7.0, 5 + yrs: 55.9 ± 6.3; p = .009). Within bvFTD, those who played American football had worse memory (z-score: -2.4 ± 1.2 vs. -1.4 ± 1.6, p = .02, d = 1.1). Conclusions Lifetime head trauma may represent a preventable environmental risk factor for FTD/PPA. Dose-dependent exposure to TBI or RHI influences FTD/PPA symptom onset and memory function in bvFTD. Clinico-pathological studies are needed to better understand the neuropathological correlates linking RHI or TBI to FTD/PPA onset and symptoms.