An Update on H3K27M-altered Diffuse Midline Glioma: Diagnostic and Therapeutic Challenges in Clinical Practice.

H3K27-altered diffuse midline glioma (DMG H3K27-altered) is a relatively newly-designated WHO entity which primarily affects the midline structures of the central nervous system (CNS), including the brainstem (predominantly pontine region), thalamus, midbrain, or spinal cord, and primarily affects children and young adults. Despite the proximity of these tumors to eloquent areas in the CNS, novel stereotactic approaches have facilitated the ability to obtain tissue diagnoses without significant morbidity, providing molecular diagnostic information in more than half of patients. Conventionally fractionated radiation therapy to a total dose of 54-60 Gy in 27-30 fractions and 24 Gy in 12 fractions play a crucial role in the definitive treatment of these tumors in the primary and salvage settings, respectively. Hypofractionated regimens may allow for accelerated treatment courses in selected patients without jeopardizing disease control or survival. The decision to add concurrent or adjuvant systemic therapy mainly relies on the physicians' experience without solid evidence in the literature in favor of any particular regimen. Recently, novel agents, such as ONC201 have demonstrated promising oncologic outcomes in progressive/recurrent tumors and are currently under investigation in ongoing randomized trials. Given the scarcity of data and well-established guidelines due to the rare nature of the disease, we provide a contemporary overview on the molecular underpinnings of this disease entity, describe the role of radiotherapy and systemic therapy, and present practice management principles based on the published literature.

Characteristics and outcomes of COVID-19 patients admitted to hospital with and without respiratory symptoms.

Background: COVID-19 is primarily known as a respiratory illness; however, many patients present to hospital without respiratory symptoms. The association between non-respiratory presentations of COVID-19 and outcomes remains unclear. We investigated risk factors and clinical outcomes in patients with no respiratory symptoms (NRS) and respiratory symptoms (RS) at hospital admission. Methods: This study describes clinical features, physiological parameters, and outcomes of hospitalised COVID-19 patients, stratified by the presence or absence of respiratory symptoms at hospital admission. RS patients had one or more of: cough, shortness of breath, sore throat, runny nose or wheezing; while NRS patients did not. Results: Of 178,640 patients in the study, 86.4 % presented with RS, while 13.6 % had NRS. NRS patients were older (median age: NRS: 74 vs RS: 65) and less likely to be admitted to the ICU (NRS: 36.7 % vs RS: 37.5 %). NRS patients had a higher crude in-hospital case-fatality ratio (NRS 41.1 % vs. RS 32.0 %), but a lower risk of death after adjusting for confounders (HR 0.88 [0.83-0.93]). Conclusion: Approximately one in seven COVID-19 patients presented at hospital admission without respiratory symptoms. These patients were older, had lower ICU admission rates, and had a lower risk of in-hospital mortality after adjusting for confounders.

Outcomes associated with initial narrow-spectrum versus broad-spectrum antibiotics in children hospitalized with urinary tract infections.

OBJECTIVE: The aim of this study is to describe the proportion of children hospitalized with urinary tract infections (UTIs) who receive initial narrow- versus broad-spectrum antibiotics across children's hospitals and explore whether the use of initial narrow-spectrum antibiotics is associated with different outcomes. DESIGN, SETTING AND PARTICIPANTS: We performed a retrospective cohort analysis of children aged 2 months to 17 years hospitalized with UTI (inclusive of pyelonephritis) using the Pediatric Health Information System (PHIS) database. MAIN OUTCOME AND MEASURES: We analyzed the proportions of children initially receiving narrow- versus broad-spectrum antibiotics; additionally, we compiled antibiogram data for common uropathogenic organisms from participating hospitals to compare with the observed antibiotic susceptibility patterns. We examined the association of antibiotic type with adjusted outcomes including length of stay (LOS), costs, and 7- and 30-day emergency department (ED) revisits and hospital readmissions. RESULTS: We identified 10,740 hospitalizations for UTI across 39 hospitals. Approximately 5% of encounters demonstrated initial narrow-spectrum antibiotics, with hospital-level narrow-spectrum use ranging from <1% to 25%. Approximately 80% of hospital antibiograms demonstrated >80% Escherichia coli susceptibility to cefazolin. In adjusted models, those who received initial narrow-spectrum antibiotics had shorter LOS (narrow-spectrum: 33.1 (95% confidence interval [CI]: 30.8-35.4) h versus broad-spectrum: 46.1 (95% CI: 44.1-48.2) h) and reduced costs [narrow-spectrum: $4570 ($3751-5568) versus broad-spectrum: $5699 ($5005-$6491)]. There were no differences in ED revisits or hospital readmissions. In summary, children's hospitals have low rates of narrow-spectrum antibiotic use for UTIs despite many reporting high rates of cefazolin-susceptible E. coli. These findings, coupled with the observed decreased LOS and costs among those receiving narrow-spectrum antibiotics, highlight potential antibiotic stewardship opportunities.

Antibiotic impregnated catheters and intrathecal antibiotics for CSF shunt infection prevention in children undergoing low-risk CSF shunt surgery.

BACKGROUND: Cerebrospinal fluid (CSF) shunts allow children with hydrocephalus to survive and avoid brain injury (J Neurosurg 107:345-57, 2007; Childs Nerv Syst 12:192-9, 1996). The Hydrocephalus Clinical Research Network implemented non-randomized quality improvement protocols that were shown to decrease infection rates compared to pre-operative prophylactic intravenous antibiotics alone (standard care): initially with intrathecal (IT) antibiotics between 2007-2009 (J Neurosurg Pediatr 8:22-9, 2011), followed by antibiotic impregnated catheters (AIC) in 2012-2013 (J Neurosurg Pediatr 17:391-6, 2016). No large scale studies have compared infection prevention between the techniques in children. Our objectives were to compare the risk of infection following the use of IT antibiotics, AIC, and standard care during low-risk CSF shunt surgery (i.e., initial CSF shunt placement and revisions) in children. METHODS: A retrospective observational cohort study at 6 tertiary care children's hospitals was conducted using Pediatric Health Information System + (PHIS +) data augmented with manual chart review. The study population included children ≤ 18 years who underwent initial shunt placement between 01/2007 and 12/2012. Infection and subsequent CSF shunt surgery data were collected through 12/2015. Propensity score adjustment for regression analysis was developed based on site, procedure type, and year; surgeon was treated as a random effect. RESULTS: A total of 1723 children underwent initial shunt placement between 2007-2012, with 1371 subsequent shunt revisions and 138 shunt infections. Propensity adjusted regression demonstrated no statistically significant difference in odds of shunt infection between IT antibiotics (OR 1.22, 95% CI 0.82-1.81, p = 0.3) and AICs (OR 0.91, 95% CI 0.56-1.49, p = 0.7) compared to standard care. CONCLUSION: In a large, observational multicenter cohort, IT antibiotics and AICs do not confer a statistically significant risk reduction compared to standard care for pediatric patients undergoing low-risk (i.e., initial or revision) shunt surgeries.

Clinical application of an institutional fractionated stereotactic radiosurgery (FSRS) program for brain metastases delivered with MRIdianⓇ BrainTx™.

Single-fraction stereotactic radiosurgery (SRS) or fractionated SRS (FSRS) are well established strategies for patients with limited brain metastases. A broad spectrum of modern dedicated platforms are currently available for delivering intracranial SRS/FSRS; however, SRS/FSRS delivered using traditional CT-based platforms relies on the need for diagnostic MR images to be coregistered to planning CT scans for target volume delineation. Additionally, the on-board image guidance on traditional platforms yields limited inter-fraction and intra-fraction real-time visualization of the tumor at the time of treatment delivery. MR Linacs are capable of obtaining treatment planning MR and on-table MR sequences to enable visualization of the targets and organs-at-risk and may subsequently help identify anatomical changes prior to treatment that may invoke the need for on table treatment adaptation. Recently, an MR-guided intracranial package (MRIdian A3i BrainTxTM) was released for intracranial treatment with the ability to perform high-resolution MR sequences using a dedicated brain coil and cranial immobilization system. The objective of this report is to provide, through the experience of our first patient treated, a comprehensive overview of the clinical application of our institutional program for FSRS adaptive delivery using MRIdian's A3i BrainTx system-highlights include reviewing the imaging sequence selection, workflow demonstration, and details in its delivery feasibility in clinical practice, and dosimetric outcomes.

Spending on public benefit programs and exposure to adverse childhood experiences.

BACKGROUND: Adverse childhood experiences are associated with poverty, and public benefit programs are increasingly used as primary prevention for negative child outcomes. OBJECTIVE: To estimate the association between spending on benefit programs and cumulative exposure to ACEs among children. PARTICIPANTS AND SETTING: Children aged 0-17 years in the United States during 2016-17 as reported in National Survey of Children's Health. METHODS: We examined the sum of state and federal spending on 5 categories of public benefit programs at the state-level. The primary exposure was mean annual spending per person living below the Federal poverty limit across 2010-2017 Federal fiscal years. The primary outcome was children <18 years old having ever been exposed to ≥ 4 ACEs. RESULTS: Nationally, 5.7 % (95 % confidence interval [CI] 5.3 % - 6.0 %) of children had exposure to ≥ 4 ACEs. After adjustment for children's race and ethnicity, total spending on benefit programs was associated with lower exposure to ≥ 4 ACEs (odds 0.96 [95 % CI: 0.95, 0.97]; p < 0.001). Increased spending in each individual benefit category was also associated with decreased cumulative ACEs exposure (all p < 0.05). Inverse associations were largely consistent when children were stratified by race and ethnicity and income strata. CONCLUSIONS: Investments in public benefit programs may not only decrease poverty but also have broad positive effects on near- and long-term child well-being beyond the programs' stated objectives. Findings support federal and state efforts to prioritize families' economic stability as part of a public health model to prevent ACEs.

Availability and utilization of endoscopic retrograde cholangiopancreatography at children's hospitals.

OBJECTIVES: No study has explored whether availability of endoscopic retrograde cholangiopancreatography (ERCP) is adequate and equitable across US children's hospitals. We hypothesized that ERCP availability and utilization differs by geography and patient factors. METHODS: Healthcare encounter data from 2009 to 2019 on children with pancreatic and biliary diseases from the Pediatric Health Information System were analyzed. ERCP availability was defined as treatment at a hospital that performed pediatric ERCP during the year of service. RESULTS: From 2009 to 2019, 37,946 children (88,420 encounters) had a potential pancreatic or biliary indication for ERCP; 7066 ERCPs were performed. The commonest pancreatic diagnoses leading to ERCP were chronic (47.2%) and acute pancreatitis (43.2%); biliary diagnoses were calculus (68.3%) and obstruction (14.8%). No ERCP was available for 25.0% of pancreatic encounters and 8.1% of biliary encounters. In multivariable analysis, children with public insurance, rural residence, or of Black race were less likely to have pancreatic ERCP availability; those with rural residence or Asian race were less likely to have biliary ERCP availability. Black children or those with public insurance were less likely to undergo pancreatic ERCP where available. Among encounters for calculus or obstruction, those of Black race or admitted to hospitals in the West were less likely to undergo ERCP when available. CONCLUSIONS: One-in-four children with pancreatic disorders and one-in-12 with biliary disorders may have limited access to ERCP. We identified racial and geographic disparities in availability and utilization of ERCP. Further studies are needed to understand these differences to ensure equitable care.

Clinical validation of an aggregate learning ratio from the neuropsychological assessment battery.

Quantifying learning deficits provides valuable information in identifying and diagnosing mild cognitive impairment and dementia. Previous research has found that a learning ratio (LR) metric, derived from the list learning test from the Neuropsychological Assessment Battery (NAB), was able to distinguish between those with normal cognition versus memory impairment. The current study furthers the NAB LR research by validating a NAB story LR, as well as an aggregate LR. The aggregate LR was created by combining the individual list and story LRs. Participants were classified as those with normal cognition (n = 51), those with MCI (n = 39) and those with dementia (n = 35). Results revealed the story LR was able to accurately distinguish normal controls from those with mild cognitive impairment and those with dementia and offers enhanced discriminability beyond the story immediate recall score (sum of trial 1 and trial 2). Further, the aggregate LR provided superior discriminability beyond the individual list and story LRs and accounted for additional variance in diagnostic group classification. The NAB aggregate LR provides improved sensitivity in detecting declines in impaired learning, which may assist clinicians in making diagnoses earlier in a disease process, benefiting the individual through earlier interventions.

Teledermatology in practice: Report of Mayo Clinic experience.

Background: Delivery of dermatologic care through telemedicine was accelerated by the COVID-19 pandemic. We sought to analyze the teledermatology experience across Mayo Clinic's health care system to identify strengths and limitations of teledermatology. Methods: Electronic health records of dermatology televisits were reviewed from multiple U.S. Mayo Clinic sites from January 2020 through January 2021. Results: A total of 13,181 dermatology televisits were conducted in 6468 unique patients. Patients were primarily female (60.2%), and mean age of all patients was 34.1 years. Synchronous / live video conferencing visits were the most common (40.0%) telecare modality. Synchronous / live audio conferencing and asynchronous / store-and-forward visits comprised 33.0% and 27.0% of appointments. In total, 3944 televisits (29.9%) were successfully concluded via a single appointment. An in-person appointment was needed for 1693 patients (26.2%) after their initial televisit. For patients with a single televisit, synchronous / live video conferencing was the most common virtual modality (58.0% vs 32.2% of patients with multiple visits, p < 0.001). Patients needing in-person follow-up visits were slightly older than those who did not (mean [SD], 38.8 [22.3] vs 35.0 [23.6] years; p < 0.001) but without any sex-based difference. Around one-third of patients needed an in-person follow-up visit after their initial asynchronous / store-and-forward visit which was higher when compared with synchronous / live audio and video conferencing. Conclusion: Single dermatology televisits effectively managed nearly one-third of patients who did not require in-person follow-up. An initial synchronous / live video conferencing was more likely to yield a single clinical encounter, whereas asynchronous / store-and-forward visits required more in-person follow-up. Future studies are required that focus on dermatology-specific cost, diagnoses, access, quality of care, and outcomes.

Pediatric Patch Testing at Mayo Clinic Between 2016 and 2020.

Background: Allergic contact dermatitis (ACD) is a common condition within the pediatric population. Patch testing is an important way to identify relevant allergens. Objective: To provide an update of the common contact allergens seen in children based on patch testing data at our institution from 2016 to 2020. Methods: We performed a retrospective analysis of patch test data from children aged 1-18 years from 2016 to 2020 at Mayo Clinic. Reaction rates were compared to the rates reported by the Pediatric Contact Dermatitis Registry (PCDR). Results: One hundred ninety-two children aged 1-18 were patch tested to various allergens. A total of 15,457 allergens were tested, with 291 positive tests. The top 5 allergens with highest positive reaction rates were hydroperoxides of linalool, hydroperoxides of limonene, methylisothiazolinone, nickel, and cobalt. Seven of the top 38 allergens with the highest reaction rates are not currently included in the Mayo Clinic Pediatric Patch Test Series, and 11 are not currently included in the Pediatric Baseline Series (as developed by the Pediatric Contact Dermatitis Workgroup). Conclusions: Patch testing is a useful tool to diagnose children with ACD. With new products and exposures, there is an opportunity to expand current pediatric patch testing series.

Opportunities for Pharmacogenetic Testing to Guide Dosing of Medications in Youths With Medicaid.

Importance: There are an increasing number of medications with a high level of evidence for pharmacogenetic-guided dosing (PGx drugs). Knowledge of the prevalence of dispensings of PGx drugs and their associated genes may allow hospitals and clinical laboratories to determine which pharmacogenetic tests to implement. Objectives: To investigate the prevalence of outpatient dispensings of PGx drugs among Medicaid-insured youths, determine genes most frequently associated with PGx drug dispenses, and describe characteristics of youths who were dispensed at least 1 PGx drug. Design, Setting, and Participants: This serial cross-sectional study includes data from 2011 to 2019 among youths aged 0 to 17 years in the Marketscan Medicaid database. Data were analyzed from August to December 2022. Main Outcomes and Measures: PGx drugs were defined as any medication with level A evidence as determined by the Clinical Pharmacogenetics Implementation Consortium (CPIC). The number of unique youths dispensed each PGx drug in each year was determined. PGx drugs were grouped by their associated genes for which there was CPIC level A evidence to guide dosing, and a dispensing rate (No. of PGx drugs/100 000 youths) was determined for each group for the year 2019. Demographics were compared between youths dispensed at least 1 PGx drug and those not dispensed any PGx drugs. Results: The number of Medicaid-insured youths queried ranged by year from 2 078 683 youths in 2011 to 4 641 494 youths in 2017, including 4 126 349 youths (median [IQR] age, 9 [5-13] years; 2 129 926 males [51.6%]) in 2019. The proportion of Medicaid-insured youths dispensed PGx drugs increased from 289 709 youths (13.9%; 95% CI, 13.8%-14.0%) in 2011 to 740 072 youths (17.9%; 95% CI, 17.9%-18.0%) in 2019. Genes associated with the most frequently dispensed medications were CYP2C9, CYP2D6, and CYP2C19 (9197.0 drugs [95% CI, 9167.7-9226.3 drugs], 8731.5 drugs [95% CI, 8702.5-8759.5 drugs], and 3426.8 drugs [95% CI, 3408.1-3443.9 drugs] per 100 000 youths, respectively). There was a higher percentage of youths with at least 1 chronic medical condition among youths dispensed at least 1 PGx drug (510 445 youths [69.0%; 95% CI, 68.8%-69.1%]) than among 3 386 277 youths dispensed no PGx drug (1 381 544 youths [40.8%; 95% CI, 40.7%-40.9%) (P < .001) in 2019. Conclusions and Relevance: In this study, there was an increasing prevalence of dispensings for PGx drugs. This finding suggests that pharmacogenetic testing of specific drug-gene pairs should be considered for frequently prescribed PGx drugs and their implicated genes.

Dose-Escalated Preoperative Proton Therapy for Retroperitoneal Sarcomas: Initial Outcomes of a New Treatment Paradigm.

Purpose: Retroperitoneal sarcomas (RPS) have varied treatment practices with regard to the use of radiation therapy (RT). Preoperative RT ∼50 Gy is commonly used, but the Surgery With or Without Radiation Therapy in Untreated Nonmetastatic Retroperitoneal Sarcoma (STRASS-1) randomized trial demonstrated no improvement in abdominal recurrence-free survival with preoperative RT. Dose escalation has been proposed to improve the efficacy of preoperative RT. We analyzed RPS treated with preoperative intensity modulated proton therapy (IMPT) to an escalated dose of 63 Gy at a single institution. Methods and Materials: Patients who received preoperative RT with IMPT with RPS between January 2015 and October 2021 were reviewed. IMPT 63 Gy in 28 fractions to the clinical target volume high-risk and 50.4 Gy in 28 fractions to clinical target volume low-risk was used. Patient baseline characteristics, RT dose parameters, toxicities, margin status, and recurrence patterns were recorded. Local control was computed by Fine-Gray analysis and overall survival by Kaplan-Meier analysis. Results: Sixteen patients met the study criteria (n = 16): 12 primary and 4 isolated local recurrences. Median age was 62 years (IQR, 43.5-66 years) and 62.5% were male; 10 were liposarcoma. The median maximum tumor diameter was 19.9 cm (IQR, 12-24 cm). With a median follow-up of 18 months (IQR, 11.5-37 months), the estimated 3-year freedom from local failure rate was 68.2% (95% CI, 41.7%-94.7%); 3-year overall survival (OS) rate was 68.8% (95% CI, 41.9%-95.8%). No Radiation Therapy Oncology Group grade ≥3 acute or late toxicities were noted. Conclusions: In our RPS cohort, preoperative dose-escalated RT to 63 Gy demonstrated comparable local control without G3 acute toxicities. Given the high local recurrence rates of RPS, this approach warrants further study to validate these results and identify patients most likely to benefit from therapy.

Safety and pharmacokinetics of ONC201 (dordaviprone) administered two consecutive days per week in pediatric patients with H3 K27M-mutant glioma.

BACKGROUND: This study evaluated the safety and pharmacokinetics (PK) of oral ONC201 administered twice-weekly on consecutive days (D1D2) in pediatric patients with newly diagnosed DIPG and/or recurrent/refractory H3 K27M glioma. METHODS: This phase 1 dose-escalation and expansion study included pediatric patients with H3 K27M-mutant glioma and/or DIPG following ≥1 line of therapy (NCT03416530). ONC201 was administered D1D2 at 3 dose levels (DLs; -1, 1, and 2). The actual administered dose within DLs was dependent on weight. Safety was assessed in all DLs; PK analysis was conducted in DL2. Patients receiving once-weekly ONC201 (D1) served as a PK comparator. RESULTS: Twelve patients received D1D2 ONC201 (DL1, n = 3; DL1, n = 3; DL2, n = 6); no dose-limiting toxicities or grade ≥3 treatment-related adverse events occurred. PK analyses at DL2 (D1-250 mg, n = 3; D1-625 mg, n = 3; D1D2-250 mg, n = 2; D1D2-625 mg, n = 2) demonstrated variability in Cmax, AUC0-24, and AUC0-48, with comparable exposures across weight groups. No accumulation occurred with D1D2 dosing; the majority of ONC201 cleared before administration of the second dose. Cmax was variable between groups but did not appear to increase with D1D2 dosing. AUC0-48 was greater with D1D2 than once-weekly. CONCLUSIONS: ONC201 given D1D2 was well tolerated at all DLs and associated with greater AUC0-48.

Selective DRD2 antagonist and ClpP agonist ONC201 in a recurrent non-midline H3 K27M-mutant glioma cohort.

BACKGROUND: Diffuse midline glioma, H3 K27-altered (H3 K27M-altered DMG) are invariably lethal, disproportionately affecting the young and without effective treatment besides radiotherapy. The 2016 World Health Organization (WHO) Central Nervous System (CNS) Tumors Classification defined H3 K27M mutations as pathognomonic but restricted diagnosis to diffuse gliomas involving midline structures by 2018. Dordaviprone (ONC201) is an oral investigational small molecule, DRD2 antagonist, and ClpP agonist associated with durable responses in recurrent H3 K27M-mutant DMG. Activity of ONC201 in non-midline H3 K27M-mutant diffuse gliomas has not been reported. METHODS: Patients with recurrent non-midline H3 K27M-mutant diffuse gliomas treated with ONC201 were enrolled in 5 trials. Eligibility included measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma, Karnofsky/Lansky performance score ≥60, and ≥90 days from radiation. The primary endpoint was overall response rate (ORR). RESULTS: Five patients with cerebral gliomas (3 frontal, 1 temporal, and 1 parietal) met inclusion. One complete and one partial response were reported by investigators. Blinded independent central review confirmed ORR by RANO criteria for 2, however, 1 deemed nonmeasurable and another stable. A responding patient also noted improved mobility and alertness. CONCLUSIONS: H3 K27M-mutant diffuse gliomas occasionally occur in non-midline cerebrum. ONC201 exhibits activity in H3 K27M-mutant gliomas irrespective of CNS location.

Gentrification Yields Racial And Ethnic Disparities In Exposure To Contextual Determinants Of Health.

This article examines racial and ethnic disparities in the relationship between gentrification and exposure to contextual determinants of health. In our study, we focused on changes in selected contextual determinants of health (health care access, social deprivation, air pollution, and walkability) and life expectancy during the period 2006-21 among residents of gentrifying census tracts in six large US cities that have experienced different gentrification patterns and have different levels of segregation: Chicago, Illinois; Los Angeles, California; New York, New York; Philadelphia, Pennsylvania; San Francisco, California; and Seattle, Washington. We found that gentrification was associated with overall improvements in the likelihood of living in Medically Underserved Areas across racial and ethnic groups, but it was also associated with increased social deprivation and reduced life expectancy among Black people, Hispanic people, and people of another or undetermined race or ethnicity. In contrast, we found that gentrification was related to better (or unchanged) contextual determinants of health for Asian people and White people. Our findings can inform policies that target communities identified to be particularly at risk for worsening contextual determinants of health as a result of gentrification.

Prevalence of persistent SARS-CoV-2 in a large community surveillance study.

Persistent SARS-CoV-2 infections may act as viral reservoirs that could seed future outbreaks1-5, give rise to highly divergent lineages6-8 and contribute to cases with post-acute COVID-19 sequelae (long COVID)9,10. However, the population prevalence of persistent infections, their viral load kinetics and evolutionary dynamics over the course of infections remain largely unknown. Here, using viral sequence data collected as part of a national infection survey, we identified 381 individuals with SARS-CoV-2 RNA at high titre persisting for at least 30 days, of which 54 had viral RNA persisting at least 60 days. We refer to these as 'persistent infections' as available evidence suggests that they represent ongoing viral replication, although the persistence of non-replicating RNA cannot be ruled out in all. Individuals with persistent infection had more than 50% higher odds of self-reporting long COVID than individuals with non-persistent infection. We estimate that 0.1-0.5% of infections may become persistent with typically rebounding high viral loads and last for at least 60 days. In some individuals, we identified many viral amino acid substitutions, indicating periods of strong positive selection, whereas others had no consensus change in the sequences for prolonged periods, consistent with weak selection. Substitutions included mutations that are lineage defining for SARS-CoV-2 variants, at target sites for monoclonal antibodies and/or are commonly found in immunocompromised people11-14. This work has profound implications for understanding and characterizing SARS-CoV-2 infection, epidemiology and evolution.

Reassuring pregnancy outcomes in women with mild COL4A3-5-related disease (Alport syndrome) and genetic type of disease can aid personalized counseling.

Individualized pre-pregnancy counseling and antenatal care for women with chronic kidney disease (CKD) require disease-specific data. Here, we investigated pregnancy outcomes and long-term kidney function in women with COL4A3-5 related disease (Alport Syndrome, (AS)) in a large multicenter cohort. The ALPART-network (mAternaL and fetal PregnAncy outcomes of women with AlpoRT syndrome), an international collaboration of 17 centers, retrospectively investigated COL4A3-5 related disease pregnancies after the 20th week. Outcomes were stratified per inheritance pattern (X-Linked AS (XLAS)), Autosomal Dominant AS (ADAS), or Autosomal Recessive AS (ARAS)). The influence of pregnancy on estimated glomerular filtration rate (eGFR)-slope was assessed in 192 pregnancies encompassing 116 women (121 with XLAS, 47 with ADAS, and 12 with ARAS). Median eGFR pre-pregnancy was over 90ml/min/1.73m2. Neonatal outcomes were favorable: 100% live births, median gestational age 39.0 weeks and mean birth weight 3135 grams. Gestational hypertension occurred during 23% of pregnancies (reference: 'general' CKD G1-G2 pregnancies incidence is 4-20%) and preeclampsia in 20%. The mean eGFR declined after pregnancy but remained within normal range (over 90ml/min/1.73m2). Pregnancy did not significantly affect eGFR-slope (pre-pregnancy ß=-1.030, post-pregnancy ß=-1.349). ARAS-pregnancies demonstrated less favorable outcomes (early preterm birth incidence 3/11 (27%)). ARAS was a significant independent predictor for lower birth weight and shorter duration of pregnancy, next to the classic predictors (pre-pregnancy kidney function, proteinuria, and chronic hypertension) though missing proteinuria values and the small ARAS-sample hindered analysis. This is the largest study to date on AS and pregnancy with reassuring results for mild AS, though inheritance patterns could be considered in counseling next to classic risk factors. Thus, our findings support personalized reproductive care and highlight the importance of investigating kidney disease-specific pregnancy outcomes.

Intraoperative language mapping guided by real-time visualization of gamma band modulation electrocorticograms: Case report and proof of concept.

Background: Electrocorticography (ECoG) language mapping is often performed extraoperatively, frequently involves offline processing, and relationships with direct cortical stimulation (DCS) remain variable. We sought to determine the feasibility and preliminary utility of an intraoperative language mapping approach guided by real-time visualization of electrocorticograms. Methods: A patient with astrocytoma underwent awake craniotomy with intraoperative language mapping, utilizing a dual iPad stimulus presentation system coupled to a real-time neural signal processing platform capable of both ECoG recording and delivery of DCS. Gamma band modulations in response to 4 language tasks at each electrode were visualized in real-time. Next, DCS was conducted for each neighboring electrode pair during language tasks. Results: All language tasks resulted in strongest heat map activation at an electrode pair in the anterior to mid superior temporal gyrus. Consistent speech arrest during DCS was observed for Object and Action naming tasks at these same electrodes, indicating good correspondence with ECoG heat map recordings. This region corresponded well with posterior language representation via preoperative functional MRI. Conclusions: Intraoperative real-time visualization of language task-based ECoG gamma band modulation is feasible and may help identify targets for DCS. If validated, this may improve the efficiency and accuracy of intraoperative language mapping.

Pharmaceutical pollution alters the cost of bacterial infection and its relationship to pathogen load.

The relationship between pathogen proliferation and the cost of infection experienced by a host drives the ecology and evolution of host-pathogen dynamics. While environmental factors can shape this relationship, there is currently limited knowledge on the consequences of emerging contaminants, such as pharmaceutical pollutants, on the relationship between a pathogen's growth within the host and the damage it causes, termed its virulence. Here, we investigated how exposure to fluoxetine (Prozac), a commonly detected psychoactive pollutant, could alter this key relationship using the water flea Daphnia magna and its bacterial pathogen Pasteuria ramosa as a model system. Across a variety of fluoxetine concentrations, we found that fluoxetine shaped the damage a pathogen caused, such as the reduction in fecundity or intrinsic growth experienced by infected individuals, but with minimal change in average pathogen spore loads. Instead, fluoxetine modified the relationship between the degree of pathogen proliferation and its virulence, with both the strength of this trade-off and the component of host fitness most affected varying by fluoxetine concentration and host genotype. Our study underscores the potential for pharmaceutical pollution to modify the virulence of an invading pathogen, as well as the fundamental trade-off between host and pathogen fitness, even at the trace amounts increasingly found in natural waterways.

Is there a sicker sex? Dose relationships modify male-female differences in infection prevalence.

Throughout the animal kingdom, there are striking differences in the propensity of one sex or the other to become infected. However, precisely when we should expect males or females to be the sicker sex remains unclear. A major barrier to answering this question is that very few studies have considered how the susceptibility of males and females changes across the full range of pathogen doses encountered in nature. Without quantifying this 'dose-susceptibility' relationship, we have likely underestimated the scope for sex differences to arise. Here, we use the Daphnia magnia-Pasteuria ramosa system to reveal that sex differences in susceptibility are entirely dose-dependent, with pathogens having a higher probability of successfully establishing an infection in mature males at low doses, but mature females at high doses. The scope for male-female differences to emerge is therefore much greater than previously appreciated-extending to sex differences in the upper limits to infection success, per-propagule infectivity risks and density-dependent pathogen behaviour. Applying this expanded scope across the animal kingdom will help us understand when and why a sicker sex emerges, and the implications for diseases in nature-where sex ratios, age structure and pathogen densities vary drastically.