Discovery of potent small-molecule inhibitors of lipoprotein(a) formation.

Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL) particle and apolipoprotein(a) (apo(a))1,2. Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (KIV) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a) (refs. 3-7). Here we show that the first step of Lp(a) formation can be inhibited through small-molecule interactions with apo(a) KIV7-8. We identify compounds that bind to apo(a) KIV7-8, and, through chemical optimization and further application of multivalency, we create compounds with subnanomolar potency that inhibit the formation of Lp(a). Oral doses of prototype compounds and a potent, multivalent disruptor, LY3473329 (muvalaplin), reduced the levels of Lp(a) in transgenic mice and in cynomolgus monkeys. Although multivalent molecules bind to the Kringle domains of rat plasminogen and reduce plasmin activity, species-selective differences in plasminogen sequences suggest that inhibitor molecules will reduce the levels of Lp(a), but not those of plasminogen, in humans. These data support the clinical development of LY3473329-which is already in phase 2 studies-as a potent and specific orally administered agent for reducing the levels of Lp(a).

Dissecting dual roles of MyoD during lineage conversion to mature myocytes and myogenic stem cells.

The generation of myotubes from fibroblasts upon forced MyoD expression is a classic example of transcription factor-induced reprogramming. We recently discovered that additional modulation of signaling pathways with small molecules facilitates reprogramming to more primitive induced myogenic progenitor cells (iMPCs). Here, we dissected the transcriptional and epigenetic dynamics of mouse fibroblasts undergoing reprogramming to either myotubes or iMPCs using a MyoD-inducible transgenic model. Induction of MyoD in fibroblasts combined with small molecules generated Pax7+ iMPCs with high similarity to primary muscle stem cells. Analysis of intermediate stages of iMPC induction revealed that extinction of the fibroblast program preceded induction of the stem cell program. Moreover, key stem cell genes gained chromatin accessibility prior to their transcriptional activation, and these regions exhibited a marked loss of DNA methylation dependent on the Tet enzymes. In contrast, myotube generation was associated with few methylation changes, incomplete and unstable reprogramming, and an insensitivity to Tet depletion. Finally, we showed that MyoD's ability to bind to unique bHLH targets was crucial for generating iMPCs but dispensable for generating myotubes. Collectively, our analyses elucidate the role of MyoD in myogenic reprogramming and derive general principles by which transcription factors and signaling pathways cooperate to rewire cell identity.

Molecular circuitry of stem cell fate in skeletal muscle regeneration, ageing and disease.

Satellite cells are adult myogenic stem cells that repair damaged muscle. The enduring capacity for muscle regeneration requires efficient satellite cell expansion after injury, their differentiation to produce myoblasts that can reconstitute damaged fibres and their self-renewal to replenish the muscle stem cell pool for subsequent rounds of injury and repair. Emerging studies indicate that misregulation of satellite cell fate and function can contribute to age-associated muscle dysfunction and influence the severity of muscle diseases, including Duchenne muscular dystrophy (DMD). It has also become apparent that satellite cell fate during muscle regeneration and ageing, and in the context of DMD, is governed by an intricate network of intrinsic and extrinsic regulators. Targeted manipulation of this network may offer unique opportunities for muscle regenerative medicine.

The evolution of lineage-specific regulatory activities in the human embryonic limb.

The evolution of human anatomical features likely involved changes in gene regulation during development. However, the nature and extent of human-specific developmental regulatory functions remain unknown. We obtained a genome-wide view of cis-regulatory evolution in human embryonic tissues by comparing the histone modification H3K27ac, which provides a quantitative readout of promoter and enhancer activity, during human, rhesus, and mouse limb development. Based on increased H3K27ac, we find that 13% of promoters and 11% of enhancers have gained activity on the human lineage since the human-rhesus divergence. These gains largely arose by modification of ancestral regulatory activities in the limb or potential co-option from other tissues and are likely to have heterogeneous genetic causes. Most enhancers that exhibit gain of activity in humans originated in mammals. Gains at promoters and enhancers in the human limb are associated with increased gene expression, suggesting they include molecular drivers of human morphological evolution.

SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.

OBJECTIVE: Intellectual disability is often the outcome of neurodevelopmental disorders and is characterized by significant impairments in intellectual and adaptive functioning. X-linked intellectual disability (XLID) is a subset of these disorders caused by genetic defects on the X chromosome, affecting about 2 out of 1,000 males. In syndromic form, it leads to a broad range of cognitive, behavioral, ocular, and physical disabilities. METHODS: Employing exome or genome sequencing, here we identified 4 missense variants (c.475C > G; p.H159D, c.1373C > A; p.T458N, and c.1585G > A; p.E529K, c.953C > T; p.S318L) and a putative truncating variant (c.1413_1414del; p.Y471*) in the SRPK3 gene in 9 XLID patients from 5 unrelated families. To validate SRPK3 as a novel XLID gene, we established a knockout (KO) model of the SRPK3 orthologue in zebrafish. RESULTS: The 8 patients ascertained postnatally shared common clinical features including intellectual disability, agenesis of the corpus callosum, abnormal eye movement, and ataxia. A ninth case, ascertained prenatally, had a complex structural brain phenotype. Together, these data indicate a pathological role of SRPK3 in neurodevelopmental disorders. In post-fertilization day 5 larvae (free swimming stage), KO zebrafish exhibited severe deficits in eye movement and swim bladder inflation, mimicking uncontrolled ocular movement and physical clumsiness observed in human patients. In adult KO zebrafish, cerebellar agenesis and behavioral abnormalities were observed, recapitulating human phenotypes of cerebellar atrophy and intellectual disability. INTERPRETATION: Overall, these results suggest a crucial role of SRPK3 in the pathogenesis of syndromic X-linked intellectual disability and provide new insights into brain development, cognitive and ocular dysfunction in both humans and zebrafish. ANN NEUROL 2024.

Cumulative cancer locations on prostate biopsy and active surveillance outcomes in the MRI era.

BACKGROUND: To validate the use of a cumulative cancer locations (CCLO) score, a measurement of tumor volume on biopsy, and to develop a novel magnetic resonance imaging (MRI)-informed CCLO (mCCLO) score to predict clinical outcomes on active surveillance (AS). METHODS: The CCLO score is a sum of uniquely involved sextants with prostate cancer on diagnostic + confirmatory biopsy. The mCCLO score incorporates MRI findings into the CCLO score. Participants included 1284 individuals enrolled on AS between 1994 and 2022, 343 of whom underwent prostate MRI. The primary outcome was grade reclassification (GR) to grade group ≥2 disease; the secondary outcome was receipt of definitive treatment. RESULTS: Increasing CCLO and mCCLO risk groups were associated with higher risk of GR and undergoing definitive treatment (both p < 0.001). On multivariable analysis, increasing mCCLO score was associated with higher risk of GR and receipt of definitive treatment (hazard ratios [HRs] per 1-unit increase: 1.26 [95% confidence interval [CI]: 1.12-1.41] and 1.21 [95% CI: 1.07-1.36], respectively). The model using mCCLO score to predict GR (c-index: 0.671; 95% CI: 0.621-0.721) performed at least as well as models using the number of cores positive for cancer (0.664 [0.613-0.715]; p = 0.7) and the maximum percentage of cancer in a core (0.641 [0.585-0.696]; p = 0.14). CONCLUSIONS: The CCLO score is a valid, objective metric to predict GR and receipt of treatment in a large AS cohort. The ability of the MRI-informed mCCLO to predict GR is on par with traditional metrics of tumor volume but is more descriptive and may benefit from greater reproducibility. The mCCLO score can be implemented as a shorthand, informative tool for counseling patients about whether to remain on AS.

Chalcones: Potential Chemotherapeutic Compounds and Educational Tools for Closing the Loop in STEM.

The study discussed herein describes the synthesis of halogenated chalcones as potential chemotherapeutics. The synthesis work was conducted by undergraduate students participating in an Organic Chemistry II laboratory course at Tuskegee University, while the biological assays were conducted by students enrolled in a Molecular Biology I laboratory course. Chalcones were synthesized via aldol condensation and purified from hot ethanol. The impetus for the work was the fact that Tuskegee University sits positioned within the Black Belt of Alabama which, in addition to being an area of fertile soil and excellent farmland, is also an area rife with health disparities that particularly affect African-Americans. Breast cancer, specifically triple-negative breast cancer, affects African-American women at a higher rate than any other ethnic group. The work described herein addresses a practical problem [teaching undergraduate students about the interface of synthetic techniques, synthesis of specific classes of compounds, functional groups, and their relation to biological activity], as well an existential problem [the prevalence of breast cancer among African-American women, and the need to develop targeted treatments]. One of the chief aims of this approach of integrating these ideas into our laboratory courses was to facilitate the understanding of translational science, i.e. taking chalcones from benchtop to potential therapies for breast cancer. Another aim of the current approach was to, in essence, create a research problem based course and concomitantly use the results of the experiments performed in the course as a way to address the dearth of research funding that HBCUs typically receive. The pharmacological activities of chalcones and their derivatives are well documented. They are an important class of natural products that occur in edible plant derivatives such as spices, teas, fruits and various vegetables. In vitro studies have shown that chalcones inhibit proliferation of breast cancer cells by inducing apoptosis and blocking cell progression. The synthesis of chalcones with aromatic substituents has been investigated, and electron rich chalcones, i.e., chalcones with donors attached to the aromatic rings, have been studied extensively. The effect that adding electron withdrawing groups to the chalcone structural motif has on the antiproliferation ability of chalcones had been only minimally investigated at the time that our studies were being conducted. We examined the introduction of chlorine to the aromatic system of the chalcone and how these electron withdrawing substituents affect the chalcone's antiproliferative ability. It was discovered that (E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one inhibited MDA-MB-231 cell progression in a dose dependent manner and outperformed the unsubstituted (E)-1,3-diphenyl-2-propen-1-one (1) at concentrations ranging from 0 µg/mL to 20 µg/mL. Cell death was determined by MTT assay.

Molecular characterization of 13 patients with PIK3CA-related overgrowth spectrum using a targeted deep sequencing approach.

Activating variants in the PIK3CA gene cause a heterogeneous spectrum of disorders that involve congenital or early-onset segmental/focal overgrowth, now referred to as PIK3CA-related overgrowth spectrum (PROS). Historically, the clinical diagnoses of patients with PROS included a range of distinct syndromes, including CLOVES syndrome, dysplastic megalencephaly, hemimegalencephaly, focal cortical dysplasia, Klippel-Trenaunay syndrome, CLAPO syndrome, fibroadipose hyperplasia or overgrowth, hemihyperplasia multiple lipomatosis, and megalencephaly capillary malformation-polymicrogyria (MCAP) syndrome. MCAP is a sporadic overgrowth disorder that exhibits core features of progressive megalencephaly, vascular malformations, distal limb malformations, cortical brain malformations, and connective tissue dysplasia. In 2012, our research group contributed to the identification of predominantly mosaic, gain-of-function variants in PIK3CA as an underlying genetic cause of the syndrome. Mosaic variants are technically more difficult to detect and require implementation of more sensitive sequencing technologies and less stringent variant calling algorithms. In this study, we demonstrated the utility of deep sequencing using the Illumina TruSight Oncology 500 (TSO500) sequencing panel in identifying variants with low allele fractions in a series of patients with PROS and suspected mosaicism: pathogenic, mosaic PIK3CA variants were identified in all 13 individuals, including 6 positive controls. This study highlights the importance of screening for low-level mosaic variants in PROS patients. The use of targeted panels with deep sequencing in clinical genetic testing laboratories would improve diagnostic yield and accuracy within this patient population.

Legionnaires' disease in transportation, construction and other occupations in 39 US jurisdictions, 2014-2016.

BACKGROUND: Certain workers are at increased risk for acquiring Legionnaires' disease compared with other workers. This study aims to identify occupations at increased risk for acquiring Legionnaires' disease. METHODS: Using data from the US Centers for Disease Control and Prevention's Supplemental Legionnaires' Disease Surveillance System, this study identified Legionnaires' disease confirmed patients ≥16 years of age in 39 states with reported symptom onset during 2014-2016. Age-adjusted and sex-adjusted incidence rate ratios (IRR) stratified by occupation group were calculated by comparing Legionnaires' disease patients in an occupation group (eg, transportation) to those in all other occupation groups (eg, non-transportation). RESULTS: A total of 2553 patients had a known occupation group. The two occupations with the highest burden were transportation (N=287; IRR=2.11) and construction (N=269; IRR=1.82). Truck drivers comprised the majority (69.7%) of the transportation occupation group and construction labourers comprised almost half (49%) of the construction occupation group. The healthcare support occupation had the highest IRR (N=75; IRR=2.16). CONCLUSION: Transportation and construction workers, who are generally not covered by guidance related to building water systems, have increased risk of Legionnaires' disease compared with other workers. One hypothesised risk factor for truck drivers is the use of non-genuine windshield cleaner in their vehicles. A simple intervention is to use genuine windshield cleaner with bactericidal properties (ie, includes isopropanol/methanol) which can reduce the risk of Legionella growth and transmission. To improve surveillance of Legionnaires' disease and identification of similar exposures, the authors encourage the collection of occupation and industry information for all patients with Legionnaires' disease.

Changing Dermatologic Procedural Patterns in the Medicare Population: A National Trend Analysis.

BACKGROUND: Dermatologists are trained in diagnostic and therapeutic procedures for cutaneous lesions, yet comparative trends for basic dermatologic procedures across dermatology providers are lacking at the national level. OBJECTIVE: To trend common dermatologic procedures among general dermatologists, Mohs surgeons, primary care providers or primary care physicians (PCPs), and nonphysician clinicians (NPCs). METHODS: Longitudinal analysis of 2016 to 2021 Medicare Public Use Files. RESULTS: Aggregate dermatologic procedural volume decreased 3.0%. Procedural volume declined among general dermatologists (-11.7%), Mohs surgeons (-16.7%), and PCPs (-41.7%) but increased among NPCs (+57.5%). The proportion of procedures by general dermatologists decreased substantially for premalignant destructions (-6.2%), skin biopsies and shave removals (-4.7%), and malignant excisions (-4.1%) and more notably in counties that were nonmetro (-7.1%), low in income (-6.1%), and with <4.0 dermatologists per 100,000 population (-7.0%). CONCLUSION: Aggregate procedural volume decreased across the study period with general dermatologists, Mohs surgeons, and PCPs performing a progressively smaller proportion. The increase in procedures by NPCs may help to address demand but underscores the value of formalized procedural training. The procedural decline by general dermatologists in rural and low-income counties and those with baseline dermatologist shortages may exacerbate existing unmet need. Primary limitation included lack of commercial data.

Cutaneous Coccidiomycosis.

ABSTRACT: Coccidiomycosis is an infectious primary pulmonary disease caused by two highly virulent fungi, Coccidioides immitis and C. Posadasii. Coccidioides spp. are endemic to the southwestern USA, Central America, and South America with infection predominating in the summer and fall seasons. The disease commonly presents with flu-like symptoms. Cutaneous manifestations are rare and are a sign of a more serious infection with poorer outcomes. In this case, a 60-year-old female presented to the dermatology clinic with a 3-month history of a mild, non-pruritic, erythematous rash located on her proximal arms and legs. Two punch biopsies were obtained, and she was found to have a non-endemic case of disseminated coccidiomycosis.

Congenital Erythropoietic Porphyria: A Case of Hepatic Failure and Angioedema Following Ferrous Sulfate Supplementation.

This report describes an unusual case of a young anemic female who experienced acute hepatic insufficiency and angioedema after ferrous sulfate consumption. Her primary diagnosis of congenital erythropoietic porphyria (CEP) was revealed after a detailed dermatologic examination and laboratory data. The patient was treated with IV methylprednisolone along with red blood cell transfusion, vitamin supplementation, and wound care. Our case report emphasizes the importance of physician awareness of CEP since it is a rare disease that tends to mimic other chronic porphyrias, various drug reactions, and collagenopathies.

Retrospective Multicenter Observational Study of Immediate Voiding at End of Urinary Sphincter Surgery (REMOVE).

PURPOSE: Patients may remain catheterized after artificial urinary sphincter surgery to prevent urinary retention, despite a lack of evidence to support this practice. Our study aims to evaluate the feasibility of outpatient, catheter-free continence surgery using a multi-institutional database. We hypothesize that between catheterized controls and patients without a catheter, there would be no difference in the rate of urinary retention or postoperative complications. MATERIALS AND METHODS: We conducted a retrospective review of patients undergoing first-time artificial urinary sphincter placement from 2009-2021. Patients were stratified by postoperative catheter status into either no-catheter (leaving the procedure without a catheter) or catheter (postoperative indwelling catheter for ∼24 hours). The primary outcome, urinary retention, was defined as catheterization due to subjective voiding difficulty or documented postvoid residual over 250 mL. RESULTS: Our study identified 302 catheter and 123 no-catheter patients. Twenty (6.6%) catheter and 9 (7.3%) no-catheter patients developed urinary retention (P = .8). On multivariable analysis, controlling for age, cuff size, radiation history and surgeon, there was no statistically significant association between omitting a catheter and urinary retention (OR: 0.45, 95% CI: 0.13-1.58; P = .2). Furthermore, at 30 months follow-up, Kaplan-Meier survival analysis revealed that device survival was 70% (95% CI: 62%-76%) vs 69% (95% CI: 48%-82%) for the catheter and no-catheter group, respectively. CONCLUSIONS: In our multi-institutional cohort, overall retention rates were low (7%) in groups with a catheter and without. Obviating postoperative catheterization facilitates outpatient incontinence surgery without altering reoperation over medium-term follow-up.

Large Community Outbreak of Legionnaires Disease Potentially Associated with a Cooling Tower - Napa County, California, 2022.

Legionnaires disease is a serious infection acquired by inhalation of water droplets from human-made building water systems that contain Legionella bacteria. On July 11 and 12, 2022, Napa County Public Health (NCPH) in California received reports of three positive urinary antigen tests for Legionella pneumophila serogroup 1 in the town of Napa. By July 21, six Legionnaires disease cases had been confirmed among Napa County residents, compared with a baseline of one or two cases per year. NCPH requested assistance from the California Department of Public Health (CDPH) and CDC to aid in the investigations. Close temporal and geospatial clustering permitted a focused environmental sampling strategy of high-risk facilities which, coupled with whole genome sequencing results from samples and investigation of water system maintenance, facilitated potential linking of the outbreak with an environmental source. NCPH, with technical support from CDC and CDPH, instructed and monitored remediation practices for all environmental locations that tested positive for Legionella. The investigation response to this community outbreak illustrates the importance of interdisciplinary collaboration by public health agencies, laboratory support, timely communication with the public, and cooperation of managers of potentially implicated water systems. Timely identification of possible sources, sampling, and remediation of any facility testing positive for Legionella is crucial to interrupting further transmission.

Surgeon reported practice patterns related to full endoscopic cervical decompression procedures.

BACKGROUND: The microsurgical anterior approach to the cervical spine is commonplace. Fewer surgeons perform posterior cervical microsurgical procedures on a routine basis for lack of indication, more bleeding, persistent postoperative neck pain, and risk of progressive misalignment. In comparison, the endoscopic technique is preferentially performed through the posterior approach. Many spine surgeons and even surgeons versed in lumbar endoscopy are often reluctant to consider endoscopic procedures in the cervical spine. We report the results of a surgeon survey to find out why. METHODS: A questionnaire of 10 questions was sent to spine surgeons by email and chat groups in social media networks including Facebook, WeChat, WhatsApp, and LinkedIn to collect practice pattern data about microscopic and endoscopic spine surgery in the lumbar and cervical spine. The responses were cross-tabulated by surgeons' demographic data. Pearson Chi-Square measures, Kappa statistics, and linear regression analysis of agreement or disagreement were performed by analyzing the distribution of variances using the statistical package SPSS Version 27.0. RESULTS: The survey response rate was 39.7%, with 50 of the 126 surgeons who started the survey submitting a completed questionnaire. Of the 50 surgeons, 56.2% were orthopedic, and 42% neurological surgeons. Most surgeons worked in private practice (42%). Another 26% were university-employed, 18% were in private practice affiliated with a university, and the remaining 14% were hospital employed. The majority of surgeons (55.1%) were autodidacts. The largest responding surgeon groups were between 35-44 years (38%) and between 45-54 years of age (34%). Half of the responding surgeons were routinely performing endoscopic cervical spine surgery. The other half did not perform it for the main hurdle of fear of complications (50%). Lack of appropriate mentorship was listed as second most reason (25.4%). More concerns for not performing cervical endoscopic approaches were the perception of lack of technology (20.8%) and suitable surgical indication (12.5%). Only 4.2% considered cervical endoscopy too risky. Nearly a third (30.6%) of the spine surgeons treated over 80% of their cervical spine patients with endoscopic surgeries. Most commonly performed were posterior endoscopic cervical discectomy (PECD; 52%), posterior endoscopic cervical foraminotomy (PECF; 48%), anterior endoscopic cervical discectomy (AECD; 32%), cervical endoscopic unilateral laminotomy for bilateral decompression (CE-ULBD; 30%), respectively. CONCLUSION: Cervical endoscopic spine surgery is gaining traction among spine surgeons. However, by far most surgeons performing cervical endoscopic spine surgery work in private practice and are autodidacts. This lack of a teacher to shorten the learning curve as well as fear of complications are two of the major impediments to the successful implementation of cervical endoscopic procedures.

Comparative analysis of perioperative characteristics and early outcomes in transforaminal endoscopic lumbar diskectomy: general anesthesia versus conscious sedation.

PURPOSE: To better understand how anesthesia type impacts patient selection and recovery in TELD, we conducted a multicenter prospective study which evaluates the differences in perioperative characteristics and outcomes between patients who underwent TELD with either general anesthesia (GA) or conscious sedation (CS). METHODS: We prospectively collected data from all TELD performed by five neurosurgeons at five different medical centers between February and October of 2022. The study population was dichotomized by anesthesia scheme, creating CS and GA cohorts. This study's primary outcomes were the Oswetry Disability Index (ODI) and the Visual Analog Scale (VAS) for back and leg pain, assessed preoperatively and at 2-week follow-up. RESULTS: A total of 52 patients underwent TELD for symptomatic lumbar disk herniation. Twenty-three patients received conscious sedation with local anesthesia, and 29 patients were operated on under general anesthesia. Patients who received CS were significantly older (60.0 vs. 46.7, p < 0.001) and had lower BMI (28.2 vs. 33.4, p = 0.005) than patients under GA. No intraoperative or anesthetic complications occurred in the CS and GA cohorts. Improvement at 2-week follow-up in ODI, VAS-back, and VAS-leg was greater in patients receiving CS relative to patients under GA, but these differences were not statistically significant. CONCLUSION: In our multicenter prospective analysis of 52 patients undergoing TELD, we found that patients receiving CS were significantly older and had significantly lower BMI compared to patients under GA. On subgroup analysis, no statistically significant differences were found in the improvement of PROMs between patients in the CS and GA group.

A decade of diversity: using statistical indices to compare neurosurgery to other surgical specialties.

OBJECTIVE: Studies have demonstrated the benefits of diversity in neurosurgery. However, recruitment of minoritized groups within the neurosurgical workforce consistently lags other surgical specialties. While racial and gender demographics of neurosurgical residents are well documented, there has been minimal exploration into the multidimensional nature of diversity. The current study will evaluate the longitudinal diversity changes in neurosurgery residency programs compared with other surgical fields with validated diversity indices. METHODS: Nationwide reports including data about resident physicians were obtained from the American Medical Association and the Association of American Medical Colleges for the academic years 2008-2021. Self-reported race, biological sex, and medical school affiliation were recorded for surgical residents in the 10 commonly recognized surgical fields. The Gini-Simpson Diversity Index was used to calculate the effective counts (ECs) of races, sexes, and medical school types for each field. A Composite Diversity Index (CDI) comprising the aforementioned diversity traits was used to calculate the percentage of characteristics upon which two randomly selected residents within each specialty would differ. CDIs were calculated for each field in every year from 2008 to 2021. Median CDIs were compared between fields using Kruskal-Wallis testing, and p values < 0.05 were deemed statistically significant. RESULTS: Plastic surgery had the highest median sex EC (1.92, interquartile range [IQR] 1.78-1.95), indicating greater diversity, while neurosurgery had the third lowest sex EC (1.40, IQR 1.35-1.41). All surgical fields examined had fewer than 3 races effectively represented among their residents, despite there being 8 races present. Neurosurgery ranked among the top fields in effective racial diversity (EC 2.17, IQR 2.09-2.21) and medical school type diversity (EC 1.25, IQR 1.21-1.26). There were statistically significant differences in the sex, race, and school ECs between surgical specialties. While neurosurgery had a relatively low median overall diversity (CDI = 32.7, IQR 32.0-34.6), there was a consistent longitudinal increase in CDI from 2015 to 2021. CONCLUSIONS: Neurosurgery resident physicians have become increasingly diverse in the past decade but are more homogenous than residents in other surgical fields. The continued use of diversity indices to more accurately track diversity progress over time may better inform leaders in the field of how they may best focus their equity and inclusion efforts.

STRIDE: a command-line HMM-based identifier and sub-classifier of Plasmodium falciparum RIFIN and STEVOR variant surface antigen families.

BACKGROUND: RIFINs and STEVORs are variant surface antigens expressed by P. falciparum that play roles in severe malaria pathogenesis and immune evasion. These two highly diverse multigene families feature multiple paralogs, making their classification challenging using traditional bioinformatic methods. RESULTS: STRIDE (STevor and RIfin iDEntifier) is an HMM-based, command-line program that automates the identification and classification of RIFIN and STEVOR protein sequences in the malaria parasite Plasmodium falciparum. STRIDE is more sensitive in detecting RIFINs and STEVORs than available PFAM and TIGRFAM tools and reports RIFIN subtypes and the number of sequences with a FHEYDER amino acid motif, which has been associated with severe malaria pathogenesis. CONCLUSIONS: STRIDE will be beneficial to malaria research groups analyzing genome sequences and transcripts of clinical field isolates, providing insight into parasite biology and virulence.

Blatter Radicals as Bipolar Materials for Symmetrical Redox-Flow Batteries.

Redox-active organic molecules are promising charge-storage materials for redox-flow batteries (RFBs), but material crossover between the posolyte and negolyte and chemical degradation are limiting factors in the performance of all-organic RFBs. We demonstrate that the bipolar electrochemistry of 1,2,4-benzotriazin-4-yl (Blatter) radicals allows the construction of batteries with symmetrical electrolyte composition. Cyclic voltammetry shows that these radicals also retain reversible bipolar electrochemistry in the presence of water. The redox potentials of derivatives with a C(3)-CF3 substituent are the least affected by water, and moreover, these compounds show >90% capacity retention after charge/discharge cycling in a static H-cell for 7 days (ca. 100 cycles). Testing these materials in a flow regime at a 0.1 M concentration of the active material confirmed the high cycling stability under conditions relevant for RFB operation and demonstrated that polarity inversion in a symmetrical flow battery may be used to rebalance the cell. Chemical synthesis provides insight in the nature of the charged species by spectroscopy and (for the oxidized state) X-ray crystallography. The stability of these compounds in all three states of charge highlights their potential for application in symmetrical organic redox-flow batteries.

Rising Incidence of Legionnaires' Disease and Associated Epidemiologic Patterns, United States, 1992-2018.

Reported Legionnaires' disease (LD) cases began increasing in the United States in 2003 after relatively stable numbers for >10 years; reasons for the rise are unclear. We compared epidemiologic patterns associated with cases reported to the Centers for Disease Control and Prevention before and during the rise. The age-standardized average incidence was 0.48 cases/100,000 population during 1992-2002 compared with 2.71 cases/100,000 in 2018. Reported LD incidence increased in nearly every demographic, but increases tended to be larger in demographic groups with higher incidence. During both periods, the largest number of cases occurred among White persons, but the highest incidence was in Black or African American persons. Incidence and increases in incidence were generally largest in the East North Central, Middle Atlantic, and New England divisions. Seasonality was more pronounced during 2003-2018, especially in the Northeast and Midwest. Rising incidence was most notably associated with increasing racial disparities, geographic focus, and seasonality.