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OBJECTIVE The study objective was to create a novel milestones evaluation form for neurosurgery sub-interns and assess its potential as a quantitative and standardized performance assessment to compare potential residency applicants. In this pilot study, the authors aimed to determine the form’s interrater reliability, relationship to percentile assignments in the neurosurgery standardized letter of recommendation (SLOR), ability to quantitatively differentiate tiers of students, and ease of use. METHODS Medical student milestones were either adapted from the resident Neurological Surgery Milestones or created de novo to evaluate a student’s medical knowledge, procedural aptitude, professionalism, interpersonal and communication skills, and evidence-based practice and improvement. Four milestone levels were defined, corresponding to estimated 3rd-year medical student through 2nd-year resident levels. Faculty and resident evaluations as well as student self-evaluations were completed for 35 sub-interns across 8 programs. A cumulative milestone score (CMS) was computed for each student. Student CMSs were compared both within and between programs. Interrater reliability was determined with Kendall’s coefficient of concordance (Kendall’s W). Student CMSs were compared against their percentile assignments in the SLOR using analysis of variance with post hoc testing. CMS-derived percentile rankings were assigned to quantitatively distinguish tiers of students. Students and faculty were surveyed on the form’s usefulness. RESULTS The average faculty rating overall was 3.20, similar to the estimated competency level of an intern. Student and faculty ratings were similar, whereas resident ratings were lower (p < 0.001). Students were rated most highly in coachability and feedback (3.49 and 3.67, respectively) and lowest in bedside procedural aptitude (2.90 and 2.85, respectively) in both faculty and self-evaluations. The median CMS was 26.5 (IQR 21.75–29.75, range 14–32) with only 2 students (5.7%) achieving the highest rating of 32. Programs that evaluated the most students differentiated the highest-performing students from the lowest by at least 13 points. A program with 3 faculty raters demonstrated scoring agreement across 5 students (p = 0.024). The CMS differed significantly between SLOR percentile assignments, despite 25% of students being assigned to the top fifth percentile. CMS-driven percentile assignment significantly differentiated the bottom, middle, and top third of students (p < 0.001). Faculty and students strongly endorsed the milestones form. CONCLUSIONS The medical student milestones form was well received and differentiated neurosurgery sub-interns both within and across programs. This form has potential as a replacement for numerical Step 1 scoring as a standardized, quantitative performance assessment for neurosurgery residency applicants.

Summary This article uses three fictitious case vignettes to raise questions and educate on how clinicians can appropriately approach patients experiencing spiritually significant hallucinations. Religious hallucinations are common but are not pathognomonic of mental illness. They are often intimate experiences for the patient that raise complex questions about psychopathology for clinicians. When assessing a patient with religious hallucinations it is important that clinicians hold at the centre that person's personal experience and create a safe space in which they are listened to and epistemic injustices are avoided. Involvement of chaplaincy services is important not just to support the patient but also to ensure that as clinicians we seek support in understanding the religious nature of these experiences.

Trisomy 13 is a rare genetic condition with a characteristic set of severe congenital abnormalities. Traditionally, the standard of care was to provide palliative care only. However, there has been a recent shift towards life-prolonging care, including surgery. This study seeks to describe surgical outcomes in patients with trisomy 13 and compare them to comorbidity-matched controls.Using the ACS NSQIP Pediatric 2012-2019 Participant Use Data Files, patients with trisomy 13 were identified and described. A nearest-neighbor 10:1 propensity score match was performed using demographics, comorbidities, and procedural details. This yielded 254 patients with trisomy 13 and 2,422 controls. Risk ratios for morbidity and mortality by trisomy 13 status were determined using modified Poisson regression. The primary outcomes were thirty-day mortality and the occurrence of any morbidity.The median age of patients with trisomy 13 was 16 months (IQR 87 months). 126 were male (49.6%) and 128 were female (50.4%). There were no differences in overall morbidity compared to controls (31.8% vs. 29.7%, RR 1.06, 95%CI 0.87-1.28, p = 0.554), but patients with trisomy 13 had markedly higher mortality (7.9% vs. 1.8%, RR 4.43, 95%CI 2.28-8.61, p0.001).We conclude that patients with trisomy 13 undergoing surgery have frequent morbidity and an elevated although not prohibitive risk of death. Compared to patients with similar comorbidities, they have similar rates of morbidity but a markedly higher risk of mortality. Parents of children with trisomy 13 require thorough counseling on these risks before deciding on surgery.

We have determined the 1.8 Å X-ray crystal structure of nonlipidated (i.e., N-terminally truncated) nontypeable Haemophilus influenzae (NTHi; H. influenzae) protein D. Protein D exists on outer membranes of H. influenzae strains and acts as a virulence factor that helps invade human cells. Protein D is a proven successful antigen in animal models to treat obstructive pulmonary disease (COPD) and otitis media (OM), and when conjugated to polysaccharides also has been used as a carrier molecule for human vaccines, for example in GlaxoSmithKline Synflorix™. NTHi protein D shares high sequence and structural identify to the Escherichia coli (E. coli) glpQ gene product (GlpQ). E. coli GlpQ is a glycerophosphodiester phosphodiesterase (GDPD) with a known dimeric structure in the Protein Structural Database, albeit without an associated publication. We show here that both structures exhibit similar homodimer organization despite slightly different crystal lattices. Additionally, we have observed both the presence of weak dimerization and the lack of dimerization in solution during size exclusion chromatography (SEC) experiments yet have distinctly observed dimerization in native mass spectrometry analyses. Comparison of NTHi protein D and E. coli GlpQ with other homologous homodimers and monomers shows that the E. coli and NTHi homodimer interfaces are distinct. Despite this distinction, NTHi protein D and E. coli GlpQ possess a triose-phosphate isomerase (TIM) barrel domain seen in many of the other homologs. The active site of NTHi protein D is located near the center of this TIM barrel. A putative glycerol moiety was modeled in two different conformations (occupancies) in the active site of our NTHi protein D structure and we compared this to ligands modeled in homologous structures. Our structural analysis should aid in future efforts to determine structures of protein D bound to substrates, analog intermediates, and products, to fully appreciate this reaction scheme and aiding in future inhibitor design.

Andy Kranenburg,1 Gabriel Garcia-Diaz,2 Judson H Cook,3 Michael Thambuswamy,4 Whitney James,5 David Stevens,6 Adam Bruggeman,7 Ying Chen,8 Robyn Capobianco,9 W Carlton Reckling,9 Joel D Siegal10 1Southern Oregon Orthopedics, Medford, OR, USA; 2OrthoSpine Advance Health, Inc, Merced, CA, USA; 3Central Texas Brain and Spine, Austin, TX, USA; 4Oklahoma Spine & Brain Institute, Tulsa, OK, USA; 5James Marco Health, Prescott, AZ, USA; 6Utah Spine Specialists, Bountiful, UT, USA; 7Texas Spine Care Center, San Antonio, TX, USA; 8OrthoNeuro Inc, New Albany, OH, USA; 9SI-BONE Inc, Santa Clara, CA, USA; 10Key Clinics LLC, Mayfield Heights, OH, USACorrespondence: Andy Kranenburg, Tel +1 541-864-0263, Email andy.kranenburg@gmail.com

Objective: This report examines associations between everyday discrimination, microaggressions, and CRP to gain insight on potential mechanisms that may underlie increased CVD risk among sexual minority male young adults.Methods: The sample consisted of 60 participants taken from the P18 cohort between the ages of 24 and 28 years. Multinomial logistic regression models were used to examine the association between perceived everyday discrimination and LGBQ microaggressions with C-reactive protein cardiovascular risk categories of low-, average-, and high-risk, as defined by the American Heart Association and Centers for Disease Control. Adjustments were made for BMI.Results: Individuals who experienced more everyday discrimination had a higher risk of being classified in the high-risk CRP group compared to the low-risk CRP group (RRR = 3.35, p = 0.02). Interpersonal LGBQ microaggressions were not associated with CRP risk category.Conclusions: Everyday discrimination, but not specific microaggression based on sexual orientation, were associated with elevated levels of CRP among young sexual minority men (YSMM). Thus, to implement culturally and age-appropriate interventions, further researcher is needed to critically examine the specific types of discrimination and the resultant impact on YSMM’s health.

Supplementary Data. CYP2A6 genotype and oxidative metabolism Supplementary Table 1. SNP capture for each gene region in Europeans and Africans Supplementary Table 2. Correlations between covariates and glucuronidation phenotypes Supplementary Table 3. Glucuronidation phenotypes by gender and menthol smoking status Supplementary Table 4. Genotyped variants in UDP-glucuronyl transferase gene loci Supplementary Figure 1. UGT1A locus linkage disequilibrium plot Supplementary Figure 2. UGT2B locus linkage disequilibrium plot

Background: Identifying sources of variation in the nicotine and nitrosamine metabolic inactivation pathways is important to understanding the relationship between smoking and cancer risk. Numerous UGT1A and UGT2B enzymes are implicated in nicotine and nitrosamine metabolism in vitro; however, little is known about their roles in vivo.Methods: Within UGT1A1, UGT1A4, UGT1A9, UGT2B7, UGT2B10, and UGT2B17, 47 variants were genotyped, including UGT2B10*2 and UGT2B17*2. The association between variation in these UGTs and glucuronidation activity within European and African American current smokers (n = 128), quantified as urinary ratios of the glucuronide over unconjugated compound for nicotine, cotinine, trans-3′-hydroxycotinine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), was investigated in regression models assuming a dominant effect of variant alleles.Results: Correcting for multiple testing, three UGT2B10 variants were associated with cotinine glucuronidation, rs2331559 and rs11726322 in European Americans and rs835309 in African Americans (P ≤ 0.0002). Additional variants predominantly in UGT2B10 were nominally associated with nicotine (P = 0.008–0.04) and cotinine (P = UGT2B10*2 in European Americans (P = 0.01, P < 0.001). UGT2B17*2 (P = 0.03) in European Americans and UGT2B7 variants (P = 0.02–0.04) in African Americans were nominally associated with 3HC glucuronidation. UGT1A (P = 0.007–0.01), UGT2B10 (P = 0.02), and UGT2B7 (P = 0.02–0.03) variants in African Americans were nominally associated with NNAL glucuronidation.Conclusions: Findings from this initial in vivo study support a role for multiple UGTs in the glucuronidation of tobacco-related compounds in vivo, in particular UGT2B10 and cotinine glucuronidation.Impact: Findings also provide insight into ethnic differences in glucuronidation activity, which could be contributing to ethnic disparities in the risk for smoking-related cancers. Cancer Epidemiol Biomarkers Prev; 24(1); 94–104. ©2014 AACR.

Although oncogenic driver mutations in RAS occur in 20% of cancers, heterogeneity in the biologic outputs of different RAS mutants has hampered efforts to develop effective treatments for RAS-mutated cancers. In this issue of Science Signaling, Huynh et al. show that even among KRAS(Q61) mutants, the specific amino acid that is substituted substantially affects mutant KRAS biologic activity and oncogenicity.

We present photometric light curves of the stellar occultation event of the star UCAC4 341-187633 on 2018 August 15 by the minor planet (134340) Pluto. Photometric observations were carried out using the 2.1-m telescope at the San Pedro Mártir Observatory and the 1.3-m telescopes at Sites 2 and 3 of the Trans-Neptunian Automated Occultation Survey (TAOS II) project, and using a portable 0.4-m telescope from Bahía Asunción, Baja California Sur, Mexico. Different filters were used with the 2.1-m telescope and the TAOS II telescopes, whilst observations with the portable system were performed with no filter. The resulting light curves from the San Pedro Mártir Observatory show clear structures, with at least two bright spikes observed on ingress and one more observed on egress as the star traverses the atmosphere of the dwarf planet. The light curve from the portable telescope (440 km away) measured a longer duration for the occultation event, because the shadow of Pluto was observed at a lower latitude. Normalized light curves were created for the 2.1-m telescope, the Site 3 telescope of the TAOS II and the portable telescope. These normalized light curves show a difference in amplitude.

In particle therapy, determination of range by measurement or calculation can be a significant source of uncertainty. This work investigates the development of a bespoke Range Length Phantom (RaLPh) to allow independent determination of proton range in tissue. This phantom is intended to be used as an audit device.RaLPh was designed to be compact and allows different configurations of tissue substitute slabs, to facilitate measurement of range using radiochromic film. Fourteen RaLPh configurations were tested, using two types of proton fluence optimised water substitutes, two types of bone substitute, and one lung substitute slabs. These were designed to mimic different complex tissue interfaces. Experiments were performed using a 115 MeV mono-energetic scanning proton beam to investigate the proton range for each configuration. Validation of the measured film ranges was performed via Monte Carlo simulations and ionisation chamber measurements. The phantom was then assessed as an audit device, by comparing film measurements with Treatment Planning System (TPS) predicted ranges.Varying the phantom slab configurations allowed for measurable range differences, and the best combinations of heterogeneous material gave agreement between film and Monte Carlo on average within 0.2% and on average within 0.3% of ionisation chamber measurements. Results against the TPS suggest a material density override is currently required to enable the phantom to be an audit device.This study found that a heterogeneous phantom with radiochromic film can provide range verification as part of a dedicated audit for clinical proton therapy beams.

BACKGROUND: Most existing studies of lumbar anatomy do not consider ethnic influence and recruit mostly white participants. Recent studies have considered other populations; however, none have assessed Māori, the indigenous people of New Zealand (NZ). A computed tomography study of vertebral body (VB) and canal dimensions was performed for lumbar vertebrae of Māori and NZ European patients to evaluate for ethnic variation. METHODS: Lumbar vertebrae from 196 patients were measured using computed tomography. After interrater and intrarater reliability analyses, a single trained examiner measured VB heights, VB lengths, segmental angle, pedicle height and width, and vertebral canal length (VCL) and vertebral canal width for each level. Canal:body ratio was calculated. Demographic data recorded included age, sex, and ethnicity. RESULTS: VCL remained relatively constant through the lumbar spine; canal width increased to a maximum of 28.2 mm at L5. Canal:body ratios and pedicle height decreased while pedicle width increased to a maximum of 16.1 mm at L5. There were few differences between Māori and NZ Europeans except at the L5 level, where VCL and canal:body ratio were larger in NZ Europeans (P < 0.05), and pedicle height, width, and VB pediculolaminar length were larger in Māori (P < 0.05). Females had generally smaller measurements and age was a positive predictor of measured values (P < 0.05). CONCLUSIONS: This study is the first to characterize lumbar anatomy in a Māori cohort. Adequately powered results demonstrated few differences between Māori and NZ Europeans. Isolated differences observed at L5 may be due to sacropelvic differences, which represent an area for further investigation. LEVEL OF EVIDENCE: 3. CLINICAL RELEVANCE: Diagnosis, surgical planning, ethnic differences.

Pathogenic Rickettsia are obligate intracellular bacteria and the etiologic agents of many life-threatening infectious diseases. Due to the serious nature of these infections, it is imperative to both identify the responsive immune sensory pathways and understand the associated immune mechanisms that restrict Rickettsia proliferation. Previous studies have demonstrated that the mammalian complement system is both activated during Rickettsia infection and contributes to the immune response to infection. To further define this component of the mammalian anti-Rickettsia immune response, we sought to identify the mechanism(s) of complement activation during Rickettsia infection. We have employed a series of in vitro and in vivo models of infection to investigate the role of the classical complement activation pathway during Rickettsia infection. Depletion or elimination of complement activity demonstrates that both C1q and pre-existing IgM contribute to complement activation; thus implicating the classical complement system in Rickettsia-mediated complement activation. Elimination of the classical complement pathway from mice increases susceptibility to R. australis infection with both increased bacterial loads in multiple tissues and decreased immune activation markers. This study highlights the role of the classical complement pathway in immunity against Rickettsia and implicates resident Rickettsia-responsive IgM in the response to infection.

The use of broad consent to store human biospecimens to be used in future research studies has increased over the years. However, it is currently unknown how young sexual minority men (YSMM) perceive broad consent in these specific types of studies. Therefore, in this study we aimed to determine the extent to which YSMM are comfortable with providing broad consent concerning their identifiable biological specimens to a variety of entities, including external researchers and pharmaceutical companies and to examine the relationship between mistrust based on racial/ethnic identity or sexual orientation and attitudes toward broad consent. YSMM (N = 239) ages 24–27 years were recruited from a prospective cohort study in New York City in 2018 to complete a survey assessing attitudes about the use of broad consent concerning biospecimens for secondary research. We found that YSMM were most willing to provide broad consent to the researcher from the study they were enrolled in (85.3%), other researchers within the same university (82.4%), and researchers at other universities (74.5%). Participants were least willing to provide broad consent to government organizations (64.4%) and pharmaceutical companies (53.8%). Further, we found that medical mistrust based on racial/ethnic identity or sexual orientation was associated with attitudes toward the use of broad consent. Research institutions should consider modifying consent procedures around the use of broad consent in order to maximize recruitment and retention, especially among minority populations. Supplementary Information The online version contains supplementary material available at 10.1007/s10508-021-01964-3.

The diurnal cycle of rainfall in the Lake Victoria Basin of East Africa results from the super positioning of regional circulations driven by lake/land temperature differences and topography in the presence of the large-scale flow. Analysis of a triple-nested regional model simulation with a convective-permitting inner domain shows how these elements combine to produce the observed regionality of precipitation, including diurnal cycling, in boreal fall. A single diurnal rainfall peak occurs throughout the basin, but the time of maximum rainfall varies within the basin. The rainy period over the lake begins with precipitation over the northern part of the lake near 02Z (0500 LT), so it is not simply nighttime rain driven by lake/land breezes. Onset of the rainy period occurs only when low geopotential heights over the relatively warm lake cause a southward branch of the Turkana Jet to form. The formation of the jet depends on nighttime cooling over the Eastern Rift Mountains, which acts to direct the large-scale, moist flow around the topography. Topography also plays a role in the daytime rainy period over land in the Lake Victoria Basin. Moist divergence over the lake supports convergence and precipitation over the shore regions. Precipitation rates are twice the magnitude over the eastern shore compared with the western shore because daytime warming of the high elevations of the Eastern Rift Mountains allows the large-scale easterly flow to go over the mountains. This easterly flow converges with the lake/land circulation and doubles precipitation rates over the eastern shore.

This article details the rationale and creative process behind a collaborative – or more accurately in this case, dialogic – sound composition undertaken as part of research into the acoustic ecologies of people in the early stages of a dementia. Changes in abilities around hearing and listening are among the first symptoms of many types of dementia, making such auditory phenotypes an increasingly common part of lived experiences of sound. Following acoustic ecology practice in doing and presenting research in sound, and more specifically Steven Feld in doing so in dialogic or polyvocal ways, co-composition can be a way of exploring the particularities of others’ hearing, listening and sound practices, which is less reliant on the discursive frames of interlocutors and researchers. The process of making sound art together draws attention to particular sounds and experiences, creating dialogic situations of companion listening, discussion and mutual learning. It also provides a framework for engaging interlocutors in soundscape and ethnographic fieldwork methods. The composition discussed here, Trevurr, documents my time working with Trevor, a keen amateur musician in Cornwall who has mild cognitive impairment, and gradually comes to simulate his experience of hyperacusis in a piece of dialogic, auraldiversity-oriented composition.

Observed surface warming trends over the Arabian Peninsula are a factor of 1.4–2.1 greater than the tropical mean and a factor of 2.3–3.1 greater than the global mean. The primary reason for the amplified warming is the absence of latent cooling over the dry surface, not trends in net longwave heating or solar fluxes. Well-validated regional model simulations with 30-km resolution are used to evaluate the implications of the amplified warming for the regional climate through the twenty-first century. Projected warming rates are similar to the observed ongoing warming, and low-level specific humidity increases by 50% by the end of the century. Precipitation increases occur only in summer in the southwest corner of the peninsula in association with enhanced orographic precipitation. Concurrent evaporation increases ameliorate and can even reverse increases in surface water availability associated with higher rainfall. A strengthening of the low-level negative meridional geopotential height gradient between the Arabian Peninsula and the Horn of Africa strengthens the zonal branch of the Somali jet, increasing westerly moisture transport into the Ethiopian Highlands and enhancing summer rainfall in northern Ethiopia by 20% at mid-century and by 35% by the end of the century. Confidence in the results is supported by the similarity of the projections with observed modes of variability and current trends.

Leah is a woman in her 40s hearing voices in the context of a recently diagnosed first episode of psychosis. Her voices represent a dynamic interplay between conflicting psychological and spiritual forces within her, which are various externalized, collaborated with, and related to, in an attempt to cope with, and make meaning amidst, multiple traumatic life events. This brief case study shows not only that voices may be meaningful and beneficially attended to, but also that an episode of psychosis may provide the context for spiritual growth and positive religious coping.

Whereas previous research in the medical humanities has tended to neglect theology and religious studies, these disciplines sometimes have a very important contribution to make. The hearing of spiritually significant voices provides a case in point. The context, content and identity of these voices, all of which have typically not been seen as important in the assessment of auditory–verbal hallucinations (AVHs) within psychiatry, are key to understanding their spiritual significance. A taxonomy of spiritually significant voices is proposed, which takes into account frequency, context, affect and identity of the voice. In a predominantly Christian sample of 58 people who reported having heard spiritually significant voices, most began in adult life and were infrequent experiences. Almost 90% reported that the voice was divine in identity and approximately one-third were heard in the context of prayer. The phenomenological characteristics of these voices were different from those in previous studies of voice hearing (AVHs). Most comprised a single voice; half were auditory; and a quarter were more thought-like (the rest being a mixture). Only half were characterful, and one-third included commands or prompts. The voices were experienced positively and as meaningful. The survey has implications for both clinical and pastoral work. The phenomenology of spiritually significant voices may be confused with that of psychopathology, thus potentially leading to misdiagnosis of normal religious experiences. The finding of meaning in content and context may be important in voice hearing more widely, and especially in coping with negative or distressing voices.