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Objectives To evaluate the relationship between gingival phenotype and tooth location based on selected index teeth ("Ramfjord") and assess possible differences between women and men. Material and methods Thirty-six women and 20 men voluntarily participated in this investigation with an average age of 23 years (min: 19; max: 37). Gingival phenotypes (GP) were assessed by transparency of a periodontal probe through the buccal gingival margin. Results A comparable and similar GP on all index teeth was only found in seven out of the 56 subjects, that is, thin or thick only: Five participants (three male/two female) showed a uniform and constantly thick and two females a constantly thin GP. While the majority of molars (94.6%; p = 0.006) showed a thick GP, premolars (61.6%; p = 0.09) as well as incisors (70.5%; p = 0.046) were predominantly categorized as thin. In addition, significantly thicker GP was in general observed for maxillary teeth (p = 0.001) but without differences between genders (p = 0.722). Conclusion No constant GP can be expected within one dentition. The use of the "Ramfjord teeth" may serve as a quick overview and reliable method to screen GP distribution.

Imbalance in the metabolic pathway linking excitatory and inhibitory neurotransmission has been implicated in multiple psychiatric and neurologic disorders. Recently, we described enantiomer-specific effects of 2-methylglutamate, which is not decarboxylated to the corresponding methyl analogue of gamma-aminobutyric acid (GABA): 4-aminopentanoic acid (4APA). Here we tested the hypothesis that 4APA also has enantiomer-specific actions in brain. Mouse cerebral synaptosome uptake (nmol/mg protein over 30 min) of (R)-4APA or (S)-4APA was time- and temperature dependent; however, the R enantiomer had greater uptake, reduction of endogenous GABA concentration, and release following membrane depolarization than did the S enantiomer. (S)-4APA exhibited some weak agonist (GABAA α4β3δ, GABAA α5β2γ2, and GABAB B1/B2) and antagonist (GABAA α6β2γ2) activity while (R)-4APA showed weak agonist activity only with GABAA α5β2γ2. Both 4APA enantiomers (100 mg/kg IP) were detected in mouse brain 10 min after injection, and by one hour had reached concentrations that were stable over six hours; both enantiomers were cleared rapidly from mouse serum over six hours. Two-month old mice had no mortality following 100 to 900 mg/kg IP of each 4APA enantiomer but ded have similar dose-dependent reduction in distance moved in a novel cage. Neither enantiomer at 30 or 100 mg/kg impacted outcomes in twenty-three measures of well-being, activity chamber, or withdrawal from hotplate. Our results suggest that enantiomers of 4APA are active in mouse brain, and that (R)-4APA may act as a novel false neurotransmitter of GABA. Future work will focus on disease models and on possible applications as neuroimaging agents.

Gut microorganisms modulate host phenotypes and are associated with numerous health effects in humans, ranging from host responses to cancer immunotherapy to metabolic disease and obesity. However, difficulty in accurate and high-throughput functional analysis of human gut microorganisms has hindered efforts to define mechanistic connections between individual microbial strains and host phenotypes. One key way in which the gut microbiome influences host physiology is through the production of small molecules1–3, yet progress in elucidating this chemical interplay has been hindered by limited tools calibrated to detect the products of anaerobic biochemistry in the gut. Here we construct a microbiome-focused, integrated mass-spectrometry pipeline to accelerate the identification of microbiota-dependent metabolites in diverse sample types. We report the metabolic profiles of 178 gut microorganism strains using our library of 833 metabolites. Using this metabolomics resource, we establish deviations in the relationships between phylogeny and metabolism, use machine learning to discover a previously undescribed type of metabolism in Bacteroides, and reveal candidate biochemical pathways using comparative genomics. Microbiota-dependent metabolites can be detected in diverse biological fluids from gnotobiotic and conventionally colonized mice and traced back to the corresponding metabolomic profiles of cultured bacteria. Collectively, our microbiome-focused metabolomics pipeline and interactive metabolomics profile explorer are a powerful tool for characterizing microorganisms and interactions between microorganisms and their host. A microbiome-focused metabolomics pipeline and interactive metabolomics profile explorer are a powerful tool for the characterization of gut-resident microorganisms and the interactions between microorganisms and their host.

BACKGROUND Nutritional rickets is believed to result from the interaction of inadequate serum 25-hydroxyvitamin D [25(OH)D] concentration and dietary calcium intake, but this interaction has not been confirmed in children with rickets. Determining the vitamin D requirements to prevent nutritional rickets has been thwarted by inconsistent case definition, inadequate adjustment for calcium intake and other confounders, and 25(OH)D assay variability. OBJECTIVES To model the 25(OH)D concentration associated with nutritional rickets in calcium-deprived Nigerian children, adjusted for confounding factors, and develop a general approach to define vitamin D status while accounting for calcium intake. METHODS Logistic regression was used to model the association of serum 25(OH)D with having rickets adjusted for calcium intake in a reanalysis of a case-control study in Nigerian children. The matching variables age, sex, weight-for-age z score, and 4 additional significant variables were selected [religion, age began walking, phosphorus intake, and the 25(OH)D × calcium intake interaction] using a rigorous 7-step algorithm. RESULTS Cases had significantly (P

X-linked adrenoleukodystrophy (X-ALD) is a rare genetic disorder characterized by progressive demyelination ranging from mild myelopathic forms (adrenomyeloneuropathy [AMN]) to severe cerebral variants (adult cerebral adrenoleukodystrophy [ACALD]). The aim of this study was to compare cognitive function in adult-onset X-ALD phenotypes.Cognitive function in various domains (intelligence, attention, memory, executive function, and processing speed) was assessed in 172 adults (117 with AMN, 30 with arrested ACALD, and 25 with acute ACALD) using comprehensive neuropsychological batteries. Phenotype differences were examined by analyses of variance.X-ALD phenotypes significantly differed in nonverbal intelligence, sustained attention, verbal encoding, nonverbal recognition, and processing speed (ps 0.050). No group differences emerged regarding verbal intelligence, verbal retrieval and recognition, and executive function (ps 0.050). Specifically, patients with acute ACALD showed severe cognitive deficits compared to AMN and normal data, with largest effects on processing speed. Contrary, cognition was overall intact in patients with AMN, independent of sex and corticospinal tract involvement, and those with arrested ACALD showed mild cognitive dysfunction, particularly in verbal encoding and processing speed.Cerebral demyelination in patients with X-ALD causes white matter dementia, mainly characterized by an extreme slowdown in processing speed associated with deficits in attention and learning. Most patients with AMN show intact cognitive function. Future prospective, longitudinal studies with more sensitive imaging techniques are required to clarify whether early mild cognitive dysfunction found in some patients with AMN may be associated with subtle myelin abnormalities that do not yet appear as white matter lesions on cerebral MRI (cMRI) but have the potential to serve as early predictors of later cerebral progression. ANN NEUROL 2021;90:266-273.

Context Nutritional rickets results from the interaction of low vitamin D status and limited calcium intake. Serum alkaline phosphatase (AP) activity is a biomarker of impaired mineralization in rickets. Objective To assess the performance of serum AP activity in identifying nutritional rickets in calcium-deprived Nigerian children. Methods We reanalyzed data from a case-control study of children with active rickets and matched control subjects without rickets, using a multivariate logistic regression to assess the odds of rickets associated with AP activity, adjusting for age, sex, and weight-for-age z-score. Results A total of 122 children with rickets and 119 controls were included. Rachitic children had a mean (±SD) age of 54 ± 29 months, and 55 (45.1%) were male. Cases and controls had low dietary calcium intakes (216 ± 87 and 214 ± 96 mg/day, respectively). Serum AP activity levels in cases and controls were 812 ± 415 and 245 ± 78 U/L, respectively (P 350 U/L identified nutritional rickets in Nigerian children with sensitivity 0.93, specificity 0.92, positive likelihood ratio 11.3, and negative likelihood ratio 0.07. Conclusion An AP > 350 U/L effectively discriminated between Nigerian children with and without nutritional rickets. AP is a low-cost biochemical test that could be used to screen for nutritional rickets, but cutoff values require validation in other populations, and laboratory values need to be standardized for widespread population studies.

Imbalance of excitatory and inhibitory neurotransmission is implicated in a wide range of psychiatric and neurologic disorders. Here we tested the hypothesis that insertion of a methyl group on the stereogenic alpha carbon of l-Glu or l-Gln would impact the γ-aminobutyric acid (GABA) shunt and the glutamate-glutamine cycle. (S)-2-methylglutamate, or (S)-2MeGlu, was efficiently transported into brain and synaptosomes where it was released by membrane depolarization in a manner equivalent to endogenous l-Glu. (R)-2MeGlu was transported less efficiently into brain and synaptosomes but was not released by membrane depolarization. Each enantiomer of 2MeGlu had limited activity across a panel of over 30 glutamate and GABA receptors. While neither enantiomer of 2MeGlu was metabolized along the GABA shunt, (S)-2MeGlu was selectively converted to (S)-2-methylglutamine, or (S)-2MeGln, which was subsequently slowly hydrolyzed back to (S)-2MeGlu in brain. rac-2MeGln was also transported into brain, with similar efficiency as (S)-2MeGlu. A battery of behavioral tests in young adult wild type mice showed safety with up to single 900 mg/kg dose of (R)-2MeGlu, (S)-2MeGlu, or rac-2MeGln, suppressed locomotor activity with single ≥ 100 mg/kg dose of (R)-2MeGlu or (S)-2MeGlu. No effect on anxiety or hippocampus-dependent learning was evident. Enantiomers of 2MeGlu and 2MeGln show promise as potential pharmacologic agents and imaging probes for cells that produce or transport l-Gln.

To evaluate learning motivation barriers in infection control and feedback competences, we conducted a national online survey in Germany. Among 767 healthcare workers, overconfidence effects could be detected independent from age, gender, profession, education, and hospital-size. The identified effects may impair learning motivation relevant for supervisors and educators in infection control.

STUDY DESIGN Retrospective cohort study. OBJECTIVE The goals of this study were to (A) evaluate preoperative bone quality assessment and intervention practice over time and (B) review the current evidence for bone evaluation in spine fusion surgery. SUMMARY OF BACKGROUND DATA Deformity spine surgery has demonstrated improved quality of life in patients; however, its cost has made it controversial. If preoperative bone quality can be optimized then potentially these treatments could be more durable; however, at present, no clinical practice guidelines have been published by professional spine surgical organizations. METHODS A retrospective cohort review was performed on patients who underwent a minimum five-level primary or revision fusion. Preoperative bone quality metrics were evaluated over time from 2012 to 2017 to find potential trends. Subgroup analysis was conducted based on age, sex, preoperative diagnosis, and spine fusion region. RESULTS Patient characteristics including preoperative rates of pseudarthrosis and junctional failure did not change. An increasing trend of physician bone health documentation was noted (P = 0.045) but changes in other metrics were not significant. A sex bias favored females who had higher rates of preoperative DXA studies (P = 0.001), Vitamin D 25-OH serum labs (P = 0.005), Vitamin D supplementation (P = 0.022), calcium supplementation (P

Background Dynamic contrast-enhanced magnetic resonance imaging has the potential to show disease activity of rheumatoid arthritis even in complex anatomic areas as the atlantodental region. Purpose To demonstrate the technical feasibility of measuring synovial volume and perfusion characteristics with dynamic contrast-enhanced magnetic resonance imaging of the atlantodental region in patients with rheumatoid arthritis. Material and Methods Ten patients with rheumatoid arthritis and cervical spine involvement underwent dynamic contrast-enhanced magnetic resonance imaging of the cervical spine at 1.5 T. For each patient, 80 3D datasets were acquired using the commercialized Time Resolved Imaging of Contrast KineticS (TRICKS) sequence. Volumes of synovia with active synovitis on anatomical and parametric images were segmented. Synovial tissue perfusion parameters, namely plasma flow (Fp), relative plasma volume (vp), and the permeability-surface area product (PS), were calculated using a two-compartment uptake model. Statistical analysis included calculation of intra- and inter-reader agreement and a correlation of perfusion parameters with Outcome Measures in Rheumatology Clinical Trials (OMERACT) criteria. Results Dynamic contrast-enhanced magnetic resonance imaging as well as quantification of volume and perfusion characteristics of synovia was successful in most patients (80%). Intra- and inter-reader agreement was excellent (0.89–0.99). There was a positive correlation between OMERACT score and the permeability-surface product. Conclusion Dynamic contrast-enhanced magnetic resonance imaging using a 4D angiography sequence for the atlantodental region in patients with rheumatoid arthritis for quantitative and qualitative assessment of synovial volume and perfusion characteristics is technically feasible.

With rapid progress in medicine, a thorough understanding of pharmacology remains crucial. Currently, lecturers are implementing competency-based learning objectives in medical curricula around the world. Advancing teaching modalities need to be integrated into pharmacology courses in a reasonable way. At Ludwig-Maximilians-Universität (LMU) Munich Medical Faculty, a systematic evidence-based approach was used to modernize pharmacology classes. The needs assessment was conducted by final-year students. It included focus groups and a large-scale online survey, which was distributed among all medical students at LMU, with 1018 students participating (response rate 20%). Survey results showed that most of the students (92%) aimed to become pharmacology-adept doctors. Also, a majority (88%) stated that their goal was to understand the material most critical to application of pharmacology concepts as well as prescribing practice. Only 38% of the students reported satisfaction with the current curriculum, and 93% supported modernization. Thus far, pharmacology teaching at LMU Munich had mainly consisted of lectures attended by 200 students. Now, students advocated for a stronger integration of clinical pharmacology teaching into clinical subjects in the last 2 years of medical school. Specifically, they called for classes with smaller groups of students including problem-based learning as well as video podcasts. These results provided the foundation for change in curriculum at the LMU medical school. In conclusion, a structured approach for curriculum development that considers students' views is feasible and can reveal their actual goals and demands. The approach has proven successful at LMU Munich and is transferrable to other universities.

Background: Every encounter a healthcare professional has with new or expecting parents offers an opportunity for addressing improved early nutrition and lifestyle. Evidence-based qualification programmes via e-learning offer valuable tools for attenuating the world’s huge double burden of both under- and overnutrition in early childhood. We evaluated use and learner satisfaction of a global e-learning programme on early nutrition and lifestyle addressing international healthcare professionals. Methods: We implemented the Early Nutrition Specialist Programme (ENS) with six interactive e-learning courses on early nutrition building on more than ten years of experience with global e-learning platforms, expert knowledge and an international network in the subject field. We collected descriptive and explorative evaluation data on usage and learner satisfaction with a questionnaire and log data over three years among 4003 learners from 48 countries. Results: Results show high completion of the ENS programme, with 85.5% of learners finalizing the programme after enrollment into the first of six courses. Very good results were provided for learner satisfaction with the courses (96.7% of users), for increasing understanding of the topic (97.4%) and matching the indicated time investment (94.4%). Most predominant themes in the open text fields of user feedback questionnaires were “Increase interactivity or number of audio-visuals”, “Content suggestions or more examples” and “Technical (quality) issues or navigation problems”. Conclusions: The ENS programme evaluation shows high completion rates and level of satisfaction by learners from numerous countries. The different needs for Continuing Medical Education (CME) of healthcare professionals in diverse healthcare system settings can be met by a joint e-learning qualification programme. Further optimizations will be implemented based on user feedback. More research with a learning analytics approach may help to further identify the most effective and efficient didactic and pedagogic elements of e-learning.

AIM To elucidate possible causal relationships on climate change and intracranial haematomas. MATERIAL AND METHODS In a retrospective study we examined all patients (N=1169) treated for subarachnoid haemorrhage (SAH; n=484), intracerebral haemorrhage (ICH; n=417) or chronic subdural haematoma (CSDH; n=268) in our department over a 7-yearperiod between 1st June 2005 until 31th May 2012. The date of admission was correlated with the corresponding meteorological parameters which included; mean daily temperature (°C), relative humidity (%), vapor pressure (hPa), barometric pressure (hPa), cloud amount (/8), and wind speed (m/s). RESULTS Incidence of SAH tended to increase in April, ICH in January and CSDH in July, respectively, but ?² test did not reveal any statistical significance in seasonality for the three bleeding pathologies. Comparing the arithmetic average of meteorological key parameters of uneventful and eventful days by using student?s t-test within the three groups (SAH, ICH, CSDH) we could not demonstrate any statistical significance (p > 0.05). For SAH, logistic regression analyses revealed an increased risk associated with a decrease of barometric pressure (p=0.021). CONCLUSION Although our data suggest seasonal variabilities of SAH, ICH and CSDH, the single weather parameters do not demonstrate causal relationships with the incidence of cerebrovascular events. However, incidence of SAH tended to increase with changes of barometric pressure which confirms previously published results and might indicate a possible underlying relationship.

Objective: Emotion-handling skills are key components for interpersonal communication by medical professionals. The Verona Coding Definitions of Emotional Sequences (VR-CoDES) appears useful to develop a Situational Judgment Test (SJT) for assessing emotion-handling skills. Methods: In phase 1 we used a multi-stage process with expert panels (npanel1 = 16; npanel2 = 8; npanel3 = 20) to develop 12 case vignettes. Each vignette includes (1) video representing a critical incident containing concern(s) and/or cue(s), (2) standardized lead-in-question, (3) five response alternatives. In phase 2 we piloted the SJT to assess validity via an experimental study with medical students (n = 88). Results: Experts and students rated most of the ‘Reduce space’ responses as inappropriate and preferred ‘Explicit’ responses. Women scored higher than men and there was no decline of empathy according to students’ year of study. There were medium correlations with self-assessment instruments. The students’ acceptance of the SJT was high. Conclusion: The use of VR-CoDES, authentic vignettes, videos and expert panels contributed to the development and validity of the SJT. Practice implications: Development costs were high but could be made up over time. The agreement on a proper score and the implementation of an adequate feedback structure seem to be useful.

Background Understanding clinical reasoning is a major challenge in medical education research. Little is known about the influence of scaffolding and feedback on the clinical reasoning of medical students. The aim of this study was to measure the effects of problem representation (cognitive representation of a clinical case) and structured scaffolding for reflection with or without feedback on the diagnostic efficiency and characterization of diagnostic errors of medical students. Methods One hundred and forty-eight advanced medical students were randomly assigned to one of five groups (2 × 2 design with a control group). They worked on 15 virtual clinical cases (five learning cases, five initial assessment cases, and five delayed assessment cases) in an electronic learning environment. After each case, they stated their presumed diagnosis and explained their diagnostic conclusion. Diagnostic accuracy, efficiency, and error distribution were analyzed. Results The diagnostic accuracy (number of correctly solved cases) and efficiency (solved cases/total time) did not differ significantly between any of the groups in the two different assessment phases [mean = 2.2–3.3 (standard deviation [SD] = 0.79–1.31), p = 0.08/0.27 and mean = 0.07–0.12 (SD = 0.04–0.08), p = 0.16/0.32, respectively]. The most important causes for diagnostic errors were a lack of diagnostic skills (20%), a lack of knowledge (18%), and premature closure (17%). Conclusions Neither structured reflections nor representation scaffolding improved diagnostic accuracy or efficiency of medical students compared to a control group when working with virtual patients.

An outbreak of coronavirus disease 2019 (COVID-19), which is caused by a novel coronavirus (named SARS-CoV-2) and has a case fatality rate of approximately 2%, started in Wuhan (China) in December 20191,2. Following an unprecedented global spread3, the World Health Organization declared COVID-19 a pandemic on 11 March 2020. Although data on COVID-19 in humans are emerging at a steady pace, some aspects of the pathogenesis of SARS-CoV-2 can be studied in detail only in animal models, in which repeated sampling and tissue collection is possible. Here we show that SARS-CoV-2 causes a respiratory disease in rhesus macaques that lasts between 8 and 16 days. Pulmonary infiltrates, which are a hallmark of COVID-19 in humans, were visible in lung radiographs. We detected high viral loads in swabs from the nose and throat of all of the macaques, as well as in bronchoalveolar lavages; in one macaque, we observed prolonged rectal shedding. Together, the rhesus macaque recapitulates the moderate disease that has been observed in the majority of human cases of COVID-19. The establishment of the rhesus macaque as a model of COVID-19 will increase our understanding of the pathogenesis of this disease, and aid in the development and testing of medical countermeasures.

1. Simrit K. Warring, MS* 2. Richmond Castillo, MS* 3. Kelsey Klaas, MD† 4. Nathaniel Taggart, MD‡ 5. Philip R. Fischer, MD† 1. *Mayo Clinic School of Medicine, 2. †Department of General Pediatric and Adolescent Medicine, and 3. ‡Department of Pediatric Cardiology, Mayo Clinic, Rochester, MN A 14-month-old boy is referred to our clinic after his parents noted that he had stretchy skin and looked thinner than his siblings did at his age. The patient was born to a 32-year-old gravida 3 para 3 woman in Saudi Arabia. The pregnancy was complicated by maternal hypertension and gestational diabetes. He was born by cesarean delivery at term gestation due to maternal hypertension. There was no premature onset of labor, bleeding, or leakage of amniotic fluid. The mother reports that he seemed fine in the newborn nursery. He had no difficulty breathing; however, he had asymptomatic bilateral inguinal hernias and a minor diaphragmatic hernia, all of which were repaired when he was 2 weeks of age without complications. At the time of his surgery, a heart murmur was found, and echocardiography revealed that he had a dilated ascending aorta. There were no vision or hearing concerns. He did not have any feeding or developmental problems. The patient’s family history reveals that the patient’s maternal grandfather and father are first cousins. The patient has 2 first cousins who had surgical correction of vascular abnormalities. A maternal grandmother had multiple valve operations as an adult. There is no history of aortic dissection or rupture. On physical examination his height is 31.6 in (80.2 cm) (81st percentile) and weight is 22.7 lb (10.3 kg) (57th percentile). The patient’s blood pressure is 125/35 mm Hg, heart rate is 115 beats/min, and temperature is 97.9°F (36.6°C). The patient is in no apparent distress and is breathing comfortably. A normal precordial impulse is present, with normal S1 …

Objective: We analyze the extent to which students of human, veterinary and dental medicine complete study-related stays abroad (frequency, type and duration of stays abroad and countries visited). Furthermore, we investigate the possible correlations between completed stays abroad and the duration of studies, the completion of a doctorate and entering professional life. Methods: The data come from a written cross-sectional survey of 742 graduates of their respective study programs at Bavarian universities. The evaluation was carried out using descriptive and inferential statistical methods. Results: Slightly more than half of the surveyed students completed study-associated stays abroad, with notable differences between the three study programs. The students most frequently completed internships abroad lasting an average of nine weeks. Switzerland was the most common country of destination for the stays abroad. Furthermore, there were no or only weak correlations between stays abroad, the duration of studies and progress towards a doctorate or the commencement of professional employment abroad. There were no correlations with the stress experienced as part of initial employment after graduation. Conclusion: The results clearly indicate that stays abroad are quite usual for students in the medical disciplines and are almost standard in the study of human medicine. The selection of the countries visited indicates that the primary goal of the students' stays abroad is to deepen their competence with a view to later employment in their home country., Zielsetzung: Wir analysieren das Ausmaß, in dem Studierende der Human-, Tier- und Zahnmedizin studienbezogene Auslandsaufenthalte absolvieren (Häufigkeit, Art und Dauer von Auslandsaufenthalten und besuchte Länder). Außerdem gehen wir der Frage nach, welche Zusammenhänge sich zwischen absolvierten Auslandsaufenthalte und der Studiendauer, der Absolvierung einer Promotion und dem Berufseinstieg zeigen. Methodik: Die Daten stammen aus einer schriftlichen, querschnittlichen Befragung von 742 Absolvent/innen der entsprechenden Studiengänge an bayrischen Universitäten. Die Auswertung erfolgte durch deskriptive und inferenzstatistische Methoden. Ergebnisse: Etwas mehr als die Hälfte der befragten Studierenden absolvierte studienassoziierte Auslandsaufenthalte, wobei sich starke Unterschiede zwischen den drei Studiengängen zeigten. Die Studierenden absolvierten am häufigsten Auslandspraktika, die im Schnitt neun Wochen dauerten. Am häufigsten war die Schweiz Zielland der Auslandsaufenthalte. Weiterhin zeigten sich keine bis schwache Zusammenhänge zwischen Auslandsaufenthalten, der Studiendauer und dem Fortschritt im Promotionsprozess oder der Aufnahme einer Berufstätigkeit im Ausland. Keine Zusammenhänge zeigten sich mit dem Belastungserleben im Rahmen der ersten Tätigkeit nach dem Studium. Schlussfolgerung: Die Ergebnisse machen deutlich, dass Auslandsaufenthalte für Studierende medizinischer Fächer üblich, im Studium der Humanmedizin fast Standard sind. Die Auswahl der besuchten Länder deutet darauf hin, dass die Studierenden durch Auslandsaufenthalte primär das Ziel verfolgen, ihre Kompetenz im Hinblick auf eine spätere Berufstätigkeit im Inland zu vertiefen., GMS Journal for Medical Education; 37(3):Doc34

The N-acyl amino acids are a family of bioactive lipids with pleiotropic physiologic functions, including in energy homeostasis. Their endogenous levels are regulated by an extracellular mammalian N-acyl amino acid synthase/hydrolase called PM20D1 (peptidase M20 domain containing 1). Using an activity-guided biochemical approach, we report the molecular identification of fatty acid amide hydrolase (FAAH) as a second intracellular N-acyl amino acid synthase/hydrolase. In vitro, FAAH exhibits a more restricted substrate scope compared to PM20D1. In mice, genetic ablation or selective pharmacological inhibition of FAAH bidirectionally dysregulates intracellular, but not circulating, N-acyl amino acids. Dual blockade of both PM20D1 and FAAH reveals a dramatic and non-additive biochemical engagement of these two enzymatic pathways. These data establish FAAH as a second intracellular pathway for N-acyl amino acid metabolism and underscore enzymatic division of labor as an enabling strategy for the regulation of a structurally diverse bioactive lipid family.

Aim: Evaluate quality of life (QoL) in patients with advanced non-small cell lung cancer treated with second or third line nab-paclitaxel ± durvalumab. Patients & methods: Longitudinal QoL was assessed using Lung Cancer Symptom Scale, EuroQoL Five-Dimensions Five-Levels and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item core. Results: QoL was generally stable through eight treatment cycles (both arms). Clinically meaningful improvement from baseline was noted in Lung Cancer Symptom Scale (overall constitutional score and three-item index [nab-paclitaxel + durvalumab]) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item core (global health status/QoL and emotional functioning [both arms] and pain [nab-paclitaxel + durvalumab]) analyses. EuroQoL Five-Dimensions Five-Levels domains were stable/improved or completely resolved at least once in 19–56% and 9–51% of patients, respectively. Conclusion: While QoL trends were promising, additional data are required to support these regimens in this setting.

Summary N-acyl amino acids are a family of cold-inducible circulating lipids that stimulate thermogenesis. Their biosynthesis is mediated by a secreted enzyme called PM20D1. The extracellular mechanisms that regulate PM20D1 or N-acyl amino acid activity in the complex environment of blood plasma remains unknown. Using quantitative proteomics, here we show that PM20D1 circulates in tight association with both low- and high-density lipoproteins. Lipoprotein particles are powerful co-activators of PM20D1 activity in vitro and N-acyl amino acid biosynthesis in vivo. We also identify serum albumin as a physiologic N-acyl amino acid carrier, which spatially segregates N-acyl amino acids away from their sites of production, confers resistance to hydrolytic degradation, and establishes an equilibrium between thermogenic “free” versus inactive “bound” fractions. These data establish lipoprotein particles as principal extracellular sites of N-acyl amino acid biosynthesis and identify a lipoprotein-albumin network that regulates the activity of a circulating thermogenic lipid family.

Introduction Clinical reasoning has been fostered with varying case formats including the use of virtual patients. Existing literature points to different conclusions regarding which format is most beneficial for learners with diverse levels of prior knowledge. We designed our study to better understand which case format affects clinical reasoning outcomes and cognitive load, dependent on medical students’ prior knowledge. Methods Overall, 142 medical students (3 rd to 6 th year) were randomly assigned to either a whole case or serial cue case format. Participants worked on eight virtual patients in their respective case format. Outcomes included diagnostic accuracy, knowledge, and cognitive load. Results We found no effect of case format on strategic knowledge scores pre- vs post-test (whole case learning gain = 3, 95% CI. -.01 to .01, serial cue learning gain = 3, 95% CI. -.06 to .00 p = .50). In both case formats, students with high baseline knowledge (determined by median split on the pre-test in conceptual knowledge) benefitted from learning with virtual patients (learning gain in strategic knowledge = 5, 95% CI .03 to .09, p = .01) while students with low prior knowledge did not (learning gain = 0, 95%CI −.02 to .02). We found no difference in diagnostic accuracy between experimental conditions (difference = .44, 95% CI −.96 to .08, p = .22), but diagnostic accuracy was higher for students with high prior knowledge compared to those with low prior knowledge (difference = .8, 95% CI 0.31 to 1.35, p p Conclusions The whole case and serial cue case formats alone did not affect students’ knowledge gain or diagnostic accuracy. Students with lower knowledge experienced increased cognitive load and appear to have learned less from their interaction with virtual patients. Cognitive load should be taken into account when attempting to help students learn clinical reasoning with virtual patients, especially for students with lower knowledge.

Study design A retrospective review of the Scoliosis Research Society (SRS) morbidity and mortality (M&M) database. Objective The aim of this study was to investigate visual related complications in spinal deformity patients undergoing spine surgery. Summary of background data The SRS compiles surgeon-reported complications into an M&M database, tracking postoperative complications including visual loss, neurological deficits, infections, and death. Limited literature exists on postoperative visual complications, a rare but devastating complication following spine surgery. Methods We utilized the SRS M&M database to determine demographics, perioperative risk factors, and prognosis for visual related complications in spinal deformity patients undergoing corrective spine surgery from 2009 to 2012. Results A total of 167,972 spinal deformity patients from 2009 to 2012 were identified with a visual acuity complication (VAC) rate of 0.01%, or 12.5 per 100,000 patients. VAC rates for patients with kyphosis were significantly higher than patients with scoliosis (0.049% vs. 0.010%, P = 0.002) and spondylolisthesis (0.049% vs. 0.005%, P = 0.001). Postoperative visual loss rates significantly decreased from 2010 to 2012 (0.022% vs. 0.004%, P = 0.029). Twenty-one patients identified with VACs had a mean age of 34.8 ± 24.3 years. Two (9.5%) patients had preoperative vision changes, two (9.5%) were diabetic, two (9.5%) had vascular disease, one (4.8%) had a history of thromboembolic disease, and five (23.8%) had hypertension. Extent of VAC was bilateral-partial in four (19.0%), bilateral-total in five (23.8%), unilateral-partial in eight (38.1%), and unilateral-total in three (14.3%) patients. Four (19.0%) patients developed anterior ischemic optic neuropathy, four (19.0%) had posterior ischemic optic neuropathy (PION), five (23.8%) had central retinal artery occlusion, and five (23.8%) developed cortical blindness (CB). Greater than 50% of the VACs occurred on, or before, the first postoperative day. Ten (47.6%) patients recovered complete vision and four (19.0%) improved. All patients with CB and 50% with posterior ischemic optic neuropathy experienced complete resolution. Conclusion VACs occur in approximately 12.5 per 100,000 deformity patients, with a rate five times higher in patients with kyphosis. More than 50% of these complications occur within 24 hours postoperatively. Nearly half of these complications resolve completely, and another 19% improve postoperatively. Level of evidence 4.

Intensive pain rehabilitation programs are effective in increasing functioning for youth with chronic pain (CP). However, the utility of such programs for youth with CP and co-morbid postural orthostatic tachycardia syndrome (POTS) is rarely examined. In addition, studies examining mediators of treatment for CP are sparse. This paper compares treatment outcomes for youth with CP (n = 117) and youth with CP + POTS (n = 118). Additionally, depression and pain catastrophizing were tested as potential mediators of treatment effects. Significant treatment improvements were found for functional disability, depression, pain catastrophizing, and perceived pain intensity but with no differences between groups. Improvements in depressed mood, pain catastrophizing (helplessness subscale), and pain severity partially mediated functioning improvement. Pain severity was not a significant mediator in the CP + POTS group. We concluded that depression and pain catastrophizing, especially the helplessness domain, can impact functioning improvement in adolescents with CP and POTS and are particularly important to target in treatment.

Endoparasitism is a common disease in dogs throughout their lifetime despite the widespread availability of inexpensive diagnostic tests and effective treatments. The consequences of host parasite interactions in otherwise apparently healthy dogs remains largely unknown. This cross-sectional study used complete blood count, serum biochemistry, and fecal flotation data collected from 3,018 young dogs (P = 0.004), lower RBC count (P = 0.01), higher neutrophil count (P = 0.002), and higher platelet count (P <0.001) as compared to parasite negative dogs. It was also concluded that dogs living in rural areas were more likely to have endoparasites than those living in suburban areas. Epidemiological data is crucial for the design and monitoring of prevention and control strategies. Identification of endoparasites by fecal testing is an essential tool to identify susceptible and resistant animals that can act as spreaders and reservoirs of intestinal parasites thereby enabling appropriate therapy and reducing the risk of new infection to animals and humans. Further epidemiological studies are needed to prevent, monitor, and develop new strategies to control endoparasites.

We found a positive relationship between bone density in Nigerian children with and without rickets and that of their mothers. After treatment, children with rickets had greater bone density than children without rickets, indicating that children genetically programmed to have greater bone density may have a higher risk of rickets.To determine the relationship between bone density in children with and without rickets and that of their mothers METHODS: Using an unmatched case-control design, forearm areal bone mineral density (aBMD) was measured in 52 and 135 Nigerian children with and without rickets and their mothers, respectively. We performed multivariate linear regression analyses to assess the relationship between maternal and child aBMD Z-scores.Forearm aBMD Z-scores in children were associated with maternal aBMD Z-scores at metaphyseal (effect estimate 0.23; 95% CI 0.08 to 0.37) and diaphyseal (effect estimate 0.16; 0.01 to 0.30) sites, after adjustment for rickets in the child, child's age and sex, height-for-age Z-score, and weight-for-age Z-score. In the adjusted model, rickets was inversely associated with child's aBMD Z-score at the diaphyseal site only (- 0.45, - 0.65 to - 0.24). The positive relationship between maternal and child aBMD Z-scores was marginally greater in children with rickets (slope 0.56, r = 0.47) than without rickets (slope 0.19, r = 0.20) at the diaphyseal site only (P = 0.06 for interaction) but not at the metaphyseal site (slopes 0.35 and 0.30, respectively, P = 0.48). After treatment with calcium for 6 months, metaphyseal aBMD Z-scores were greater in children with treated rickets (effect estimate 0.26; 95% CI 0.02 to 0.49) than in those without rickets.In Nigerian children with and without rickets, forearm aBMD Z-scores were positively associated with maternal aBMD Z-scores. Active rickets in the child marginally modified the relationship at the diaphyseal site only. After treatment, children with rickets had greater metaphyseal aBMD Z-scores than children without rickets.

Background Spinopelvic fixation is an integral part of achieving solid fusion across the lumbosacral junction, especially in deformity procedures requiring substantial correction or long-segment constructs. Traditional S2-alar-iliac (S2AI) screw-placement techniques utilize fluoroscopy, increasing operative time and radiation exposure to the patient and surgeon. We describe a novel free-hand technique for S2AI screw placement in patients with adult spinal deformity. Methods We reviewed the records of 45 consecutive patients who underwent spinopelvic fixation performed with use of S2AI screws by the senior surgeon and various fellows or residents over a 12-month period (2015 to 2016). In each case, the S2AI screws were placed utilizing a free-hand technique without fluoroscopic or image guidance. Screw position and accuracy were assessed by intraoperative O-arm imaging and analyzed using 3-dimensional interactive manipulation of computed tomography images. Results A total of 100 screws were placed, 51 by the senior surgeon and 49 by trainees. The mean patient age was 57.4 ± 12.7 years at the time of surgery; 37 (82.2%) of the patients were female. Preoperative diagnoses included adult idiopathic scoliosis (n = 19), adult degenerative scoliosis (n = 15), flatback syndrome (n = 2), fixed sagittal imbalance (n = 6), and distal junctional kyphosis (n = 3). Five (5%) of the screws were placed with moderate to severe cortical breaches, all of which perforated the pelvis posteriorly, with no clinically notable neurovascular or visceral complications. The breach rate did not differ significantly between the senior surgeon and trainees. Conclusions The free-hand technique for S2AI screw placement, when performed in a standardized manner, was demonstrated to be safe and reliable in constructs requiring spinopelvic fixation. The accuracy of screw placement relies on visible and palpable anatomic landmarks that obviate the need for intraoperative fluoroscopy or image guidance, potentially reducing operative time and radiation exposure. Level of evidence Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Background Combination of selumetinib plus docetaxel provided clinical benefit in a previous phase II trial for patients with KRAS-mutant advanced non-small-cell lung cancer (NSCLC). The phase II SELECT-2 trial investigated safety and efficacy of selumetinib plus docetaxel for patients with advanced or metastatic NSCLC. Patients and methods Patients who had disease progression after first-line anti-cancer therapy were randomized (2 : 2 : 1) to selumetinib 75 mg b.i.d. plus docetaxel 60 or 75 mg/m2 (SEL + DOC 60; SEL + DOC 75), or placebo plus docetaxel 75 mg/m2 (PBO + DOC 75). Patients were initially enrolled independently of KRAS mutation status, but the protocol was amended to include only patients with centrally confirmed KRAS wild-type NSCLC. Primary end point was progression-free survival (PFS; RECIST 1.1); statistical analyses compared each selumetinib group with PBO + DOC 75 for KRAS wild-type and overall (KRAS mutant or wild-type) populations. Results A total of 212 patients were randomized; 69% were KRAS wild-type. There were no statistically significant improvements in PFS or overall survival for overall or KRAS wild-type populations in either selumetinib group compared with PBO + DOC 75. Overall population median PFS for SEL + DOC 60, SEL + DOC 75 compared with PBO + DOC 75 was 3.0, 4.2, and 4.3 months, HRs: 1.12 (90% CI: 0.8, 1.61) and 0.92 (90% CI: 0.65, 1.31), respectively. In the overall population, a higher objective response rate (ORR; investigator assessed) was observed for SEL + DOC 75 (33%) compared with PBO + DOC 75 (14%); odds ratio: 3.26 (90% CI: 1.47, 7.95). Overall the tolerability profile of SEL + DOC was consistent with historical data, without new or unexpected safety concerns identified. Conclusion The primary end point (PFS) was not met. The higher ORR with SEL + DOC 75 did not translate into prolonged PFS for the overall or KRAS wild-type patient populations. No clinical benefit was observed with SEL + DOC in KRAS wild-type patients compared with docetaxel alone. No unexpected safety concerns were reported. Trial identifier Clinicaltrials.gov NCT01750281.

Background: Delayed study progress in medical school is a challenging issue for the tax paying community, the faculty and the medical students themselves. Reasons for a delay might be different from known risk factors for academic difficulties. Methods: An online survey regarding delays in the study progress and including a personality test (BFI-10) was presented to medical students from four German medical schools after completion of their 3rd year of study. Results: Of 617 students, 51.2% reported a mean delay of 2.1 ± 1.5 semesters. Frequent risk factors were secondary employment (69.5%, odds ratio (OR) 1.7, p = 0.004), female gender (69.8%, OR 1.6, p = 0.007), work or study abroad (35.9%, OR 1.5, p = 0.02), a late graduation (5.9%, OR 2.4, p = 0.02), as well as support through scholarship or mentoring (19.9%, OR 1.8, p = 0.004). “Working on doctoral thesis” (11.3%, OR 1.9, p = 0.03) and structural curricular issues (36.6%, OR 0.9, p = 0.7) were frequently identified as obstacles. “Support by friends/family” was considered helpful by 24.1% (OR 1.4, p = 0.09), as well as a high intrinsic motivation (19.1%, OR 0.5, p = 0.01). In the BFI-10, students with study delay were more prone to openness and agreeableness. Conclusions: Risk factors for delay are not identical to those for academic difficulties. To decrease the risk for delays, firm curricular structures should be identified and alleviated. Intrinsic motivation is a strong impetus of study progress and additionally might be strengthened by curricular changes.

Background Memory impairment (MI) is a common symptom of MS. Previous studies were conflicting in respect to the possible existence of early MI and the role of hippocampal atrophy. The objective of this study was to investigate MI and structural MRI correlates in homogenous groups of early and late MS, controlling for a potential information-processing speed (IPS) deficit, and utilizing multiple memory test paradigms. Methods 152 individually matched subjects were recruited: early MS (EMS, N = 25, disease duration 1.0 ± 0.8 years), late MS (LMS, N = 52, 16.5 ± 5.2 years), and corresponding controls. Five memory tests were utilized to account for differences in learning material (verbal, visual), encoding (incidental, intentional), and retrieval (free recall, recognition, recurring recognition). Performance was related to IPS, memory-specific (hippocampal volumes), and unspecific MRI measures (T1/T2LL, brain volume, cortical thickness). Results Memory was impaired across all tests in LMS, but not in EMS. LMS-patients were also significantly impaired in IPS which was correlated with several memory scores. Regression analyses revealed IPS and cortical thickness as predictors for visual MI, and IPS, sex, and left hippocampal volume as predictors for verbal MI. Conclusion Additionally to direct destructions in memory specific tracts such as the hippocampus, memory decline in MS may also be related to a general factor comprising slowed information-processing and global tissue loss.

INTRODUCTION A recent U-2 fatigue study, in which 10 subjects completed 2 simulated long-duration missions breathing either 100% oxygen or air in a hypobaric chamber, offered an opportunity to compare subjects' pulmonary function before and after remaining seated in a confined cockpit for 12 h. METHODS In one U-2 mission configuration, the subject wore a full pressure suit and breathed aviator's breathing oxygen while chamber pressure was maintained at 4572 m (15,000 ft) above mean sea level. In the second mission configuration, subjects wore standard aircrew flight equipment and breathed air while chamber pressure was maintained at 2438 m (8000 ft) above mean sea level. Subjects' pulmonary function was assessed before and after the mission using four metrics: forced vital capacity, forced expiratory volume in 1 s, peak expiratory flow, and forced expiratory volume in 1 s/forced vital capacity ratio. RESULTS Subjects showed significant declines for all four pulmonary metrics (2.7%, 6.4%, 13.9%, and 3.5%, respectively) after 12 h seated in the cockpit in both full pressure suit and aircrew flight equipment conditions. DISCUSSION While the declines at both altitudes amounted to modest percentages of subjects' total pulmonary capacities, they emerged after a single, acute sedentary exposure and appear to be unrelated to the percentage of oxygen in the breathing gas. This might have operational implications in confined mission environments where physiological demands are interspersed with long periods of inactivity.Beer J, Dart TS, Fischer J, Kisner J. Pulmonary effects from a simulated long-duration mission in a confined cockpit. Aerosp Med Hum Perform. 2017; 88(10):952-957.

Females demonstrate less robust Frank-Starling mechanism with respect to cardiac preload than males at rest. We asked whether this phenomenon would also affect cardiac performance during exercise. We hypothesized that stroke volume (SV) response to exercise would be more limited in deconditioned females such that cardiac output would be mainly rate dependent, compared with males. We conducted a chart audit of clinical exercise tests performed by adolescents with chronic fatigue. Oxygen uptake (V˙O2) was measured breath-by-breath at rest and during cycle ergometry, while cardiac output was measured by acetylene rebreathing at rest plus 2-3 subthreshold workloads. SV response was analyzed in two ways: after normalization for body surface area (SV index, SVI) and as percentage change from resting values. Among 304 adolescents (78% females) with chronic fatigue, 189 (80%) of 236 females and 52 (76%) of 68 males were deconditioned (peakV˙O2

To compare free text (FTR) and structured reports (SR) of videofluoroscopic swallowing studies (VFSS) and evaluate satisfaction of referring otolaryngologists and speech therapists. Both standard FTR and SR of 26 patients with VFSS were acquired. A dedicated template focusing on oropharyngeal phases was created for SR using online software with clickable decision-trees and concomitant generation of semantically structured reports. All reports were evaluated regarding overall quality and content, information extraction and clinical decision support (10-point Likert scale (0 = I completely disagree, 10 = I completely agree)). Two otorhinolaryngologists and two speech therapists evaluated FTR and SR. SR received better ratings than FTR in all items. SR were perceived to contain more details on the swallowing phases (median rating: 10 vs. 5; P < 0.001), penetration and aspiration (10 vs. 5; P < 0.001) and facilitated information extraction compared to FTR (10 vs. 4; P < 0.001). Overall quality was rated significantly higher in SR than FTR (P < 0.001). SR of VFSS provide more detailed information and facilitate information extraction. SR better assist in clinical decision-making, might enhance the quality of the report and, thus, are recommended for the evaluation of VFSS. • Structured reports on videofluoroscopic exams of deglutition lead to improved report quality. • Information extraction is facilitated when using structured reports based on decision trees. • Template-based reports add more value to clinical decision-making than free text reports. • Structured reports receive better ratings by speech therapists and otolaryngologists. • Structured reports on videofluoroscopic exams may improve the comparability between exams.

Background Hypoxia continues to present risks in military aviation. Hypoxia symptoms include sensory and cognitive effects; of these, it is important to identify which components of operator performance are most vulnerable to hypoxia-induced decline in order to determine which sensory modality is most effective for alerting an impaired aviator of an imminent hypoxic episode. Methods A study was performed in a hypobaric chamber to characterize deterioration of cognitive performance under moderate (MH) and severe (SH) hypoxia conditions, culminating in subjects' inability to perform tasks. Subjects operated a synthetic workstation, performing multiple simultaneous tasks during hypobaric exposures equivalent to 5486 m (18,000 ft) MH and 7620 m (25,000 ft) SH ascents. Performance was compared across baseline, altitude exposure, and recovery periods within MH vs. SH altitude profiles. Ascents lasted until at least one of a list of termination criteria was met, at which point the chamber was returned to ground level pressure and the subject resumed workstation performance during recovery. Results SH conditions generated greater deficits than MH conditions, and these more severe effects hastened the termination of exposures (5 vs. 18 min mean duration, respectively). Workstation performance collapsed rapidly on SH exposure, with Mathematics and Auditory Monitoring tasks proving vulnerable to breakdown. In MH exposures, these tasks exhibited impaired accuracy (declining 11% and 9%, respectively) and speed, with declines in Auditory Monitoring lingering into recovery. Discussion The relative robustness of memory and visual monitoring vs. the vulnerability of mathematical and auditory processing suggest that care should be taken designing purely auditory cockpit hypoxia warning alerts.Beer JMA, Shender BS, Chauvin D, Dart TS, Fischer J. Cognitive deterioration in moderate and severe hypobaric hypoxia conditions. Aerosp Med Hum Perform. 2017; 88(7):617-626.

Enzymes catalyze fundamental biochemical reactions that control cellular and organismal homeostasis. Here we present an approach for de novo biochemical pathway discovery across entire enzyme families using parallel viral transduction in mice and untargeted liquid chromatography-mass spectrometry. Applying this method to the mammalian M20 peptidases uncovers both known pathways of amino acid metabolism as well as a previously unknown CNDP2-regulated pathway for threonyl dipeptide catabolism. Ablation of CNDP2 in mice elevates threonyl dipeptides across multiple tissues, establishing the physiologic relevance of our biochemical assignments. Taken together, these data underscore the utility of parallel in vivo metabolomics for the family-wide discovery of enzymatic pathways. Enzymes catalyze fundamental biochemical reactions that control cellular and organismal homeostasis. Here we present an approach for de novo biochemical pathway discovery across entire enzyme families using parallel viral transduction in mice and untargeted liquid chromatography-mass spectrometry. Applying this method to the mammalian M20 peptidases uncovers known pathways of amino acid metabolism mediated by ACY1 (hydrolysis of N-acetyl amino acids) and CNDP2 (hydrolysis of carnosine). We also uncover a previously unknown CNDP2-regulated pathway for threonyl dipeptide catabolism. Ablation of CNDP2 in mice elevates threonyl dipeptides across multiple tissues, establishing the physiologic relevance of our biochemical assignments. Taken together, these data underscore the utility of parallel in vivo metabolomics for the family-wide discovery of enzymatic pathways.

OBJECTIVE Orthostatic intolerance (OI) and autonomic dysfunction (AD) are common in adolescents and young adults. Patients experience multisystem symptoms including gastrointestinal (GI), postural orthostatic tachycardia syndrome (POTS), orthostatic hypotension (OH), or only symptoms of OI (SOI) without significant findings on 70-degree head-up tilt testing (HUT). We hypothesize that patients with POTS, OH, and SOI show differences in GI symptoms and motility test and that heart rate (HR) changes on HUT predict severity of GI dysmotility. STUDY DESIGN From medical records of patients (

Improvement of health-related quality of life (HRQoL) is a prioritized treatment target in systemic lupus erythematosus (SLE). A retrospective chart review of patients with repeated HRQoL measurements from the outpatient department was conducted in order to better understand which factors drive HRQoL in established SLE. Of particular interest was the association between HRQoL and disease activity.The medical outcomes study short form 36 (SF-36), systemic lupus activity measure (SLAM) and routine clinical data of 169 patients (83% female, mean age 40.3 ± 13 years, disease duration 9.4 ± 7 years) over an average of 7.1 ± 4.2 years were available for analysis by linear mixed modelling. Factors associated with the physical component summary (PCS) and mental component summary (MCS) of the SF-36 were assessed. The proportion of HRQoL which could be explained by the variables was estimated by marginal RAt baseline, SLE patients showed a reduced HRQoL in all subscales of the SF-36 including PCS and MCS with the exception of vitality. A higher PCS over time was significantly associated with concurrent parameters, such as intake of antimalarial drugs, no glucocorticoid use, less fatigue, lower disease activity as well as to the baseline parameters of younger age and higher PCS (mRThe use of antimalarial drugs and no glucocorticoid intake as well as low current disease activity are modifiable factors associated with a better physical HRQoL. The mental component of HRQoL was poorly represented by conventional parameters and not associated with parameters of disease activity in the present study cohort.

BACKGROUND Lumbar herniated nucleus pulposus (HNP) is a common spinal pathology often treated by microscopic lumbar discectomy (MLD), though prior reports have not demonstrated which preoperative MRI factors may contribute to significant clinical improvement after MLD. PURPOSE To analyze the MRI characteristics in patients with HNP that predict meaningful clinical improvement in health-related quality of life scores (HRQoL) after MLD. STUDY DESIGN/SETTING Retrospective clinical and radiological study of patients undergoing MLD for HNP at a single institution over a 2-year period. PATIENT SAMPLE Eighty-eight patients receiving MLD treatment for HNP. OUTCOME MEASURES Cephalocaudal Canal Migration; Canal & HNP Anterior-Posterior (AP) Lengths and Ratio; Canal & HNP Axial Areas and Ratio; Hemi-Canal & Hemi-HNP Axial Areas and Ratio; Disc appearance (black, gray, or mixed); Baseline (BL); and 3-month (3M) postoperative HRQoL scores. METHODS Patients >18 years old who received MLD for HNP with BL and 3M HRQoL scores of PROMIS (Physical Function, Pain Interference, and Pain Intensity), ODI, VAS Back, and VAS Leg scores were included. HNP and spinal canal measurements of cephalocaudal migration, AP length, area, hemi-area, and disc appearance were performed using T2 axial and sagittal MRI. HNP measurements were divided by corresponding canal measurements to calculate AP, Area, and Hemi-Area ratios. Using known minimal clinically important differences (MCID) for each ΔHRQoL score, patients were separated into two groups based on whether they reached MCID (MCID+) or did not reach MCID (MCID–). The MCID for PROMIS pain intensity was calculated using a decision tree. A linear regression illustrated correlations between PROMIS vs ODI and VAS Back/Leg scores. Independent t-tests and chi-squared tests were utilized to investigate significant differences in HNP measurements between the MCID+ and MCID– groups. RESULTS There were 88 MLD patients included in the study (Age=44.6±14.9, 38.6% female). PROMIS pain interference and pain intensity were strongly correlated with ODI and VAS Back/Leg (R≥0.505), and physical function correlated with ODI and VAS Back/Leg (R=−0.349) (all p 116.6 mm2), and Hemi-Area Ratio (>51.8%). MCID+ patients were 2.7 times more likely to have a gray HNP MRI signal than a mixed or black HNP MRI signal in five out of six HRQoL score comparisons (p CONCLUSIONS Patients who met MCID after MLD had larger HNP areas and larger Hemi-HNP Areas than those who did not meet MCID. These patients were also 2.7× more likely to have a gray MRI signal than a mixed or black MRI signal. When accounting for HNP area relative to canal area, patients who met MCID had greater Hemi-HNP canal occupation than patients who did not meet MCID. The results of this study suggest that preoperative MRI parameters can be useful in predicting patient-reported improvement after MLD.

A retrospective cohort study from a single institution.The aim of this study was to assess the thresholds for postoperative opioid consumption, which are predictive of continued long-term opioid dependence.The specific sum total of inpatient opioid consumption as a risk factor for long-term use after transforaminal lumbar interbody fusion (TLIF) has not been previously studied.Charts of patients who underwent a one, two, or three-level primary TLIF between 2014 and 2017 were reviewed. Total morphine milligram equivalents (MME) consumed was tabulated and separated into three categories based on ROC curve analysis of opioid utilization at 6-month follow-up. Multivariate binary regression analysis assessed these MME dosage categories. A further subanalysis grouped patients on the basis of whether they had used opioids preoperatively.One hundred seventy-two patients met the inclusion criteria and were separated into groups who received less than 250 total inpatient MME (44%), between 250 and 500 total inpatient MME (26%), and greater than 500 total inpatient MME (27%). Patients undergoing a TLIF who received250 total MME in the immediate postoperative period had a 3.73 (odds ratio) times smaller probability of requiring opioids at 6-month follow-up [P = 0.027, 95% confidence interval (95% CI) 0.084-0.86]. Patients who received500 total MME had a 4.84 times greater probability (P = 0.002, 95% CI 1.8-13) of requiring opioids at 6-month follow-up. A subanalysis demonstrated individuals with preoperative opioid use who received250 total MME had a 7.09 times smaller probability (P = 0.033, 95% CI 0.023-0.85) of requiring opioids at 6-month follow-up while those who received500 total MME had a 5.43 times greater probability (P = 0.033, 95% CI 1.6-18) of requiring opioids at 6-month follow-up.Exceeding the threshold of 500 total MMEs in the immediate postoperative period after a TLIF is a significant risk factor that predicts continued opioid use at 6-month follow-up, particularly among patients with a history of preoperative opioid utilization.3.

In the current value-based healthcare climate where spine surgery is shifting to the ambulatory setting, factors influencing postop length of stay (LOS) are important to surgeons and hospital administrators. Pre-op patient factors including diagnosis of radiculopathy and myelopathy have yet to be investigated in this context. Operative pts ≥ 18Y with primary diagnoses of cervical myelopathy (M), radiculopathy (R), or myeloradiculopathy (MR) were included and propensity score matched by invasiveness score (Mirza et al.). Top-quartile LOS was defined as extended. M&R patients were compared using Chi2 & independent t-tests. Univariate tests assessed differences in preop patient and surgical data in M&R pts and extended/non-extended LOS. Stepwise regression analysis explored factors predictive of LOS. 718 operative pts (54.5 yrs, 41.1%F, 29.1 kg/m2, mean CCI 1.11) included (177 M, 383 R, and 158 MR). After PSM, 345 patients remained (115 in each diagnosis). 102 patients had E-LOS (Avg: 5.96 days), 41 M patients (mean 7.1 days), 28 R (5.9 days), and 33 MR (4.6 days). Regression showed predictors of E-LOS in R pts (R2 = 0.532, p = 0.043): TS-CL, combined and posterior approach, LIV, UIV, op time, Lactated Ringer’s, postoperative complications. Predictors of E-LOS in M pts (R2 = 0.230, p

ObjectivesWe sought to establish the feasibility of chunking crew resource management (CRM) training into micro-size interventions and to compare different training approaches in the context of micro-learning.DesignWe evaluated whether participants in micro-learning CRM activities achieved learning objectives following training. In a between-subjects design, groups were observed for behaviour during a simulation that was part of a 15-minute modular intervention and tested for recollection afterwards.ParticipantsThe 129 participants recruited for this study were medical students, who already had relevant experience treating patients.InterventionsThe experimental setting involved three 5-minute components: video, simulation, and debriefing. Different groups viewed videos involving different didactic concepts: one group observed a videotaped concrete example of a medical care team applying a CRM tool (example group), and one group observed a videotaped lecture on the same topic (lecture group).Main outcome measuresAll simulations were videotaped and coded in detail for the occurrence of and time spent engaging in team behaviour and medical care. Questionnaires were administered before, immediately after, and two weeks after the intervention. We compared the groups' behaviour during the simulation (team cooperation and medical care), retention of knowledge from the training content, and results of the evaluation.ResultsBoth groups exhibited most of the behaviours included in the content of the instructional videos during the simulations and recollected information 2 weeks later. The example group exhibited significantly more of the training content during the simulation and demonstrated better retention 2 weeks later. Although the example group spent more time on team coordination, there was no difference in the number of executed medical measures.ConclusionDelivering CRM training in chunks of relatively short and highly standardised interventions appears feasible. In this study, the form of didactical presentation caused a difference in learning success between groups: a traditional lecture was outperformed by an instructional video demonstrating a practical example.

STUDY DESIGN Retrospective cohort study. OBJECTIVE To evaluate the ability of patient reported outcome measurement information system (PROMIS) assessments to capture disability related to cervical sagittal alignment and secondarily to compare these findings to legacy outcome measures. SUMMARY OF BACKGROUND DATA PROMIS is a validated patient-reported outcome metric that is increasing in popularity due to its speed of administration relative to legacy metrics. The ability of PROMIS to capture disability from sagittal alignment and baseline health status in patients with neck pain has not been investigated. METHODS Patients presenting with a chief complaint of neck pain from December 2016 to July 2017 were included. Demographics and comorbidities were retrospectively collected. All patients prospectively completed the neck disability index (NDI), EQ-5D, visual analog scale (VAS) neck, VAS arm, PROMIS physical function, PROMIS pain intensity, and PROMIS pain interference metrics. Cervical sagittal alignment parameters were measured on standing X-rays. The correlations between outcome measures, health status indexes, psychiatric diagnoses, and sagittal alignment were analyzed. RESULTS Two hundred twenty-six patients were included. The sample was 58.4% female with a mean age of 55.1 years. In patients with neck pain, PROMIS physical function correlated strongly with the NDI (r = -0.763, P

Between 1998 and 2014, recurrent mortality events were reported in the Dresser's subspecies of the Common Eider ( Somateria mollissima dresseri) on Cape Cod, Massachusetts, US near Wellfleet Harbor. The early die-offs were attributed to parasitism and emaciation, but beginning in 2006 a suite of distinct lesions was observed concomitant with the isolation of a previously unknown RNA virus. This novel pathogen was identified as an orthomyxovirus in the genus Quaranjavirus and was named Wellfleet Bay virus (WFBV). To assess evidence of exposure to this virus in Common Eiders, we conducted a longitudinal study of the prevalence of WFBV antibodies at multiple locations from 2004-14; we collected 2,258 serum samples from six locations and analyzed each using a microneutralization assay. Results corroborate the emergence of WFBV in 2006 based on the first detection of antibodies in that year. Significantly higher prevalence was detected in Common Eiders sampled in Massachusetts compared to those in Maine, Nova Scotia, and Québec. For birds breeding and wintering in Massachusetss, viral exposure varied by age, sex, and season of sampling, and prevalence by season and sex were highly interrelated with greater numbers of antibody-positive males in the autumn and females in the spring. No evidence of viral exposure was detected in the Northern subspecies ( Somateria mollissima borealis). Among the locations sampled, Massachusetts appears to be the epicenter of Common Eider exposure to WFBV. Further research is warranted to understand the factors controlling the epidemiology of WFBV in Massachussetts, including those that may be limiting geographic expansion of this virus.

Adolescents with postural orthostatic tachycardia syndrome (POTS) often have pain and functional impairment. This study evaluated how parental attributions of children’s symptoms relate to child functional impairment. Adolescents with chronic pain and clinical symptoms suggestive of autonomic dysfunction (fatigue, dizziness, nausea) that attended a multidisciplinary chronic pain clinic completed measures of depression, anxiety, and functioning (n = 141). Parents of 114 of these patients completed the Parent Pain Attribution Questionnaire (PPAQ), a measure indicating the extent they believe physical and psychosocial factors account for their child’s health condition. Patients were retrospectively grouped as to whether or not they had significant POTS on tilt table testing (n = 37). Greater parental attribution to physical causes was associated with increased levels of functional disability whether patients had POTS ( r = 0.45, P = .006) or not ( r = 0.25, P = .03). These results suggest that providers should advocate a more comprehensive family-oriented rehabilitative approach to treatment.

BACKGROUND Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. PATIENTS AND METHODS Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). RESULTS Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682). CONCLUSION PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. CLINICAL TRIAL INFORMATION NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).

Significant functional impairment and psychological distress have been observed in adolescent patients with postural orthostatic tachycardia syndrome (POTS). Interdisciplinary rehabilitation programs have been shown to be beneficial in the treatment of chronic pain in adults and adolescents. Only preliminary data have examined interdisciplinary rehabilitation efforts in patients with POTS. This study evaluated the impact of an interdisciplinary rehabilitation program on the functional impairment and psychological distress in 33 adolescents diagnosed with POTS. Patients included in the study were adolescents ages 11 to 18 diagnosed with POTS. Measures completed at admission and discharge from the program included the Functional Disability Index, Center for Epidemiological Studies-Depression-Child scale, and the Pain Catastrophizing Scale for Children. After participation in the 3-week program, adolescents with POTS demonstrated a significant increase in overall functional ability and significant reductions in depression and catastrophizing.

The effects of low-grade hypoxia on cognitive function are reported in this paper. The study compared cognitive function during short exposures at four different altitudes.Ninety-one subjects were exposed to simulated altitudes of ground level, 1524, 2438, and 3658 m (5000, 8000, and 12,000 ft) in the Brooks City-Base altitude pressure chamber in a balanced design. Oxygen saturation, heart rate, and cognitive performance on seven different cognitive tasks were measured. In addition, subjects indicated their symptoms from a 33-item subjective symptom survey.As designed, oxygen saturation decreased and heart rate increased with higher altitudes. Very small degradations in performance were found at the two highest altitudes for only two of the cognitive tasks (continuous performance and grammatical reasoning). In the subjective symptom survey, 18 of the 33 possible symptoms were more common at 3658 m (12,000 ft) than at ground level.The findings indicated a minimal influence of low-grade hypoxia on cognitive performance in contrast to some existing classic symptoms of hypoxia. Pilmanis AA, Balldin UI, Fischer JR. Cognition effects of low-grade hypoxia. Aerosp Med Hum Perform. 2016; 87(7):596-603.

To determine the clinical course of adolescent-onset postural orthostatic tachycardia syndrome (POTS) and to assess health-related quality of life, 2-10 years after diagnosis.Pediatric patients, 13-18 years of age, diagnosed with POTS at Mayo Clinic, Rochester, from 2003 to 2010 were mailed a questionnaire if they were at least 18 years of age at the time of the mailing. The primary outcome measures were norm-based, age- and sex-adjusted, 36-Item Short Form Health Survey physical composite score and mental composite score.The survey was mailed to 502 patients with a response rate of 34% (n = 172). The mean duration from diagnosis to survey completion was 5.4 (SD, 1.9) years; the mean age of the respondents at the time of the survey was 21.8 (2.2) years. The responders were predominantly females (84% vs 68% of nonresponders; P .001). Only 33 (19%) respondents reported complete resolution of symptoms, and an additional 51% reported persistent but improved symptoms, and 28 (16%) had only intermittent symptoms. The majority (71%) consider their health at least "good." The mean physical composite score was significantly lower than the population norm (mean [SD], 36.6 [15.8] vs 50; P .001), however, the corresponding mean mental composite score was normal (50.1 [11.2]).Overall, 86% of adolescents with POTS report resolved, improved, or just intermittent symptoms, when assessed via questionnaire at an average of 5 years after initial treatment. Patients with persistent symptoms have more physical than mental health concerns.