Perinatal Azithromycin Provides Limited Neuroprotection in an Ovine Model of Neonatal Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Hypoxic-ischemic brain injury/encephalopathy affects about 1.15 million neonates per year, 96% of whom are born in low- and middle-income countries. Therapeutic hypothermia is not effective in this setting, possibly because injury occurs significantly before birth. Here, we studied the pharmacokinetics, safety, and efficacy of perinatal azithromycin administration in near-term lambs following global ischemic injury to support earlier treatment approaches. METHODS: Ewes and their lambs of both sexes (n=34, 141-143 days) were randomly assigned to receive azithromycin or placebo before delivery as well as postnatally. Lambs were subjected to severe global hypoxia-ischemia utilizing an acute umbilical cord occlusion model. Outcomes were assessed over a 6-day period. RESULTS: While maternal azithromycin exhibited relatively low placental transfer, azithromycin-treated lambs recovered spontaneous circulation faster following the initiation of cardiopulmonary resuscitation and were extubated sooner. Additionally, peri- and postnatal azithromycin administration was well tolerated, demonstrating a 77-hour plasma elimination half-life, as well as significant accumulation in the brain and other tissues. Azithromycin administration resulted in a systemic immunomodulatory effect, demonstrated by reductions in proinflammatory IL-6 (interleukin-6) levels. Treated lambs exhibited a trend toward improved neurodevelopmental outcomes while histological analysis revealed that azithromycin supported white matter preservation and attenuated inflammation in the cingulate and parasagittal cortex. CONCLUSIONS: Perinatal azithromycin administration enhances neonatal resuscitation, attenuates neuroinflammation, and supports limited improvement of select histological outcomes in an ovine model of hypoxic-ischemic brain injury/encephalopathy.

Grit: what is it and why does it matter in medicine?

Grit refers to the combination of passion and perseverance for long-term goals. Grit has emerged as a recent topic of interest within the medical community. With ever-increasing rates of burnout and psychological distress, increasing attention has been directed towards modulatory or protective factors for these deleterious outcomes. Grit has been studied in regard to a variety of outcomes and variables in medicine. This article reviews the current literature on grit in medicine and summarises the current research on grit and performance metrics, personality characteristics, longitudinal progression, psychological well-being, diversity, equity and inclusion, burnout and residency attrition. While there is inconclusive evidence on the influence of grit on performance metrics in medicine, research consistently demonstrates a positive correlation between grit and psychological well-being and a negative correlation between grit and burnout. After discussing some of the inherent limitations of this type of research, this article suggests some possible implications and future areas for research and their potential role in cultivating psychologically healthy physicians and promoting successful careers in medicine.

Grit: what is it and why does it matter in medicine?

Grit refers to the combination of passion and perseverance for long-term goals. Grit has emerged as a recent topic of interest within the medical community. With ever-increasing rates of burnout and psychological distress, increasing attention has been directed towards modulatory or protective factors for these deleterious outcomes. Grit has been studied in regard to a variety of outcomes and variables in medicine. This article reviews the current literature on grit in medicine and summarises the current research on grit and performance metrics, personality characteristics, longitudinal progression, psychological well-being, diversity, equity and inclusion, burnout and residency attrition. While there is inconclusive evidence on the influence of grit on performance metrics in medicine, research consistently demonstrates a positive correlation between grit and psychological well-being and a negative correlation between grit and burnout. After discussing some of the inherent limitations of this type of research, this article suggests some possible implications and future areas for research and their potential role in cultivating psychologically healthy physicians and promoting successful careers in medicine.

Investigating the Association between Aortic Arch Variants and Intracranial Aneurysms.

BACKGROUND: There is an association between anterior cerebral artery vessel asymmetry and anterior communicating artery aneurysm, presumably based on flow dynamics. The purpose of this study is to investigate the potential relationship between aortic arch branching patterns and incidence of intracranial aneurysm. METHODS: This study included patients scanned over 1 year at our tertiary care center who underwent high-resolution imaging (computed tomography angiography or digital subtracted angiogram) of the head and neck arteries, aortic arch, and superior mediastinum. Exclusion criteria included patients with suboptimal images. Patient age, gender, aortic arch branching pattern, and the presence, location, and number of aneurysms were documented. RESULTS: Among the 1082 patients analyzed, 250 (23%) patients had a variant aortic arch branching pattern, 22 (8.8%) of whom had aneurysms. There were 104 patients with 126 aneurysms, with majority of patients with normal aortic arch branching pattern (n = 82, 79%). The most common variant was a common origin of the left common carotid artery and brachiocephalic trunk with or without direct origin of the left vertebral artery. Twenty-two patients with aneurysms had an aberrant aortic arch (21%), compared to 232 patients without an aneurysm (24%). Fischer exact test showed no statistically significant difference between the incidence of aneurysm with different aortic arch variant groups (two-tailed p-value = 0.715). CONCLUSION: To our knowledge, this is the first study to examine the association between aortic arch branching patterns and incidence of intracranial aneurysm. No significant association was found between aortic arch branching pattern and the incidence of intracranial aneurysm.

Coordination and Pilot Implementation of a Standardized Data Collection for Touching Hands.

PURPOSE: Touching Hands is an American Society for Surgery of the Hand program that provides hand surgeries to the world's underserved communities. The purpose of this study was to develop and implement a systematic data collection method for Touching Hands to assess patient outcomes, volunteer impact, alleviated disease burden, and cost-effectiveness. METHODS: Research electronic data capture (REDCap) was used as the secure software platform to facilitate data collection. The Quick Disabilities of the Arm, Shoulder and Hand questionnaire was used to assess pre-and postoperative patient-reported outcomes. The Maslach Burnout Inventory-Human Services (Medical Personnel) survey was administered to volunteers before and after the mission to measure impact on volunteers. Case information was collected to calculate disability-adjusted life years and cost-effectiveness. RESULTS: The data collection system was implemented in some capacity in 4 domestic and 3 international mission sites during 2020 and 2021. CONCLUSIONS: Substantial limitations exist for the implementation of a systematic data collection framework for Touching Hands and warrant further modification and optimization. CLINICAL RELEVANCE: A REDCap database can be used for standardized and centralized patient and volunteer data collection for Touching Hands missions.

Feasibility of deconvolution-based multiphase CT angiography perfusion maps in acute ischemic stroke: Simulation and concordance with CT perfusion.

OBJECTIVES: Integration of CT perfusion (CTP) with requisite non-contrast CT and CT angiography (CTA) stroke imaging may allow efficient stroke lesion volume measurement. Using surrogate images from CTP, we simulated the feasibility of using multiphase CTA (mCTA) to generate perfusion maps and assess target mismatch profiles. MATERIALS AND METHODS: Patients with acute ischemic stroke who received admission CTP were included in this study. Four CTP images (surrogate mCTA, one pre-contrast and three post-contrast, starting at the arterial peak then at 8 s intervals) were selected according to the CTP arterial time-density curve to simulate non-contrast CT and mCTA images. Cerebral blood flow (CBF) and Tmax maps were calculated using the same model-based deconvolution algorithm for the standard CTP and surrogate mCTA studies. Infarct and penumbra were delineated with CBF < 20% and Tmax > 6 s threshold, respectively. Classification accuracy of surrogate mCTA target mismatch (infarct <70 ml; penumbra ≥15 ml; mismatch ratio ≥1.8) with respect to standard CTP was assessed. Agreement between infarct and penumbra volumes from standard CTP and surrogate mCTA maps were evaluated by Bland-Altman analysis. RESULTS: Of 34 included patients, 28 had target mismatch and 6 did not by standard CTP. Accuracy of classifying target mismatch profiles with surrogate mCTA was 79% with respect to that from standard CTP. Mean  ±  standard deviation of differences (standard CTP minus surrogate mCTA) of infarct and penumbra volumes were 9.8 ± 14.8 ml and 20.1 ± 45.4 ml, respectively. CONCLUSIONS: Surrogate mCTA ischemic lesion volumes agreed with those from standard CTP and may be an efficient alternative when CTP is not practical.

Ultra-High Field 7-Tesla Magnetic Resonance Imaging and Electroencephalography Findings in Epilepsy.

PURPOSE: Assessment of patients for temporal lobe epilepsy (TLE) surgery requires multimodality input, including EEG recordings to ensure optimal surgical planning. Often EEG demonstrates abnormal foci not detected on 1.5T MRI. Ultra-high field MRI at 7T provides improved resolution of the brain. We investigated the utility of 7T MRI to detect potential anatomical abnormalities associated with EEG changes. METHODS: Ultra-high field data were acquired on a 7T MRI scanner for 13 patients with history of drug resistant TLE who had had EEG telemetry recordings. Qualitative evaluation of 7T imaging for presence of focal abnormalities detected on EEG was performed. Correlation of 7T MRI findings with EEG recordings of focal slowing or interictal epileptic spikes (IEDs), and seizures was performed. RESULTS: Assessment of 7T MRI demonstrated concordance with TLE as determined by the multidisciplinary team in 61.5% of cases (n = 8). Among these, 3 patients exhibited supportive abnormal 7T MRI abnormalities not detected by 1.5T MRI. In patients who underwent surgery, 72.7% had concordant histopathology findings with 7T MRI findings (n = 8). However, qualitative assessment of 7T images revealed focal anatomical abnormalities to account for EEG findings in only 15.4% of patients (n = 2). Other regions that were found to have localized IEDs in addition to the lesional temporal lobe, included the contralateral temporal lobe (n = 5), frontal lobe (n = 3), and parieto-occipital lobe (n = 2). CONCLUSION: Ultra-high field 7T MRI findings show concordance with clinical data. However, 7T MRI did not reveal anatomical findings to account for abnormalities detected by EEG.

BOOSTED NONPARAMETRIC HAZARDS WITH TIME-DEPENDENT COVARIATES.

Given functional data from a survival process with time-dependent covariates, we derive a smooth convex representation for its nonparametric log-likelihood functional and obtain its functional gradient. From this we devise a generic gradient boosting procedure for estimating the hazard function nonparametrically. An illustrative implementation of the procedure using regression trees is described to show how to recover the unknown hazard. The generic estimator is consistent if the model is correctly specified; alternatively an oracle inequality can be demonstrated for tree-based models. To avoid overfitting, boosting employs several regularization devices. One of them is step-size restriction, but the rationale for this is somewhat mysterious from the viewpoint of consistency. Our work brings some clarity to this issue by revealing that step-size restriction is a mechanism for preventing the curvature of the risk from derailing convergence.

Is Grit Associated with Burnout and Well-being in Orthopaedic Resident and Faculty Physicians? A Multi-institution Longitudinal Study Across Training Levels.

BACKGROUND: Grit has been defined as "perseverance and passion for long-term goals" and is characterized by maintaining focus and motivation toward a challenging ambition despite setbacks. There are limited data on the impact of grit on burnout and psychologic well-being in orthopaedic surgery, as well as on which factors may be associated with these variables. QUESTIONS/PURPOSES: (1) Is grit inversely correlated with burnout in orthopaedic resident and faculty physicians? (2) Is grit positively correlated with psychologic well-being in orthopaedic resident and faculty physicians? (3) Which demographic characteristics are associated with grit in orthopaedic resident and faculty physicians? (4) Which demographic characteristics are associated with burnout and psychologic well-being in orthopaedic resident and faculty physicians? METHODS: This study was an institutional review board-approved interim analysis from the first year of a 5-year longitudinal study of grit, burnout, and psychologic well-being in order to assess baseline relationships between these variables before analyzing how they may change over time. Orthopaedic residents, fellows, and faculty from 14 academic medical centers were enrolled, and 30% (335 of 1129) responded. We analyzed for the potential of response bias and found no important differences between sites in low versus high response rates, nor between early and late responders. Participants completed an email-based survey consisting of the Duckworth Short Grit Scale, Maslach Burnout Inventory-Human Services (Medical Personnel) Survey, and Dupuy Psychological Well-being Index. The Short Grit Scale has been validated with regard to internal consistency, consensual and predictive validity, and test-retest stability. The Psychological Well-being Index has similarly been validated with regard to reliability, test-retest stability, and internal consistency, and the Maslach Burnout Inventory has been validated with regard to internal consistency, reliability, test-retest stability, and convergent validity. The survey also obtained basic demographic information such as survey participants' age, gender, race, ethnicity, marital status, current year of training or year in practice (as applicable), and region of practice. The studied population consisted of 166 faculty, 150 residents, and 19 fellows. Beyond the expected age differences between sub-populations, the fellow population had a higher proportion of women than the faculty and resident populations did. Pearson correlations and standardized ß coefficients were used to assess the relationships of grit, burnout, psychologic well-being, and continuous participant characteristics. RESULTS: We found moderate, negative relationships between grit and emotional exhaustion (r = -0.30; 95% CI -0.38 to -0.21; p < 0.001), depersonalization (r = -0.34; 95% CI -0.44 to -0.23; p < 0.001), and the overall burnout score (r = -0.39; 95% CI -0.48 to -0.31; p < 0.001). The results also showed a positive correlation between grit and personal accomplishment (r = 0.39; 95% CI 0.29 to 0.48; p < 0.001). We also found a moderate, positive relationship between grit and psychologic well-being (r = 0.39; 95% CI 0.30 to 0.49; p < 0.001). Orthopaedic surgeons with 21 years or more of practice had higher grit scores than physicians with 10 to 20 years of practice. Orthopaedic surgeons in practice for 21 years or more also had lower burnout scores than those in practice for 10 to 20 years. Married physicians had higher psychologic well-being than unmarried physicians did. CONCLUSION: Among orthopaedic residents, fellows, and faculty, grit is inversely related to burnout, with lower scores for emotional exhaustion and depersonalization and higher scores for personal accomplishment as grit increases. CLINICAL RELEVANCE: The results suggest that grit could be targeted as an intervention for reducing burnout and promoting psychologic well-being among orthopaedic surgeons. Other research has suggested that grit is influenced by internal characteristics, life experiences, and the external environment, suggesting that there is potential to increase one's grit. Residency programs and faculty development initiatives might consider measuring grit to assess for the risk of burnout, as well as offering curricula or training to promote this psychologic characteristic.

How to Host A Domestic Hand Surgery Outreach Day.

Domestic outreach is an integral yet often overlooked aspect of medical volunteerism. Since 2016, the American Society for Surgery of the Hand's Touching Hands initiative has supported domestic outreach Hand Days in the United States. The purpose of this article is to provide information and guidance to hand surgeons interested in hosting their own domestic hand surgery outreach. Thorough planning is essential to a successful outreach, particularly because each outreach site will have unique considerations. Surgeon team leaders must navigate the infrastructure and legal factors specific to their practice site. Outreach patients should be screened for both financial and surgical eligibility, although there are multiple pathways for the referral and screening process. Patient evaluation also requires coordination of imaging and diagnostic testing for a low-resource population. Multidisciplinary volunteer teams are necessary to provide all perioperative services and are typically recruited from the host practice site. Some potential challenges of domestic outreach include institutional charity care policies, legal concerns, and operative space availability. Because of complex socioeconomic situations, it may be difficult to contact and coordinate care for outreach patients. Despite these potential barriers, domestic outreach offers tremendous benefit for patients who otherwise lack access to surgical care. Even one yearly outreach day can avert years of disability and can have an incredible impact on patients' functional ability and quality of life. Volunteer teams also reap the benefits of outreach by promoting intraorganizational volunteerism, renewing commitment to medical professionalism, and decreasing symptoms of burnout. Hand surgeons have a unique opportunity to provide subspecialized surgical care to underserved patients as the Touching Hands initiative continues to grow and develop. We hope that hand surgeons will consider participating in advancing the Touching Hands mission to provide life-changing surgical care in the world's poorest communities, including our own.

Symptomatic Radial Neck Nonunion Following Traumatic Impacted Radial Neck Fracture.

PURPOSE: Minimally displaced or impacted radial neck fractures are commonly sustained after elbow trauma, although few require surgical treatment or result in lasting complications. Whereas they are rare, radial neck nonunion after this injury can have adverse implications for patient function and quality of life. The current study presents a case series of 8 radial neck nonunions after minimally displaced or impacted radial neck fractures. METHODS: Using our institution's electronic medical record database, referred to as the Synthetic Derivative database, we performed a retrospective review of all radial neck fractures that presented to our institution over 15 years. RESULTS: Of 472 minimally displaced or impacted radial neck fractures, 8 progressed to symptomatic nonunion. Average age of these patients was 54 ± 9.3 years. One patient presented with bilateral radial neck nonunions. CONCLUSIONS: Nonunion after an impacted radial neck fracture is a rare yet frustrating outcome for patients and providers alike. Our results estimate the rate of symptomatic radial neck nonunion after minimally displaced or impacted radial neck fractures to be 1.7%. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

Identification of a novel synaptic protein, TMTC3, involved in periventricular nodular heterotopia with intellectual disability and epilepsy.

Defects in neuronal migration cause brain malformations, which are associated with intellectual disability (ID) and epilepsy. Using exome sequencing, we identified compound heterozygous variants (p.Arg71His and p. Leu729ThrfsTer6) in TMTC3, encoding transmembrane and tetratricopeptide repeat containing 3, in four siblings with nocturnal seizures and ID. Three of the four siblings have periventricular nodular heterotopia (PVNH), a common brain malformation caused by failure of neurons to migrate from the ventricular zone to the cortex. Expression analysis using patient-derived cells confirmed reduced TMTC3 transcript levels and loss of the TMTC3 protein compared to parental and control cells. As TMTC3 function is currently unexplored in the brain, we gathered support for a neurobiological role for TMTC3 by generating flies with post-mitotic neuron-specific knockdown of the highly conserved Drosophila melanogaster TMTC3 ortholog, CG4050/tmtc3. Neuron-specific knockdown of tmtc3 in flies resulted in increased susceptibility to induced seizures. Importantly, this phenotype was rescued by neuron-specific expression of human TMTC3, suggesting a role for TMTC3 in seizure biology. In addition, we observed co-localization of TMTC3 in the rat brain with vesicular GABA transporter (VGAT), a presynaptic marker for inhibitory synapses. TMTC3 is localized at VGAT positive pre-synaptic terminals and boutons in the rat hypothalamus and piriform cortex, suggesting a role for TMTC3 in the regulation of GABAergic inhibitory synapses. TMTC3 did not co-localize with Vglut2, a presynaptic marker for excitatory neurons. Our data identified TMTC3 as a synaptic protein that is involved in PVNH with ID and epilepsy, in addition to its previously described association with cobblestone lissencephaly.

Percutaneous Ozone Treatment for Herniated Lumbar Discs: 1-Year Follow-up of a Multicenter Pilot Study of a Handheld Disposable Ozone-Generating Device.

PURPOSE: To evaluate the safety and efficacy of oxygen-ozone treatment delivered via a novel, handheld ozone-generating device for improving pain and function in herniated disc patients. MATERIALS AND METHODS: A total of 39 patients with contained herniated lumbar discs received oxygen-ozone treatment at 1 of 3 centers. Treatment consisted of injection of 2% ozone (10 mL): 3 mL delivered into the nucleus pulposus and 7 mL delivered into the adjacent paravertebral tissues. The first 8 patients received only ozone injections, whereas subsequent patients also received periganglionic methylprednisolone (40 mg) and 0.5% bupivacaine (1 mL) injections. Patients were evaluated at baseline and at 1 month, 6 months, and 12 months after treatment using the Oswestry Disability Index (ODI) and the Visual Analogue Scale (VAS) for leg pain and for back pain. Analgesic medication use was also assessed at each timepoint. RESULTS: Overall, 91% (32/35) of the per-protocol patients (those who completed follow-up and did not have significant protocol deviations) showed detectable improvement in ODI at 1-month follow-up; this increased to 93% (26/28) of patients at 12-months follow-up. At 1 month after treatment, 60% (21/35) of patients showed significant improvement in ODI scores (P = .01); 54% (19/35) showed significant improvement in VAS scores for leg pain (P = .05); and 49% (17/35) showed significant improvement in VAS scores for back pain (P = .12). At 6 months after treatment, 67% (22/33) of patients showed significant improvement in ODI scores (P = .02); 64% (21/33) showed significant improvement in VAS scores for leg pain (P = .01); and 52% (17/33) showed significant improvement in VAS scores for back pain (P = .12). At 12 months after treatment, 68% (19/28) of patients showed significant improvement in ODI scores (P < .01); 64% (18/28) showed significant improvement in VAS scores for leg pain (P < .01); and 61% (17/28) showed significant improvement in VAS scores for back pain (P = .09). Leg pain typically subsided more quickly than back pain. Use of analgesic medications also significantly decreased at all follow-up timepoints compared to baseline (P < .01). There were no adverse events or device-related issues. CONCLUSIONS: At 1, 6, and 12 months after treatment, patients experienced significant improvements in pain and function as well as significantly decreased use of analgesic medication. Taken together with the absence of adverse events at 1-year follow-up, these data suggest that oxygen-ozone treatment is a safe and effective therapy for contained herniated discs.

Radiology reporting of low-grade glioma growth underestimates tumor expansion.

BACKGROUND: An important aspect in the management of patients with diffuse low-grade gliomas (LGGs) involves monitoring the lesions via serial magnetic resonance imaging (MRI). However, radiological interpretations of LGG interval scans are often qualitative and thus difficult to use clinically. METHODS: To contextualize these assessments, we retrospectively compared radiological interpretations of LGG growth or stability to volume change measured by manual segmentation. Tumor diameter was also measured in one, two, and three dimensions to evaluate reported methods for assessment of glioma progression, including RECIST criteria, Macdonald/RANO criteria, and mean tumor diameter/ellipsoid method. RESULTS: Tumors evaluated as stable by radiologists grew a median volume of 5.1 mL (11.1%) relative to the comparison scan, and those evaluated as having grown had a median volume increase of 13.3 mL (23.7%). Diameter-based measurements corresponded well but tended to overestimate gold standard segmented volumes. In addition, agreement with segmented volume measurements improved from 17.6 ± 8.0 to 4.5 ± 5.8 to 3.9 ± 3.6 mm for diameter and from 104.0 ± 96.6 to 25.3 ± 36.8 to 15.9 ± 21.3 mL for volume with radiological measurements in one, two, and three dimensions, respectively. Measurement overestimation increased with tumor size. CONCLUSIONS: Given accumulating evidence that LGG volume and growth are prognostic factors, there is a need for objective lesion measurement. Current radiological reporting workflows fail to appreciate and communicate the true expansion of LGGs. While volumetric analysis remains the gold standard for assessment of growth, careful diametric measurements in three dimensions may be an acceptable alternative.

Parvovirus Capsid Structures Required for Infection: Mutations Controlling Receptor Recognition and Protease Cleavages.

Parvovirus capsids are small but complex molecular machines responsible for undertaking many of the steps of cell infection, genome packing, and cell-to-cell as well as host-to-host transfer. The details of parvovirus infection of cells are still not fully understood, but the processes must involve small changes in the capsid structure that allow the endocytosed virus to escape from the endosome, pass through the cell cytoplasm, and deliver the single-stranded DNA (ssDNA) genome to the nucleus, where viral replication occurs. Here, we examine capsid substitutions that eliminate canine parvovirus (CPV) infectivity and identify how those mutations changed the capsid structure or altered interactions with the infectious pathway. Amino acid substitutions on the exterior surface of the capsid (Gly299Lys/Ala300Lys) altered the binding of the capsid to transferrin receptor type 1 (TfR), particularly during virus dissociation from the receptor, but still allowed efficient entry into both feline and canine cells without successful infection. These substitutions likely control specific capsid structural changes resulting from TfR binding required for infection. A second set of changes on the interior surface of the capsid reduced viral infectivity by >100-fold and included two cysteine residues and neighboring residues. One of these substitutions, Cys270Ser, modulates a VP2 cleavage event found in ∼10% of the capsid proteins that also was shown to alter capsid stability. A neighboring substitution, Pro272Lys, significantly reduced capsid assembly, while a Cys273Ser change appeared to alter capsid transport from the nucleus. These mutants reveal additional structural details that explain cell infection processes of parvovirus capsids. IMPORTANCE: Parvoviruses are commonly found in both vertebrate and invertebrate animals and cause widespread disease. They are also being developed as oncolytic therapeutics and as gene therapy vectors. Most functions involved in infection or transduction are mediated by the viral capsid, but the structure-function correlates of the capsids and their constituent proteins are still incompletely understood, especially in relation to identifying capsid processes responsible for infection and release from the cell. Here, we characterize the functional effects of capsid protein mutations that result in the loss of virus infectivity, giving a better understanding of the portions of the capsid that mediate essential steps in successful infection pathways and how they contribute to viral infectivity.

Use of AAScatterPlot tool for monitoring the evolution of the hemagglutinin cleavage site in H9 avian influenza viruses.

MOTIVATION: Viruses rapidly evolve due to their error-prone genome replication, and identifying which mutations are selected for during evolution is critical for virus surveillance efforts. Here we introduce a scatter plot tool (AAScatterPlot) that easily shows the selection and avoidance of certain protein mutations based on biochemical properties. We demonstrate its utility for monitoring the evolution of H9 avian influenza viruses from China between 2005 and 2015, particularly at the hemagglutinin (HA) proteolytic cleavage site (PCS) that can affect virus activation and pathogenicity. RESULTS: Given genome sequences, the AAScatterPlot tool compacts into a single plot, information about the hydropathy index, Van der Waals volume, chemical property and occurrence frequency of amino acid residues. The tool also shows the range of residues that could arise from a single point mutation in the genome, which can then be compared against the observed residues to identify mutation constraints. Through this approach, we found that the 2nd position towards the N-terminus side of the HA PCS (P2 position) avoided hydrophobic residues, whereas the P3 position avoided hydrophilic residues. AVAILABILITY AND IMPLEMENTATION: AAScatterPlot is available at https://github.com/WhittakerLab/AAScatterPlot. CONTACT: gary.whittaker@cornell.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A Helping Hand: The Case for Volunteerism.

Medical professionals are often regarded as influential community figures, yet their actual civic engagement may not match these expectations. Physicians certainly have a commitment to their own patients, but principles of medical ethics and professionalism suggest that physicians are also responsible for treating patients who lack access to care. Physician volunteerism is beneficial for entire communities, but can be particularly transformative for uninsured, underinsured, or geographically isolated patients. Volunteerism also yields countless benefits for physicians themselves, including professional development, skill building, and reduction of burnout. Despite evidence for the positive results of volunteerism, some physicians are discouraged by the time commitments, working conditions, and ethical controversies. Yet for interested physicians, diverse opportunities exist in medical and nonmedical activities and domestic and international areas.

Opioid Use After Upper Extremity Surgery.

Ever since the institution of pain as the fifth vital sign, there has been a rising opioid epidemic in the United States, with Americans now consuming 80% of the global opioid supply while representing only 5% of the world's population. Surgeons are tasked with the duty of both managing patients' pain in the perioperative period and following responsible prescribing behaviors. Several articles have been published with the goal of evaluating opioid use after upper extremity surgery, risk factors for opioid misuse/abuse, the impact of anesthetic type, and the role of multimodal pain management regimens. These studies have found that, on average, surgeons prescribe 2 to 5 times more opioids than patients consume. Multimodal pain management strategies are effective for decreasing postoperative opioid consumption. Risk factors for prolonged opioid use and/or misuse are younger age, history of substance abuse, psychological disorders, and previous pain diagnoses. Use of regional blockade anesthesia, particularly with long-acting agents or indwelling catheters, can be helpful in the management of postoperative pain. This review article summarizes the available literature regarding opioid use after upper extremity surgery to provide the surgeon with additional information to make informed decisions regarding postoperative opioid prescription.

Morphological and Genetic Analysis of Four Color Morphs of Bean Leaf Beetle.

Bean leaf beetle (BLB), Cerotoma trifurcata (Forster; Coleoptera: Chrysomelidae), exhibits considerable color variation but little is known about the underlying genetic structure and gene flow among color phenotypes. Genetic and morphological variation among four color phenotypes-green with spots (G+S), green without spots (G-S), red with spots (R+S) and red without spots (R-S)-were analyzed using amplified fragment length polymorphisms (AFLP) and morphometrics, respectively. AFLP generated 175 markers that showed ≥80% polymorphism. Analysis of molecular variance (AMOVA) indicated that genetic variation was greatest within phenotypes (82.6-84.0%); gene flow among the four phenotypes was relatively high (Nm = 3.82). The dendrogram and STRUCTURE analysis indicated some population divergence of G-S from the other phenotypes. Morphological parameters were similar among phenotypes except that R+S showed significant differences in weight and body-length. Canonical variables 1 and 2, based on average morphometric characters, accounted for 98% of the total variation; some divergence was indicated between G+S and R+S from each other and from the G-S/R-S BLB color morphs. The pattern of genetic variation indicated potential divergence of G-S and G+S from each other and from R-S and R+S. Although these results indicate that the four different color morphs are not genetically or reproductively isolated, there is some genetic differentiation/structure and morphological dissimilarity suggesting weak/incomplete isolation.

Single-Particle Tracking Shows that a Point Mutation in the Carnivore Parvovirus Capsid Switches Binding between Host-Specific Transferrin Receptors.

Determining how viruses infect new hosts via receptor-binding mechanisms is important for understanding virus emergence. We studied the binding kinetics of canine parvovirus (CPV) variants isolated from raccoons-a newly recognized CPV host-to different carnivore transferrin receptors (TfRs) using single-particle tracking. Our data suggest that CPV may utilize adhesion-strengthening mechanisms during TfR binding and that a single mutation in the viral capsid at VP2 position 300 can profoundly alter receptor binding and infectivity.