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Objective: Although peer difficulties and sluggish cognitive tempo (SCT) are related, studies have yet to examine environmental factors that may advance further understanding of this association. The current study tested whether peer difficulties, specifically social competence and peer victimization, interacted with school support, a component of school climate, in relation to adolescents' SCT symptoms. Further, we explored whether these relations would be differentially associated with SCT in adolescents with and without attention-deficit/hyperactivity disorder (ADHD).Method: Adolescents (N = 288; Mage = 14.08, 45% female, 82.6% White; 52% with ADHD) completed measures of social competence, peer victimization, school climate support, and SCT and ADHD inattentive (IN) symptoms. Parents also reported on adolescents' social competence, SCT, and ADHD-IN symptoms.Results: Results indicated that adolescent and parent ratings of lower social competence were both associated with higher adolescent-reported SCT symptoms in the context of low, but not high, school support. Relational and nonphysical victimization were associated with higher self-reported SCT symptoms in the context of low school support. Lower adolescent- and parent-reported social competence were also related to higher parent-reported SCT symptoms, with these associations not moderated by school support. These results remained after controlling for demographics and ADHD-IN symptoms and were similar across adolescents with and without ADHD.Conclusions: Findings from the current study are the first to provide evidence that peer difficulties and school climate are jointly related to adolescents' self-reported SCT and underscore the importance of continued research investigating social adversity and environmental factors in relation to SCT.

Background Reconstructive surgery for upper extremity manifestations of cerebral palsy (CP) has been demonstrated to be safe and effective, yet many potential candidates are never evaluated for surgery. The purpose of this study was to determine barriers to upper extremity reconstruction for patients with CP in a cohort of upper extremity surgeons and nonsurgeons. Methods We sent a questionnaire to 4167 surgeons and nonsurgeon physicians, aggregated responses, and analyzed for differences in perceptions regarding surgical efficacy, patient candidacy for surgery, compliance with rehabilitation, remuneration, complexity of care, and physician comfort providing care. Results Surgeons and nonsurgeons did not agree on the literature support of surgical efficacy (73% vs 35% agree or strongly agree, respectively). Both surgeons and nonsurgeons felt that many potential candidates exist, yet there was variability in their confidence in identifying them. Most surgeons (59%) and nonsurgeons (61%) felt comfortable performing surgery and directing the associated rehabilitation, respectively. Neither group reported that patient compliance, access to rehabilitation services, and available financial resources were a major barrier, but surgeons were more likely than nonsurgeons to feel that remuneration for services was inadequate (37% vs 13%). Both groups agreed that surgical treatments are complex and should be performed in the setting of a multidisciplinary team. Conclusions Surgeons and nonsurgeons differ in their views regarding upper extremity reconstructive surgery for CP. Barriers to reconstruction may be addressed by performing higher level research, implementing multispecialty educational outreach, developing objective referral criteria, increasing surgical remuneration, improving access to trained upper extremity surgeons, and implementing multidisciplinary CP clinics.

Background:Approximately 10% of patients report allergies to penicillin, yet >90% of these allergies are not clinically significant. Patients reporting penicillin allergies are often treated with second-line, non–β-lactam antibiotics that are typically broader spectrum and more toxic. Orders for β-lactam antibiotics for these patients trigger interruptive alerts, even when there is electronic health record (EHR) data indicating prior β-lactam exposure.Objective:To describe the rate that interruptive penicillin allergy alerts display for patients who have previously had a β-lactam exposure.Design:Retrospective EHR review from January 2013 through June 2018.Setting:A nonprofit health system including 1 large tertiary-care medical center, a smaller associated hospital, 2 emergency departments, and ˜250 outpatient clinics.Participants:All patients with EHR-documented of penicillin allergies.Methods:We examined interruptive penicillin allergy alerts and identified the number and percentage of alerts that display for patients with a prior administration of a penicillin class or other β-lactam antibiotic.Results:Of 115,081 allergy alerts that displayed during the study period, 8% were displayed for patients who had an inpatient administration of a penicillin antibiotic after the allergy was noted, and 49% were displayed for patients with a prior inpatient administration of any β-lactam.Conclusions:Many interruptive penicillin allergy alerts display for patients who would likely tolerate a penicillin, and half of all alerts display for patients who would likely tolerate another β-lactam.

BACKGROUND AND OBJECTIVES Bilateral subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson's disease (PD) can have detrimental effects on eye movement inhibitory control. To investigate this detrimental effect of bilateral STN DBS, we examined the effects of manipulating STN DBS amplitude on inhibitory control during the antisaccade task. The prosaccade error rate during the antisaccade task, that is, directional errors, was indicative of impaired inhibitory control. We hypothesized that as stimulation amplitude increased, the prosaccade error rate would increase. MATERIALS AND METHODS Ten participants with bilateral STN DBS completed the antisaccade task on six different stimulation amplitudes (including zero amplitude) after a 12-hour overnight withdrawal from antiparkinsonian medication. RESULTS We found that the prosaccade error rate increased as stimulation amplitude increased (p

To describe a potential case of pentosan polysulfate maculopathy that seemed to manifest nearly 3 years after drug cessation.Complete ophthalmic examination, including multimodal fundus imaging, electroretinography, automated perimetry, and molecular testing, was performed.A 44-year-old woman with a 435 g cumulative exposure to pentosan polysulfate sodium presented 38 months after drug cessation with 6 months of worsening metamorphopsia and prolonged dark adaptation. Fundus examination and multimodal fundus imaging demonstrated characteristic features of pentosan polysulfate maculopathy, and molecular testing was unremarkable. By contrast, color fundus photographs of the same patient acquired at an outside facility 25 months before did not display features consistent with pentosan polysulfate sodium maculopathy.This case suggests that new-onset clinically detectable pentosan polysulfate maculopathy may develop years after drug cessation. If corroborated, this finding has important ramifications for pentosan polysulfate sodium dosing and surveillance guidelines.

AIMS Patients with type 2 diabetes mellitus (T2DM) have reduced vasodilatory responses during exercise partially attributable to low nitric oxide (NO) levels. Low NO contributes to greater α-adrenergic mediated vasoconstriction in contracting skeletal muscle. We hypothesized boosting NO bioavailability via 8wks of active beetroot juice (BRA, 4.03 mmol nitrate, 0.29 mmol nitrite, n = 19) improves hyperemia, via reduced α-mediated vasoconstriction, during handgrip exercise relative to nitrate/nitrite-depleted beetroot juice (BRP, n = 18) in patients with T2DM. METHODS Forearm blood flow (FBF) and vascular conductance (FVC) were calculated at rest and during handgrip exercise (20%max, 20contractions·min-1). Phenylephrine (α1-agonist) and dexmedetomidine (α2-agonist) were infused intra-arterially during independent trials to determine the influence of α-mediated vasoconstriction on exercise hyperemia. Vasoconstriction was quantified as the percent-reduction in FVC during α-agonist infusion, relative to pre-infusion, as well as the absolute change in %FVC during exercise relative to the respective rest trial (magnitude of sympatholysis). RESULTS ΔFBF (156 ± 69 to 175 ± 73 ml min-1) and ΔFVC (130 ± 54 to 156 ± 63 ml min-1·100 mmHg-1, both P

BACKGROUND International Statistical Classification of Disease and Related Health Problems, 10th Revision codes (ICD-10) are used to characterize cohort comorbidities. Recent literature does not demonstrate standardized extraction methods. OBJECTIVE Compare COVID-19 cohort manual-chart-review and ICD-10-based comorbidity data; characterize the accuracy of different methods of extracting ICD-10-code-based comorbidity, including the temporal accuracy with respect to critical time points such as day of admission. METHODS Design: Retrospective cross-sectional study. MEASUREMENTS ICD-10-based-data performance characteristics relative to manual-chart-review. RESULTS Discharge billing diagnoses had a sensitivity of 0.82 (95% Confidence Interval [CI]: 0.79-0.85; comorbidity range 0.35-0.96). The past medical history table had a sensitivity of 0.72 (95% CI: 0.69-0.76; range 0.44-0.87). The active problem list had a sensitivity of 0.67 (95% CI: 0.63-0.71; range 0.47-0.71). On day of admission, the active problem list had a sensitivity of 0.58 (95% CI: 0.54-0.63; range 0.30-0.68) and past medical history table had a sensitivity of 0.48 (95% CI: 0.43-0.53; range 0.30-0.56). CONCLUSIONS AND RELEVANCE ICD-10-based comorbidity data performance varies depending on comorbidity, data source, and time of retrieval; there are notable opportunities for improvement. Future researchers should clearly outline comorbidity data source and validate against manual-chart-review. This article is protected by copyright. All rights reserved.

PURPOSE In adolescent idiopathic scoliosis (AIS), the rib prominence is a major cosmetic concern which can be improved using thoracoplasties. We sought to determine if the use of deep drains helps minimize the development of pleural effusions after thoracoplasties. METHODS Retrospective study of 45 patients with AIS undergoing posterior spinal fusion (PSF) and thoracoplasties. RESULTS Thirty six out of 45 patients (80.0%) required placement of a deep surgical drain, and 16 out of 45 (35.6%) developed pleural effusions after PSF with concomitant thoracoplasty. Of the 16 patients who developed pleural effusion, 12 of 36 (33.3%) required a placement of a deep drain (p > 0.05). Of the total 45 patients in this cohort, 3 patients (6.7%) required chest tubes, and 4 patients (8.9%) developed surgical site infections (SSIs). We found that deep drains were associated with a lower incidence of SSI (2.8% vs 33.3%; p = 0.021). Patients who had a pleural effusion had longer ICU stays (p = 0.037) and longer requirements of nasal oxygen (p = 0.025). DISCUSSION The presence of a pleural effusion in patients with AIS undergoing PSF with thoracoplasty was associated with longer oxygen requirements and length of hospital ICU admission. Thirty six percent of patients with thoracoplasties developed pleural effusions, but deep subfascial drains did not significantly decrease the incidence of pleural effusions.

Coxiella burnetii, the causative bacterium of the zoonotic disease Q fever, has been documented in many different species. We describe documented turtles that were PCR positive for C. burnetii from multiple locations in Illinois and Wisconsin, USA. Assessing the conservation implications, reservoir potential, and zoonotic risk requires further research.

Background Magnetic resonance imaging (MRI) is standard of care for rotator cuff evaluation, with clinical interpretation usually limited to qualitative judgments. The reliability of MRI-based measurements and scoring systems has been evaluated only preoperatively or ≥6 months following rotator cuff repair, when repairs are in the later stages of healing. This study describes the MRI assessments and inter-rater agreement of various rotator cuff tendon and muscle parameters evaluated preoperatively and 4 times during the first postoperative year. Methods Two musculoskeletal radiologists independently assessed MRI scans of 42 patients preoperatively and 3, 12, 26, and 52 weeks after rotator cuff repair. Using standardized reading rules, readers assessed tendon integrity (5-point Sugaya classification), tear dimensions, muscle fat (5-point Goutallier classification) and atrophy (4-point Warner classification), muscle cross-sectional areas, and myotendinous junction distance. Raw exact agreement proportions, κ statistics, and correlation coefficients were used to quantify inter-rater agreement. Results Readers showed moderate to substantial above-chance agreement in scoring rotator cuff tendon integrity and supraspinatus muscle atrophy and good to excellent agreement on tear dimensions and muscle cross-sectional areas but only fair to moderate agreement for fatty infiltration and myotendinous junction distance. Only fatty infiltration grades evidenced observer bias. Inter-rater agreement did not appear time dependent. Conclusion By use of defined reading rules in a research setting, MRI evaluations of rotator cuff tendon integrity, tear dimensions, muscle atrophy, and cross-sectional areas have reasonable reliability at all time points in the first postoperative year. However, the presence of clinically significant disagreements, even in such favorable circumstances, indicates the need for improved imaging tools for precise rotator cuff evaluation.

BACKGROUND: Depression hinders obesity treatment; elucidating mechanisms may enable treatment enhancements. OBJECTIVES: The aim was to investigate whether changes in neural targets in the negative affect circuit following psychotherapy mediate subsequent changes in weight and behaviors. METHODS: Adults (n = 108) with obesity and depression were randomly assigned to usual care or an intervention that delivered problem-solving therapy (PST) for depression over 2 mo. fMRI for brain imaging was performed at baseline and 2 mo. BMI, physical activity, and diet were measured at baseline and 12 mo. Mediation analysis assessed between-group differences in neural target changes using t test and correlations between neural target changes and outcome changes (simple and interaction effect) using ordinary least-squares regression. RESULTS: Compared with usual care, PST led to reductions in left amygdala activation (−0.75; 95% CI: −1.49, −0.01) and global scores of the negative affect circuit (−0.43; −0.81, −0.06), engaged by threat stimuli. Increases in amygdala activation and global circuit scores at 2 mo correlated with decreases in physical activity outcomes at 12 mo in the usual-care group; these relations were altered by PST. In relation to change in leisure-time physical activity, standardized β-coefficients were −0.67 in usual care and −0.01 in the intervention (between-group difference: 0.66; 0.02, 1.30) for change in left amygdala activation and −2.02 in usual care and −0.11 in the intervention (difference: 1.92; 0.64, 3.20) for change in global circuit scores. In relation to change in total energy expenditure, standardized β-coefficients were −0.65 in usual care and 0.08 in the intervention (difference: 0.73; 0.29, 1.16) for change in left amygdala activation and −1.65 in usual care and 0.08 in the intervention (difference: 1.74; 0.85, 2.63) for change in global circuit scores. Results were null for BMI and diet. CONCLUSIONS: Short-term changes in the negative affect circuit engaged by threat stimuli following PST for depression mediated longer-term changes in physical activity. This trial was registered at www.clinicaltrials.gov as NCT02246413 (https://clinicaltrials.gov/ct2/show/NCT02246413).

Treatment of acute ischemic stroke (AIS) with intravenous alteplase within 4.5 h of symptom onset is associated with neurologic improvement. High baseline blood pressure (BP) and BP variability during the first 24 h of AIS is associated with increased early adverse events and death. The purpose of this study is to characterize the incidence of poor neurologic outcome in patients treated with alteplase for AIS who received antihypertensive medications prior to and within the first 24 h following alteplase administration compared with patients who did not.This was a multicenter, retrospective cohort of patients18 years diagnosed with AIS from January 1, 2011 through December 31, 2015 who received one or more antihypertensive medication in the first 24 h of AIS in patients receiving alteplase compared to controls. The primary endpoint was poor neurologic outcome at 90 days, according to modified Rankin Scale ≥3. Univariate analysis was conducted using Chi-square, Fisher's exact test, or Mann-Whitney U test. Multivariable logistic regression was conducted to determine independent predictors of poor outcome.Of the 587 patients evaluated, 351 (59.7%) were included, of which 127 (36.2%) received antihypertensive(s). More patients in the antihypertensive treatment group had a history of hypertension (88.2% vs. 69.6%, p0.01), diabetes (37% vs. 25.5%, p = 0.03) and chronic kidney disease (19.7% vs. 8.5%, p0.01). Intravenous push labetalol was most commonly administered (81.2%), followed by nicardipine (44.1%), and hydralazine (22%). More patients in the antihypertensive treatment group experienced poor neurologic outcome at 90 days (53.5% vs. 38.8%, p0.01), however, this finding was not observed after multivariable logistic regression.Antihypertensive treatment in the first 24 h of AIS was associated with poor neurologic outcomes at 90 days. However, after controlling for other clinical factors in a multivariable logistic regression, this association was no longer observed.

OBJECTIVES Implantable pulse generator (IPG) site pain following neuromodulation procedures is a recognized complication. The site of the IPG placement varies depending on the neuromodulation type and physician preference. The incidence of IPG site pain as a function of the site of IPG implantation has not been studied systematically. MATERIALS AND METHODS We performed a multicenter cross-sectional survey of the incidence, severity, and quality of IPG site pain, location of the IPG, the pain management needs, functional impairment, and cosmetic appearance related to the IPG placement. Contingency table analysis was conducted for categorical variables, and logistic regression analysis and linear regression model was used. RESULTS The survey response rate was 60.5% (n = 510). Overall, 31.0% of patients reported pain at the IPG site in the last 72 hours with 31.4% reporting moderate to severe pain and 7.6% reporting severe pain. Older age was inversely associated with IPG-related pain (OR = 0.97, 95% CI = 0.96-0.99, p = 0.001). IPG implantation site did not have a statistically significant interaction with IPG site pain (p > 0.05). The most important factor for IPG site-associated pain was having a spinal cord stimulator implanted as compared to a deep brain stimulator, or sacral nerve stimulator. Most subjects reported no functional impairment related to IPG site pain (91%), found the IPG site pain as expected (80%), and found IPG site cosmetic appearance as expected (96%). CONCLUSIONS The incidence of IPG site pain is an important complication of invasive neuromodulation. The anatomic location of the IPG placement does not appear to affect the incidence or severity of IPG site pain. However, the presence of a pre-implant chronic pain disorder does appear to affect the frequency and severity of IPG site pain.

Fremanezumab is a humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide and is approved in Europe for migraine prevention in adults with ≥4 migraine days/month. The Pan-European Real Life (PEARL) study is a 24-month, prospective, observational study of fremanezumab in chronic or episodic migraine. End points include proportion of patients with ≥50% reduction in monthly migraine days during 6 months of treatment (primary); changes in monthly migraine days, disability scores and acute headache medication use; adherence and persistence; and effectiveness in patients switching from another calcitonin gene-related peptide pathway-targeting monoclonal antibody. PEARL is being conducted in approximately 100 centers in 11 European countries (estimated n = 1100). PEARL will generate important real-world data on effectiveness of fremanezumab and treatment patterns in patients with chronic migraine or episodic migraine.Lay abstract Fremanezumab is an injectable biologic medication that targets calcitonin gene-related peptide, a substance released in the nerves and blood vessels during a migraine attack that plays a role in migraine pain. Fremanezumab is approved in Europe for preventing migraine in adults who experience ≥4 migraine days/month. The Pan-European Real Life (PEARL) study is a 24-month long study that will observe patients with migraine who are starting treatment with fremanezumab in a clinical practice setting under the care of their treating physician. The major goals of the study are to evaluate the effectiveness of fremanezumab for reducing days with migraine attacks in a month, disability associated with migraine and use of acute headache medications to treat migraine, including in patients switching from other biologic migraine therapies in the same drug class. The extent to which patients follow their recommended treatment schedule per their providers’ instructions and whether patients discontinue treatment will also be evaluated. The PEARL study will include1000 patients in 100 centers across 11 European countries. The study will provide important information on effectiveness for patients with migraine receiving fremanezumab in the normal course of their treatment, as well as on patients’ use of fremanezumab according to their prescribing physicians’ recommendations. Trial registration number: EUPAS35111 (European Network of Centres for Pharmacoepidemiology and Pharmacovigilance).

During tumor progression, cancer cells come into contact with various non-tumor cell types, but it is unclear how tumors adapt to these new environments. Here, we integrate spatially resolved transcriptomics, single-cell RNA-seq, and single-nucleus RNA-seq to characterize tumor-microenvironment interactions at the tumor boundary. Using a zebrafish model of melanoma, we identify a distinct “interface” cell state where the tumor contacts neighboring tissues. This interface is composed of specialized tumor and microenvironment cells that upregulate a common set of cilia genes, and cilia proteins are enriched only where the tumor contacts the microenvironment. Cilia gene expression is regulated by ETS-family transcription factors, which normally act to suppress cilia genes outside of the interface. A cilia-enriched interface is conserved in human patient samples, suggesting it is a conserved feature of human melanoma. Our results demonstrate the power of spatially resolved transcriptomics in uncovering mechanisms that allow tumors to adapt to new environments., During tumor progression, cancer cells contact different neighboring cell types, but it is unclear how these interactions affect cancer cell behavior. Here, the authors use spatially resolved transcriptomics and single-cell RNA-seq to study the role of cilia at the tumormicroenvironment interface.

Rationale: Primary graft dysfunction (PGD) is a severe form of acute lung injury, leading to increased early morbidity and mortality after lung transplant. Obesity is a major health problem, and recipient obesity is one of the most significant risk factors for developing PGD. Objectives: We hypothesized that T-regulatory cells (Tregs) are able to dampen early ischemia–reperfusion events and thereby decrease the risk of PGD, whereas that action is impaired in obese recipients. Methods: We evaluated Tregs, T cells, and inflammatory markers, plus clinical data, in 79 lung transplant recipients and 41 liver or kidney transplant recipients and studied two groups of mice on a high-fat diet (HFD), which did (“inflammatory” HFD) or did not (“healthy” HFD) develop low-grade inflammation with decreased Treg function. Measurements and Main Results: We identified increased levels of IL-18 as a previously unrecognized mechanism that impairs Tregs’ suppressive function in obese individuals. IL-18 decreases levels of FOXP3, the key Treg transcription factor, decreases FOXP3 di- and oligomerization, and increases the ubiquitination and proteasomal degradation of FOXP3. IL-18–treated Tregs or Tregs from obese mice fail to control PGD, whereas IL-18 inhibition ameliorates lung inflammation. The IL-18–driven impairment in Tregs’ suppressive function before transplant was associated with an increased risk and severity of PGD in clinical lung transplant recipients. Conclusions: Obesity-related IL-18 induces Treg dysfunction that may contribute to the pathogenesis of PGD. Evaluation of Tregs’ suppressive function together with evaluation of IL-18 levels may serve as a screening tool to identify obese individuals with an increased risk of PGD before transplant.

Background: The current classification system of invasive fungal sinusitis (IFS) includes acute (aIFS) and chronic (cIFS) phenotypes. Both phenotypes display histopathologic evidence of tissue necrosis, but differ by presence of angioinvasion, extent of necrosis, and disease progression. aIFS is defined by a rapid onset of symptoms, while cIFS slowly progresses over ≥12 weeks. However, a subset of IFS patients do not fit into the clinical presentation and histopathologic characteristics of either aIFS or cIFS. Objectives: To investigate the demographic, clinical, and histopathologic characteristics of a distinct subset of IFS. Methods: Retrospective review of patients with IFS from a single tertiary-care institution (2010-2020). Patients with symptoms for ≤4 weeks were classified as aIFS if they displayed endoscopic evidence of mucosal necrosis or fungal angioinvasion on pathology. Patients with slowly progressive IFS for ≥12 weeks were classified as cIFS. Patients with symptom duration between 4 and 12 weeks with evidence of invasive fungal disease were classified as a new entity and were further investigated. Results: Of the 8 patients identified, 50% were immunosuppressed at presentation. The mean symptom duration prior to presentation was 50.5 days (SD 16.8), and common symptoms included facial pain (100%), vision change (87.5%), and blindness (37.5%). Two patients (25%) died of their disease. Sites of fungal involvement confirmed by histopathology included sphenoid (62.5%) and ethmoid sinuses (12.5%), orbital apex (25%), optic nerve (12.5%), pterygopalatine fossa (12.5%), and clivus (12.5%). Fungal elements but without obvious angioinvasion, were identified in all specimens, and fungus balls (50%), granulomas (37.5%), and giant cells (25%) were also observed on histopathology. CT and MRI radiographic imaging showed findings consistent with orbital, intracranial, or skull base involvement in all patients. Conclusion: We propose intermediate IFS as a new subgroup of patients with IFS who do not fit into the standard classification of aIFS or cIFS.

As the popularity of scuba diving increases internationally, physicians interacting with divers in the clinical setting must be familiar with the cardiovascular stresses and risks inherent to this activity. Scuba presents a formidable cardiovascular challenge by combining unique environmental conditions with the physiologic demands of underwater exercise. Haemodynamic stresses encountered at depth include increased hydrostatic pressure leading to central shifts in plasma volume coupled with cold water stimuli leading to simultaneous parasympathetic and sympathetic autonomic responses. Among older divers and those with underlying cardiovascular risk factors, these physiologic changes increase acute cardiac risks while diving. Additional scuba risks, as a consequence of physical gas laws, include arterial gas emboli and decompression sickness. These pathologies are particularly dangerous with altered sensorium in hostile dive conditions. When present, the appropriate management of patent foramen ovale (PFO) is uncertain, but closure of PFO may reduce the risk of paradoxical gas embolism in divers with a prior history of decompression sickness. Finally, similar to other Masters-level athletes, divers with underlying traditional cardiovascular risk should undergo complete cardiac risk stratification to determine ‘fitness-to-dive’. The presence of undertreated coronary artery disease, occult cardiomyopathy, channelopathy and arrhythmias must all be investigated and appropriately treated in order to ensure diver safety. A patient-centred approach facilitating shared decision-making between divers and experienced practitioners should be utilised in the management of prospective scuba divers.

Objectives To compare patient-reported side effects and tolerability of full-dose Bacillus Calmette-Guerin (BCG), reduced-dose BCG, and gemcitabine one week after administration. Methods All patients from July 2019 to November 2020 receiving intravesical therapy (IVT) for non-muscle invasive bladder cancer (NMIBC) at our institution were surveyed before repeat instillation. Survey questions recorded IVT retention times and the duration and severity of the following side effects: bladder symptoms, fatigue, body aches, hematuria, fever, chills, and other. All responses were collected and quantified in a de-identified, password-protected database. Statistical analysis was performed using SAS JMP 13. Results Of 592 surveys completed, symptoms of any kind were reported on 463 surveys (78%) with the most common symptoms including bladder symptoms (59%), fatigue (52%), body aches (26%), and hematuria (18%). Patients were able to hold full-dose BCG, reduced-dose BCG, and gemcitabine for the protocol-specified duration 87%, 95%, and 71% of the time (P Conclusion Significant differences in the side effects and tolerability of full-dose BCG, reduced-dose BCG, and gemcitabine were demonstrated using this novel survey, and these differences are of value for informing IVT selection. Evaluation of IVTs other than gemcitabine and BCG will further inform selection of therapies for NMIBC.

ObjectiveTo describe outcomes of acute coronavirus disease 2019 in paediatric and young adult patients with underlying cardiac disease and evaluate the association between cardiac risk factors and hospitalisation.Study designWe conducted a retrospective single-institution review of patients with known cardiac disease and positive severe acute respiratory syndrome coronavirus 2 RT-PCR from 1 March, 2020 to 30 November, 2020. Extracardiac comorbidities and cardiac risk factors were compared between those admitted for coronavirus disease 2019 illness and the rest of the cohort using univariate analysis.ResultsForty-two patients with a mean age of 7.7 ± 6.7 years were identified. Six were 18 years of age or more with the oldest being 22 years of age. Seventy-six percent were Hispanic. The most common cardiac diagnoses were repaired cyanotic (n = 7, 16.6%) and palliated single ventricle (n = 7, 16.6%) congenital heart disease. Fourteen patients (33.3%) had underlying syndromes or chromosomal anomalies, nine (21%) had chronic pulmonary disease and eight (19%) were immunosuppressed. Nineteen patients (47.6%) reported no symptoms. Sixteen (38.1%) reported only mild symptoms. Six patients (14.3%) were admitted to the hospital for acute coronavirus disease 2019 illness. Noncardiac comorbidities were associated with an increased risk of hospitalisation (p = 0.02), particularly chronic pulmonary disease (p = 0.01) and baseline supplemental oxygen requirement (p = 0.007). None of the single ventricle patients who tested positive required admission.ConclusionsHospitalisations for coronavirus disease 2019 were rare among children and young adults with underlying cardiac disease. Extracardiac comorbidities like pulmonary disease were associated with increased risk of hospitalisation while cardiac risk factors were not.

This study examined whether the association between cybervictimization and internalizing symptoms was moderated by adolescents’ emotional connectedness to their social media. Participants were 288 adolescents (54.9% male participants) with (n = 151) and without (n = 137) attention-deficit/hyperactivity disorder (ADHD) between the ages of 13 and 15 years (M = 14.09, SD = 0.36). Adolescents reported on social integration and emotional connection (SIEC) to social media and parents reported on their impression of their adolescent’s SIEC to social media. Adolescents also reported on cybervictimization experiences and internalizing symptoms. Adolescents with ADHD had higher cybervictimization scores than adolescents without ADHD and were also more likely to report multiple experiences of cybervictimization over the past month. Emotional investment in social media moderated the relations between cybervictimization and internalizing symptoms such that cybervictimization was associated with higher anxiety and depression symptoms at higher levels of emotional investment in social media. Results were consistent across both parent and adolescent report of social integration and emotional connection to social media. These findings indicate that cybervictimization may be associated with negative outcomes specifically among adolescents with a strong emotional connection to their social media use.

While the contribution of several physiological systems to arterial blood pressure regulation has been studied extensively, the role of normal and disrupted sleep as a modifiable determinant of blood pressure control, and in the pathophysiology of hypertension, has only recently emerged. Several sleep disorders, including sleep apnea and insomnia, are thought to contribute to the development of hypertension, although less attention is paid to the relationship between sleep duration and blood pressure independent of sleep disorders per se. Accordingly, this review focuses principally on the physiology of sleep and the consequences of abnormal sleep duration both experimentally and at the population level. Clinical implications for patients with insomnia who may or may not have abbreviated sleep duration are explored. As a corollary, we further review studies of the effects of sleep extension on blood pressure regulation. We also discuss epidemiological evidence suggesting that long sleep may also be associated with hypertension and describe the parabolic relationship between total sleep time and blood pressure. We conclude by highlighting gaps in the literature regarding the potential role of gut microbial health in the cross-communication of lifestyle patterns (exercise, diet, and sleep) with blood pressure regulation. Additionally, we discuss populations at increased risk of short sleep, and specifically the need to understand mechanisms and therapeutic opportunities in women, pregnancy, the elderly, and in African Americans.

Cellular fibroma of tendon sheath (CFTS) is a rare, benign myofibroblastic neoplasm of tenosynovial soft tissues closely resembling nodular fasciitis (NF), but is histomorphologically distinct from classic fibroma of tendon sheath (FTS). We report a case of a pediatric patient with thumb swelling clinically concerning for arthritis with a biopsy demonstrating myofibroblastic proliferation with features consistent with NF/CFTS, and molecular studies confirming the presence of a USP6 gene fusion (TNC-USP6). This case highlights a unique clinical presentation of CFTS in a pediatric patient mimicking an inflammatory or reactive/non-neoplastic musculoskeletal disorder and the increasingly crucial role of molecular testing to differentiate a reactive myofibroblastic process from a neoplasm. Moreover, this report identifies TNC as a new fusion partner to USP6 fusion partner adding to our growing understanding of the USP6-rearranged family of tumors.

PURPOSE: Without a standard test for pancreatic carcinomas, this highly lethal disease is normally diagnosed at its advanced stage, leading to a low survival rate of patients. Trophoblast cell-surface antigen 2 (Trop-2), a transmembrane glycoprotein, is associated with cell proliferation and highly expressed in most of solid epithelial tumors, including pancreatic cancer. A non-invasive method of imaging Trop-2 would greatly benefit clinical diagnosis and monitoring of pancreatic cancer. In the current study, (89)Zr-labeled anti-Trop-2 antibody (AF650) was recruited for the systemic evaluation of Trop-2 as an immunoPET target for pancreatic cancer imaging. METHODS: AF650 was conjugated with desferrioxamine (DFO) and then radiolabeled with (89)Zr. Trop-2 expression levels were determined in three pancreatic cancer cell lines (BxPC-3, MIA PaCa-2, and AsPC-1) via western blot, flow cytometry, saturation binding assay, and immunofluorescence staining. The targeting capacity of (89)Zr-DFO-AF650 was evaluated in mouse models with subcutaneous xenograft of pancreatic cancers via PET imaging and bio-distribution studies. In addition, a Trop-2-positive orthotopic cancer model was recruited for further validating the targeting specificity of (89)Zr-DFO-AF650. RESULTS: BxPC-3 cells expressed high levels of Trop-2, while AsPC-1 and MIA PaCa-2 cells expressed low levels of Trop-2. Additionally, (89)Zr-DFO-AF650 exhibited high specificity to Trop-2 in BxPC-3 cells (K(d) = 22.34 ± 2.509 nM). In subcutaneous xenograft models, about 28.8 ± 7.63%ID/g tracer accumulated in the BxPC-3 tumors at 120 h post injection, which was much higher than those reaching MIA PaCa-2 (6.76 ± 2.08%ID/g) and AsPC-1 (3.51 ± 0.69%ID/g) tumors (n = 4). More importantly, (89)Zr-DFO-AF650 could efficiently distinguish primary tumors in the orthotopic BxPC-3 cancer model, showing high correlation between PET imaging and bio-distribution and sensitivity. CONCLUSIONS: (89)Zr-DFO-AF650 can be effectively used to detect pancreatic cancer via Trop-2-mediated immunoPET in vivo, clearly revealing the great potential of Trop-2-based non-invasive imaging in pancreatic cancer detection and treatment monitoring.

PURPOSE Nearly all men with prostate cancer treated with androgen receptor (AR) signaling inhibitors (ARSIs) develop resistance via diverse mechanisms including constitutive activation of the AR pathway, driven by AR genomic structural alterations, expression of AR splice variants (AR-Vs), or loss of AR dependence and lineage plasticity termed neuroendocrine prostate cancer. Understanding these de novo acquired ARSI resistance mechanisms is critical for optimizing therapy. MATERIALS AND METHODS A novel liquid biopsy technology was used to collect mRNA from circulating tumor cells (CTCs) to measure expression of AR-Vs, AR targets, and neuroendocrine prostate cancer markers. An institutional review board–approved prospective cohort (N = 99) was used to identify patterns of gene expression. Two prospective multicenter phase II clinical trials of ARSIs for men with castration-resistant prostate cancer (ClinicalTrials.gov: NCT01942837 [enzalutamide, N = 21] and NCT02025010 [abiraterone, N = 27]) were used to further validate these findings. RESULTS Hierarchical clustering of CTC transcripts identified two distinct clusters. Cluster 2 (C2) exhibited increased expression of AR-regulated genes and was associated with worse overall survival (median 8.6 v 22.4 months; P < .01; hazard ratio [HR] = 3.45 [1.9 to 6.14]). In multivariable analysis, C2 was prognostic independent of other clinicopathologic variables. AR-V status was not significant when accounting for C2. Upon further validation in pooled multicenter phase II trials, C2 was associated with worse overall survival (15.2 months v not reached; P < .01; HR = 8.43 [2.74 to 25.92]), prostate-specific antigen progression-free survival (3.6 v 12 months; P < .01; HR = 4.64 [1.53 to 14.11]), and radiographic progression-free survival (2.7 v 40.6 months; P < .01; HR = 4.64 [1.82 to 17.41]). CONCLUSION We demonstrate that a transcriptional profile detectable in CTCs obtained from liquid biopsies can serve as an independent prognostic marker beyond AR-V7 in patients with metastatic prostate cancer and can be used to identify the emergence of multiple ARSI resistance mechanisms. This is currently being investigated in additional prospective trials.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common childhood disorders. Professional practice guidelines recommend combined treatment, psychopharmacological and psychosocial, for youth with ADHD. There have been multiple reviews of pharmacological prescription practices and utilization, however, less is known about predictors of ADHD psychosocial service utilization. Given the importance of accessing psychosocial treatment in relation to improving functional impairment, this review synthesizes evidence on predictors of ADHD psychosocial intervention utilization in clinic, community, and school settings. Eighteen studies were identified and included in the review. Findings are summarized across informant profile factors, predisposing characteristics, and barriers and facilitators. The most robust findings were for the impact of symptom severity/impairment, the presence of comorbidities, and age on ADHD psychosocial service utilization. Race/ethnicity, sex, parental knowledge of the disorder and insurance coverage were also identified as key factors. Future avenues of research are provided, and clinical and policy implications targeted at reducing psychosocial treatment disparities in youth with ADHD are discussed.

Although therapeutic options for patients with advanced renal cell carcinoma (RCC) have increased in the past decade, no biomarkers are yet available for patient stratification or evaluation of therapy resistance. Given the dynamic and heterogeneous nature of clear cell RCC (ccRCC), tumor biopsies provide limited clinical utility, but liquid biopsies could overcome these limitations. Prior liquid biopsy approaches have lacked clinically relevant detection rates for patients with ccRCC. This study employed ccRCC‐specific markers, CAIX and CAXII, to identify circulating tumor cells (CTC) from patients with metastatic ccRCC. Distinct subtypes of ccRCC CTCs were evaluated for PD‐L1 and HLA‐I expression and correlated with patient response to therapy. CTC enumeration and expression of PD‐L1 and HLA‐I correlated with disease progression and treatment response, respectively. Longitudinal evaluation of a subset of patients demonstrated potential for CTC enumeration to serve as a pharmacodynamic biomarker. Further evaluation of phenotypic heterogeneity among CTCs is needed to better understand the clinical utility of this new biomarker., Circulating tumor cells (CTCs) were evaluated for their expression of programmed death ligand‐1 (PD‐L1) and human leukocyte antigen class I (HLA‐I), so that biomarkers of therapeutic resistance of clear cell renal cell carcinoma can be developed. CTCs were captured with antibody‐conjugated magnetic beads against EpCAM and CAIX then probed for CAXII and CK expression using microfluidic technology.

Castration-resistant prostate cancer (CRPC) is driven by AR gene aberrations that arise during androgen receptor (AR)-targeted therapy. AR amplification and mutations have been profiled in circulating tumor cells (CTCs), but whether AR gene rearrangements can be assessed in CTCs is unknown. In this study, we leveraged CRPC cell lines with defined AR gene rearrangements to develop and validate a CTC DNA analysis approach that utilized whole genome amplification and targeted DNA-sequencing of AR and other genes important in CRPC. We tested the utility of this approach by analyzing matched CTC DNA and plasma cell-free DNA (cfDNA) from a case series of ten CRPC patients. One of ten CTC samples and two of ten cfDNA samples were positive for AR gene rearrangements. All AR gene rearrangements were discordant between matched liquid biopsy samples. One patient harbored separate AR gene rearrangements in CTC DNA and cfDNA, but concordant AR amplification and AR T878A mutation. This patient also displayed concordant loss of TP53 and PTEN, but the loss of RB1 in cfDNA only. The overall frequency of discordant alterations in these genes between matched CTC DNA and cfDNA was high. This study establishes the technical feasibility of analyzing structural rearrangements, mutations, and copy number variants in AR and other CRPC genes using two different sources of DNA from a single blood sample. Paired CTC DNA and cfDNA analysis may have utility for capturing the heterogeneity of genetic alterations in CRPC patients.

Background The purpose of this study was to evaluate radiographic-based classification systems for osteochondritis dissecans (OCD) of the capitellum and determine their agreement with intraoperative findings. Methods Using PRISMA guidelines, we analyzed 44 studies utilizing a total of 19 classification systems. Results Magnetic resonance imaging (MRI)-based systems showed better predictive value of intraoperative staging, and the Itsubo and Kohyama classifications showed best predictive value for lesion stability. Conclusions No classification system effectively correlated with intraoperative findings. A combination of radiograph, MRI, and computed tomography will most accurately determine OCD lesion stability. Level of evidence IV, Systematic Review.

Meticulous risk stratification is essential when considering intubation of a patient with decompensated pulmonary hypertension (dPH). It is paramount to understand both the pathophysiology of dPH (and associated right ventricular failure) and the complications related to a high-risk intubation before attempting the procedure. There are few recommendations in this area and the literature, guiding these recommendations, is limited to expert opinion and very few case reports/case series. This review will discuss the complex pathophysiology of dPH, the complications associated with intubation, the debates surrounding induction agents, and the available options for the intubation procedure, with specific emphasis on the emerging role for awake fiberoptic intubation. All patients should be evaluated for candidacy for veno-arterial extracorporeal membrane oxygen as a bridge to recovery, lung transplantation, or pulmonary endarterectomy prior to intubation. Only an experienced proceduralist who is both comfortable with high-risk intubations and the pathophysiology of dPH should perform these intubations.

Fontan palliation has improved survival for single ventricle patients, but long-term complications persist including cardiovascular dysfunction, neurohormonal abnormalities, and protein-losing enteropathy (PLE). Although chronic inflammation contributes to morbidity, an association between inflammation and vascular dysfunction has not been studied. We assessed inflammation and vascular function in 31 Fontan-palliated patients (52% male, median age 14.3 years), including 10 PLE+. Fontan circulation was associated with altered inflammatory cytokines (TNF-α: mean 2.5 ± 1.4 vs. 0.7 ± 0.2 pg/ml, p0.0001; sTNFR2: 371 ± 108 vs. 2694 ± 884 pg/ml, p0.0001) and vascular dysfunction [log-transformed reactive hyperemia index (lnRHI) 0.28 ± 0.19 vs. 0.47 ± 0.26, p0.01; augmentation index (AI) -2.9 ± 13.8 vs. -16.3 ± 12.0, p = 0.001; circulating endothelial progenitor cells (cEPCs) 5.0 ± 8.1 vs. 22.8 ± 15.9, p = 0.0002)]. Furthermore, PLE+ patients showed greater inflammation (IFN-γ 6.3 ± 2.2 vs. 11.5 ± 7.9 pg/ml, p = 0.01; sTNFR1: 1181 ± 420 vs. 771 ± 350 pg/ml, p = 0.01) and decreased arterial compliance (AI: 5.4 ± 17.1 vs. -6.8 ± 10.2, p = 0.02) than PLE- patients. Circulating EPCs, but not inflammatory cytokines, were inversely associated with arterial stiffness in Fontan patients. In conclusion, chronic inflammation and vascular dysfunction are observed after Fontan operation, with greater inflammation and arterial stiffness in Fontan patients with active PLE. However, there is no clear association between inflammatory cytokines and vascular dysfunction, suggesting these pathophysiologic processes are not mechanistically linked.

We present a unique case of side-to-side metacarpal fusion for reconstruction after an isolated gunshot wound to the right hand of a 19-year-old woman. There was a traumatic segmental loss of the proximal right second metacarpal base with considerable comminution of the trapezium and trapezoid. Reconstructive options were limited because of the destruction of the distal carpus and carpometacarpal (CMC) joint. Digital ray amputation was offered but deferred because of patient preference. The reconstruction was performed via metacarpal fusion of the second metacarpal remnant to the third metacarpal base, bypassing the previously destroyed second CMC joint. The fusion of the second and third metacarpals offers acceptable results when the radial CMC joints are traumatized with extensive bone loss.

Background Allergy to opioids is the second most common drug allergy label in electronic health records (EHR). Adverse drug reactions (ADR) to opioids cause significant morbidity and contribute to healthcare costs, while incorrect opioid allergy labels may unnecessarily complicate patient management. Aims To examine the documentation of opioid ADR in a large-scale hospital-based EHR. Methods A cross-sectional retrospective review of EHR documentation of opioid ADR at four public hospitals in South Australia was conducted. Data were extracted from all ADR entries including the reported allergen, ADR category (allergy or intolerance) and reaction details. Expert criteria were used to determine consistency of ADR categorisation as allergy or intolerance. Results Of 86 727 unique ADR reports, there were 13 781 ADR to opioids with most being entered as allergy (n = 8913, 64.7%) rather than intolerance (n = 4868, 35.3%). The most commonly documented reactions were nausea/vomiting (n = 3912, 28%), rash (n = 647, 5%), itch (n = 642, 5%) and hallucinations (n = 527, 4%). There were 362 (3%) ADR labels of anaphylaxis. Of those ADR containing a reaction description (n = 11 868), 89% of reports entered as allergy had a reaction description that was consistent with intolerance and 8% of the entered intolerances had descriptions consistent with allergy when assessed using predefined criteria. Conclusions This large EHR-based study demonstrates the high rate of opioid ADR labels in EHR. The majority of these labels were for symptoms suggestive of pharmacological intolerance. Reactions consistent with true allergy were uncommon. Systematic review of ADR by a dedicated clinical service would improve the accuracy of documentation.

Background and Aim While many studies have reported on liver injury in patients with coronavirus disease 2019 (COVID‐19), none have specifically addressed the significance of hepatic jaundice. We aimed to determine the clinical consequences and etiologies of jaundice in patients with COVID‐19. Methods We retrospectively analyzed clinical features, laboratory abnormalities, and rates of survival and intensive care unit admission in 551 patients with COVID‐19, hospitalized between 1 March 2020, and 31 May 2020 at a tertiary care academic medical center. Hepatic jaundice was defined as a serum total bilirubin concentration >2.5 mg/dL and a direct bilirubin concentration >0.3 mg/dL that was >25% of the total. Liver injury was characterized as cholestatic, mixed, or hepatocellular at the time of peak serum total bilirubin concentration by calculating the R factor. Results Hepatic jaundice was present in 49 (8.9%) patients and associated with a mortality rate of 40.8% and intensive care unit admission rate of 69.4%, both significantly higher than for patients without jaundice. Jaundiced patients had an increased frequency of fever, leukopenia, leukocytosis, thrombocytopenia, hypotension, hypoxemia, elevated serum creatinine concentration, elevated serum procalcitonin concentration, and sepsis. Nine jaundiced patients had isolated hyperbilirubinemia. Of the 40 patients with abnormally elevated serum alanine aminotransferase or alkaline phosphatase activities, 62.5% had a cholestatic, 20.0% mixed, and 17.5% hepatocellular pattern of liver injury. Conclusion Hepatic jaundice in patients with COVID‐19 is associated with high mortality. The main etiologies of liver dysfunction leading to jaundice appear to be sepsis, severe systemic inflammation, and hypoxic/ischemic hepatitis., Jaundice is a hallmark of liver dysfunction. We show that hepatic jaundice in patients with COVID‐19 is associated with high mortality, similar to that observed with invasive mechanical ventilation. The main etiologies of liver dysfunction leading to jaundice appear to be sepsis, severe systemic inflammation, and hypoxic/ischemic hepatitis.

Introduction Myriad cardiovascular manifestations have been reported with COVID‐19. We previously reported that failure of PR interval shortening with increasing heart rate (HR) in patients with COVID‐19 is associated with adverse outcomes. Here, we report on heart rate variability (HRV) and clinical outcomes in patients with chronic atrial fibrillation (cAF) hospitalized for COVID‐19. Methods A retrospective review of admitted COVID‐19 patients with cAF between 1 March 2020 to 30 June 2020 was performed. HRV in cAF was compared during pre‐COVID‐19 and COVID‐19 admissions; we selected pre‐COVID‐19 ECGs with HRs that were within 10 beats per minute of the COVID‐19 ECGs. Mean HR and each RR interval were recorded. Time‐domain measurements of HR variability were then calculated (SDSD, RMSSD, pNN50). Clinical outcomes during COVID‐19 were correlated to indices of HRV. Results A total of 184 ECGs (95 pre‐COVID‐19, 89 COVID‐19) from 38 cAF in‐patients were included. Mean age 78.6 ± 11.4 years, male 44.7%. The mean number of ECGs analyzed per patient pre‐COVID‐19 was 2.50 and during COVID‐19 was 2.34. Comparing pre‐COVID‐19 versus COVID‐19 ECGs showed: mean HR (95.9 ± 24.3 vs. 101.6 ± 22.8 BPM; P = .10), SDSD (109.0 ± 50.6 vs. 90.3 ± 37.2 ms; P, The electrophysiologic effects of COVID‐19 in patients with chronic atrial fibrillation (cAF) have not been described. Anecdotally, we observed that patients hospitalized for COVID‐19 with comorbid cAF demonstrated more regularized ventricular rates. This observation prompted further analysis of heart rate variability (HRV) and clinical outcomes in patients with cAF hospitalized for COVID‐19. We found that in patients with cAF, the HRV was reduced during COVID‐19 compared with prior illnesses at similar average heart rates. Patients with the most depressed HRV as measured by pNN50 had an associated increase in mortality compared to patients whose HRV was preserved. Thus, the depressed HRV in AF may reflect changes in autonomic control of AV conduction, and if confirmed, may be another marker of cardiac injury in COVID‐19.

Background Migraine is associated with depression as well as negative impact on quality of life and work productivity. Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa), selectively targets the calcitonin gene-related peptide and has proven efficacy for the preventive treatment of migraine. Objective In this open-label extension (OLE) of the phase 3b FOCUS study, we assessed patient-reported outcomes (PROs) over time. Methods Patients with episodic migraine (EM) and chronic migraine (CM) completing the 12-week, double-blind (DB) period of the FOCUS trial entered the 12-week OLE and received three monthly doses of fremanezumab (225 mg). PROs included the Migraine-Specific Quality of Life (MSQoL) questionnaire (role function-restrictive [RFR], role function-preventive [RFP], and emotional function [EF] domains), EuroQol-5-Dimension-5-Level (EQ-5D-5L) questionnaire, Patient Global Impression of Change (PGIC) assessment, Work Productivity and Activity Impairment (WPAI) questionnaire, and 9-Item Patient Health Questionnaire (PHQ-9). Results A total of 838 patients were randomized in the DB period, 807 entered the OLE at 3 months, and 772 were still enrolled at 6 months. At 6 months, patients in the quarterly fremanezumab, monthly fremanezumab, and placebo DB randomization groups, respectively, reported improvements in RFR (mean [standard deviation] change from baseline: 24.6 [21.9]; 22.9 [21.3]; 20.8 [26.5]), RFP (19.6 [20.0]; 18.3 [19.7]; 16.0 [19.9]), and EF (22.5 [24.2]; 19.1 [23.6]; 17.2 [24.7]) domains of the MSQoL questionnaire, the EQ-5D-5L questionnaire (8.0 [19.6]; 7.3 [21.1]; 6.6 [21.0]), all four domains of the WPAI questionnaire, and the PHQ-9 (-2.4 [5.3]; -1.6 [5.5]; -2.0 [4.9]); 77.1% (209/271), 75.4% (205/272), and 68.8% (181/263) of patients were identified as PGIC responders. Conclusion Among patients with EM or CM and prior inadequate response to multiple migraine-preventive medication classes, progressive improvements in MSQoL, depression, and work productivity were achieved during 6 months of fremanezumab treatment.

Malaria and visceral leishmaniasis coexist in the same geographical regions. However, dual co-infection with parasites causing these diseases and their impact on public health is poorly documented. Interactions between these parasites may play a role in disease outcome. The present study set out to evaluate the clinical and immunological parameters following Leishmania donovani and Plasmodium berghei co-infection in BALB/c mice. Mice were divided into four groups; L. donovani- only, L. donovani-P. berghei, P. berghei- only and naive. Body weight, parasite burden, total IgG, IFN-γ and IL-4 responses were determined. To determine the survival rate, four mice were used from each group. Tissues for histological analysis were taken from spleen, liver and brain. Results indicated significant differences in body weight (PL. donovani parasite load (P), L. donovani IgG (PP. berghei parasitemia (P= 0.0222), P. berghei IgG (P= 0.002), IFN-γ (PL. donovani parasite load and IgG responses in single or dual infections, while there was a positive relationship of P. berghei parasitemia and IgG responses in the dual infection group only. Plasmodium berghei had the highest mortality rate compared to L. donovani- only and L. donovani- P. berghei infected mice groups. Histological analyses showed enlarged red and white pulps and pathological changes in the spleen, liver and brain tissues which were less pronounced in co-infected group. We conclude that L. donovani and P. berghei co-infection reduces disease severity and these changes seem to correlate with variation in serum IgG and cytokines (IFN-γ and IL-4). Therefore, the study recommends the importance of inclusion of early screening of malaria in Visceral Leishmaniasis patients in regions where malaria is co- endemic.

Studies have suggested imatinib mesylate (ImM) as a potential treatment for systemic lupus erythematosus nephritis (SLEN). However, ImM has limited renal excretion. The goal of the current research was to develop an ImM containing nanoformulation, conduct studies to evaluate pharmacokinetics, and determine whether kidney deposition can be enhanced in a mouse model of SLEN. A fish oil–based ImM oil-in-water nanoemulsion was developed and characterized for particle size, zeta potential, pH, and stability. MRL/MpJ-Faslrp (model of SLEN) and MRL/MpJ (control) mice (12–13 weeks) received one dose of ImM as either a nanoemulsion or naked drug. Pharmacokinetics and kidney deposition studies were performed. Statistics were conducted with a student’s T-test. The nanoemulsion characteristics included particle size range of 60–80 nm, zeta potential of −6.6 to −7.8 mV, polydispersity index

Pediatric orthopedic surgeons must accurately assess the skeletal stage of adolescent idiopathic scoliosis (AIS) patients for selection and timing of optimal treatment. Successful treatment using vertebral growth modulation is highly dependent on skeletal growth remaining. We sought to evaluate the current-state use of the Sanders Skeletal Maturity System (SSMS) in regard to precision and accuracy. We hypothesized that pediatric orthopedic surgeons currently use SSMS with moderate precision and accuracy. Eight practicing pediatric orthopedic surgeons who perform vertebral body tethering surgery without specific training in SSMS were asked to assign the SSMS stage for 34 de-identified hand radiographs from AIS patients. Precision was evaluated as inter-rater reliability, using both Krippendorff’s α and Weighted Cohen’s kappa statistics, and as intra-rater reliability, using only Weighted Cohen’s kappa statistics. Surgeon accuracy was evaluated using Weighted Cohen’s kappa statistics with comparison of surveyed surgeons’ responses to the gold standard rating. Inter-rater reliability across the surveyed surgeons indicated moderate to substantial agreement using both statistical methods (α = 0.766, κ = 0.627) with the majority of discord occurring when assigning SSMS stages 2 through 4. The surveyed surgeons displayed substantial accuracy when compared to the gold standard (κ = 0.627) with the majority of inaccuracy involving the identification of stage 3B. When re-surveyed, the surgeons showed substantial intra-rater reliability (κ = 0.71) with increased inconsistencies when deciding between SSMS stage 3A and stage 3B. The current-state use of SSMS across pediatric orthopedic surgeons for evaluation of AIS patients displays adequate but imperfect precision and accuracy with difficulties delineating SSMS stages 2 through 4, which correlate with adolescent growth periods germane to scoliosis growth modulation surgery. Centralized assessment of hand-bone age may help ensure standardized reporting for non-fusion scoliosis research.

Biologics have recently been approved for use in chronic rhinosinusitis with nasal polyps patients. While effective in controlling disease on subjective and objective short-term outcome measures, limited data suggest that biologics have the potential to be used long term. The current wholesale acquisition costs for biologics are quite high. Widespread, prolonged use of these medications may create a large burden to our healthcare system. Cost-effectiveness analyses, particularly for specific patient cohorts, are needed to determine appropriate use of these medications. The ethics of patient preference of various treatment options, counseling regarding side effect profiles, and healthcare economics also need to be addressed.

Purpose of review The purpose of this review is to summarize complications of treatment for retinopathy of prematurity (ROP) and to compare complications of laser and intravitreal antivascular endothelial growth factor (VEGF) injections. Recent findings Poor structural outcomes and myopia are more common with laser for severe ROP than with anti-VEGF. Clinical trial data show unfavourable outcomes in 9.1-9.5% of laser treated, and 1.4-3.6% of anti-VEGF treated eyes. Additional randomized trial data show risk for very high myopia (≥-8.00D) to be 3.8 and 51.4% for zone I eyes treated with bevacizumab and laser, respectively. However, anti-VEGF may be complicated by late recurrence and is more likely to require retreatment than laser. Laser often necessitates general anaesthesia with its attendant risks, including worse short-term respiratory outcomes. Neurodevelopmental complications have been reported with anti-VEGF, but existing studies are subject to bias. Summary Treatment complications are substantially different for the two modalities in common use today. In more severe cases, risk of poor structural outcome and myopia favour treatment with anti-VEGF. In less severe ROP, risk of recurrence and the need for additional treatments may favour laser. Additional data are needed to establish comparative risks of neurodevelopmental complications.

Acute colonic pseudo-obstruction (ACPO) and volvulus are two disease processes that affect the colon causing abdominal distension and may necessitate operation intervention. ACPO may be associated with multiple comorbidities, infectious diseases, and cardiac dysfunction. It may be treated with conservative management including endoscopic decompression or neostigmine. If the distension is not addressed, high mortality may result if peritonitis develops. Volvulus most commonly occurs in the sigmoid colon or cecum. If left-sided, endoscopic decompression may resolve the obstruction if detorsion is successful, although sigmoid colectomy should be performed during the admission. If cecal volvulus is identified, right hemicolectomy should be performed.

Neurosurgery is considered to have one of the greatest risks of medical malpractice claims. However, medicolegal issues in neurosurgery are often disregarded and underrated worldwide. Medical errors in the neurosurgical field can be attributed to multiple factors, including highly morbid pathologies, the technical difficulty of neurosurgical procedures, and the involvement and interaction of a multidisciplinary team in the care of neurosurgical patients. Health care providers worldwide are at risk of lawsuits, sometimes even when no deviation from the standard of care had occurred in a given case. Often, governments use additional tactics to decrease the burden on compensators and extrajudicial institutions and to decrease the court's flow of irrational litigation. Continuous amendments to health care acts and newer reforms to address these issues have materialized worldwide. In the present narrative review, we have reviewed the global perspectives of medicolegal issues, with a focus on neurosurgical discipline.

Background Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) selectively targets the calcitonin gene-related peptide and has proven efficacy for the preventive treatment of migraine. In this study, we evaluated the long-term efficacy, safety, and tolerability of monthly and quarterly fremanezumab. Methods Episodic migraine and chronic migraine patients completing the 12-week double-blind period of the FOCUS trial entered the 12-week open-label extension and received 3 monthly doses of fremanezumab (225 mg). Changes from baseline in monthly migraine days, monthly headache days of at least moderate severity, days of acute headache medication use, days with photophobia/phonophobia, days with nausea or vomiting, disability scores, and proportion of patients achieving a ≥50% or ≥75% reduction in monthly migraine days were evaluated. Results Of the 807 patients who completed the 12-week double-blind treatment period and entered the open-label extension, 772 patients completed the study. In the placebo, quarterly fremanezumab, and monthly fremanezumab dosing regimens, respectively, patients had fewer average monthly migraine days (mean [standard deviation] change from baseline: − 4.7 [5.4]; − 5.1 [4.7]; − 5.5 [5.0]), monthly headache days of at least moderate severity (− 4.5 [5.0]; − 4.8 [4.5]; − 5.2 [4.9]), days per month of acute headache medication use (− 4.3 [5.2]; − 4.9 [4.6]; − 4.8 [4.9]), days with photophobia/phonophobia (− 3.1 [5.3]; − 3.4 [5.3]; − 4.0 [5.2]), and days with nausea or vomiting (− 2.3 [4.6]; − 3.1 [4.5]; − 3.0 [4.4]). During the 12-week open-label extension, 38%, 45%, and 46% of patients, respectively, achieved a ≥50% reduction and 16%, 15%, and 20%, respectively, achieved a ≥75% reduction in monthly migraine days. Disability scores were substantially improved in all 3 treatment groups. There were low rates of adverse events leading to discontinuation ( Conclusion Fremanezumab demonstrated sustained efficacy up to 6 months and was well tolerated in patients with episodic migraine or chronic migraine and documented inadequate response to multiple migraine preventive medication classes. Trial registration ClinicalTrials.gov NCT03308968 (FOCUS).

BACKGROUND Anterior vertebral body tethering (aVBT) has emerged as a novel treatment option for patients with idiopathic scoliosis. We present the results from the first U.S. Food and Drug Administration (FDA) Investigational Device Exemption (IDE) study on aVBT. METHODS In this prospective review of a retrospective data set, eligible patients underwent aVBT at a single center from August 2011 to July 2015. Inclusion criteria included skeletally immature patients with Lenke type-1A or 1B curves between 30° and 65°. Clinical and radiographic parameters were collected, with the latter measured by an independent reviewer. RESULTS Fifty-seven patients (49 girls and 8 boys), with a mean age (and standard deviation) of 12.4 ± 1.3 years (range, 10.1 to 15.0 years), were enrolled in the study. The patients had a mean of 7.5 ± 0.6 levels tethered, the mean operative time was 223 ± 79 minutes, and the mean estimated blood loss was 106 ± 86 mL. The patients were followed for an average of 55.2 ± 12.5 months and had a mean Risser grade of 4.2 ± 0.9 at the time of the latest follow-up. The main thoracic Cobb angle was a mean of 40.4° ± 6.8° preoperatively and was corrected to 18.7° ± 13.4° at the most recent follow-up. In the sagittal plane, T5-T12 kyphosis measured 15.5° ± 10.0° preoperatively, 17.0° ± 10.1° postoperatively, and 19.6° ± 12.7° at the most recent follow-up. Eighty percent of patients had curves of

Background The high negative predictive value (NPV) of a negative nasal methicillin-resistant Staphylococcus aureus (MRSA) result in suspected MRSA pneumonia is well established; however, data are limited on the NPV of samples collected prior to hospital admission for critically ill patients. Objective To evaluate the predictive characteristics of MRSA nares screening performed prior to hospital admission in critically ill adult patients diagnosed with pneumonia. Methods A retrospective analysis was conducted in critically ill patients with pneumonia and MRSA nares screening within 60 days of respiratory culture. The primary outcome was NPV of MRSA nares for MRSA pneumonia using samples within 60 days compared to in-hospital respiratory cultures. A sensitivity analysis was performed for samples within 30 days. Secondary outcomes were prevalence, positive predictive value (PPV), sensitivity, specificity, and MRSA pneumonia risk factors. Results The NPV for MRSA nares screening collected prior to hospital admission was high at 98% (95% CI = 96%-99%) for samples collected within 60 days (n = 243) and 99% (95% CI: 94%-99.9%) for samples within 30 days (n = 119). Specificity for MRSA nares collected 60 days prior to admission (96%, 95% CI: 93-98) and 30 days (96%, 95% CI: 91%-99%) were both high. PPV and sensitivity were lower. Risk factors for MRSA pneumonia were similar. Conclusion and Relevance MRSA nares screening within 60 days of intensive care unit admission has a high NPV and specificity for MRSA pneumonia in critically ill patients and may be a powerful stewardship tool for avoidance of empirical anti-MRSA therapy.

Objective To evaluate the impact of fremanezumab on the severity and duration of remaining migraine attacks in patients with chronic migraine (CM) or episodic migraine (EM). Background Fremanezumab is a fully humanized monoclonal antibody (IgGΔa) that selectively targets calcitonin gene‐related peptide and is efficacious in reducing migraine frequency. Methods This exploratory post hoc analysis included data from three randomized, double‐blind, 12‐week, phase 3 studies (HALO CM, HALO EM, and FOCUS). In all three studies, patients with CM or EM were randomized 1:1:1 to receive subcutaneous quarterly fremanezumab (month 1/2/3: 675 mg/placebo/placebo), monthly fremanezumab (month 1/2/3: 675 mg [CM], 225 mg [EM]/225 mg/225 mg), or matched monthly placebo. Changes from baseline were evaluated in the proportion of headache days of at least moderate severity, peak severity of headache days, mean monthly headache hours (of any severity and at least moderate severity), and mean headache hours per headache day of any severity. Results A total of 2843 patients were randomized with 2823 patients included in the efficacy analyses across all studies (HALO CM, N = 1121; HALO EM, N = 865; FOCUS, N = 837). At study baseline, mean (standard deviation [SD]) monthly number of headache days rated moderate or severe in the quarterly fremanezumab, monthly fremanezumab, and placebo groups, respectively, were 13.2 (5.5), 12.8 (5.8), and 13.3 (5.8) in HALO CM; 7.2 (3.1), 6.8 (2.9), and 6.9 (3.1) in HALO EM; and 12.4 (5.8), 12.7 (5.8), and 12.8 (5.9) in FOCUS. Patients experienced significant least‐squares mean (LSM; 95% confidence interval) percent reductions from baseline in monthly number of headache days rated moderate or severe during the 12 weeks: HALO CM, quarterly fremanezumab, 34.5% (−39.8, −29.2) and monthly fremanezumab, 36.2% (−41.4, −31.0) vs. placebo, 19.6% (−20.0, −14.3); HALO EM, quarterly fremanezumab, 40.7% (−47.8, −33.5) and monthly fremanezumab, 43.4% (−50.4, −36.3) vs. placebo, 17.9% (−24.9, −11.0); and FOCUS, quarterly fremanezumab, 36.5% (−41.9, −31.1) and monthly fremanezumab, 38.6% (−44.0, −33.3) vs. placebo, 3.5% (−8.9, 1.8); all p