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OBJECTIVE: To determine if surgery and anesthesia in the elderly may promote Alzheimer’s Disease and Related Dementias (ADRD). BACKGROUND: There is a substantial conflicting literature concerning the hypothesis that surgery and anesthesia promotes ADRD. Much of the literature is confounded by indications for surgery or has small sample size. This study examines elderly patients with appendicitis, a common condition that strikes mostly at random after controlling for some known associations. METHODS: A matched natural experiment of patients undergoing appendectomy for appendicitis versus control patients without appendicitis using Medicare data from 2002 to 2017, examining 54,996 patients without previous diagnoses of ADRD, cognitive impairment, or neurological degeneration, who developed appendicitis between ages 68 through 77 years and underwent an appendectomy (the “Appendectomy” treated group), matching them 5:1 to 274,980 controls, examining the subsequent hazard for developing ADRD. RESULTS: The hazard ratio (HR) for developing ADRD or death was lower in the Appendectomy group than controls: HR = 0.96 (95% CI 0.94, 0.98), P < 0.0001, (28.2% in Appendectomy versus 29.1% in controls, at 7.5 years). The HR for death was 0.97 (0.95, 0.99), P = 0.002, (22.7% versus 23.1% at 7.5 years). The HR for developing ADRD alone was 0.89 (0.86, 0.92), P < 0.0001, (7.6% in Appendectomy versus 8.6% in controls, at 7.5 years). No subgroup analyses found significantly elevated rates of ADRD in the Appendectomy group. CONCLUSIONS: In this natural experiment involving 329,976 elderly patients, exposure to appendectomy surgery and anesthesia did not increase the subsequent rate of ADRD.

Recent series have raised concerns about the oncologic outcomes of transanal total mesorectal excision for mid and low rectal cancer. There is a paucity of large data sets from the United States to contribute to the ongoing international discourse.This study aimed to investigate the rate of local recurrence and other oncologic outcomes in patients undergoing transanal total mesorectal excision for rectal adenocarcinoma.This study is a retrospective review of patients undergoing transanal total mesorectal excision for primary rectal cancer from January 2014 to December 2019.This study was conducted at a single academic tertiary care medical center in the United States.Consecutive patients aged ≥18 years undergoing surgical resection for primary rectal cancer were selected.The transanal total mesorectal excision procedures were performed utilizing a 2-team approach.Primary outcomes were pathologic quality, local and distant recurrence, treatment-related complications, and overall- and cancer-specific survival.Seventy-nine consecutive patients were included. The median age was 58 years (interquartile range, 50-64), and median BMI was 28 kg/m2 (interquartile range, 24.6-32.4). The mesorectum was complete in 69 patients (87.3%), nearly complete in 9 (11.4%), and incomplete in 1 (1.3%). There was circumferential resection margin involvement (1 mm) in 4 patients (5.1%), and no patients had a positive distal margin (1 mm) or intraoperative rectal perforation. Composite optimal pathology was achieved in 94.9% of specimens. Median follow-up was 29 months (range, 6-68). There were no local recurrences. Distant metastases were found in 10 (13.5%) patients and diagnosed after a median of 14 months (range, 0.6-53). Disease-free survival was 91.2% at 2 years, and overall survival was 94.7% at 2 years.Retrospective design, a single center, and relatively short follow-up period were limitations of this study.The oncologic outcomes of this cohort support the use of transanal total mesorectal excision in the surgical management of mid to low rectal cancer at centers with appropriate expertise. See Video Abstract at http://links.lww.com/DCR/B723.ANTECEDENTES:Estudios recientes han suscitado preocupación sobre los resultados oncológicos de la excisión total del mesorecto por vía transanal en casos de cáncer de recto medio y bajo. Existe una gran escasez de conjuntos de datos en los Estados Unidos, para contribuir en el actual discurso internacional sobre el tema.OBJETIVO:Investigar la tasa de recurrencia local y otros resultados oncológicos en pacientes sometidos a una excisión total del mesorrecto por vía transanal por adenocarcinomas de recto.DISEÑO:Revisión retrospectiva de pacientes sometidos a excisión total del mesorecto por vía transanal en casos de cáncer de recto primario desde enero de 2014 hasta diciembre de 2019.AJUSTE:Centro médico Universitario de atención terciaria único en los Estados Unidos.PACIENTES:Aquellos pacientes consecutivos de ≥ 18 años de edad, sometidos a resección quirúrgica por cáncer de recto primario.INTERVENCIÓN:Los procedimientos de excisión total del mesorecto por vía transanal se realizaron utilizando un enfoque de dos equipos.PRINCIPALES MEDIDAS DE RESULTADO:Los resultados primarios fueron la calidad anatomo-patológica de las piezas, la recidiva local y a distancia, las complicaciones relacionadas con el tratamiento y la sobrevida global específica para el cáncer.RESULTADOS:Se incluyeron 79 pacientes consecutivos. La mediana de edades fue de 58 años (IQR, 50-64) y la mediana del índice de masa corporal fue de 28 kg / m (IQR, 24,6-32,4). El mesorrecto se encontraba completo en 69 pacientes (87,3%), casi completo en 9 (11,4%) e incompleto en 1 (1,3%). Hubo afectación de CRM (1 mm) en 4 pacientes (5,1%) y ningún paciente tuvo un margen distal positivo (1 mm) o perforación rectal intraoperatoria. La histopatología óptima compuesta se logró en el 94,9% de las muestras. La mediana de seguimiento fue de 29 meses (rango 6-68). No se presentaron recurrencias locales. Se encontraron metástasis a distancia en 10 (13,5%) pacientes y se diagnosticaron después de una mediana de 14 meses (rango 0,6-53). La sobrevida libre de enfermedad fue del 91,2% a los 2 años y la sobrevida global fue del 94,7% a los 2 años.LIMITACIONES:Diseño retrospectivo, unicéntrico y período de seguimiento relativamente corto.CONCLUSIÓN:Los resultados oncológicos de este estudio de cohortes, apoyan la realización de excisión total del mesorecto por vía transanal para el tratamiento quirúrgico del cáncer de recto medio y bajo, en centros con la experiencia adecuada. Consulte Video Resumen en http://links.lww.com/DCR/B723. (Traducción-Dr. Xavier Delgadillo).

Objectives Oncologists estimate patients' prognosis to guide care. Evidence suggests oncologists tend to overestimate life expectancy, which can lead to care with questionable benefits. Information obtained from geriatric assessment may improve prognostication for older adults. In this study, we created a geriatric assessment-based prognostic model for older adults with advanced cancer and compared its performance to alternative models. Materials and methods We conducted a secondary analysis of a trial (URCC 13070; PI: Mohile) capturing geriatric assessment and vital status up to one year for adults age ≥ 70 years with advanced cancer. Oncologists estimated life expectancy as 0–6 months, 7–12 months, and > 1 year. Three statistical models were developed: (1) a model including age, sex, cancer type, and stage (basic model), (2) basic model + Karnofsky Performance Status (≤50, 60–70, and 80+) (KPS model), and (3) basic model +16 binary indicators of geriatric assessment impairments (GA model). Cox regression was used to model one-year survival; c-indices and time-dependent c-statistics assessed model discrimination and stratified survival curves assessed model calibration. Results We included 484 participants; mean age was 75; 48% had gastrointestinal or lung cancer. Overall, 43% of patients died within one year. Oncologists classified prognosis accurately for 55% of patients, overestimated for 35%, and underestimated for 10%. C-indices were 0.61 (basic model), 0.62 (KPS model), and 0.63 (GA model). The GA model was well-calibrated. Conclusions The GA model showed moderate discrimination for survival, similar to alternative models, but calibration was improved. Further research is needed to optimize geriatric assessment-based prognostic models for use in older adults with advanced cancer.

Hypertensive intracerebral hemorrhage (ICH) is commonly provoked by rupture of basal ganglia and thalamus supplying lenticulostriate arteries (LSAs). The purpose of this study was to identify regions within the LSAs that are prone to rupture. A two-dimensional mathematical model of the LSAs was created in order to identify the location of vascular rupture and a parallel-plate flow chamber was used to evaluate the role of shear stresses on endothelial cell damage. Areas within the LSAs that were prone to rupture were distal parts of the vessels supplying the basal ganglia and thalamus, those located in close proximity to the trunk of the middle cerebral artery (MCA), as well as the vessel wall at the bifurcation point of the LSAs. Furthermore, more severe endothelial cell damage was observed at the origin of the LSAs. This study identified susceptible sites of blood vessel rupture within the LSAs, which, in the future, could be used to anticipate and potentially prevent the occurrence of clinical hypertensive ICH.

OBJECTIVES To examine the efficacy and safety of radiotherapy for the prevention of heterotopic ossification (HO) about the elbow. DESIGN Retrospective chart review. SETTING Level 1 Trauma Center. PATIENTS/PARTICIPANTS Two hundred and twenty-nine patients who received prophylactic radiotherapy (XRT) over a 15 year period were identified. Patients were included if they received XRT to the elbow joint and had at least 12 weeks of follow up after XRT. Fifty-four patients were ultimately included. INTERVENTION All patients were treated with a single dose of 7 Gy. 98% of patients received XRT within 24 hours after surgery, and all patients received XRT within 72 hours after surgery. MAIN OUTCOMES MEASUREMENTS The primary study measures evaluated were the presence or absence of clinically symptomatic HO and the presence of radiographic HO after XRT to the elbow joint. RESULTS Eighteen patients were treated with XRT after a traumatic injury requiring surgery (primary prophylaxis), and 36 were treated with XRT after excision surgery to remove HO which had already formed (secondary prophylaxis). In the primary cohort, 16.7% developed symptomatic HO after XRT, and 11.1% required surgery to resect heterotopic bone. In the secondary cohort, 11.1% developed symptomatic HO after surgery and XRT, and 5.5% required resection surgery. No secondary malignancies were identified. CONCLUSIONS Our findings suggest that XRT for elbow HO may be safe and effective for both primary and secondary HO. XRT for HO was not shown to be associated with radiation-induced sarcoma in this series, at least in the short term. Further study in a large patient population with extended follow up is required to better characterize populations at high risk for development of HO and secondary malignancy. [ZERO WIDTH SPACE]. LEVEL OF EVIDENCE Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

To describe the baseline characteristics of patients with positivity for antiphospholipid antibodies (aPLs) who were enrolled in an international registry, the Antiphospholipid Syndrome (APS) Alliance for Clinical Trials and International Networking (APS ACTION) clinical database and repository, overall and by clinical and laboratory subtypes.The APS ACTION registry includes adults who persistently had positivity for aPLs. We evaluated baseline sociodemographic and aPL-related (APS classification criteria and "non-criteria") characteristics of patients overall and in subgroups (aPL-positive without APS, APS overall, thrombotic APS only, obstetric APS only, and both thrombotic APS/obstetric APS). We assessed baseline characteristics of patients tested for the presence of three aPLs (lupus anticoagulant [LAC] test, anticardiolipin antibody [aCL], and anti-βThe 804 aPL-positive patients assessed in the present study had a mean age of 45 ± 13 years, were 74% female, and 68% White; additionally, 36% had other systemic autoimmune diseases. Of these 804 aPL-positive patients, 80% were classified as having APS (with 55% having thrombotic APS, 9% obstetric APS, and 15% thrombotic APS/obstetric APS). In the overall cohort, 71% had vascular thrombosis, 50% with a history of pregnancy had obstetric morbidity, and 56% had experienced at least one non-criteria manifestation. Among those with three aPLs tested (n = 660), 42% were triple aPL-positive. While single-, double-, and triple aPL-positive subgroups had similar frequencies of vascular, obstetric, and non-criteria events, these events were lowest in the single aPL subgroup, which consisted of aCLs or anti-βOur study demonstrates the heterogeneity of aPL-related clinical manifestations and laboratory profiles in a multicenter international cohort. Within single aPL positivity, LAC may be a major contributor to clinical events. Future prospective analyses, using standardized core laboratory aPL tests, will help clarify aPL risk profiles and improve risk stratification.

Low-grade serous ovarian cancer (LGSC) is a morphologically and molecularly distinct subtype of ovarian cancer, accounting for ~10% of serous carcinomas. Women typically present at a younger age and have a protracted clinical course compared with the more common, high-grade serous ovarian cancer. Currently, the primary treatment of LGSC is the same as other epithelial ovarian cancer subtypes, with treatment for most patients comprised of debulking surgery and platinum/taxane chemotherapy. Primary surgical cytoreduction to no visible residual disease remains a key prognostic factor; however, the use of platinum-based chemotherapy in both upfront and relapsed setting is being questioned due to low response rates in LGSC. Most LGSC expresses steroid hormone receptors, and selected patients may benefit from endocrine maintenance therapy following chemotherapy, in particular, those with evidence of residual disease at completion of surgery. In the recurrent setting, while hormonal therapies may offer disease stabilisation with relatively low toxicity, objective response rates remain low. Strategies to increase response rates, including combining with CDK4/6 inhibitors, are being investigated. LGSC has a high prevalence of activating somatic mutations in mitogen-activated protein kinase pathway genes, most commonly in KRAS, BRAF and NRAS. Trametinib, a MEK inhibitor, has shown efficacy over chemotherapy and endocrine therapy. The use of combination targeted therapies, immunotherapy and anti-angiogenic agents, remain active areas of investigation for the treatment of LGSC.

BACKGROUND T-cell leukemia/lymphoma accounts for roughly 30% of all types of lymphoproliferative neoplasia in dogs. Two forms of T-cell lymphoma (T-zone and peripheral T-cell lymphoma) exhibit breed-specific predilections. During the course of routine immunophenotyping, we observed a breed-specific presentation of a unique form of T-cell leukemia in young English bulldogs. OBJECTIVE To describe the clinical presentation and outcome of a novel T-cell leukemia in English bulldogs and determine the frequency of this neoplasm in other breeds. METHODS The Clinical Hematopathology database, containing immunophenotyping data from peripheral blood of nearly 11,900 dogs, was queried for the phenotype observed in young English bulldogs: CD45+ CD4- CD8- CD5+ CD3+ class II major histocompatibility complex (MHC)ᶫ° T-cell leukemia. Clinical presentation, treatment, and survival data were collected for a subset of cases. RESULTS Fifty-five English bulldog cases and 64 cases of other breeds were identified. No other breed was represented by >5 cases. Complete medical records were obtained for 50 bulldogs. Median age at diagnosis was 3 years and 76% of cases were male. Median lymphocyte count was 44,286 lymphocytes/ul (range, 1,800-317,684/ul) and lymphocytes were described as small to intermediate-sized. Many dogs were thrombocytopenic and had liver and spleen involvement, but not lymphadenopathy. Bulldogs that received multi-agent chemotherapy had longer median survival times (83 days) compared to dogs that received no treatment (6 days) or less aggressive therapy (15 days) (p=0.001). Non-bulldogs had similar outcomes. CONCLUSION CD4- CD8- class II MHCᶫ° T-cell leukemia has an aggressive clinical course and predilection for young English bulldogs. Breed-specific presentation suggests an underlying genetic cause. This article is protected by copyright. All rights reserved.

Aims Evaluate whether UK National Institute for Health & Care Excellence (NICE) chronic heart failure (HF) guidelines can be safely and effectively refined through specialist referral management. Methods and results All referrals to a UK centre 1/3/2019–30/5/2019 and 1/6/2020–31/7/2020 were reviewed by HF specialists. Patients were triaged to specialist assessment in HF clinic, according to the NICE HF diagnostic pathway [urgency based on N‐terminal pro brain natriuretic peptide (NTproBNP) levels], or the referrer given remote Advice & Guidance (A&G), to aid primary care management. Standardized triage criteria for recommending primary care management were (i) presentation inconsistent with HF, (ii) competing comorbidity/frailty meant specialist assessment in clinic not in patient's best interests, (iii) recent assessment for same condition, or (iv) patient had known HF. Following triage patients managed in the primary care were categorized as low or high risk of adverse outcomes. Outcome measures were 90 day all‐cause and HF hospital admission and mortality rates. Four hundred and eighty‐six patients had the median age of 80 (74–86) years, and 253 (52%) were male. Two hundred and six (42%) had NTproBNP > 2000 pg/mL. Primary care management was recommended for 128 patients (26%): 105 (22%) A&G alone and 23 input from community HF nurse specialists. Primary care management was recommended due to the following: presentation inconsistent with HF 53 (42%), more important competing comorbidity/frailty 35 (27%), recent assessment 17 (13%), and known HF 23 (18%). Patients managed in primary care had higher rates of all‐cause hospitalization (30% vs. 19%; P = 0.018) and death (7% vs. 2%; P = 0.0054) than those seen in HF clinic. Of those managed in primary care, 50 (39%) were determined to be at low risk and 78 (61%) at high risk. High‐risk patients were older (87 vs. 80 years; P = 0.0026), had much higher NTproBNP (2666 vs. 697 pg/mL; P

PURPOSE Genomic tests improve accuracy of risk prediction for early breast cancers but these are expensive. This study evaluated the clinical utility of EndoPredict®, in terms of impact on adjuvant therapy recommendations and identification of parameters to guide selective application. METHODS Patients with ER-positive, HER2-negative, and early-stage invasive breast cancer were tested with EndoPredict®. Two cohorts were recruited: one consecutively and another at clinical team discretion. Systemic treatment recommendations were recorded before and after EndoPredict® results were revealed to the multidisciplinary team. RESULTS 233 patients were recruited across five sites: 123 consecutive and 110 at clinical team discretion. In the consecutive cohort 50.6% (62/123) cases were classified high risk of recurrence by EndoPredict®, compared with 62.7% (69/110) in the selective cohort. A change in treatment recommendation was significantly more likely (p

This invited opinion article reviews current uses and controversies in vernacular and pharmacological cannabidiol use in pediatric neurologic disorders. Since the recent emergence of cannabidiol availability to the general public and recent Food and Drug Administration approval, it is important to highlight and expand understanding about CBD mechanism of action, long-term use, safety, and indications in children with neurological disorders.

Brain derived neutrophic factor (BDNF) is a protein and a member of the neurotrophin family of growth factors, supports the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses. The BDNF gene Val66Met polymorphism (rs6265/G196A) is responsible for BDNF synthesis that impact BDNF function that includes memory and cognition. This study investigated whether the BDNF gene Val66Met polymorphism (rs6265/G196A) is associated with cognitive function changes in both Alzheimer disease (AD) patients and elderly participants. In addition the impact of SSRI use on cognition improvement will be assessed. Healthy young, middle ages (25-59 years old) and elderly (more than 60 years old) participants (140) as well as 40 AD patients of whom are both of Saudi Arabian origin were recruited. The genotyping for the association study was performed by real-time PCR using Taqman chemistry in the ABI Prism 7900HT Sequence Detection System. Both Mini-Mental Status Examination (MMSE) and Clinical Dementia Rating (CDR) were used to assess cognitive function of healthy and AD participants, respectively. The findings showed that the BDNF Val66Met genotype distributions and allele frequencies have significant association with cognitive performance in both elderly control group and AD patients. The main findings showed that carriers of GG homozygotes (Val/Val) have superior cognitive performance among AD patients and elderly control subjects. In addition the use of SSRIs in 13 AD patients and 17 elderly participants positively improved cognitive function in elderly (p>0.001) but not in AD patients (p=0.1).

OBJECTIVE: Alexithymia is common among people who abuse alcohol, yet the mechanisms by which alexithymia exerts its influence remain unclear. This analysis tested a model whereby the three subscales of the Toronto Alexithymia Scale exert an indirect effect on alcohol problems through difficulties with emotion regulation and psychological distress. METHOD: Men and women (n=141) seeking alcohol use disorder (AUD) treatment completed the Toronto Alexithymia Scale, the Difficulties with Emotion Regulation Scale, the Brief Symptom Inventory, the Short Inventory of Problems, and the Alcohol Dependence Scale. RESULTS: The Difficulty Identifying Feelings subscale of the Toronto Alexithymia Scale was positively associated with alcohol problems through emotion dysregulation and psychological distress. The other two subscales, Difficulty Describing Feelings and Externally-oriented Thinking, were not associated with any other variables. CONCLUSION: People with alexithymia may consume alcohol to help regulate undifferentiated states of emotional arousal. Given the prevalence of alexithymia among people who abuse alcohol, treatment supplements that enhance the identification of emotions are needed.

BACKGROUND AND PURPOSE Lasmiditan is a novel selective 5-HT1F receptor agonist, recently approved for acute treatment of migraine. 5-HT1F receptors are widely expressed in the CNS and trigeminovascular system. Here, we have explored the therapeutic effects of 5-HT1F receptor activation in preclinical models of migraine and cluster headache. EXPERIMENTAL APPROACH Electrical stimulation of the dura mater or the superior salivatory nucleus in anaesthetised rats evoked trigeminovascular or trigeminal-autonomic reflex activation at the level of the trigeminocervical complex. Additionally, cranial autonomic manifestations in response to trigeminal-autonomic reflex activation were measured, via anterior choroidal blood flow alterations. These responses were then challenged with lasmiditan. We explored the tissue distribution of mRNA for 5-HT1F receptors in human post-mortem tissue and of several 5-HT1 receptor subtypes in specific tissue beds. KEY RESULTS Lasmiditan dose-dependently reduced trigeminovascular activation in a preclinical model of migraine. Lasmiditan also reduced superior salivatory nucleus-evoked activation of the trigeminal-autonomic reflex, but had no effect on cranial autonomic activation. mRNA profiling in human tissue showed expression of the 5-HT1F receptor in several structures relevant for migraine and cluster headache. CONCLUSION AND IMPLICATIONS Our data suggest that lasmiditan acts, at least in part, as an anti-migraine agent by reducing trigeminovascular activation. Furthermore, our results highlight a clear action for lasmiditan in a preclinical model of cluster headache. Given the proven translational efficacy of this model, our data support the potential utility of lasmiditan as a therapeutic option for the acute treatment of cluster headache attacks.

The blood-brain barrier is the selectively permeable vasculature of the brain vital for maintaining homeostasis and neurological function. Low permeability is beneficial in the presence of toxins and pathogens in the blood. However, in the presence of metastatic brain tumors, it is a challenge for drug delivery. Although the blood-tumor barrier is slightly leaky, it still is not permissive enough to allow the accumulation of therapeutic drug concentrations in brain metastases. Herein, we discuss the differences between primary brain tumors and metastatic brain tumors vasculature, effects of therapeutics on the blood-tumor barrier, and characteristics to be manipulated for more effective drug delivery.

Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype–phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.

Oxidative DNA damage induces changes in the neuronal cell cycle and activates a DNA damage response (DDR) to promote repair, but these processes may be altered under a chronic oxidative environment, leading to the accumulation of unrepaired DNA damage and continued activation of a DDR. Failure to repair DNA damage can lead to apoptosis or senescence, which is characterized by a permanent cell cycle arrest. Increased oxidative stress and accumulation of oxidative DNA damage are features of brain ageing and neurodegeneration, but the effects of persistent DNA damage in neurons are not well characterized. We developed a model of persistent oxidative DNA damage in immortalized post-mitotic neurons in vitro by exposing them to a sublethal concentration of hydrogen peroxide following a 'double stress' protocol and performed a detailed characterization of the neuronal transcriptome using microarray analysis. Persistent DNA damage significantly altered the expression of genes involved in cell cycle regulation, DDR and repair mechanisms, and mitochondrial function, suggesting an active DDR response to replication stress and alterations in mitochondrial electron transport chain. Quantitative polymerase chain reaction (qPCR) and functional validation experiments confirmed hyperactivation of mitochondrial Complex I in response to persistent DNA damage. These changes in response to persistent oxidative DNA damage may lead to further oxidative stress, contributing to neuronal dysfunction and ultimately neurodegeneration.

Background Acute type A aortic dissection (AAAD) is a life-threatening condition with high mortality within 24 hours. We hypothesized if there is a correlation between seasonal weather changes and the occurrence of AAAD. The aim of the present study was to identify seasonal specific weather and patient characteristics predicting the occurrence of AAAD. Methods This is a retrospective analysis of all consecutive patients of our department with AAAD between January 1st 2006 and December 31st 2016. The national meteorological department provided the data of temperature, humidity and air pressure during the study period. The occurrence of AAAD, preoperative neurological impairment and mortality were analyzed in correlation with the obtained daily weather data within the entire cohort and in patients with and without hypertension separately. Results A total of 517 patients were included. Mean age was 63.4±13 years, 69.4% were male and 68.8% had documented hypertension. In-hospital mortality was 17.7%. In the whole cohort, the occurrence of AAAD was significantly increased in March, October, December (P=0.016). In hypertensive patients, the occurrence was increased 34% with rising temperature (0.1-9.6 °C, OR1.34, 95% CI: 1.06-1.69, P=0.015). There was no correlation between weather variables and preoperative neurological impairment or mortality. Conclusions Our data suggests a relation between an increasing number of events of AAAD and certain months within our catchment area and a significantly increased occurrence with rising temperatures (independent from absolute temperature at time of the event) in hypertensive patients.

Background The reported incidence of venous thromboembolism (VTE) in COVID-19 patients varies widely depending on patient populations sampled and has been predominately studied in hospitalized patients. The goal of this study was to assess the evolving burden of COVID-19 and the timing of associated VTE events in a systems-wide cohort. Methods COVID-19 PCR positive hospitalized and non-hospitalized patients ≥18 years of age tested between 1/1/2020 through 12/31/2020 were retrospectively analyzed using electronic medical records from multiple states across the Mayo Clinic enterprise. Radiology reports within 90 days before and after confirmed COVID-19 diagnosis were examined for VTE outcomes using validated Natural Language Processing (NLP) algorithms. Results A 29-fold increased rate of VTE compared to the pre-COVID-19 period was noted during the first week following the first positive COVID-19 test (RR: 29.39; 95% CI 21.77-40.03). The rate of VTE steadily decreased and returned to baseline by the 6th week. Among 366 VTE events, most occurred during (n = 243, 66.3%) or after (n = 111, 30.3%) initial hospitalization. Only 11 VTE events were identified in patients who did not require hospitalization (3.0% of total VTE events). VTE and mortality increased with advancing age with a pronounced increased each decade in older patients. Conclusion We observed a profoundly increased risk of VTE within the first week after positive testing for COVID-19 that returned to baseline levels after 6 weeks. VTE events occurred almost exclusively in patients who were hospitalized, with the majority of VTE events identified within the first days of hospitalization.

Background Overuse of cardiac telemetry monitoring (telemetry) can lead to alarm fatigue, discomfort for patients, and unnecessary medical costs. Currently there are evidence-based recommendations describing appropriate telemetry use, but many providers are unaware of these guidelines. Objectives At our multihospital health system, our goal was to support providers in ordering telemetry on acute care in accordance with evidence-based guidelines and discontinuing telemetry when it was no longer medically indicated. Methods We implemented a multipronged electronic health record (EHR) intervention at two academic medical centers, including: (1) an order set requiring providers to choose an indication for telemetry with a recommended duration based on American Heart Association guidelines; (2) an EHR-generated reminder page to the primary provider recommending telemetry discontinuation once the guideline-recommended duration for telemetry is exceeded; and (3) documentation of telemetry interpretation by telemetry technicians in the notes section of the EHR. To determine the impact of the intervention, we compared number of telemetry orders actively discontinued prior to discharge and telemetry duration 1 year pre- to 1 year post-intervention on acute care medicine services. We evaluated sustainability at years 2 and 3. Results Implementation of the EHR initiative resulted in a statistically significant increase in active discontinuation of telemetry orders prior to discharge: 15% (63.4–78.7%) at one site and 13% at the other (64.1–77.4%) with greater improvements on resident teams. Fewer acute care medicine telemetry orders were placed on medicine services across the system (1,503–1,305) despite an increase in admissions and the average duration of telemetry decreased at both sites (62 to 47 hours, p Conclusion Our study showed that a low-cost, multipart, EHR-based intervention with active provider engagement and no additional education can decrease telemetry usage on acute care medicine services.

OBJECTIVE: To determine the potential longer-term effects of maternal antenatal respiratory syncytial virus (RSV) vaccination, we examined the association between cord-blood RSV-neutralizing antibodies (RSV-NA) and RSV infections in the first 2-years of life, RSV-NA at 3-years, and respiratory health to age 5-years. METHODS: Two community-based Australian birth cohorts were combined. For children with at least one atopic parent, paired serum RSV-NA levels were compared in cord-blood and at age 3-years. Weekly nasal swabs were collected in one cohort and during acute respiratory infections (ARI) in the other. Wheeze history up to age 5-years and physician-diagnosed asthma at 5-years was collected by parent report. RESULTS: In 264 children, each log10 increase of cord-blood RSV-NA level was associated with 37% decreased risk (adjusted incidence-rate-ratio (aIRR) 0.63; 95% confidence interval (CI): 0.40-1.01) of RSV-ARI and 49% decreased risk (aIRR 0.51; 95%CI: 0.25-1.02) of RSV acute lower respiratory infections (ALRI) at 12-24 months of age. However, higher cord-blood RSV-NA was associated with increased risk of all-cause ALRI (aIRR 1.29; 95%CI: 0.99-1.69), wheeze-associated ALRI (aIRR 1.75; 95%CI: 1.08-2.82) and severe ALRI (aIRR 2.76; 95%CI: 1.63-4.70) at age 6

Rationale: Cigarette smoke (CS) inhalation triggers oxidative stress and inflammation, leading to accelerated lung aging, apoptosis, and emphysema, as well as systemic pathologies. Metformin is beneficial for protecting against aging-related diseases. Objectives: We sought to investigate whether metformin may ameliorate CS-induced pathologies of emphysematous chronic obstructive pulmonary disease (COPD). Methods: Mice were exposed chronically to CS and fed metformin-enriched chow for the second half of exposure. Lung, kidney, and muscle pathologies, lung proteostasis, endoplasmic reticulum (ER) stress, mitochondrial function, and mediators of metformin effects in vivo and/or in vitro were studied. We evaluated the association of metformin use with indices of emphysema progression over 5 years of follow-up among the COPDGene (Genetic Epidemiology of COPD) study participants. The association of metformin use with the percentage of emphysema and adjusted lung density was estimated by using a linear mixed model. Measurements and Main Results: Metformin protected against CS-induced pulmonary inflammation and airspace enlargement; small airway remodeling, glomerular shrinkage, oxidative stress, apoptosis, telomere damage, aging, dysmetabolism in vivo and in vitro; and ER stress. The AMPK (AMP-activated protein kinase) pathway was central to metformin’s protective action. Within COPDGene, participants receiving metformin compared with those not receiving it had a slower progression of emphysema (−0.92%; 95% confidence interval [CI], −1.7% to −0.14%; P = 0.02) and a slower adjusted lung density decrease (2.2 g/L; 95% CI, 0.43 to 4.0 g/L; P = 0.01). Conclusions: Metformin protected against CS-induced lung, renal, and muscle injury; mitochondrial dysfunction; and unfolded protein responses and ER stress in mice. In humans, metformin use was associated with lesser emphysema progression over time. Our results provide a rationale for clinical trials testing the efficacy of metformin in limiting emphysema progression and its systemic consequences.

Many autistic children have co-occurring behavioural problems influencing core autism symptomology potentially relevant for intervention planning. Parental Expressed Emotion – reflecting critical, hostile and overprotective comments – contributes to understanding and predicting behaviour in autistic school-aged children, adolescents and adults and is typically measured using the Five-Minute Speech Sample. However, limitations exist for its use with parents of younger autistic children and so the Autism-Specific Five-Minute Speech Sample was adapted with the goal of better measuring parent Expressed Emotion in the context of childhood autism. The Autism-Specific Five-Minute Speech Sample has not yet been used to explore Expressed Emotion in parents of autistic preschoolers, nor has the relative predictive utility of the Autism-Specific Five-Minute Speech Sample and Five-Minute Speech Sample been evaluated in the same sample. We compared the two measures from speech samples provided by 51 Australian parents with newly diagnosed autistic preschoolers, including investigating their predictive value for concurrent and subsequent child internalising and externalising behaviour problems. While Autism-Specific Five-Minute Speech Sample Expressed Emotion and Five-Minute Speech Sample Expressed Emotion were associated in this sample, only Autism-Specific Five-Minute Speech Sample codes contributed significant predictive value for concurrent and subsequent child problem behaviour. These preliminary data strengthen the position that the Autism-Specific Five-Minute Speech Sample may better capture Expressed Emotion, than the Five-Minute Speech Sample, among parents of autistic preschool-aged children. Lay abstract Parental Expressed Emotion refers to the intensity and nature of emotion shown when a parent talks about their child, and has been linked to child behaviour outcomes. Parental Expressed Emotion has typically been measured using the Five-Minute Speech Sample; however, the Autism-Specific Five-Minute Speech Sample was developed to better capture Expressed Emotion for parents of children on the autism spectrum. In each case, parents are asked to talk for 5 min about their child and how they get along with their child. Parents’ statements are then coded for features such as number of positive and critical comments, or statements reflecting strong emotional involvement. While both the Five-Minute Speech Sample and Autism-Specific Five-Minute Speech Sample have been used with parents of autistic school-aged children, their relative usefulness for measuring Expressed Emotion in parents of preschool-aged children – including their links to child behaviour problems in this group – is unclear. We collected speech samples from 51 parents of newly diagnosed autistic preschoolers to investigate similarities and differences in results from the Five-Minute Speech Sample and Autism-Specific Five-Minute Speech Sample coding schemes. This included exploring the extent to which the Five-Minute Speech Sample and Autism-Specific Five-Minute Speech Sample, separately, or together, predicted current and future child behaviour problems. While the two measures were related, we found only the Autism-Specific Five-Minute Speech Sample – but not the Five-Minute Speech Sample – was related to child behavioural challenges. This adds support to the suggestion that the Autism-Specific Five-Minute Speech Sample may be a more useful measure of parental Expressed Emotion in this group, and provides a first step towards understanding how autistic children might be better supported by targeting parental Expressed Emotion.

OBJECTIVE To determine the degree to which electrocochleography (ECoG) correlates with auditory and vestibular outcomes after repair of superior semicircular canal dehiscence (SSCD) via transmastoid (TM) and middle cranial fossa (MCF) approaches. STUDY DESIGN Retrospective review. SETTING Academic tertiary referral center. PATIENTS Adults with SSCD who underwent repair between 2005 and 2019. INTERVENTION Pre-, intra-, and postoperative ECoG. MAIN OUTCOME MEASURES Patient-reported vestibular and auditory symptoms; pre-, intra-, and postoperative ECoG measures, dizziness handicap inventory (DHI) scores. RESULTS Forty-six patients underwent SSCD repair (40 unilateral, six bilateral) between 2005 and 2019, including 24 MCF and 28 TM approaches. There were no differences in preoperative, intraoperative, or postrepair ECoG SP/AP values between the MCF and TM groups (p 0.12, 0.77, 0.58). Patients had subjective improvement in vestibular symptoms (or stable vestibular function in patients operated for predominantly auditory manifestations) with both approaches (MCF: 87.5%; TM: 92.3%; p 0.64). A successful outcome correlated with intraoperative SP/AP ratio normalization (p 0.0005). Similarly, DHI scores were similar in both groups preoperatively (p 0.66) and returned to their preoperative baseline postoperatively with both (p 0.52). Reported vestibular symptoms persisted or worsened more often in patients with migraine (66.6% vs. 28.9%, p 0.03), and with persistently abnormal ECoG measures, though the latter was not statistically significant in this population (38% vs. 15%, p 0.10). Patients had subjective improvement or stability in auditory symptoms using either approach (MCF: 96%; TM: 100%; p 0.62), also correlating with SP/AP ratio normalization (p 0.008). CONCLUSIONS Correction of abnormal preoperative ECoG reliably correlates to patient symptom improvement after SSCD repair. No significant differences in postoperative outcomes were noted between patients undergoing TM versus MCF repair. Circumspection regarding the likelihood of an ideal outcome after SSCD repair should be exercised when counseling patients with concomitant migraine. DEFINE PROFESSIONAL PRACTICE GAP AND EDUCATIONAL NEED It is not certain whether outcomes differ between the two dominant approaches for SSCD repair. Surgeons and patients would benefit from an intraoperative metric that reflects satisfactory plugging of SSCD. LEARNING OBJECTIVE To highlight the reliability and unique utility of intraoperative ECoG and demonstrate the correlation between ECoG correction and symptom improvement for SSCD repair. DESIRED RESULT To report subjective and objective outcomes following SSCD repair and encourage adoption of intraoperative ECoG monitoring. LEVEL OF EVIDENCE Level V. INDICATE IRB OR IACUC IRB review considers this study exempt (HUM00169949).

Background Click-evoked auditory brainstem response (ABR) alterations are associated with autism spectrum disorder (ASD), but the specificity of these findings to the disorder is unclear. We therefore performed a meta-analysis on ABRs and attention-deficit/hyperactivity disorder (ADHD), a neurodevelopmental disorder that shares some etiologic and symptom overlap with ASD. Methods Seven papers compared ABR latency components (I, III, V, I-III, III-V, and I-V) between participants with and without ADHD. We used random-effects regression to generate component-specific estimates (Hedges's g) that adjusted for study sample sizes and the number of studies contributing to each estimate. We compared these estimates to our recently published meta-analysis of ABRs and ASD. Results All ADHD studies employed cross-sectional designs. ADHD was associated with longer latencies for waves III and V (g = 0.6, 95% confidence interval (CI) 0.3, 1.0 and g = 0.6, 95% CI 0.3, 0.9) and waves I-III and I-V (g = 0.7, 95% CI 0.2, 1.3 and g = 0.6, 95% CI 0.3, 1.0). Effect sizes from the ASD and ADHD meta-analyses did not differ from each other. Conclusions Similar patterns of ABR alterations are observed in ADHD and ASD. However, studies rarely screen for middle ear dysfunction or hearing loss and rely upon cross-sectional designs. Addressing these issues will inform the viability of ABRs as a prognostic and/or etiologic biomarker for these disorders. Impact Click-evoked ABR alterations are associated with ASD, but the specificity of these findings to the disorder is unclear. We therefore performed a meta-analysis of the association between ABRs and ADHD, a disorder that shares some etiologic and symptom overlap with ASD. ADHD was associated with longer ABR latencies for several components. These components are identical to those implicated in ASD. Effect sizes were similar in magnitude across disorders. The viability of ABRs as prognostic and/or etiologic biomarkers for neurodevelopmental risk requires addressing limitations in the literature (e.g., cross-sectional data, non-standardized ABR protocols, minimal characterization of symptom heterogeneity).

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development.

Objectives The aim of this study was to investigate the incidence of May-Thurner anatomy (MTA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and identify its predictors. Background MTA is an anatomical variant characterized by compression of left common iliac vein by the overlying right iliac artery. Over time, this leads to venous intimal scarring, blood flow stasis, and the development of deep vein thrombosis (DVT). DVT is a known risk factor for the development of CTEPH. The prevalence of this anatomical variation in patients with CTEPH is unknown. Methods A retrospective chart review was conducted in patients referred to Temple University Hospital’s cardiac catheterization laboratory for the evaluation of CTEPH between January 2016 and June 2020. Among these patients, those who underwent invasive venography were evaluated for the presence of angiographic MTA. Multivariate regression was used to identify factors associated with presence of MTA. Results A total of 193 patients with CTEPH were referred for pulmonary angiography, of whom 148 patients underwent invasive venography. MTA was identified in 44 patients (29.7%). Factors associated with the presence of MTA were lower extremity DVT (odds ratio: 3.5; 95% confidence interval: 1.58-7.8; P = 0.002), and left lower extremity post-thrombotic syndrome (odds ratio: 2.0; 95% confidence interval: 0.98-4.1; P = 0.05). Patients with MTA were more likely to undergo pulmonary thromboendarterectomy than patients without MTA (79.5% vs 58.7%; P = 0.015). Conclusions MTA is very common in patients with CTEPH. History of lower extremity DVT and or left lower extremity post-thrombotic syndrome was associated with the presence of MTA.

Background: Although religion and spirituality are important to adults with cancer and their family caregivers, few studies have tested spiritual care interventions in the outpatient setting. Aim: To determine the feasibility, acceptability, and preliminary effects of chaplain-delivered, semi-structured spiritual care to adult outpatients with advanced cancer and their caregivers. Design: In this pre/post pilot intervention study, board-certified chaplains utilized the Spiritual Care Assessment and Intervention (SCAI) framework during 4 individual sessions. Surveys at baseline and at 1, 6, and 12 weeks post-intervention assessed spiritual well-being, quality of life, depression, anxiety, and religious coping. Setting/Participants: We enrolled U.S. adult outpatients with or without an eligible family caregiver. Eligible patients were at least 18 years old and at least 2 weeks post-diagnosis of incurable and advanced-stage lung or gastrointestinal (GI) cancer. Results: Of 82 eligible patients, 24 enrolled (29.3%); of 22 eligible caregivers, 18 enrolled (81.8%). Four planned chaplain visits were completed by 87.5% of patients and 77.8% of caregivers. All enrolled participants completed baseline surveys, and more than 75% completed follow-up surveys at 2 of 3 time points. More than 80% of patients and caregivers reported they would recommend the sessions to a friend or family member. Patients’ spiritual well-being improved significantly at all timepoints compared to baseline: 1-week post (p < .006), 6-weeks post (p < .001), and 12-weeks post (p < .004). Conclusions: Spiritual care through SCAI is feasible, acceptable, and shows promise in improving spiritual well-being and other important outcomes in advanced-stage cancer patients and family caregivers. Further investigation is warranted.

OBJECTIVE: Research has identified several potential mechanisms of behavior change (MOBCs) in cognitive–behavioral therapy for alcohol use disorder, including alcohol abstinence self-efficacy (AASE), negative affect (NA), and positive affect (PA). However, little is known about when MOBCs affect clinical outcomes during alcohol use disorder treatment. Such information could advance MOBC research by identifying relationships between specific treatment content and variations in MOBCs. This study examined three MOBCs simultaneously to determine their timing and relative influence on percent days abstinent (PDA) and drinks per day (DPD). METHOD: Data were derived from a parent study assessing pretreatment change in drinking. Participants (n = 205) received 12 sessions of cognitive–behavioral therapy for alcohol use disorder. AASE, NA, and PA were measured at each treatment session, and time-varying effect models (TVEM) were used to examine their association with PDA and DPD. RESULTS: All three MOBCs were associated with PDA and DPD but varied with regard to time course, strength, and direction. For PDA, AASE was positively associated throughout treatment, NA was negatively associated from Sessions 1 to 10, and PA was positively associated from Sessions 1 to 3 and 11 to 12. For DPD, AASE was positively associated from Session 5 to the end of treatment, NA was positively associated throughout treatment although the strength of the association varied and was strongest at the beginning of treatment, and PA was positively associated from Sessions 5 to 12. CONCLUSIONS: Results show that MOBCs exert their effects at different times during treatment. In addition to replicating these results, future research should attempt to manipulate MOBCs directly and examine their influence on alcohol outcomes.

Aim To test the effectiveness of a ketogenic diet and virtual coaching intervention in controlling markers of diabetes care and healthcare utilization. Materials and methods Using a difference-in-differences analysis with a waiting list control group-a quasi-experimental methodology-we estimated the 5-month change in HbA1c, body mass index, blood pressure, prescription medication use and costs, as well as healthcare utilization. The analysis included 590 patients with diabetes who were also overweight or obese, and who regularly utilize the Veterans Health Administration (VA) for healthcare. We used data from VA electronic health records from 2018 to 2020. Results The ketogenic diet and virtual coaching intervention was associated with significant reductions in HbA1c (-0.69 [95% CI -1.02, -0.36]), diabetes medication fills (-0.38, [-0.49, -0.26]), body mass index (-1.07, [-1.95, -0.19]), diastolic blood pressure levels (-1.43, [-2.72, -0.14]), outpatient visits (-0.36, [-0.70, -0.02]) and prescription drug costs (-34.54 [-48.56, -20.53]). We found no significant change in emergency department visits (-0.02 [-0.05, 0.01]) or inpatient admissions (-0.01 [-0.02, 0.01]). Conclusions This real-world assessment of a virtual coaching and diet programme shows that such an intervention offers short-term benefits on markers of diabetes care and healthcare utilization in patients with diabetes.

OBJECTIVES Computed tomography angiography (CTA) is broadly used for long-term follow-up of graft patency after coronary artery bypass graft surgery (CABG). However, its clinical value in the early postoperative setting has not been established yet. We evaluated the benefit of adding CTA to the routine clinical work-up after CABG on patient management. METHODS A total of 305 consecutive patients (269 males, median age 68 years) underwent CABG and postoperative CTA with a median of 6 days after surgery. Graft patency and additional imaging findings were assessed and their influence on diagnosis and clinical management was evaluated. RESULTS Graft occlusion or high-grade stenosis was found in 15% of the patients. Additional findings were reported in 44% of the patients, including pericardial (2%) and pleural effusion (27%), large pneumothorax (11%), pulmonary infection (4%), cardiac or vascular thrombus (2%), pulmonary embolism (2%), sternal dehiscence (1%) and additional incidental findings requiring follow-up (6%). CT findings initiated new diagnostic and/or therapeutic measures in 15% of the patients, 47% of those with diseased grafts and 19% of patients with non-graft-related findings. No adverse events related to CTA were documented. CONCLUSIONS Early routine postoperative assessment of CABG with CTA reveals both cardiac and non-cardiac findings with a high frequency, affecting clinical management in a substantial proportion of patients.

OBJECTIVE To understand intraocular pressure (IOP) response after switching from intravitreal bevacizumab (IVB) and/or ranibizumab (IVR) to intravitreal aflibercept (IVA) for treatment-resistant neovascular age-related macular degeneration (nAMD) in patients with and without coexisting glaucoma-related diagnoses. METHODS Retrospective, cross-sectional comparative case series of 62 eyes of 58 patients treated with intravitreal injection for nAMD from March 2010 to April 2018. Patients with glaucoma-related diagnoses, defined here as open-angle glaucoma or suspicion of open-angle glaucoma, ocular hypertension, and/or narrow-angle glaucoma, were compared to those without glaucoma. IOP data were collected at baseline, at the three visits where patients received loading doses of IVB/IVR, and at all of the visits following the switch to IVA through the end of follow-up. RESULTS 19 eyes with pre-existing glaucoma-related diagnoses were compared to 43 eyes without such diagnoses. Baseline IOP was similar for glaucoma and non-glaucoma patients. The loading doses of IVB/IVR did not impact IOP; however, a small, sustained rise in IOP was noted among patients with glaucoma-related diagnoses by the final IVB/IVR injections before the switch to IVA (∆IOP 1.61 ± 0.52 mmHg, P

Background Riverine species of tsetse (Glossina) transmit Trypanosoma brucei gambiense, which causes Gambian human African trypanosomiasis (gHAT), a neglected tropical disease. Uganda aims to eliminate gHAT as a public health problem through detection and treatment of human cases and vector control. The latter is being achieved through the deployment of ‘Tiny Targets’, insecticide-impregnated panels of material which attract and kill tsetse. We analysed the spatial and temporal distribution of cases of gHAT in Uganda during the period 2010–2019 to assess whether Tiny Targets have had an impact on disease incidence. Methods To quantify the deployment of Tiny Targets, we mapped the rivers and their associated watersheds in the intervention area. We then categorised each of these on a scale of 0–3 according to whether Tiny Targets were absent (0), present only in neighbouring watersheds (1), present in the watersheds but not all neighbours (2), or present in the watershed and all neighbours (3). We overlaid all cases that were diagnosed between 2000 and 2020 and assessed whether the probability of finding cases in a watershed changed following the deployment of targets. We also estimated the number of cases averted through tsetse control. Results We found that following the deployment of Tiny Targets in a watershed, there were fewer cases of HAT, with a sampled error probability of 0.007. We estimate that during the intervention period 2012–2019 we should have expected 48 cases (95% confidence intervals = 40–57) compared to the 36 cases observed. The results are robust to a range of sensitivity analyses. Conclusions Tiny Targets have reduced the incidence of gHAT by 25% in north-western Uganda. Graphical abstract

Objective In this review we will focus on doctor-patient communication as one of the most important modifiable factors which may have a significant impact especially on the important transition between the ambulatory and terminal phases of cancer. Background High quality communication about prognosis for cancer patients is a critical component of advance care planning, and it plays a critical role among all the complex factors that affect end of life care decisions. In this review we focus on doctor-patient communication as the most important modifiable factor impacting the transitional period between the ambulatory phase and the terminal phase of cancer. We also discuss how prognostic understanding among advanced cancer patients influences decisions in regard to their cancer care. Methods We investigated studies that examined advanced cancer patients and prognosis-related communication. Conclusions We believe that oncologists' skills, experience, and comfort level in managing patients' reactions to negative information is a principal barrier that contributes substantially to the deficit of high-quality prognosis-related communication described in the literature. We also believe that it is useful to categorize oncologists with regard to their ability to engage in high quality communication, and we suggest category-specific strategies to improve oncologists' skills to conduct more effective prognosis related communication with their patients.

Synopsis The novel Coronavirus disease 2019 (SARS-CoV-2/COVID-19) has multiple systemic manifestations, including disease entities relevant to neuro-ophthalmologic practices, including Ischemic and hemorraghic strokes, cranial nerve palsies, Miller Fisher and Guillan-Barre syndrome, optic neuritis, and intracranial hypertension. The delivery of health care in Neuro-ophthalmology clinics has evolved to expand the role of telehealth and new management decisions regarding immunosuppresive treatment of pre-existing neuro-ophthalmologic diseases, and prone positioning causing ischemic optic neuropathy. This review article aims to summarize the associations between COVID-19 and neuro-ophthalmologic conditions based on a systematic review of current literature on the topic.

This study assessed the completeness of clinical information provided by ophthalmological and optometric referrals to glaucoma specialists consulting for open-angle glaucoma (OAG). A retrospective, cross-sectional study of 72 internal referrals for evaluation of OAG in a multispecialty group practice was performed. The quality of the referral was assessed based on: (1) the completeness of the clinical triad of intraocular pressure measurement, visual field (VF), and cup-to-disk ratio for each eye; (2) the availability of the data necessary to calculate an ocular hypertension treatment study (OHTS) score; and (3) the presence of retinal nerve fiber layer (RNFL) imaging by mean of optical coherence tomography. The clinical triad was available in 57% of referrals, whereas an OHTS score was calculable in 24% of referrals (p

To survive inside red blood cells (RBCs), malaria parasites export many proteins to alter their host cell's physiological properties. Although most proteins of this exportome are involved in immune avoidance or in the trafficking of exported proteins to the host membrane, about 20% are essential for parasite survival in culture but little is known about their biological functions. Here, we have combined information from large-scale genetic screens and targeted gene-disruption studies to tabulate all currently known Plasmodium falciparum exported proteins according to their likelihood of being essential. We also discuss the essential functional pathways that exported proteins might be involved in to help direct research efforts towards a more comprehensive understanding of host-cell remodelling.

Purpose To investigate corneal stiffness parameters (SPs) as predictors of future progression risk in glaucoma suspect eyes. Design Prospective, longitudinal study. Participants Three hundred seventy-one eyes from 228 primary open-angle glaucoma suspects, based on optic disc appearance, with normal baseline Humphrey Visual Field (HVF; Carl Zeiss Meditec) results. Methods Baseline corneal SPs were measured using Corvis ST (Oculus Optikgerate GmbH). Participants were followed up every 6 months with clinical examination, HVF testing, and OCT. The baseline SP at first applanation (SP-A1) and highest concavity predicted the prospective outcome measures. Main Outcome Measures Structural progression was measured by the OCT rate of thinning of the retinal nerve fiber layer (RNFL) and ganglion cell–inner plexiform layer (GCIPL). Functional progression was assessed by permutation analysis of pointwise linear regression criteria on HVF testing. Results Stiffness parameters correlated positively with central corneal thickness (CCT), which was adjusted for in all analyses. A higher SP-A1, suggestive of a stiffer cornea, was associated with a faster rate of RNFL thinning (P Conclusions Glaucoma suspect eyes with higher corneal SPs and lower CCT, suggestive of thin and stiff corneas, are at greater risk of progression. Corneal SPs seem to act synergistically with CCT as risk factors for glaucoma progression.

Purpose: Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency. Methods: Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously. We add 21 individuals with similar PRR12 variants identified via matchmaking platforms, bringing the total number to 24. Results: We observed 12 frameshift, 6 nonsense, 1 splice-site, and 2 missense variants and one patient with a gross deletion involving PRR12. Three individuals had additional genetic findings, possibly confounding the phenotype. All patients had developmental impairment. Variable structural eye defects were observed in 12/24 individuals (50%) including anophthalmia, microphthalmia, colobomas, optic nerve and iris abnormalities. Additional common features included hypotonia (61%), heart defects (52%), growth failure (54%), and kidney anomalies (35%). PrediXcan analysis showed that phecodes most strongly associated with reduced predicted PRR12 expression were enriched for eye- (7/30) and kidney- (4/30) phenotypes, such as wet macular degeneration and chronic kidney disease. Conclusion: These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities. Graphic Abstract: [Figure not available: see fulltext.]

Breast cancer bone metastasis is currently incurable, ~75% of patients with late-stage breast cancer develop disease recurrence in bone and available treatments are only palliative. We have previously shown that production of the pro-inflammatory cytokine interleukin-1B (IL-1B) by breast cancer cells drives bone metastasis in patients and in preclinical in vivo models. In the current study, we have investigated how IL-1B from tumour cells and the microenvironment interact to affect primary tumour growth and bone metastasis through regulation of the immune system, and whether targeting IL-1 driven changes to the immune response improves standard of care therapy for breast cancer bone metastasis. Using syngeneic IL-1B/IL1R1 knock out mouse models in combination with genetic manipulation of tumour cells to overexpress IL-1B/IL1R1, we found that IL-1B signalling elicited an opposite response in primary tumours compared with bone metastases. In primary tumours, IL-1B inhibited growth, by impairing the infiltration of innate immune cell subsets with potential anti-cancer functions but promoted enhanced tumour cell migration. In bone, IL-1B stimulated the development of osteolytic metastases. In syngeneic models of breast cancer, combining standard of care treatments (Doxorubicin and Zoledronic acid) with the IL-1 receptor antagonist Anakinra inhibited both primary tumour growth and metastasis. Anakinra had opposite effects on the immune response compared to standard of care treatment, and its anti-inflammatory signature was maintained in the combination therapy. These data suggest that targeting IL-1B signalling may provide a useful therapeutic approach to inhibit bone metastasis and improve efficacy of current treatments for breast cancer patients.

Purpose Intraocular pressure (IOP) elevations may occur in early morning or outside office hours and can be missed during routine in-clinic IOP measurements. Such fluctuations or peaks likely contribute to glaucoma progression. We sought to investigate the relationship between an IOP polygenic risk score (PRS) and short-term IOP profile. Design Cross-sectional study. Participants Four hundred seventy-three eyes from 239 participants with suspected or established primary open-angle glaucoma sampled from 4 outpatient clinics in Australia between August 2016 and December 2019. Methods Participants underwent Icare HOME (Icare Oy, Vanda, Finland) tonometer measurements to record IOP 4 times daily for 5 days. Unreliable measurements were excluded. A minimum of 2 days with at least 3 reliable measurements were required. We used a validated IOP PRS derived from 146 IOP-associated variants in a linear regression model adjusted for central corneal thickness and age. Main Outcome Measures Highest recorded early morning IOP and mean IOP within and outside office hours. Early morning IOP spikes were defined by a higher early morning IOP than the maximum in-office hours IOP. Results Reliable measurements were obtained from 334 eyes of 176 participants (mean age, 64 ± 9 years). Eyes in the highest IOP PRS quintile showed an early morning IOP increase of 4.3 mmHg (95% confidence interval [CI], 1.4–7.3; P = 0.005) and mean increase in IOP outside office hours of 2.7 mmHg (95% CI, 0.61–4.7; P = 0.013) than the lowest quintile, which were significant independently after accounting for a recent in-clinic IOP measured by Goldmann applanation tonometry. Eyes in the highest PRS quintile were 5.4-fold more likely to show early morning IOP spikes than the lowest quintile (odds ratio 95% CI, 1.3–23.6; P = 0.023). Conclusions A validated IOP PRS was associated with higher early morning IOP and mean IOP outside office hours. These findings support a role for genetic risk prediction of susceptibility to elevated IOP that may not be apparent during in-clinic hours, requiring more detailed clinical phenotyping using home tonometry, the results of which may guide additional interventions to improve IOP control.

Tumoral obstruction is a small, but broadly defined, category of pulmonary hypertension that encompasses microvascular tumor emboli, tumor thrombotic microangiopathy, and macrovascular tumor obstruction within the pulmonary circulation. We present 4 patients with solid tumors, severe pre-capillary pulmonary hypertension, right ventricular failure, and pulmonary veno-occlusive–like disease. (Level of Difficulty: Advanced.), Central Illustration

Angiogenesis is essential for the sustained growth of solid tumors. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of angiogenesis and constitutive activation of HIF-1 is frequently observed in human cancers. Therefore, understanding the mechanisms governing the activation of HIF-1 is critical for successful therapeutic targeting of tumor angiogenesis. Herein, we establish a new regulatory mechanism responsible for the constitutive activation of HIF-1α in cancer, irrespective of oxygen tension. PIM1 kinase directly phosphorylates HIF-1α at threonine 455, a previously uncharacterized site within its oxygen-dependent degradation domain. This phosphorylation event disrupts the ability of prolyl hydroxylases to bind and hydroxylate HIF-1α, interrupting its canonical degradation pathway and promoting constitutive transcription of HIF-1 target genes. Moreover, phosphorylation of the analogous site in HIF-2α (S435) stabilizes the protein through the same mechanism, indicating post-translational modification within the oxygen-dependent degradation domain as a mechanism of regulating the HIF-α subunits. In vitro and in vivo models demonstrate that expression of PIM1 is sufficient to stabilize HIF-1α and HIF-2α in normoxia and stimulate angiogenesis in a HIF-1-dependent manner. CRISPR mutants of HIF-1α (Thr455D) promoted increased tumor growth, proliferation, and angiogenesis. Moreover, HIF-1α-T455D xenograft tumors were refractory to the anti-angiogenic and cytotoxic effects of PIM inhibitors. These data identify a new signaling axis responsible for hypoxia-independent activation of HIF-1 and expand our understanding of the tumorigenic role of PIM1 in solid tumors.

Cholangiocarcinoma (CC) is an uncommon malignancy with increasing incidence and dismal prognosis. We conducted a comprehensive analysis of the CC tumor immune microenvironment (TIME) based on tumor location to identify therapeutic targets. We hypothesized that the TIME of CC would vary by primary tumor location and that high tumor infiltration by CD8+ T cells and low infiltration by M2 macrophages would be associated with improved survival. A retrospective analysis was conducted of 99 CC tumor samples surgically resected between 2000 and 2014. Tissue microarrays were constructed from each tumor and stained by immunohistochemistry for 24 markers of immune cells, immune activation or inhibition, programmed cell death-ligand 1, and mesothelin. Most tumors were amply infiltrated with by CD4+, CD8+, and FoxP3+ T cells, as well as by myeloid cells. Mesothelin expression ≥1+ by immunohistochemistry was found in 68% of tumors. We identified higher densities of M1 macrophages in primary distal extrahepatic CC, as well as metastatic lesions. Mesothelin expression was also significantly higher in distal extrahepatic CC. There was no association with survival of infiltration by CD4+, CD8+, or FoxP3+ T cells, mesothelin expression, or programmed cell death-ligand 1 percentage expression, however, high CD14+ myeloid cells and high CD163+ M2 macrophages were associated with worse survival. In conclusion, the CC TIME is a heterogenous milieu highly infiltrated by innate and adaptive immune cells, which differs based on primary tumor location and between primary tumors and metastatic lesions. The correlation of intratumoral M2 macrophages and myeloid cells with a worse prognosis may suggest promising immunotherapeutic targets in CC.

Background Practice variation has been well documented across the US health care system but has not been explored in reconstructive surgical choice after keratinocyte carcinoma (KC) extirpation. Objective Assess practice variation in utilization of complex (flap or graft) reconstruction after excision of KC on the nose among a multidisciplinary group of reconstructive surgeons (Mohs micrographic and plastic surgery). Materials and methods A randomly selected subset of surgically treated, routine, primary, invasive KCs on the nose between 2000 to 2012 at the Veterans Affairs (VA)-Boston Healthcare System were assessed. Patient factors, tumor factors, and individual surgeons with sufficient case volume were fit to a multivariate logistic regression model to assess between-surgeon differences in the odds of performing a complex reconstruction. Results Ten surgeons met the case volume threshold for analysis, encompassing 338 KC on the nose excised and reconstructed from 2000 to 2012. After adjusting for patient age, tumor diameter, and location, 6 surgeons performed significantly more complex reconstructions than the reference surgeon, and the case-adjusted predicted probability of complex reconstruction ranged from 7% to 99% (p ≤ .0001). Conclusion Marked practice variation in reconstruction choice exists among surgeons after extirpation of KC on the nose at one VA health care system. High-quality comparative studies regarding optimal nasal reconstruction after extirpation of KC are needed.

Objective To examine the impact of three sequential statewide policy and legislative interventions on opioid prescribing practices among privately insured individuals in North Carolina. Methods An interrupted time series approach was used to examine level and trajectory changes of new and prevalent opioid prescription rates, days’ supply, and daily morphine milligram equivalents before and after implementation of a 1) prescription drug monitoring program, 2) state medical board initiative, and 3) legislative action. Analyses were conducted using individual-level claims data from a large private health insurance provider serving North Carolina residents, ages 18–64 years, from January 2006 to August 2018. Results Rates of new and prevalent prescription opioid patients were relatively unaffected by the prescription monitoring program but sharply declined in the months immediately following both medical board (−3.7 new and −19.3 prevalent patients per 10,000 person months) and legislative (−14.1 new and −26.7 prevalent patients) actions. Among all opioid prescriptions, days’ supply steadily increased on average over the study period but declined after legislative action (−1.5 days’ supply per year). Conclusions The voluntary prescription drug monitoring program launched in 2010 only marginally affected opioid prescribing patterns on its own, but its redeployment as an investigative and clinical tool in multifaceted public policy approaches by the state medical board and legislature later in the decade plausibly contributed to notable declines in prescription rates and days’ supply. This study lends new emphasis to the importance of enforcement mechanisms for state and national policies seeking to reverse this critical public health crisis.

Alzheimer's disease (AD) is a neurodegenerative disorder with multiple pathological features. Therefore, a multitarget-directed ligands (MTDLs) strategy has been developed to treat AD. We have previously designed and synthesized dimeric tacrine(10)-hupyridone (A10E), a novel tacrine derivative with acetylcholinesterase (AChE) inhibition and brain-derived neurotrophic factor (BDNF) activation activity, by linking tacrine and a fragment of huperzine A. However, it was largely unknown whether A10E could act on other AD targets and produce cognitive-enhancing ability in AD animal models. In this study, A10E could prevent cognitive impairments in APP/PS1 transgenic mice and β-amyloid (Aβ) oligomers-treated mice, with higher potency than tacrine and huperzine A. Moreover, A10E could effectively inhibit Aβ production and deposition, alleviate neuroinflammation, enhance BDNF expression, and elevate cholinergic neurotransmission in vivo. At nanomolar concentrations, A10E could inhibit Aβ oligomers-induced neurotoxicity via the activation of tyrosine kinase receptor B (TrkB)/Akt pathway in SH-SY5Y cells. Furthermore, Aβ oligomerization and fibrillization could be directly disrupted by A10E. Importantly, A10E at high concentrations did not produce obvious hepatotoxicity. Our results indicated that A10E could produce anti-AD neuroprotective effects via the inhibition of Aβ aggregation, the activation of the BDNF/TrkB pathway, the alleviation of neuroinflammation, and the decrease of AChE activity. As MTDLs could produce additional benefits, such as overcoming the deficits of drug combination and enhancing the compliance of AD patients, our results also suggested that A10E might be developed as a promising MTDL lead for the treatment of AD.

Determine the efficacy of intraoperative traction (IOT) on curve correction in AIS. A prospective, multicenter, longitudinal database identified patients with major thoracic AIS (Lenke 1–4) treated with surgery using IOT and follow-up of 2 years. These cases were matched to comparable cases treated without traction (non-IOT). All patients were treated with single-stage posterior only surgery with pedicle screw constructs. Perioperative, radiographic and clinical outcome data at 2 years post-op were compared between the groups. 104 cases treated with IOT were matched to 104 treated without IOT. Operating room time was significantly greater in the IOT group (339 vs. 306 min, p = 70° (IOT 72% vs. non-IOT 64%, p = 0.04). IOT was associated with a significant reduction in 2D T5–T12 kyphosis measurements (IOT − 6.5° vs non-IOT + 0.48°, p

Pancreatic neuroendocrine tumors (PanNETs) are increasingly common. Experts debate whether small tumors should be resected. Tumor destruction via injection of cytotoxic agents could offer a minimal invasive approach to this controversy. We hypothesize that a new drug delivery system comprising chondroitin sulfate (CS) hydrogels loaded with sunitinib (SUN) suppresses tumor growth in PanNET cells. Injectable hydrogels composed of CS modified with methacrylate groups (MA) were fabricated and loaded with SUN. Loading target was either 200 µg (SUN200-G) or 500 µg (SUN500-G) as well as sham hydrogel with no drug loading (SUN0-G). SUN release from hydrogels was monitored in vitro over time and cytotoxicity induced by the released SUN was evaluated using QGP-1 and BON1 PanNET cell lines. QGP-1 xenografts were developed in 35 mice and directly injected with 25 µL of either SUN200-G, SUN500-G, SUN0-G, 100 µL of Sunitinib Malate (SUN-inj), or given 40 mg/kg/day oral sunitinib (SUN-oral). SUN-loaded CSMA hydrogel retained complete in vitro cytotoxicity toward the QGP-1 PanNET and BON-1 PanNET cell lines for 21 days. Mouse xenograft models with QGP-1 PanNETs showed a significant delay in tumor growth in the SUN200/500-G, SUN-inj and SUN-oral groups compared with SUN0-G (p = 0.0014). SUN500-G hydrogels induced significantly more tumor necrosis than SUN0-G (p = 0.04). There was no difference in tumor growth delay between SUN200/500G, SUN-inj, and SUN-oral. This study demonstrates that CSMA hydrogels loaded with SUN suppress PanNETs growth. This drug delivery could approach represents a novel way to treat PanNETs and other neoplasms via intratumoral injection.

The epidemic emergence of relatively rare and geographically isolated flaviviruses adds to the ongoing disease burden of viruses such as dengue. Structural analysis is key to understand and combat these pathogens. Here, we present a chimeric platform based on an insect-specific flavivirus for the safe and rapid structural analysis of pathogenic viruses. We use this approach to resolve the architecture of two neurotropic viruses and a structure of dengue virus at 2.5 Å, the highest resolution for an enveloped virion. These reconstructions allow improved modelling of the stem region of the envelope protein, revealing two lipid-like ligands within highly conserved pockets. We show that these sites are essential for viral growth and important for viral maturation. These findings define a hallmark of flavivirus virions and a potential target for broad-spectrum antivirals and vaccine design. We anticipate the chimeric platform to be widely applicable for investigating flavivirus biology., Understanding virus assembly could identify potential drug targets. Here the authors use a safe and efficient method to solve pathogenic flavivirus structures, revealing two lipid-like ligands within highly conserved pockets of the stem region of envelope protein that are important for virus maturation.