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BACKGROUND Obstructive sleep apnoea (OSA) episode related blood pressure (BP) surge may mediate the association of OSA with cardiovascular disease. However, BP is not measured during a clinical sleep study. METHOD We tested the feasibility of incorporating the Caretaker physiological monitor, which utilizes a novel continuous beat-to-beat (b-b) BP monitoring technology, into polysomnography (PSG) and aimed to characterize BP surges related to obstructive respiratory events. B-b BP was concurrently collected and merged with PSG data on a posthoc basis. We compared BP surge between mean respiratory (apnoea, hypopnea and desaturation-alone events) and nonrespiratory events (spontaneous or leg movement-related arousals). We examined the association of the degree of oxygen desaturation with BP surge in a given respiratory event combining all events. A total of 17 consecutive patients (12 men, mean 52 years old, nine diagnostic and eight split-night PSGs) undergoing clinically indicated PSG were included after excluding one patient with poor signal quality due to excessive movement. RESULTS Caretaker was well tolerated. Mean respiratory BP surge ranged from 5 to 19 mmHg [Median (IQR) = 13.9 (9.5--16.2)]. Mean BP surge between the respiratory and nonrespiratory events was similar [13.8 (4.5) vs. 14.9 (5.3) mmHg, P = 0.13]. Accounting for the count distribution of desaturation/BP surge data pair events, there was a linear correlation between the degree of oxygen desaturation and BP surge (R = 0.57, P

Better management of head and neck squamous cell carcinomas (HNSCCs) requires a clearer understanding of tumor biology and disease risk. Bitter taste receptors (T2Rs) have been studied in several cancers, including thyroid, salivary, and GI, but their role in HNSCC has not been explored. We found that HNSCC patient samples and cell lines expressed functional T2Rs on both the cell and nuclear membranes. Bitter compounds, including bacterial metabolites, activated T2R-mediated nuclear Ca2+ responses leading to mitochondrial depolarization, caspase activation and ultimately apoptosis. Buffering nuclear Ca2+ elevation blocked caspase activation. Furthermore, increased expression of T2Rs in HNSCCs from The Cancer Genome Atlas is associated with improved overall survival. This work suggests that T2Rs are potential biomarkers to predict outcomes and guide treatment selection, may be leveraged as therapeutic targets to stimulate tumor apoptosis, and may mediate tumor-microbiome crosstalk in HNSCC.

BACKGROUND Due to inherent impact on quality of life, metastatic head and neck cancer patients are well-suited to benefit from palliative care (PC). Our objective was to examine factors that shape PC utilization and implications for overall survival in stage IVc head and neck cancer patients. METHODS A retrospective study of patients with stage IVc head and neck cancer in the National Cancer Database from 2004 and 2015 was conducted. RESULTS 7794 cases met inclusion criteria, of which 19.3% received PC. PC use was associated with more recent years of diagnosis, Northeast facility geography, and non-private insurances (p

PURPOSE OF THE REVIEW: Hypertension is the foremost risk factor for cardiovascular disease (CVD) and death. This review highlights recent findings that apply to the prevention, detection and management of high BP, in the context of the 2017 American College of Cardiology/American Heart Association blood pressure (BP) guideline. RECENT FINDINGS: Several new findings on the association of BP measurement with CVD outcomes are now available. (1) Beginning with a systolic BP (SBP) as low as 90 mm Hg, coronary artery calcium deposition and the risk of incident ASCVD increased in stepwise fashion with increasing SBP levels within the normal range in adults at low risk for ASCVD. (2) Isolated diastolic hypertension was not associated with atherosclerotic cardiovascular disease (ASCVD), heart failure or chronic kidney disease. (3) Nocturnal BP appeared to be better associated with CVD outcomes than office or daytime BP. (4) In a head-to-head comparison, home BP monitoring had higher reliability and predictive value than office or ambulatory BP to detect left ventricular hypertrophy, an intermediate form of hypertension-related target organ damage. In addition, new information indicates that autonomous aldosterone production is present in a substantially larger percentage of adults with hypertension than previously recognized. Finally, intensive BP lowering is associated with a significant reduction in the incidence of mild cognitive impairment, a precursor of dementia. SUMMARY: Ongoing research has made significant progress in the prevention, detection, and management of high blood pressure, clarifying, amplifying and/or supporting the 2017 ACC/AHA BP guideline recommendations.

Latino immigrant men have high rates of unhealthy alcohol use, a wide range of behaviors, from drinking above the recommended limits to severe alcohol use disorder, yet have low levels of treatment-seeking. Little is known about their preferred sources of care and barriers to care. Using survey data from a community-based sample of Latino immigrant men (N=121) with unhealthy alcohol use (AUDIT≥6), we described help-seeking patterns and perceived barriers to care. The mean AUDIT score was 20 (SD 10; range 6-40), and 49% of men had severe levels of unhealthy alcohol use (AUDIT score ≥ 20). We observed low help-seeking rates and high levels of perceived internal and external barriers. Thirty percent reported having sought help for drinking. Most men reported wanting to solve their drinking problem on their own (65%). Our findings were consistent with previous research. Future studies should further describe barriers to treatment among low-income Latino immigrant men with unhealthy alcohol use and identify ways to increase access to low-cost, high-quality treatment options.

Several important findings bearing on the prevention, detection, and management of hypertension have been reported since publication of the 2017 American College of Cardiology/American Heart Association Blood Pressure Guideline. This review summarizes and places in context the results of relevant observational studies, randomized clinical trials, and meta-analyses published between January 2018 and March 2021. Topics covered include blood pressure measurement, patient evaluation for secondary hypertension, cardiovascular disease risk assessment and blood pressure threshold for drug therapy, lifestyle and pharmacological management, treatment target blood pressure goal, management of hypertension in older adults, diabetes, chronic kidney disease, resistant hypertension, and optimization of care using patient, provider, and health system approaches. Presenting new information in each of these areas has the potential to increase hypertension awareness, treatment, and control which remain essential for the prevention of cardiovascular disease and mortality in the future.

Objective A paucity of literature is available discussing the associated risk factors, treatment options (including the use of minimally invasive surgery), and outcomes related to lumbar disc herniation (LDH) in children. We have discussed the risk factors for disc disease among pediatric patients and evaluated the efficacy of the minimally invasive approach. Methods A retrospective review of pediatric patients with lumbar disc disease who had undergone microdiscectomy at our institution from 2005 to 2016 was conducted. The preoperative presentation, hospital course, postoperative course, and follow-up data (≥3 years) were reviewed. We evaluated the risk factors for LDH and the surgical outcomes for both groups. Results A total of 52 pediatric patients had undergone 61 lumbar disc surgeries for LDH in our department from 2005 to 2016. Their average age at surgery was 16.65 years. Of the 61 procedures, 48 (78.7%) had been performed via the minimally invasive spine microdiscectomy approach and 13 (21.3%) via the open microdiscectomy approach. The average body mass index for all cases was 29.3 kg/m2. The average interval to diagnosis was 7.9 months. Of the 61 cases, 21 (34.4%) had been required for patients who were competitive athletes. In addition, 15 had been for LDH related to trauma (24.6%). In 46 of the 61 cases, complete resolution of the symptoms had occurred at the 1-year follow-up visit (79.2% of minimally invasive spine microdiscectomy vs 61.5% of open microdiscectomy). Conclusion Risk factors similar to those for adult LDH, such as an elevated body mass index, can be seen in the pediatric population. However, some unique risk factors such as post-traumatic LDH were found in the pediatric age group. Minimally invasive techniques are demonstrably safe and useful in this patient population.

Much of routine cancer care has been disrupted due to the perceived susceptibility to SARS-CoV-2 infection in cancer patients. Here, we systematically review the current evidence base pertaining to the prevalence, presentation and outcome of COVID-19 in cancer patients, in order to inform policy and practice going forwards. A keyword-structured systematic search was conducted on Pubmed, Cochrane, Embase and MedRxiv databases for studies reporting primary data on COVID-19 in cancer patients. Studies were critically appraised using the NIH National Heart, Lung and Blood Institute's quality assessment tool set. The pooled prevalence of cancer as a co-morbidity in patients with COVID-19 and pooled in-hospital mortality risk of COVID-19 in cancer patients were derived by random-effects meta-analyses. In total, 110 studies from 10 countries were included. The pooled prevalence of cancer as a co-morbidity in hospitalised patients with COVID-19 was 2.6% (95% confidence interval 1.8%, 3.5%, I2: 92.0%). Specifically, 1.7% (95% confidence interval 1.3%, 2.3%, I2: 57.6.%) in China and 5.6% (95% confidence interval 4.5%, 6.7%, I2: 82.3%) in Western countries. Patients most commonly presented with non-specific symptoms of fever, dyspnoea and chest tightness in addition to decreased arterial oxygen saturation, ground glass opacities on computer tomography and non-specific changes in inflammatory markers. The pooled in-hospital mortality risk among patients with COVID-19 and cancer was 14.1% (95% confidence interval 9.1%, 19.8%, I2: 52.3%). We identified impeding questions that need to be answered to provide the foundation for an iterative review of the developing evidence base, and inform policy and practice going forwards. Analyses of the available data corroborate an unfavourable outcome of hospitalised patients with COVID-19 and cancer. Our findings encourage future studies to report detailed social, demographic and clinical characteristics of cancer patients, including performance status, primary cancer type and stage, as well as a history of anti-cancer therapeutic interventions.

1. Aviva P. Aiden, MD, PhD*,†,‡ 2. McKenna E. Boyd, MS§ 3. John M. Carey, MD* 4. Shabana Yusuf, MD, MEd* 1. *Division of Pediatrics Emergency Medicine, Department of Pediatrics, 2. †Department of Molecular & Human Genetics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX; 3. ‡Department of Bioengineering, Rice University, Houston, TX; 4. §Office of Student Affairs, Baylor College of Medicine, Houston, TX 1. Address correspondence to Shabana Yusuf, MD, MEd, Associate Professor of Pediatrics, Division of Pediatrics Emergency Medicine, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, 6621 Fannin St A2210, Houston, TX 77030-2399. E-mail: syusuf{at}bcm.edu A 15-year-old boy presented to the emergency department (ED) with headache and swelling to his right forehead after a fall. The fall was unwitnessed, but the patient reports he hit his head and briefly lost consciousness. It was unclear if the patient had a syncopal event leading to the fall, or had a loss of consciousness due to the head injury resulting from the fall. On review of systems, he reported a headache that had started after the fall earlier that day, and nasal congestion with rhinorrhea for the past several days. Almost 2 weeks before, he had a headache which lasted for 1 day. The remainder of the review of systems was negative. The patient reported a vague history of a cardiac problem, and the patient’s mother reported that he was supposed to avoid sports, but had not been evaluated by a cardiologist and had not been prescribed any medications. No records were available regarding this medical history, and the patient and parent were unable to elaborate further. There was no family history of congenital heart disease, sudden death, or arrhythmias. On arrival to the ED, he was febrile to 102°F (38.9°C) and tachycardic at 118 beats/min. On physical examination, he was noted to have tender right frontal scalp swelling without fluctuance. He had nasal congestion but no other facial tenderness and normal dentition. His mental status, neurological examination, and the remainder of his physical examination including his cardiac and lung examination were all normal. Evaluation with noncontrast computed tomography (CT) scan of the head revealed “paranasal sinus disease with fluid levels in the frontal …

To investigate stroke survivors' activity participation 3-months after stroke, reasons for activity participation and the change in reason for activity participation.Thirty stroke survivors were administered the Activity Card Sort-Australia concurrent with a semi-structured interview about their activity participation. Data were analyzed using descriptive statistics and spiral content analysis.Participants had returned, in part, to 96% of their previous leisure, social/educational and household activities 3-months after-stroke; retaining more sedentary and home-based activities but fewer physically demanding and community-based activities. Thirteen participants described a change in their reasons for their activity participation. Personal, environmental and temporal dimensions explained these reasons for activity participation, as well as the changes in reason for activity participation. Full activity participation involved participants' orchestrating a dynamic mix of fulfilling their personal desires according to their current physical, mental and emotional capacity; their social, organizational and physical environmental demands and obligations; and their routines, available time and future plans.Qualitative interviews extend our understanding of the process of returning to participation in life activities and occupations following stroke to reveal that it involves the stroke survivor in a dynamic adaptation process of synchronizing personal, environmental and temporal dimensions in their daily lives.IMPLICATIONS FOR REHABILITATIONRehabilitation professionals need to recognize the unique knowledge and ability stroke survivors have to manage their capacities, activities, occupations and environments.Client-centered practice involving true collaborative partnerships are needed to ensure stroke survivors return more satisfactorily to their activities and occupations.Rehabilitation professionals need to continually consider the ongoing changing relationships that occur between the person, their capacities, social, organizational and physical environments, and the person's activity/occupational participation during recovery from stroke.Returning to full activity/occupational participation after stroke is a dynamic and continuous process.Rehabilitation needs to be provided in different forms at different stages beyond the immediate post-stroke time so that stroke survivors benefit from the "right rehabilitation" at the "right time" throughout their recovery journey.

Hypertension is a well-established and modifiable risk factor for stroke and other cardiovascular diseases. Notably, stroke is the second leading cause of death worldwide and the second most common cause of disability-adjusted life-years. As such, we provide a viewpoint on blood pressure management in stroke and emphasize blood pressure control or management for first and recurrent stroke prevention, acute stroke treatment, and for prevention of cognitive impairment or dementia.

Background Primary aldosteronism is a nonsuppressible renin-independent aldosterone production that causes hypertension and cardiovascular disease. Objective To characterize the prevalence of nonsuppressible renin-independent aldosterone production, as well as biochemically overt primary aldosteronism, in relation to blood pressure. Design Cross-sectional study. Setting 4 U.S. academic medical centers. Participants Participants with normotension (n = 289), stage 1 hypertension (n = 115), stage 2 hypertension (n = 203), and resistant hypertension (n = 408). Measurements Participants completed an oral sodium suppression test, regardless of aldosterone or renin levels, as a confirmatory diagnostic for primary aldosteronism and to quantify the magnitude of renin-independent aldosterone production. Urinary aldosterone was measured in participants in high sodium balance with suppressed renin activity. Biochemically overt primary aldosteronism was diagnosed when urinary aldosterone levels were higher than 12 μg/24 h. Results Every blood pressure category had a continuum of renin-independent aldosterone production, where greater severity of production was associated with higher blood pressure, kaliuresis, and lower serum potassium levels. Mean adjusted levels of urinary aldosterone were 6.5 μg/24 h (95% CI, 5.2 to 7.7 μg/24 h) in normotension, 7.3 μg/24 h (CI, 5.6 to 8.9 μg/24 h) in stage 1 hypertension, 9.5 μg/24 h (CI, 8.2 to 10.8 μg/24 h) in stage 2 hypertension, and 14.6 μg/24 h (CI, 12.9 to 16.2 μg/24 h) in resistant hypertension; corresponding adjusted prevalence estimates for biochemically overt primary aldosteronism were 11.3% (CI, 5.9% to 16.8%), 15.7% (CI, 8.6% to 22.9%), 21.6% (CI, 16.1% to 27.0%), and 22.0% (CI, 17.2% to 26.8%). The aldosterone-renin ratio had poor sensitivity and negative predictive value for detecting biochemically overt primary aldosteronism. Limitation Prevalence estimates rely on arbitrary and conventional thresholds, and the study population may not represent nationwide demographics. Conclusion The prevalence of primary aldosteronism is high and largely unrecognized. Beyond this categorical definition of primary aldosteronism, there is a prevalent continuum of renin-independent aldosterone production that parallels the severity of hypertension. These findings redefine the primary aldosteronism syndrome and implicate it in the pathogenesis of "essential" hypertension. Primary funding source National Institutes of Health.

Introduction Maternal nutrient partitioning, uteroplacental blood flow, transporter activity, and fetoplacental metabolism mediate nutrient delivery to the fetus. Inadequate availability or delivery of nutrients results in intrauterine growth restriction (IUGR), a leading cause of neonatal morbidity and mortality. Maternal nutrient restriction can result in IUGR, but only in an unforeseeable subset of individuals. Methods To elucidate potential mechanisms regulating fetal nutrient availability, singleton sheep pregnancies were generated by embryo transfer. Pregnant ewes received either a 50% NRC (NR; n = 24) or 100% NRC (n = 7) diet from gestational Day 35 until necropsy on Day 125. Maternal weight did not correlate with fetal weight; therefore, the six heaviest (NR Non-IUGR) and five lightest (NR IUGR) fetuses from nutrient-restricted ewes, and seven 100% NRC fetuses, were compared to investigate differences in nutrient availability. Results Insulin, multiple amino acids, and their metabolites, were reduced in fetal circulation of NR IUGR compared to NR Non-IUGR and 100% NRC pregnancies. In contrast, glucose in fetal fluids was not different between groups. There was a nearly two-fold reduction in placentome volume and fetal/maternal interface length in NR IUGR compared to NR Non-IUGR and 100% NRC pregnancies. Changes in amino acid concentrations were associated with altered expression of cationic (SLC7A2, SLC7A6, and SLC7A7) and large neutral (SLC38A2) amino acid transporters in placentomes. Discussion Results establish a novel approach to study placental adaptation to maternal undernutrition in sheep and support the hypothesis that amino acids and polyamines are critical mediators of placental and fetal growth in sheep.

Objective: Evaluate the impact of a patient phone calls and virtual wound checks within 72 hours of discharge on reducing emergency room (ER) visits and readmissions. Methods: Single arm trial with comparison to historical control data of patients undergoing multi subsite head and neck cancer operations or laryngectomy between July 2017 and June 2018 at a tertiary academic medical center. Patients were contacted within 72 hours of hospital discharge. As a supplement to the call, patients were given the opportunity to video conference with and/or send pictures to the provider with additional questions via a designated wound care phone. Results: Ninety-one patients met inclusion criteria, of whom 83 (91.2%) were contacted. Six patients (7%) were readmitted, of whom three had not been able to be reached. The patients who had been unable to be contacted were readmitted for dysphagia (2), and a urinary tract infection (1). The contacted patients were advised to go the ER during the call for concerns for postoperative bleeding (2) and gastrointestinal bleeding (1). Twenty-five patients (30%) utilized the wound care phone. 18 patients (21.7%) reported that the phone call survey prevented them from going to the ER. When compared to the prior year, there was as statistically significant decrease in ER visits ( P < .05), and no change in readmissions. Conclusions: Implementation of a phone call in the early postoperative period has the potential to decrease unnecessary ER visits and enhance patient satisfaction. This may decrease strain on the health care system and improve patient care. Level of Evidence: 4

International audience; The wealth of data in the National Cancer Database (NCDB) has allowed numerous studies investigating patient, disease, and treatment-related factors in oral cavity squamous cell carcinoma (OCSCC); however, to date, no summation of these studies has been performed. The aim of this study was to provide a concise review of the NCDB studies on OCSCC, with the hopes of providing a framework for future, novel studies aimed at enhancing our understanding of clinical parameters related to OCSCC. Two databases were searched, and 27 studies published between 2002 and 2020 were included. The average sample size was 13,776 patients (range 356- 50,896 patients). Four areas of research focus were identified: demographic and socioeconomic status, diagnosis, prognosis, and treatment. This review highlights the impact of age, sex, ethnicity, and socioeconomic status on the prognosis and management of OCSCC, describes the prognostic factors, and details the modalities and indications for neck dissection and adjuvant therapy in OCSCC. In conclusion, the NCDB is a very valuable resource for clinicians and researchers involved in the management of OCSCC, offering an incomparable perspective on a large dataset of patients. Future developments regarding hospital information management, review of data accuracy and completeness, and wider accessibility will help clinicians to improve the care of patients affected by OCSCC.

Purpose: The aim of this study was to explore experiences of upper limb somatosensory discrimination retraining in persons with stroke. Methods: A qualitative methodology was used within the context of a randomized control trial of somatosensory retraining: the CoNNECT trial. Participants in the CoNNECT trial completed a treatment program, known as SENSe therapy, to retrain upper limb somatosensory discrimination and recognition skills, and use of these skills in personally valued activities. Eight participants were interviewed on their experience of this therapy. Data were analyzed using Interpretative Phenomenological Analysis (IPA). Results: Five themes represented participants' experiences of upper limb somatosensory retraining after stroke: (1) loss of sensation and desire to reclaim normality; (2) harnessing positivity in the therapeutic relationship and specialized therapy; (3) facing cognitive and emotional challenges; (4) distinct awareness of gains and differences in bodily sensations; and (5) improved functioning: control and choice in daily performance. Persons with stroke experienced somatosensory retraining as a valuable treatment that provided them with sensory and functional gains. Conclusion: Upper limb somatosensory retraining is a treatment that persons with stroke perceived as challenging and rewarding. People who have experienced stroke believed that somatosensory retraining therapy assisted them to improve their sensation, functional arm use, as well as daily performance and participation in life.

Inhaled corticosteroids and inhaled bronchodilators are the cornerstones of therapy for a variety of airways diseases, most notably asthma and chronic obstructive pulmonary disease (COPD). Studies of new compounds, formulations, delivery devices, and drug therapy combinations are advancing our understanding of the risks and benefits of these drugs in patients with obstructive and reactive airway diseases. In addition, pharmacovigilance data have provided new insights into the safety and toxicity profile of montelukast, an oral leukotriene receptor antagonist for adult and pediatric asthma. A report on roflumilast, an oral phosphodiesterase inhibitor used for advanced COPD, provides new information on the risks of adverse neuropsychiatric events within the first few weeks of starting therapy. New reports are also available for sildenafil and vardenafil, oral phosphodiesterase inhibitors used for pulmonary hypertension, that describe rare, but serious, adverse events associated with these agents. Sildenafil has also been evaluated as an adjunctive therapy for idiopathic pulmonary fibrosis (IPF). The only two drugs currently available for IPF are the oral anti-fibrotic agents nintedanib and pirfenidone. Nintedanib has been evaluated for a related condition, familial pulmonary fibrosis, and it continues to be evaluated for its potential anti-cancer activity. A case report on pirfenidone, on the other hand, describes a possible cancer-inducing effect of this drug. Lastly, the advent of monoclonal antibody therapy continues to improve outcomes associated with uncontrolled severe asthma. Long-term safety data are starting to emerge, and data on the safety and efficacy of a new agent, dupilumab, with a novel mechanism of action, are now available.

Oropharyngeal squamous cell carcinoma (OPSCC) represents the most common HPV-related malignancy in the United States with increasing incidence. There is heterogeneity between the behavior and response to treatment of HPV-positive oropharyngeal squamous cell carcinoma that may be linked to the tumor virome. In this prospective study, a pan-pathogen microarray (PathoChip) was used to determine the virome of early stage, p16-positive OPSCC and neck metastasis treated with transoral robotic surgery (TORS) and neck dissection. The virome findings of primary tumors and neck lymph nodes were correlated with clinical data to determine if specific organisms were associated with clinical outcomes. A total of 114 patients were enrolled in the study. Double-stranded DNA viruses, specifically Papillomaviridae, showed the highest hybridization signal (viral copies) across all viral families in the primary and positive lymph node samples. High hybridization signals were also detected for signatures of Baculoviridae, Reoviridae, Siphoviridae, Myoviridae, and Polydnaviridae in most of the cancer specimens, including the lymph nodes without cancer present. Across all HPV signatures, HPV16 and 18 had the highest average hybridization signal index and prevalence. To our knowledge, this is the first study that has identified the viral signatures of OPSCC tumors. This will serve as a foundation for future research investigating the role of the virome in OPSCC. Further investigation into the OPSCC microbiome and its variations may allow for improved appreciation of the impact of microbial dysbiosis on risk stratification, oncologic outcomes, and treatment response which has been shown in other cancer sites.

OBJECTIVE Recent studies have suggested that prediabetes is associated with an increased risk for cardiovascular disease (CVD) only among individuals with concomitant hypertension. RESEARCH DESIGN AND METHODS We analyzed the association between prediabetes and CVD by hypertension status among 3,313 black adults in the Jackson Heart Study (JHS) without diabetes or a history of CVD at baseline (2000–2004). Prediabetes was defined as fasting plasma glucose between 100 and 125 mg/dL or hemoglobin A1c between 5.7 and 6.4% (39 and 46 mmol/mol). Hypertension was defined as systolic/diastolic blood pressure ≥140/90 mmHg and/or self-reported antihypertensive medication use. Participants were followed for incident CVD events and all-cause mortality through 31 December 2014. RESULTS Overall, 35% of JHS participants did not have prediabetes or hypertension, 18% had prediabetes alone, 22% had hypertension alone, and 25% had both prediabetes and hypertension. Compared with participants without either condition, the multivariable-adjusted hazard ratios for CVD events among participants with prediabetes alone, hypertension alone, and both prediabetes and hypertension were 0.86 (95% CI 0.51, 1.45), 2.09 (1.39, 3.14), and 1.93 (1.28, 2.90), respectively. Among participants with and without hypertension, there was no association between prediabetes and an increased risk for CVD (0.78 [0.46, 1.34] and 0.94 [0.70, 1.26], respectively). No association was present between prediabetes and all-cause mortality among participants with or without hypertension. CONCLUSIONS Regardless of hypertension status, prediabetes was not associated with an increased risk for CVD or all-cause mortality in this cohort of black adults.

OBJECTIVE Diabetes guidelines focus on target glycated hemoglobin (HbA1c) levels. Long-term variability in HbA1c may be predictive of hospitalization or mortality, but its importance at different average levels or trajectories is unclear. RESEARCH DESIGN AND METHODS Using English primary care data, 58,832 patients with type 2 diabetes had HbA1c average (mean of annual means), variability (coefficient of variation), and trajectory (annual regression slope) estimated during 2006–2009. Hazard ratios (HRs) for mortality and emergency hospitalization during 2010–2015, with adjustment for age, sex, smoking, BMI, duration of diabetes, and deprivation, were estimated using Cox regression. The simultaneous impact of HbA1c average, variability, and trajectory was estimated using percentiles. RESULTS In mutually adjusted models, HbA1c variability showed a consistent dose-response relationship with all-cause mortality, while average level was only important among individuals in the highest or lowest 10% of the distribution, and trajectory had no independent effect. Individuals with the most unstable HbA1c (top 10%) were almost twice as likely to die (HR 1.93 [95% CI 1.72–2.16]) than were those with the most stable (bottom 10%)—an association attenuated but not explained by hypoglycemia. For emergency hospitalizations, similar trends were seen except for coronary artery disease (CAD) and ischemic stroke (IS), where increasing average rather than variability was predictive. CONCLUSIONS HbA1c variability was strongly associated with overall mortality and emergency hospitalization and not explained by average HbA1c or hypoglycemic episodes. Only for CAD and IS hospitalizations was no association found, with average HbA1c strongly predictive. Targets should focus on both stability and absolute level of HbA1c.

Background: Seizures have the potential to cause significant morbidity and mortality, and are a common reason emergency medical services (EMS) are requested for a child. An evidence-based guideline (EBG) for pediatric prehospital seizures was published and has been implemented as protocol in multiple EMS systems. Knowledge translation and protocol adherence in medicine can be incomplete. In EMS, systems-based factors and providers' attitudes and beliefs may contribute to incomplete knowledge translation and protocol implementation. Objective: The purpose of this study was to identify paramedic attitudes and beliefs regarding pediatric seizure management and regarding potential barriers to and enablers of adherence to evidence-based pediatric seizure protocols in multiple EMS systems. Methods: This was a qualitative study utilizing semi-structured interviews of paramedics who recently transported actively seizing 0-17 year-old patients in 3 different urban EMS systems. Interviewers explored the providers' decision-making during their recent case and regarding seizures in general. Interview questions explored barriers to and enablers of protocol adherence. Two investigators used the grounded theory approach and constant comparison to independently analyze transcribed interview recordings until thematic saturation was reached. Findings were validated with follow-up member-checking interviews. Results: Several themes emerged from the 66 interviewed paramedics. Enablers of protocol adherence included point-of-care references, the availability of different routes for midazolam and availability of online medical control. Systems-level barriers included equipment availability, controlled substance management, infrequent pediatric training, and protocol ambiguity. Provider-level barriers included concerns about respiratory depression, provider fatigue, preferences for specific routes, febrile seizure perceptions, and inaccurate methods of weight estimation. Paramedics suggested system improvements to address dose standardization, protocol clarity, simplified controlled substance logistics, and equipment availability. Conclusions: Paramedics identified enablers of and barriers to adherence to evidence-based pediatric seizure protocols. The identified barriers existed at both the provider and systems levels. Paramedics identified multiple potential solutions to overcome several barriers to protocol adherence. Future research should focus on using the findings of this study to revise seizure protocols and to deploy measures to improve protocol implementation. Future research should also analyze process and outcome measures before and after the implementation of revised seizure protocols informed by the findings of this study.

Purpose To characterise the assessments and treatments that comprise “usual care” for stroke patients with somatosensory loss, and whether usual care has changed over time. Materials and methods Comparison of cross-sectional, observational data from (1) Stroke Foundation National Audit of Acute (2007–2019) and Rehabilitation (2010–2018) Stroke Services and (2) the SENSe Implement multi-site knowledge translation study with occupational therapists and physiotherapists (n = 115). Descriptive statistics, random effects logistic regression, and content analysis were used. Results Acute hospitals (n = 172) contributed 24 996 cases across audits from 2007 to 2019 (median patient age 76 years, 54% male). Rehabilitation services (n = 134) contributed organisational survey data from 2010 to 2014, with 7165 cases (median 76 years, 55% male) across 2016–2018 clinical audits (n = 127 services). Somatoensory assessment protocol use increased from 53% (2007) to 86% (2019) (odds ratio 11.4, 95% CI 5.0–25.6). Reported use of sensory-specific retraining remained stable over time (90–93%). Therapist practice reports for n = 86 patients with somatosensory loss revealed 16% did not receive somatosensory rehabilitation. The most common treatment approaches were sensory rehabilitation using everyday activities (69%), sensory re-education (68%), and compensatory strategies (64%). Conclusion Sensory assessment protocol use has increased over time while sensory-specific training has remained stable. Sensory rehabilitation in the context of everyday activities is a common treatment approach. Clinical trial registration number: ACTRN12615000933550 IMPLICATIONS FOR REHABILITATION • Only a small proportion of upper limb assessments conducted with stroke patients focus specifically on sensation; increased use of standardised upper limb assessments for sensory loss is needed. • Stroke patients assessed as having upper limb sensory loss frequently do not receive treatment for their deficits. • Therapists typically use everyday activities to treat upper limb sensory loss and may require upskilling in sensory-specific retraining to benefit patients.

Background The first wave of the COVID-19 pandemic in England resulted in an approximate 50% increase in all-cause mortality during mid-March to mid-May 2020. Previous analyses have studied COVID-related deaths, but these were under-recorded early in the pandemic due to paucity of virological testing. We propose a novel method to identify excess mortality during the pandemic by accounting for usual all-cause mortality in pre-pandemic years using a large electronic primary care database. We estimated the impact of risk factors (RFs) on excess mortality during the first wave and compared these with the impact of the same RFs on total mortality in non-pandemic times. Methods An average of 4.8 million patients aged 30–104 years active in 770 CPRD Aurum practices between 18th March and 19th May over a 6-year period (2015–2020) were included. Concurrent medical history, ethnicity, area-based deprivation and fatalities were extracted for each year. Poisson regression models fitted total mortality adjusting for age and sex, with interactions between each RF and the pandemic and reference periods. Total mortality during the pandemic was partitioned into ‘usual’ and ‘excess’ components, assuming 2015–19 rates represented ‘usual’ mortality. The association of each RF with the 2020 ‘excess’ component was derived as the excess mortality ratio (EMR), to compare with the usual mortality ratio (UMR). Results RFs where excess mortality was greatest and notably higher than usual were age >80, black ethnicity, BMI>40, dementia, learning disability, London practices and people in care-homes. For example, people of black ethnicity vs. white had an EMR=2.50 (95%CI 1.97–3.18) compared to a UMR=0.92 (95%CI 0.85–1.00). Excess mortality was more comparable to usual mortality for sex and area deprivation. The EMR for men (1.46, 95%CI 1.32–1.60) was not significantly different than the UMR=1.34 (95%CI 1.32–1.37). The EMR=2.05 (95%CI 1.76–2.38) in the most deprived quintile (vs. least) was only slightly higher than the UMR=1.70 (95%CI 1.65–1.75). Although some RFs produced EMRs significantly lower than their UMRs (Cancer, COPD), the EMRs were still >1. However, current smoking was inversely associated with excess mortality: while current smokers were 64% more likely to die than non-smokers in 2020, when the UMR=2.12 (95%CI 2.07–2.18) was accounted for, the EMR=0.80 (95%CI 0.65–0.98). Conclusion Utilising large electronic patient databases to study trends in excess mortality during the pandemic confirmed some reported findings (e.g. ethnicity, obesity and care-homes), but also highlighted important differences not apparent from studying cause specific mortality during the pandemic (e.g. smoking, sex and area deprivation).

Background Obstructive sleep apnea (OSA) is strongly associated with metabolic syndrome. Bariatric surgery is an effective available treatment for OSA; however, limited research predicts which patients undergoing bariatric surgery will undergo OSA resolution. Objectives To determine perioperative predictors for OSA resolution following bariatric surgery using a national database. Setting United Kingdom national bariatric surgery database. Methods The UK National Bariatric Surgery Registry (NBSR) was interrogated to identify all patients with OSA that underwent primary bariatric surgery between January 2009 and June 2017. Those with at least 1 follow-up recording postoperative OSA status were selected for further analysis. Demographic, pre- and postoperative outcomes were collected and analyzed. Poisson multivariate regression was conducted to identify predictors of OSA remission. Results A total of 4015 bariatric cases were eligible for inclusion: 2482 (61.8%) patients underwent laparoscopic Roux-en-Y gastric bypass (LRYGB), 1196 (29.8%) sleeve gastrectomy (LSG), and 337 (8.4%) adjustable gastric banding (LAGB). Overall, the mean excess weight loss (EWL) % for the whole group was 61.2 (SD ± 27.2). OSA resolution was recorded in 2377 (59.2%) patients. Following Poisson regression, LRYGB (risk ratio [RR], 1.49 confidence interval [CI] 1.25–1.78) and LSG (RR, 1.46 [CI 1.22–1.75] were associated with approximately 50% increased likelihood of OSA remission compared with LAGB. Greater weight loss following intervention was associated with greater likelihood of OSA remission, while both greater age and greater preoperative body mass index (BMI) were associated with reduced likelihood of OSA remission (P Conclusion This study demonstrated that metabolic surgery results in OSA remission in the majority of patients with obesity. Younger age, lower BMI preprocedure, greater %EWL and the use of LSG or LRYGB positively predicted OSA remission.

Background Large-scale electronic primary care datasets can provide up-to-date, accurate epidemiological information on rarer diseases. In the UK, approximately 70,000 people are estimated to be living with neuromuscular disease (NMD), but this approximation is over 10 years old and used historical estimates from different sources. While GPs are unlikely to make NMD diagnoses themselves, specialist diagnoses from hospital discharges and clinic letters are well recorded and electronically searchable within primary care records. The recent expansion of the Clinical Practice Research Datalink (CPRD) allows timely reporting on the recorded incidence and prevalence of NMD in the UK over the last 20 years. Methods A harmonised dataset of CPRD GOLD and Aurum was developed to provide annual denominators of actively registered patients between 2000 and 2019. A Read code hierarchy was developed for a wide range of NMDs; the database was then searched electronically to estimate incidence and (lifetime) prevalence rates in each year. To compare trends over time, rates were age standardised to the most recent CPRD population (2019). Results The combined CPRD database contained approximately 13 million patients actively registered in each year. By 2019, 28,230 active patients had ever received a Read code for one of the NMDs (223.6 per 100,000), which would scale up to approximately 149,000 people in the UK. Lifetime prevalence rates per 100,000 were higher among males (239.0) than females (208.3). The most common classifications were Guillain-Barre syndrome (40.1), myasthenia gravis (33.7), muscular dystrophy (29.5), Charcot-Marie-Tooth (29.5) and inflammatory myopathies (25.0). Since 2000, overall prevalence grew by 63% but incidence remained steady over time. All age groups showed an increase in prevalence, with the largest increases seen at older ages (≥65-years). Among individual conditions since about 2008, incidence of myasthenia gravis has been steadily rising while new cases of muscular dystrophy fell over the same period. Conclusions Lifetime recording of many NMDs on primary care records exceeds current estimates of people living with these conditions; these are important data for health service and care planning. Temporal trends suggest this number is steadily increasing and there may be twice as many people living with these conditions than currently thought. While this may be partially due to increases in recording, it cannot be simply explained by new cases as incidence is largely unchanged over time. The increase in prevalence among older ages suggest increases in life expectancy among those living with NMDs may have taken place.

Objectives Sex differences in surgically treated HPV-associated oropharyngeal squamous cell carcinoma are not defined due to the low number of affected women. We explored the oncologic outcomes of men and women with p16-positive oropharyngeal squamous cell carinoma treated with primary surgery. Materials and Methods Retrospective analysis of patients with HPV-related oropharyngeal cancer treated with surgery and pathology guided adjuvant therapy from 2007 to 2017. Primary end point was recurrence-free and overall survival. Results Of 468 men (86.7%) and 72 women (13.3%), women presented more often with clinical N0 nodal disease (25% vs 12.2%). There were no differences in adverse pathologic features or T stage, although women were more likely to present with N0 disease (16.7% vs 10%), less N2 disease (6.9% vs 17.7%, p = 0.03), and more stage I disease (88.9% vs 75%). As a result, women were more likely to undergo surgery alone (30.6% vs 14.1%) while men were more likely to require adjuvant radiation therapy (47.2% vs 36.1%). Four women (5.6%) and 30 men (6.4%, p = 0.8) died during follow-up. Multivariate analysis controlling for age, sex, treatment, and pathologic stage demonstrated no differences in overall survival between men and women. There were no differences in recurrence-free or overall survival between men and women at two and five years. Conclusions Although women undergoing transoral robotic surgery for HPV+ oropharyngeal squamous cell carcinoma may have less advanced disease, upfront surgery with pathology-guided adjuvant therapy produces similar oncologic results in men and women while accounting for disease burden.

Background Dementia is currently the leading certified underlying cause of death in England. We assess how dementia recording on Office for National Statistics death certificates (ONS) corresponded to recording in general practice records (GP) and Hospital Episode Statistics (HES). Methods Retrospective study of deaths (2001-15) in 153 English General Practices contributing to the Clinical Practice Research Datalink, with linked ONS and HES records. Results Of 207,068 total deaths from any cause, 19,627 mentioned dementia on the death certificate with 10,253 as underlying cause; steady increases occurred from 2001 to 2015 (any mention 5.3 to 15.4 %, underlying cause 2.7 to 10 %). Including all data sources, recording of any dementia increased from 13.2 to 28.6 %. In 2015, only 53.8 % of people dying with dementia had dementia recorded on their death certificates. Among deaths mentioning dementia on the death certificate, the recording of a prior diagnosis of dementia in GP and HES rose markedly over the same period. In 2001, only 76.3 % had a prior diagnosis in GP and/or HES records; by 2015 this had risen to 95.7 %. However, over the same period the percentage of all deaths with dementia recorded in GP or HES but not mentioned on the death certificate rose from 7.9 to 13.3 %. Conclusions Dementia recording in all data sources increased between 2001 and 2015. By 2015 the vast majority of deaths mentioning dementia had supporting evidence in primary and/or secondary care. However, death certificates were still providing an inadequate picture of the number of people dying with dementia.

Background and Purpose: Changes in connectivity of white matter fibers remote to a stroke lesion, suggestive of structural connectional diaschisis, may impact on clinical impairment and recovery after stroke. However, until recently, we have not had tract-specific techniques to map changes in white matter tracts in vivo in humans to enable investigation of potential mechanisms and clinical impact of such remote changes. Our aim was to identify and quantify white matter tracts that are affected remote from a stroke lesion and to investigate the associations between reductions in tract-specific connectivity and impaired touch discrimination function after stroke. Methods: We applied fixel-based analysis to diffusion magnetic resonance imaging data from 37 patients with stroke (right lesion =16; left lesion =21) and 26 age-matched healthy adults. Three quantitative metrics were compared between groups: fiber density; fiber-bundle cross-section; and a combined measure of both (fiber-bundle cross-section) that reflects axonal structural connectivity. Results: Compared with healthy adults, patients with stroke showed significant common fiber-bundle cross-section and fiber density reductions in 4 regions remote from focal lesions that play roles in somatosensory and spatial information processing. Structural connectivity along the somatosensory fibers of the lesioned hemisphere was correlated with contralesional hand touch function. Touch function of the ipsilesional hand was associated with connectivity of the superior longitudinal fasciculus, and, for the right-lesion group, the corpus callosum. Conclusions: Remote tract-specific reductions in axonal connectivity indicated by diffusion imaging measures are observed in the somatosensory network after stroke. These remote white matter connectivity reductions, indicative of structural connectional diaschisis, are associated with touch impairment in patients with stroke.

OBJECTIVE To analyze the patterns, risk factors, and salvage outcomes for locoregional recurrences (LRR) after treatment with transoral robotic surgery (TORS) for HPV-associated oropharyngeal squamous cell carcinoma (HPV+ OPSCC). STUDY DESIGN Retrospective analysis of HPV+ OPSCC patients completing primary TORS, neck dissection, and NCCN-guideline-compliant adjuvant therapy at a single institution from 2007 to 2017. METHODS Features associated with LRR, detailed patterns of LRR, and outcomes of salvage therapy were analyzed. Disease-free survival (DFS) and overall survival (OS) were calculated for subgroups of patients receiving distinct adjuvant treatments. RESULTS Of 541 patients who completed guideline-indicated therapy, the estimated 5-year LRR rate was 4.5%. There were no identifiable clinical or pathologic features associated with LRR. Compared to patients not receiving adjuvant therapy, those who received indicated adjuvant radiation alone had a lower risk of LRR (HR 0.28, 95% CI [0.09-0.83], P = .023), but there was no difference in DFS (P = .21) and OS (P = .86) between adjuvant therapy groups. The 5-year OS for patients who developed LRR was 67.1% vs. 93.9% for those without LRR (P

BackgroundCognition affects poststroke recovery, but meta-analyses of cognition have not yet provided a comparison of observational and intervention evidence.ObjectiveTo describe the trajectory of poststroke cognition and the factors that moderate it across intervention and observational cohorts.MethodsSix databases were searched up to January 2020. Studies describing quantitative changes in cognition in adults poststroke were included. Interventions were classified into pharmacological, therapist-led, nonroutine/alternative, and usual care. Summary estimates were compared via hierarchical mixed-effects models. Age, recovery stage, stroke etiology, cognitive domain targeted in studies, and intervention types were investigated as moderators of cognition. Recovery stage and intervention were further analyzed in a multiplicative metaregression model.ResultsA total of 43 intervention trials and 79 observation cohorts involving 28 222 stroke participants were included. Heterogeneity was significant (τ2= 0.09; CI = 0.01-0.21, P < .001) with no evidence of publication bias. Cognitive recovery was greater in intervention trials ( g = 0.47; CI = 0.37-0.58) than observational cohorts ( g = 0.28; CI = 0.20-0.36) across all moderators analyzed. Nonroutine/alternative and pharmacological trials achieved the best overall results ( g = 0.57, CI = 0.42-0.73, and g = 0.52, CI = 0.30-0.74, respectively), followed by therapist-led ( g = 0.46; CI = 0.17-0.74), and usual care ( g = 0.28; CI = 0.11-0.45) interventions. Medium recovery effects (ie, g ≥ 0.5) were observed in examining first-ever stroke, executive function, visuo-perceptual, consciousness, and psychomotor skills, 61 to 180 days poststroke, in participants aged 65 to 70 years.ConclusionCognitive recovery is possible using different controlled interventions in all recovery stages, with smaller benefits ≥2 years poststroke. Longer-term studies are needed to determine the role of nonroutine/alternative therapies and the association between cognitive recovery and performance in everyday activities.

Better management of head and neck squamous cell carcinomas (HNSCCs) requires a clearer understanding of tumor biology and disease risk. Bitter taste receptors (T2Rs) have been studied in several cancers, including thyroid, salivary, and GI, but their role in HNSCC has not been explored. We found that HNSCC patient samples and cell lines expressed functional T2Rs on both the cell and nuclear membranes. Bitter compounds, including bacterial metabolites, activated T2R-mediated nuclear Ca2+ responses leading to mitochondrial depolarization, caspase activation and ultimately apoptosis. Buffering nuclear Ca2+ elevation blocked caspase activation. Furthermore, increased expression of T2Rs in HNSCCs from The Cancer Genome Atlas (TCGA) is associated with improved overall survival. This work suggests that T2Rs are potential biomarkers to predict outcomes and guide treatment selection, may be leveraged as therapeutic targets to stimulate tumor apoptosis, and may mediate tumor-microbiome crosstalk in HNSCC.

Background: Heart failure (HF) and atrial fibrillation (AF) are growing in prevalence worldwide. Few studies have assessed to what extent stage 1 hypertension in the 2017 American College of Cardiology/American Heart Association blood pressure (BP) guidelines is associated with incident HF and AF. Methods: Analyses were conducted with a nationwide health claims database collected in the JMDC Claims Database between 2005 and 2018 (n=2 196 437; mean age, 44.0±10.9 years; 58.4% men). No participants were taking antihypertensive medication or had a known history of cardiovascular disease. Each participant was categorized as having normal BP (systolic BP Results: Over a mean follow-up of 1112±854 days, 28 056 incident HF and 7774 incident AF events occurred. After multivariable adjustment, hazard ratios for HF and AF events were 1.10 (95% CI, 1.05–1.15) and 1.07 (95% CI, 0.99–1.17), respectively, for elevated BP; 1.30 (95% CI, 1.26–1.35) and 1.21 (95% CI, 1.13–1.29), respectively, for stage 1 hypertension; and 2.05 (95% CI, 1.97–2.13) and 1.52 (95% CI, 1.41–1.64), respectively, for stage 2 hypertension versus normal BP. Population attributable fractions for HF associated with stage 1 and stage 2 hypertension were 6.1% (95% CI, 5.4%–6.8%) and 11.9% (95% CI, 11.5%–12.4%), respectively. The population attributable fractions for AF associated with stage 1 and stage 2 hypertension were 5.1% (95% CI, 3.4%–6.7%) and 7.5% (95% CI, 6.4%–8.6%), respectively. Conclusions: Both stage 1 hypertension and stage 2 hypertension were associated with a greater incidence of HF and AF in the general population. The American College of Cardiology/American Heart Association BP classification system may help identify adults at higher risk for HF and AF events.

INTRODUCTION To characterise somatosensory discrimination impairment of the upper-limb across domains of tactile discrimination, limb position sense and haptic object recognition using the sense_assess© kids and examine associations with upper-limb motor performance in children with hemiplegic cerebral palsy (CP). METHODS The sense_assess© kids was administered at one timepoint to 28 children, aged 6-15.5 years (M = 10.1, SD = 2.4), with hemiplegic CP (right hemiplegia n = 15) and Manual Ability Classification System Levels I (n = 11) and II (n = 17). Unimanual motor performance was quantified using the Box and Block Test. RESULTS Tactile discrimination was impaired in 18, limb position sense in 20, and haptic object recognition was impaired in 21 of 28 children. Over 80% (23/28) of children had impaired somatosensory discrimination in one or more domains. Low to moderate correlations were observed between each measure of somatosensory discrimination and motor performance. Manual ability classification was associated with limb position sense and haptic object recognition. A moderate inverse correlation (r = -.57, p

Airway submucosal gland serous cells are important sites of fluid secretion in conducting airways. Serous cells also express the cystic fibrosis (CF) transmembrane conductance regulator (CFTR). Protease-activated receptor 2 (PAR-2) is a G protein-coupled receptor that activates secretion from intact airway glands. We tested if and how human nasal serous cells secrete fluid in response to PAR-2 stimulation using Ca2+imaging and simultaneous differential interference contrast imaging to track isosmotic cell shrinking and swelling reflecting activation of solute efflux and influx pathways, respectively. During stimulation of PAR-2, serous cells exhibited dose-dependent increases in intracellular Ca2+. At stimulation levels >EC50for Ca2+, serous cells simultaneously shrank ∼20% over ∼90 s due to KCl efflux reflecting Ca2+-activated Cl−channel (CaCC, likely TMEM16A)-dependent secretion. At lower levels of PAR-2 stimulation (50for Ca2+), shrinkage was not evident due to failure to activate CaCC. Low levels of cAMP-elevating VIP receptor (VIPR) stimulation, also insufficient to activate secretion alone, synergized with low-level PAR-2 stimulation to elicit fluid secretion dependent on both cAMP and Ca2+to activate CFTR and K+channels, respectively. Polarized cultures of primary serous cells also exhibited synergistic fluid secretion. Pre-exposure to Pseudomonas aeruginosa conditioned media inhibited PAR-2 activation by proteases but not peptide agonists in primary nasal serous cells, Calu-3 bronchial cells, and primary nasal ciliated cells. Disruption of synergistic CFTR-dependent PAR-2/VIPR secretion may contribute to reduced airway surface liquid in CF. Further disruption of the CFTR-independent component of PAR-2-activated secretion by P. aeruginosa may also be important to CF pathophysiology.

Background Oropharyngeal squamous cell carcinoma (OPSCC) has now surpassed cervical cancer as the most common site of HPV-related cancer in the United States. HPV-positive OPSCCs behave differently from HPV-negative tumors and often present with early lymph node involvement. The bacterial microbiome of HPV-associated OPSCC may contribute to carcinogenesis, and certain bacteria may influence the spread of cancer from the primary site to regional lymphatics. Objective To determine the bacterial microbiome in patients with HPV-associated, early tonsil SCC and compare them to benign tonsil specimens. Method The microbiome of primary tumor specimens and lymph nodes was compared to benign tonsillectomy specimens with pan-pathogen microarray (PathoChip). Results A total of 114 patients were enrolled in the study. Patients with OPSCC had a microbiome that shifted towards more gram-negative. Numerous signatures of bacterial family and species were associated with the primary tumors and lymph nodes of cancer patients, including the urogenital pathogens Proteus mirabilis and Chlamydia trachomatis, Neisseria gonorrhoeae, Shigella dysenteriae, and Orientia tsutsugamushi. Conclusion Our results suggest that detection of urogenital pathogens is associated with lymph node metastasis for patients with HPV-positive OPSCCs. Additional studies are necessary to determine the effects of the OPSCC microbiome on disease progression and clinical outcomes.

Background Although bariatric surgery is well established as an effective treatment for patients with obesity and type 2 diabetes mellitus (T2DM), there exists reluctance to increase its availability for patients with severe T2DM. The aims of this study were to examine the impact of bariatric surgery on T2DM resolution in patients with obesity and T2DM requiring insulin (T2DM-Ins) using data from a national database and to develop a health economic model to evaluate the cost-effectiveness of surgery in this cohort when compared to best medical treatment (BMT). Methods and findings Clinical data from the National Bariatric Surgical Registry (NBSR), a comprehensive database of bariatric surgery in the United Kingdom, were extracted to analyse outcomes of patients with obesity and T2DM-Ins who underwent primary bariatric surgery between 2009 and 2017. Outcomes for this group were combined with data sourced from a comprehensive literature review in order to develop a state-transition microsimulation model to evaluate cost-effectiveness of bariatric surgery versus BMT for patients over a 5-year time horizon. The main outcome measure for the clinical study was insulin cessation at 1-year post-surgery: relative risks (RR) summarising predictive factors were determined, unadjusted, and after adjusting for variables including age, initial body mass index (BMI), duration of T2DM, and weight loss. Main outcome measures for the economic evaluation were total costs, total quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) at willingness-to-pay threshold of GBP£20,000. A total of 2,484 patients were eligible for inclusion, of which 1,847 had 1-year follow-up data (mean age of 51 years, mean initial BMI 47.2 kg/m2, and 64% female). 67% of patients no longer required insulin at 1-year postoperatively: these rates persisted for 4 years. Roux-en-Y gastric bypass (RYGB) was associated with a higher rate of insulin cessation (71.7%) than sleeve gastrectomy (SG; 64.5%; RR 0.92, confidence interval (CI) 0.86–0.99) and adjustable gastric band (AGB; 33.6%; RR 0.45, CI 0.34–0.60; p < 0.001). When adjusted for percentage total weight loss and demographic variables, insulin cessation following surgery was comparable for RYGB and SG (RR 0.97, CI 0.90–1.04), with AGB having the lowest cessation rates (RR 0.55, CI 0.40–0.74; p < 0.001). Over 5 years, bariatric surgery was cost saving compared to BMT (total cost GBP£22,057 versus GBP£26,286 respectively, incremental difference GBP£4,229). This was due to lower treatment costs as well as reduced diabetes-related complications costs and increased health benefits. Limitations of this study include loss to follow-up of patients within the NBSR dataset and that the time horizon for the economic analysis is limited to 5 years. In addition, the study reflects current medical and surgical treatment regimens for this cohort of patients, which may change. Conclusions In this study, we observed that in patients with obesity and T2DM-Ins, bariatric surgery was associated with high rates of postoperative cessation of insulin therapy, which is, in turn, a major driver of overall reductions in direct healthcare cost. Our findings suggest that a strategy utilising bariatric surgery for patients with obesity and T2DM-Ins is cost saving to the national healthcare provider (National Health Service (NHS)) over a 5-year time horizon., Emma Rose McGlone and colleagues report the clinical and cost- effectiveness of bariatric surgery for patients with Type 2 diabetes., Author summary Why was this study done? Bariatric or weight loss surgery can dramatically improve type 2 diabetes mellitus (T2DM) in patients with obesity, allowing many patients to stop medicines for T2DM completely. Unfortunately, there are limited resources for performing bariatric surgery. Patients with severe T2DM, who require daily insulin injections, are at risk of being considered lower priority than those with T2DM managed by tablet medications. This is because some small studies have suggested that T2DM requiring insulin (T2DM-Ins) is too advanced to be reversed by surgery. The aims of this study were to see how effective bariatric surgery is in patients with obesity and T2DM-Ins, as well as to determine if performing surgery in this group is cost-effective over a 5-year period. What did the researchers do and find? We used data from a nationwide registry of patients undergoing bariatric surgery in the UK to examine the effect of surgery on patients that require insulin for T2DM. We found that certain types of procedure (Roux en Y gastric bypass (RYGB) and sleeve gastrectomy (SG)) were associated with excellent rates of stopping insulin (approximately two-thirds of patients). We then devised an economic model to compare the costs of this type of surgery with the costs of treating patients using optimal medicines for T2DM. We found that performing surgery was less costly and more effective for the national healthcare provider (National Health Service (NHS)), over a 5-year timeline. What do these findings mean? These findings are important because they suggest that patients with obesity and T2DM-Ins are good candidates for bariatric surgery. Offering bariatric surgery to such patients could improve their health and provide cost savings to national healthcare payers.

BACKGROUND Some patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) do not receive guideline-recommended postoperative radiation therapy (PORT) following primary transoral robotic surgery (TORS). METHODS Three-hundred and sixty-four patients with treatment-naive, HPV-associated OPSCC were recommended to receive PORT based on clinicopathological features following TORS. Patients were stratified based on if they received PORT. Oncologic outcomes were compared. RESULTS The 3-year locoregional failure (LRF) was 32% in patients who did not receive PORT and 4% in patients who received PORT (P

Primary aldosteronism has traditionally been perceived as a rare cause of hypertension, but recent evidence suggests that its prevalence may be higher than previously believed. This study used gold...

Background Administration of progesterone (P4) to ewes during the first 9 to 12 days of pregnancy accelerates blastocyst development by day 12 of pregnancy, likely due to P4-induced up-regulation of key genes in uterine epithelia responsible for secretion and transport of components of histotroph into the uterine lumen. This study determined if acceleration of blastocyst development induced by exogenous P4 during the pre-implantation period affects fetal-placental development on day 125 of pregnancy. Suffolk ewes (n = 35) were mated to fertile rams and assigned randomly to receive daily intramuscular injections of either corn oil vehicle (CO, n = 18) or 25 mg progesterone in CO (P4, n = 17) for the first 8 days of pregnancy. All ewes were hysterectomized on day 125 of pregnancy and: 1) fetal and placental weights and measurements were recorded; 2) endometrial and placental tissues were analyzed for the expression of candidate mRNAs involved in nutrient transport and arginine metabolism; and 3) maternal plasma, fetal plasma, allantoic fluid, and amniotic fluid were analyzed for amino acids, agmatine, polyamines, glucose, and fructose. Results Treatment of ewes with exogenous P4 did not alter fetal or placental growth, but increased amounts of aspartate and arginine in allantoic fluid and amniotic fluid, respectively. Ewes that received exogenous P4 had greater expression of mRNAs for SLC7A1, SLC7A2, SLC2A1, AGMAT, and ODC1 in endometria, as well as SLC1A4, SLC2A5, SLC2A8 and ODC1 in placentomes. In addition, AZIN2 protein was immunolocalized to uterine luminal and glandular epithelia in P4-treated ewes, whereas AZIN2 localized only to uterine luminal epithelia in CO-treated ewes. Conclusions This study revealed that exogenous P4 administered in early pregnancy influenced expression of selected genes for nutrient transporters and the expression of a protein involved in polyamine synthesis on day 125 of pregnancy, suggesting a ‘programming’ effect of P4 on gene expression that affected the composition of nutrients in fetal-placental fluids.

Nutrient restriction (NR) has the potential to negatively impact birthweight, an indicator of neonatal survival and lifelong health. Those fetuses are termed as small for gestational age (SGA). Interestingly, there is a spectral phenotype of fetal growth rates in response to NR associated with changes in placental development, nutrient and waste transport, and lipid metabolism. A sheep model with a maternal diet, starting at Day 35, of 100% National Research Council (NRC) nutrient requirements (n = 8) or 50% NRC (n = 28) was used to assess alterations in fetuses designated NR SGA (n = 7) or NR NonSGA (n = 7) based on fetal weight at Day 135 of pregnancy. Allantoic fluid concentrations of triglycerides were greater in NR SGA fetuses than 100% NRC and NR NonSGA fetuses at Day 70 (P

Background and Aims. White blood cell (WBC) and neutrophil counts (NC) are common markers of inflammation and neurological stroke damage and could be expected to predict poststroke outcomes. Objective. The aim of this study was to explore the prognostic value of early poststroke WBC and NC to predict cognition, mood, and disability outcomes at 3 and 12 months poststroke. Methods. Routine clinical analyses WBC and NC were collected at 3 time points in the first 4 days of hospitalization from 156 acute stroke patients. Correlations using hierarchical or ordinal regressions were explored between acute WBC and NC and functional recovery, depression, and cognition at 3 and 12 months poststroke, after covarying for age and baseline stroke severity. Results. We found significant increases in NC between

Maternal nutrient restriction impairs placental growth and development, but available evidence suggests that adaptive mechanisms exist, in a subset of nutrient restricted (NR) ewes, that support normal fetal growth and do not result in intrauterine growth restriction (IUGR). This study utilized Affymetrix GeneChip Bovine and Ovine Genome 1.0 ST Arrays to identify novel placental genes associated with differential fetal growth rates within NR ewes. Singleton pregnancies were generated by embryo transfer and, beginning on Day 35 of pregnancy, ewes received either a 100% National Research Council (NRC) (control-fed group, n = 7) or 50% NRC (NR group, n = 24) diet until necropsy on Day 125. Fetuses from NR ewes were separated into NR non-IUGR (n = 6) and NR IUGR (n = 6) groups based on Day 125 fetal weight for microarray analysis. Of the 103 differentially expressed genes identified, 15 were upregulated and 88 were downregulated in NR non-IUGR compared to IUGR placentomes. Bioinformatics analysis revealed that upregulated gene clusters in NR non-IUGR placentomes associated with cell membranes, receptors, and signaling. Downregulated gene clusters associated with immune response, nutrient transport, and metabolism. Results illustrate that placentomal gene expression in late gestation is indicative of an altered placental immune response, which is associated with enhanced fetal growth, in a subpopulation of NR ewes.

Context New approaches are needed to address the evolution of the primary aldosteronism syndrome and to increase its recognition. Herein, we review evidence indicating that primary aldosteronism is a prevalent syndrome that is mostly unrecognized, and present a pragmatic and pathophysiology-based approach to improve diagnosis and treatment. Methods Evidence was gathered from published guidelines and studies identified from PubMed by searching for primary aldosteronism, aldosterone, renin, and hypertension. This evidence was supplemented by the authors’ personal knowledge, research experience, and clinical encounters in primary aldosteronism. Interpretation of Evidence Renin-independent aldosterone production is a prevalent phenotype that is diagnosed as primary aldosteronism when severe in magnitude, but is largely unrecognized when milder in severity. Renin-independent aldosterone production can be detected in normotensive and hypertensive individuals, and the magnitude of this biochemical phenotype parallels the magnitude of blood pressure elevation, the risk for incident hypertension and cardiovascular disease, and the likelihood and magnitude of blood pressure reduction with mineralocorticoid receptor antagonist therapy. Expansion of the indications to screen for primary aldosteronism, combined with the use of a pathophysiology-based approach that emphasizes inappropriate aldosterone production in the context of renin suppression, will substantially increase the diagnostic and therapeutic yields for primary aldosteronism. Conclusions The landscape of primary aldosteronism has evolved to recognize that it is a prevalent syndrome of renin-independent aldosterone production that contributes to the pathogenesis of hypertension and cardiovascular disease. Expanding screening indications and simplifying the diagnostic approach will enable implementation of targeted treatment for primary aldosteronism.

Resistant hypertension (RH) induces higher morbidity and mortality due to cardiovascular disease and stroke than hypertension without treatment resistance. New guidelines define RH as blood pressure (BP) ≥130/80 mmHg in a patient taking ≥3 antihypertensive agents of different classes or BP130/80 mmHg in a patient taking ≥4 antihypertensive drugs. According to the new definition, pseudo-resistance due to error in BP measurement, white coat effect and medication nonadherence must be excluded to make the diagnosis of RH. This 2020 update focuses on the lifestyle and antihypertensive drug management of RH and includes recent proof-of-principle trials of renal nerve ablation in hypertension. Stepwise evidence-based pharmacologic treatment of RH includes optimization of the 3-drug regimen, substitution of a thiazide-like for a thiazide diuretic and addition of a mineralocorticoid receptor antagonist as the fourth drug. Non-evidence-based recommendations include addition of a β-blocker as the fifth drug and switching to a minoxidil-based regimen as the final step in achieving BP control.

OBJECTIVE Pediatric traumatic brain injury (TBI) is the leading cause of death among children and is a significant cause of morbidity. However, the majority of injuries are mild (Glasgow Coma Scale score 13–15) without any need for neurosurgical intervention, and clinically significant neurological decline rarely occurs. Although the question of repeat imaging within the first 24 hours has been discussed in the past, the yield of short-term follow-up imaging has never been thoroughly described. In this paper, the authors focus on the yield of routine repeat imaging for pediatric mild TBI (mTBI) at the first clinic visit following hospital discharge. METHODS The authors conducted a retrospective review of patients with pediatric brain trauma who had been admitted to Johns Hopkins All Children’s Hospital (JHACH). Patients with mTBI were identified, and their presentation, hospital course, and imaging results were reviewed. Those pediatric patients with mTBI who had undergone no procedure during their initial admission (only conservative treatment) were eligible for inclusion in the study. Two distinct groups were identified: patients who underwent repeated imaging at their follow-up clinic visit and those who underwent only clinical evaluation. Each case was assessed on whether the follow-up imaging had changed the follow-up course. RESULTS Between 2010 and 2015, 725 patients with TBI were admitted to JHACH. Of those, 548 patients qualified for analysis (i.e., those with mTBI who received conservative treatment without any procedure and were seen in the clinic for follow-up evaluation within 8 weeks after the trauma). A total of 392 patients had only clinic follow-up, without any diagnostic imaging study conducted as part of their clinic visit, whereas the other 156 patients underwent repeat MRI. Only 1 patient had a symptomatic change and was admitted after undergoing imaging. For 30 patients (19.2%), it was decided after imaging to continue the neurosurgical follow-up, which is a change from the institutional paradigm after mTBI. None of these patients had a change in neurological status, and all had a good functional status. All of these patients had one more follow-up in the clinic with new MRI, and none of them required further follow-up. CONCLUSIONS Children with mTBI are commonly followed up in the ambulatory clinic setting. The authors believe that for children with mTBI, normal clinical examination, and no new symptoms, there is no need for routine ambulatory imaging since the clinical yield of such is relatively low.

Objectives Pituitary carcinoma is a rare entity with fewer than 200 total cases reported in the English literature. Analysis of the population-level data from the National Cancer Database (NCDB) affords the opportunity to study this poorly understood tumor type. Methods The NCDB was queried for site, histology, and metastasis codes corresponding to pituitary carcinoma. Statistical analyses were performed to determine factors associated with overall survival (OS). Results A total of 92 patients with pituitary carcinoma met inclusion criteria. The 1 and 5 years of OS for all patients was 93.3% (95% confidence interval [CI]: 88.2–98.6%) and 80.0% (95% CI: 71.6–89.4%), respectively. Patients with invasive primary tumor behavior had 1 and 5 years of OS of 69.2% (95% CI: 48.2–99.5%) and 52.7% (95% CI: 31.2–89.2%), respectively. Multivariate analysis demonstrated that compared with benign primary behavior, invasive behavior had increased all-cause mortality (hazard ratio [HR], 1,296, 95% CI: 15.1– > 2,000). Surgery without adjuvant radiation or chemotherapy was the most common therapy (48.9%), followed by no treatment (40.2%). Compared with surgery alone, no treatment had worse OS (HR, 11.83, 95% CI: 1.41–99.56). Increasing age and female sex were both associated with increased mortality. Conclusions The most common treatment for pituitary carcinoma is surgery alone followed by no surgery. Surgery alone has significantly better OS compared with no treatment. The efficacy of radiation, chemotherapy, and neurohormonal treatments needs to be examined with prospective studies.

A novel, non-terminal surgical procedure to remove a single placentome from the pregnant ewe for gene expression and histological analyses was recently developed in our laboratory. This technique allows for evaluation of nutritional insults on placental development at more than one stage of gestation using a single animal. Early attempts to develop a similar technique in cattle were met with complications due to inaccessibility of the gravid uterine horn because of its location and mass. One alternative is to collect a placentome from the contralateral uterine horn; however, the question remains as to whether gene expression varies among placentomes based on location relative to the fetus. Pregnant heifers were maintained on forage during early gestation and later moved into pens with a Calan gate system (American Calan, Northwood, NH). On gestational day (GD) 158, five heifers were assigned to receive a hay-based diet formulated to meet 100% of NRC requirements, and five heifers were fed 70% of NRC requirements until necropsy on GD244. At necropsy, a single representative placentome was selected for analysis from the antimesometrial side: (1) of the gravid uterine horn central to the amnion, (2) over the allantois immediately adjacent to the amnion, (3) in the tip of the gravid uterine horn, and (4) in the tip of the contralateral uterine horn. Mean placentome weight was greater (P < 0.05) for locations central to the amnion and allantois compared to locations within the tips of the ipsilateral and contralateral horns, respectively. Gene expression for angiogenic factors (FGF2, ODC1, VEGFA, and FLT1), nutrient transporters (SLC7A1 and SLC2A1), and factors associated with hormone action (ESR1, IGF1, IGFBP3, CSH1, and PAG1) were unaffected (P > 0.05) by dietary treatment or location of the placentome. Results indicate that location of the placentome in relation to the fetus does not impact gene expression, enhancing the efficacy of nonterminal methodologies for sampling gene expression in placentomes.

Background Somatosensory loss occurs often following stroke. A proportional recovery model is proposed for spontaneous motor recovery, with implication for treatment planning. It is currently unknown if initial severity of sensory impairment influences stroke survivors' response to treatment to improve sensation. Objective To examine if initial (pre-treatment) severity of upper limb somatosensory impairment is related to sensation outcomes following treatment. Methods Regression analysis was used to investigate the relationship between initial and post-treatment sensation performance. Data were pooled from two randomized controlled trials of somatosensory discrimination retraining (N = 80). Upper limb somatosensation was measured using standardized tests of sensory discrimination: Fabric Matching Test, Wrist Position Sense Test, and functional Tactile Object Recognition Test. Results Post-treatment somatosensory improvement patterns were proportional to the extent of initial pre-treatment somatosensory impairment (Texture discrimination: B = 0.74, 95% CIs [0.52, 0.96]; Proprioception: B = 0.35, 95% CIs [0.24, 0.47]; Object recognition: B = 0.85, 95% CIs [0.75, 0.95]). Conclusions The effect of somatosensory retraining on post-treatment sensation was proportional to the extent of upper limb initial somatosensory impairment. Findings suggest sensory retraining can benefit stroke survivors of varying severity of sensory impairment, including those with more severe somatosensory loss.