Stir-up Regimen After General Anesthesia in the Postanesthesia Care Unit: A Nurse Led Stepped Wedge Cluster Randomized Control Trial.

PURPOSE: To implement a standardized Stir-up Regimen (deep breathing, coughing, repositioning, mobilization [moving arms/legs], assessing and managing pain and nausea) within the first 30 minutes of arrival in the postanesthesia care unit (PACU), with a goal of decreasing recovery time in the immediate postanesthesia period (Phase I). DESIGN: A pragmatic stepped wedge cluster randomized control trial. Initially, data were collected on time in Phase I in three PACUs (control). Subsequently, the same three units were randomized to sequentially transition to the Stir-up Regimen (intervention). METHODS: A stepped wedge cluster randomized control trial design was used to implement a standardized Stir-up Regimen in three PACUs in an academic hospital for adult patients who received at least 30 minutes of general anesthesia. The measured outcome was the PACU time in minutes from patient arrival to when the patient met Phase I discharge criteria. Differences between intervention and control groups were evaluated using a generalized mixed-effects model. Nurses were educated about the Stir-up Regimen in team huddles, in-services, video demonstrations, email notifications and reminders, and immediate feedback at the bedside. Implementation science principles were used to assess the adoption of the Stir-up Regimen through a presurvey, postsurvey and spot-check observations in all three PACUs. FINDINGS: A total of 5,809 PACU adult patient admissions were included: control group (n = 2,860); intervention group (n = 2,949); males (n = 2,602), and females (n = 3,206). The intervention was associated with a reduction in overall mean Phase I recovery time of 4.9 minutes (95% CI: -8.4 to -1.4, P = .007). One PACU decreased time by 9.6 minutes (95% CI: -15.3 to -4.0, P < .001). The other units also reduced Phase I recovery time, but this did not reach statistical significance. The spot-check observations confirmed the intervention was adopted by the nurses, as most interventions were nurse-initiated versus patient-initiated during the first 30 minutes in PACU. CONCLUSIONS: Standardization of a Stir-up Regimen within 30 minutes of patient PACU arrival resulted in decreased Phase I recovery time.

Tumor volumes in T3 supraglottic cancers treated with radiotherapy in the modern era: A study of the Canadian Head & Neck Collaborative Research Initiative.

PURPOSE: To evaluate the association of primary tumor volume (TV) with overall survival (OS) and disease-free survival (DFS) in T3 N0-3M0 supraglottic cancers treated with intensity-modulated radiotherapy (IMRT). METHODS: This was a retrospective cohort study involving 239 patients diagnosed with T3 N0-3M0 supraglottic cancers between 2002 and 2018 from seven regional cancer centers in Canada. Clinical data were obtained from the patient records. Supraglottic TV was measured by neuroradiologists on diagnostic imaging. Kaplan-Meier method was used for survival probabilities, and a restricted cubic spline Cox proportional hazards regression analysis was used to analyze TV associations with OS and DFS. RESULTS: Mean (SD) of participants was 65.2 (9.4) years; 176 (73.6%) participants were male. 90 (38%) were N0, and 151 (64%) received concurrent systemic therapy. Mean TV (SD) was 11.37 (12.11) cm3 . With mean follow up (SD) of 3.28 (2.60) years, 2-year OS was 72.7% (95% CI 66.9%-78.9%) and DFS was 53.6% (47.4%-60.6%). Increasing TV was associated (per cm3 increase) with worse OS (HR, 1.01, 95% CI 1.00-1.02, p < 0.01) and DFS (HR, 1.01, 95% CI 1.00-1.02, p = 0.02). CONCLUSIONS: Increasing primary tumor volume is associated with worse OS and DFS in T3 supraglottic cancers treated with IMRT, with no clear threshold. The findings suggest that patients with larger tumors and poor baseline laryngeal function may benefit from upfront laryngectomy with adjuvant radiotherapy.

Building a collaborative cloud platform to accelerate heart, lung, blood, and sleep research.

Research increasingly relies on interrogating large-scale data resources. The NIH National Heart, Lung, and Blood Institute developed the NHLBI BioData CatalystⓇ (BDC), a community-driven ecosystem where researchers, including bench and clinical scientists, statisticians, and algorithm developers, find, access, share, store, and compute on large-scale datasets. This ecosystem provides secure, cloud-based workspaces, user authentication and authorization, search, tools and workflows, applications, and new innovative features to address community needs, including exploratory data analysis, genomic and imaging tools, tools for reproducibility, and improved interoperability with other NIH data science platforms. BDC offers straightforward access to large-scale datasets and computational resources that support precision medicine for heart, lung, blood, and sleep conditions, leveraging separately developed and managed platforms to maximize flexibility based on researcher needs, expertise, and backgrounds. Through the NHLBI BioData Catalyst Fellows Program, BDC facilitates scientific discoveries and technological advances. BDC also facilitated accelerated research on the coronavirus disease-2019 (COVID-19) pandemic.

Primary hyperparathyroidism presenting as acute hypercalcemic crisis: a case report.

BACKGROUND: Hyperparathyroid crisis, or "parathyroid storm" is a rare manifestation of primary hyperparathyroidism, characterized by sudden onset of symptomatic, severe hypercalcemia (> 3.5 mmol/L). Hemorrhage into a parathyroid adenoma has rarely been reported as an inciting or associated event. We present a case of hemorrhage into a longstanding adenoma presenting with acute onset of profound hypercalcemia and associated complications. CASE PRESENTATION: A 60-year-old male presented to hospital with sudden onset of confusion, muscle weakness, and ataxia. Initial labs showed serum calcium 4.79 mmol/L, parathyroid hormone 2043 ng/L; creatinine 364 µmol/L. Review of the patient's medical history indicated a 4-year history of recurrent nephrolithiasis, but no prior documented calcium levels. The hypercalcemia did not respond to 5 days of aggressive medical management with fluid resuscitation, denosumab and calcitonin, and later pamidronate and cinacalcet. He continued to deteriorate, requiring intubation and continuous renal replacement therapy. Imaging demonstrated 4.8 cm cystic right paratracheal mass; Technetium (Tc99m) Sestamibi scintigraphy was non-localizing. Urgent parathyroidectomy was completed, revealing a 5 × 3.3 × 1.8 cm hemorrhagic, atypical hypercellular parathyroid. Unfortunately, the patient died from complications from anticoagulation therapy for treatment of deep vein thrombosis 4 weeks after admission. His renal function had not recovered at the time of his death. CONCLUSION: This case gives potential insight into the etiology of hyperparathyroid crisis, and the difficulty in achieving control of hypercalcemia with medical means. Surgical intervention is the definitive management in these cases and should be considered urgently.

Association of Primary Tumor Volume With Survival in Patients With T3 Glottic Cancer Treated With Radiotherapy: A Study of the Canadian Head & Neck Collaborative Research Initiative.

Importance: The association of primary tumor volume with outcomes in T3 glottic cancers treated with radiotherapy with concurrent chemotherapy remains unclear, with some evidence suggesting worse locoregional control in larger tumors. Objective: To evaluate the association of primary tumor volume with oncologic outcomes in patients with T3 N0-N3 M0 glottic cancer treated with primary (chemo)radiotherapy in a large multi-institutional study. Design, Setting, and Participants: This multi-institutional retrospective cohort study involved 7 Canadian cancer centers from 2002 to 2018. Tumor volume was measured by expert neuroradiologists on diagnostic imaging. Clinical and outcome data were extracted from electronic medical records. Overall survival (OS) and disease-free survival (DFS) outcomes were assessed with marginal Cox regression. Laryngectomy-free survival (LFS) was modeled as a secondary analysis. Patients diagnosed with cT3 N0-N3 M0 glottic cancers from 2002 to 2018 and treated with curative intent intensity-modulated radiotherapy (IMRT) with or without chemotherapy. Overall, 319 patients met study inclusion criteria. Exposures: Tumor volume as measured on diagnostic imaging by expert neuroradiologists. Main Outcomes and Measures: Primary outcomes were OS and DFS; LFS was assessed as a secondary analysis, and late toxic effects as an exploratory analysis determined before start of the study. Results: The mean (SD) age of participants was 66 (12) years and 279 (88%) were men. Overall, 268 patients (84%) had N0 disease, and 150 (47%) received concurrent systemic therapy. The mean (SD) tumor volume was 4.04 (3.92) cm3. With a mean (SD) follow-up of 3.85 (3.04) years, there were 91 (29%) local, 35 (11%) regional, and 38 (12%) distant failures. Increasing tumor volume (per 1-cm3 increase) was associated with significantly worse adjusted OS (hazard ratio [HR], 1.07; 95% CI, 1.03-1.11) and DFS (HR, 1.04; 95% CI, 1.01-1.07). A total of 62 patients (19%) underwent laryngectomies with 54 (87%) of these within 800 days after treatment. Concurrent systemic therapy was associated with improved LFS (subdistribution HR, 0.63; 95% CI, 0.53-0.76). Conclusions and Relevance: Increasing tumor volumes in cT3 glottic cancers was associated with worse OS and DFS, and systemic therapy was associated with improved LFS. In absence of randomized clinical trial evidence, patients with poor pretreatment laryngeal function or those ineligible for systemic therapy may be considered for primary surgical resection with postoperative radiotherapy.

Longitudinal functional outcomes and late effects of radiation following treatment of nasopharyngeal carcinoma: secondary analysis of a prospective cohort study.

BACKGROUND: The study objectives were: provide longitudinal data on upper aerodigestive tract function and late complications following IMRT for nasopharyngeal carcinoma, and elucidate factors that might predict a worse outcome. The hypotheses were: (1) Despite advances such as IMRT, radiation will cause significant functional decline and late complications that often progress or arise years after treatment. (2) Larger radiation volume will be associated with poorer outcomes. METHODS: Longitudinal, observational cohort study of nasopharyngeal carcinoma patients with retrospective analysis of prospectively collected, population-based data. Late sequelae and validated measures of overall performance, speech, and swallowing were documented pre-treatment and 3,6,12, 24, 36 and ≥ 60-months post-treatment. RESULTS: Forty-two patients treated curatively with radiation (N = 9) or chemoradiation (N = 33) were followed for a median 74 months. Functional outcomes showed an initial nadir at 3 months associated with acute effects of treatment, followed by initial recovery. There was subsequent functional decline years post-treatment with advancing dysphagia/aspiration, trismus, muscle spasm, and hypoglossal nerve palsy. Univariable regression analysis revealed that increasing high-dose radiation volumes (PTV 70 Gy) were associated with increased likelihood of less than solid diet (Performance Status Scale (PSS)-Normalcy of Diet score < 50; p = 0.04), and reduced PSS-Understandability of Speech (p = 0.005). The probability of poor outcome increased with time. Eleven percent of patients were tube feed dependent at ≥ 5 years. CONCLUSIONS: Despite improvements in radiation delivery, late effects of radiation remain common. Higher radiation volumes are associated with poorer outcomes that worsen over time.

Selected functional outcomes in advanced oral cancer: Comparison of surgery alone versus surgery with postoperative radiotherapy.

BACKGROUND: Study objectives were to determine whether the addition of postoperative radiation (PORT) resulted in a decline in oral function relative to surgery alone and to describe the longitudinal course of oral function following treatment of advanced oral cancer. METHODS: This was a 36-month retrospectively analyzed observational cohort study of patients with stage III-IV oral cancer. Prospectively collected, oral functional outcomes were acquired pretreatment and 3, 6, 12, 24, and 36 months post-treatment. RESULTS: One hundred and eighteen patients were included. Forty-three patients treated with surgery alone were compared to 75 who received surgery with PORT. Mixed model analysis demonstrated the acute effect of PORT was associated with patient-rated xerostomia (p < 0.001) and the late or persistent effect was associated with decreased clinician-rated eating in public (p = 0.008), understandability of speech (p = 0.02), and normalcy of diet (p = 0.005) compared with surgery alone. There were no differences between surgery alone and PORT groups in clinician-rated feeding tube dependence or patient-rated speech handicap. CONCLUSIONS: The use of PORT was associated with a demonstrable decline in oral function in four of six outcomes measures relative to surgery alone.

Reimagining the IR Workflow for a Better Work-Life Balance.

Several workflow changes were implemented in a large academic interventional radiology practice, including separation of inpatient and outpatient services, early start times, and using an adaptive learning system to predict case length tailored to individual physicians. Metrics including procedural volume, on-time start, accuracy at predicting case length, and room shutdown time were assessed before and after the intervention. Considerable improvements were seen in accuracy of first case start times, predicting block times, and last case encounter ending times. It is proposed that with improved role clarity, interventional radiologists can regain control over their schedules, utilize work hours more efficiently, and improve work-life balance.

S-nitrosothiols, and other products of nitrate metabolism, are increased in multiple human blood compartments following ingestion of beetroot juice.

Ingested inorganic nitrate (NO3⁻) has multiple effects in the human body including vasodilation, inhibition of platelet aggregation, and improved skeletal muscle function. The functional effects of oral NO3⁻ involve the in vivo reduction of NO3⁻ to nitrite (NO2⁻) and thence to nitric oxide (NO). However, the potential involvement of S-nitrosothiol (RSNO) formation is unclear. We hypothesised that the RSNO concentration ([RSNO]) in red blood cells (RBCs) and plasma is increased by NO3⁻-rich beetroot juice ingestion. In healthy human volunteers, we tested the effect of dietary supplementation with NO3⁻-rich beetroot juice (BR) or NO3⁻-depleted beetroot juice (placebo; PL) on [RSNO], [NO3⁻] and [NO2⁻] in RBCs, whole blood and plasma, as measured by ozone-based chemiluminescence. The median basal [RSNO] in plasma samples (n = 22) was 10 (5-13) nM (interquartile range in brackets). In comparison, the median values for basal [RSNO] in the corresponding RBC preparations (n = 19) and whole blood samples (n = 19) were higher (p < 0.001) than in plasma, being 40 (30-60) nM and 35 (25-80) nM, respectively. The median RBC [RSNO] in a separate cohort of healthy subjects (n = 5) was increased to 110 (93-125) nM after ingesting BR (12.8 mmol NO3⁻) compared to a corresponding baseline value of 25 (21-31) nM (Mann-Whitney test, p < 0.01). The median plasma [RSNO] in another cohort of healthy subjects (n = 14) was increased almost ten-fold to 104 (58-151) nM after BR supplementation (7 × 6.4 mmol of NO3⁻ over two days, p < 0.01) compared to PL. In conclusion, RBC and plasma [RSNO] are increased by BR ingestion. In addition to NO2⁻, RSNO may be involved in dietary NO3⁻ metabolism/actions.

Repurposing of the PDE5 Inhibitor Sildenafil for the Treatment of Persistent Pulmonary Hypertension in Neonates.

Nitric oxide (NO), an important endogenous signaling molecule released from vascular endothelial cells and nerves, activates the enzyme soluble guanylate cyclase to catalyze the production of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate. cGMP, in turn, activates protein kinase G to phosphorylate a range of effector proteins in smooth muscle cells that reduce intracellular Ca2+ levels to inhibit both contractility and proliferation. The enzyme phosphodiesterase type 5 (PDE5) curtails the actions of cGMP by hydrolyzing it into inactive 5'-GMP. Small molecule PDE5 inhibitors (PDE5is), such as sildenafil, prolong the availability of cGMP and therefore, enhance NO-mediated signaling. PDE5is are the first-line treatment for erectile dysfunction but are also now approved for the treatment of pulmonary arterial hypertension (PAH) in adults. Persistent pulmonary hypertension in neonates (PPHN) is currently treated with inhaled NO, but this is an expensive option and around 1/3 of newborns are unresponsive, resulting in the need for alternative approaches. Here the development, chemistry and pharmacology of PDE5is, the use of sildenafil for erectile dysfunction and PAH, are summarized and then current evidence for the utility of further repurposing of sildenafil, as a treatment for PPHN, is critically reviewed.

Effect of Fluorescence Visualization-Guided Surgery on Local Recurrence of Oral Squamous Cell Carcinoma: A Randomized Clinical Trial.

Importance: High local recurrence rates with aggressive disease remain the main concern in oral cancer survival. Use of a translational device using fluorescence visualization (FV) approved by the US Food and Drug Administration and Health Canada, has shown a marked reduction in the 3-year local recurrence rate of high-grade oral lesions in a single-center observational study. Objective: To determine whether FV- guided surgery can improve local control rates in the treatment of in situ or T1 to T2 category oral squamous cell carcinoma (OSCC). Design, Setting, and Participants: A multicenter randomized clinical trial was conducted in a surgical setting. A total of 457 patients were enrolled between January 18, 2010, and April 30, 2015. Data analysis of the intention-to-treat population was performed from April 3, 2019, to March 20, 2020. Patients with histologically confirmed high-grade dysplasia/carcinoma in situ or T1 to T2 category OSCC were randomized to receive traditional peroral surgery or FV-guided surgery. Intervention: Fluorescence visualization during surgery. Main Outcomes and Measures: The primary outcome was local recurrence of OSCC. Secondary outcomes were failure of the first-pass margin, defined as a histologically confirmed positive margin for severe dysplasia or greater histologic change of the main specimen (ie, not the margins taken from the resection bed), regional or distant metastasis, and death due to disease. Results: Of the 457 patients enrolled in the study, 443 patients (264 [59.6%] men; mean [SD] age, 61.5 [13.3] years) completed the randomized treatment: 227 FV-guided and 216 non-FV guided surgery. The median follow-up was 52 (range, 0.29-90.8) months. In total, 45 patients (10.2%) experienced local recurrence. The 3-year local recurrence rate was 9.4% in the FV-guided group and 7.2% in the non-FV group (difference, 2.2%; 95% CI, -3.2% to 7.4%). Other similarities between the FV vs non-FV groups included failure of first-pass margin (68/227 [30.0%]) vs 65/216 [30.1%]), regional failure (39/227 [17.2%] vs 37/216 [17.1%]), disease-specific survival (23/227 [10.1%] vs 19/26 [8.8%]), and overall survival (41/227 [18.1%] vs 38/216 [17.6%]) were also similar between groups. No adverse events were judged to be related to the intervention. Conclusions and Relevance: In this randomized clinical trial, FV-guided surgery did not improve local control rates in the treatment of patients with in situ or T1 to T2 category oral cancer. Under a controlled environment, FV-guided surgery did not have an evident effect in reduction of local recurrence for localized OSCC. This result suggests that attention be directed to strategies other than improving definitions of nonapparent disease at clinical margins to identify the sources of local recurrence. Trial Registration: ClinicalTrial.gov Identifier: NCT01039298.

Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial.

BACKGROUND: Patients with human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) have substantially better treatment response and overall survival (OS) than patients with HPV-negative disease. Treatment options for HPV+ OPC can involve either a primary radiotherapy (RT) approach (± concomitant chemotherapy) or a primary surgical approach (± adjuvant radiation) with transoral surgery (TOS). These two treatment paradigms have different spectrums of toxicity. The goals of this study are to assess the OS of two de-escalation approaches (primary radiotherapy and primary TOS) compared to historical control, and to compare survival, toxicity and quality of life (QOL) profiles between the two approaches. METHODS: This is a multicenter phase II study randomizing one hundred and forty patients with T1-2 N0-2 HPV+ OPC in a 1:1 ratio between de-escalated primary radiotherapy (60 Gy) ± concomitant chemotherapy and TOS ± de-escalated adjuvant radiotherapy (50-60 Gy based on risk factors). Patients will be stratified based on smoking status (< 10 vs. ≥ 10 pack-years). The primary endpoint is OS of each arm compared to historical control; we hypothesize that a 2-year OS of 85% or greater will be achieved. Secondary endpoints include progression free survival, QOL and toxicity. DISCUSSION: This study will provide an assessment of two de-escalation approaches to the treatment of HPV+ OPC on oncologic outcomes, QOL and toxicity. Results will inform the design of future definitive phase III trials. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03210103. Date of registration: July 6, 2017, Current version: 1.3 on March 15, 2019.

Evaluating a CTSA-funded pilot grant program.

INTRODUCTION: Pilot programs are integral to catalyzing and accelerating research at Clinical and Translational Science Award (CTSA) hubs. However, little has been published about the structure and operationalization of pilot programs or how they impact the translational research enterprise at CTSAs. The North Carolina Translational and Clinical Science Institute (NC TraCS), the CTSA hub at the University of North Carolina at Chapel Hill (UNC-CH) conducted an evaluation case study to describe the pilot program structure, assess process outcomes, and provide a framework for other institutions to utilize for the evaluation of their respective pilot programs. METHODS: We describe the operationalization of our pilot program, the evaluation framework utilized to evaluate the program, and how we analyzed available data to understand how our pilot funding opportunities were utilized by investigators. We calculated application volumes and funding rates by investigator position title and pilot application type. We also reviewed feedback provided by pilot Principal Investigators (PIs) to understand how many pilot projects were completed, NC TraCS service utilization, and barriers to research. Limited data on publications and subsequent funding was also reviewed. RESULTS: Between 2009 and 2019 the NC TraCS Pilot Program received 2343 applications and funded 933 projects, ranging from $2000 to $100,000 in amount, with an overall funding rate of 39.8%. Utilization of NC TraCS services had positive impacts on both resubmission funding and project completion rates. CONCLUSION: This process evaluation indicates that the program is being operationalized in a way that successfully fulfills the program mission while meeting the needs of a diverse group of researchers.

PTH monitoring after total parathyroidectomy with forearm auto-transplantation: potential for spuriously high levels from grafted forearm.

BACKGROUND: We have identified a cause of falsely elevated parathyroid hormone (PTH) levels after total parathyroidectomy with forearm auto-transplantation (TPT-ATx). Our cases highlight the need to draw PTH samples remotely, away from forearm graft sites, to ensure accurate levels. CASE PRESENTATIONS: We report on four patients who were referred to our surgical team at an academic tertiary care center for what was perceived to be recurrent hyperparathyroidism 2-5 years following total parathyroidectomy with auto-transplantation. Further evaluation revealed highly discrepant results in these patients depending on where the blood was drawn, with spuriously high levels in blood drawn from the grafted arm (Range 337-3885 ng/l), and much lower levels when blood was drawn remotely away from the graft site (Range 9-242 ng/l). The difference in PTH level between the grafted forearm and remote site for these patients ranged between 328 and 3643 ng/l. Over the period these cases were accrued (2008-2012), 89 patients underwent TPT-ATx in our institution. Therefore, our case report series suggests that this phenomenon will be evident to a clinically important extent in at least 4% of patients. CONCLUSIONS: One can acquire spuriously high PTH levels from grafted forearms, leading to the false diagnosis of recurrent hyperparathyroidism. We recommend PTH levels be drawn remotely from graft sites to ensure accurate systemic levels are reflected.

Validation of selective use of intraoperative PTH monitoring in parathyroidectomy.

BACKGROUND: The objective of this study was to validate our approach of treating primary hyperparathyroidism using sestamibi scan directed parathyroidectomy, without routine use of intraoperative parathyroid hormone measurements (ioPTH). METHODS: We prospectively established a protocol limiting the use of ioPTH to patients with negative or equivocal sestamibi scans, and those who had risk factors for multi-gland disease. We then performed a retrospective review to determine our disease control rate. RESULTS: 128 patients underwent sestamibi-guided parathyroidectomy without (111/128 = 87%) or with (17/128 = 13%) ioPTH. The overall disease control (eucalcemia) rate was 95%. 3/111 (3%) of patients who had surgery without ioPTH measurements required re-exploration. CONCLUSIONS: Selective use of ioPTH is an effective strategy. ioPTH is best reserved for patients who have non-localizing preoperative imaging, are at risk for multi-gland disease, or require revision surgery.

Optimal Perioperative Care in Major Head and Neck Cancer Surgery With Free Flap Reconstruction: A Consensus Review and Recommendations From the Enhanced Recovery After Surgery Society.

Importance: Head and neck cancers often require complex, labor-intensive surgeries, especially when free flap reconstruction is required. Enhanced recovery is important in this patient population but evidence-based protocols on perioperative care for this population are lacking. Objective: To provide a consensus-based protocol for optimal perioperative care of patients undergoing head and neck cancer surgery with free flap reconstruction. Evidence Review: Following endorsement by the Enhanced Recovery After Surgery (ERAS) Society to develop this protocol, a systematic review was conducted for each topic. The PubMed and Cochrane databases were initially searched to identify relevant publications on head and neck cancer surgery from 1965 through April 2015. Consistent key words for each topic included "head and neck surgery," "pharyngectomy," "laryngectomy," "laryngopharyngectomy," "neck dissection," "parotid lymphadenectomy," "thyroidectomy," "oral cavity resection," "glossectomy," and "head and neck." The final selection of literature included meta-analyses and systematic reviews as well as randomized controlled trials where available. In the absence of high-level data, case series and nonrandomized studies in head and neck cancer surgery patients or randomized controlled trials and systematic reviews in non-head and neck cancer surgery patients, were considered. An international panel of experts in major head and neck cancer surgery and enhanced recovery after surgery reviewed and assessed the literature for quality and developed recommendations for each topic based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. All recommendations were graded following a consensus discussion among the expert panel. Findings: The literature search, including a hand search of reference lists, identified 215 relevant publications that were considered to be the best evidence for the topic areas. A total of 17 topic areas were identified for inclusion in the protocol for the perioperative care of patients undergoing major head and neck cancer surgery with free flap reconstruction. Best practice includes several elements of perioperative care. Among these elements are the provision of preoperative carbohydrate treatment, pharmacologic thromboprophylaxis, perioperative antibiotics in clean-contaminated procedures, corticosteroid and antiemetic medications, short acting anxiolytics, goal-directed fluid management, opioid-sparing multimodal analgesia, frequent flap monitoring, early mobilization, and the avoidance of preoperative fasting. Conclusions and Relevance: The evidence base for specific perioperative care elements in head and neck cancer surgery is variable and in many cases information from different surgerical procedures form the basis for these recommendations. Clinical evaluation of these recommendations is a logical next step and further research in this patient population is warranted.

High fructose consumption in pregnancy alters the perinatal environment without increasing metabolic disease in the offspring.

Maternal carbohydrate intake is one important determinant of fetal body composition, but whether increased exposure to individual sugars has long-term adverse effects on the offspring is not well established. Therefore, we examined the effect of fructose feeding on the mother, placenta, fetus and her offspring up to 6 months of life when they had been weaned onto a standard rodent diet and not exposed to additional fructose. Dams fed fructose were fatter, had raised plasma insulin and triglycerides from mid-gestation and higher glucose near term. Maternal resistance arteries showed changes in function that could negatively affect regulation of blood pressure and tissue perfusion in the mother and development of the fetus. Fructose feeding had no effect on placental weight or fetal metabolic profiles, but placental gene expression for the glucose transporter GLUT1 was reduced, whereas the abundance of sodium-dependent neutral amino acid transporter-2 was raised. Offspring born to fructose-fed and control dams were similar at birth and had similar post-weaning growth rates, and neither fat mass nor metabolic profiles were affected. In conclusion, raised fructose consumption during reproduction results in pronounced maternal metabolic and vascular effects, but no major detrimental metabolic effects were observed in offspring up to 6 months of age.

Activation of endothelial IKCa channels underlies NO-dependent myoendothelial feedback.

Agonist-induced vasoconstriction triggers a negative feedback response whereby movement of charged ions through gap junctions and/or release of endothelium-derived (NO) limit further reductions in diameter, a mechanism termed myoendothelial feedback. Recent studies indicate that electrical myoendothelial feedback can be accounted for by flux of inositol trisphosphate (IP3) through myoendothelial gap junctions resulting in localized increases in endothelial Ca(2+) to activate intermediate conductance calcium-activated potassium (IKCa) channels, the resultant hyperpolarization then conducting back to the smooth muscle to attenuate agonist-induced depolarization and tone. In the present study we tested the hypothesis that activation of IKCa channels underlies NO-mediated myoendothelial feedback. Functional experiments showed that block of IP3 receptors, IKCa channels, gap junctions and transient receptor potential canonical type-3 (TRPC3) channels caused endothelium-dependent potentiation of agonist-induced increase in tone which was not additive with that caused by inhibition of NO synthase supporting a role for these proteins in NO-mediated myoendothelial feedback. Localized densities of IKCa and TRPC3 channels occurred at the internal elastic lamina/endothelial-smooth muscle interface in rat basilar arteries, potential communication sites between the two cell layers. Smooth muscle depolarization to contractile agonists was accompanied by IKCa channel-mediated endothelial hyperpolarization providing the first demonstration of IKCa channel-mediated hyperpolarization of the endothelium in response to contractile agonists. Inhibition of IKCa channels, gap junctions, TRPC3 channels or NO synthase potentiated smooth muscle depolarization to agonists in a non-additive manner. Together these data indicate that rather being distinct pathways for the modulation of smooth muscle tone, NO and endothelial IKCa channels are involved in an integrated mechanism for the regulation of agonist-induced vasoconstriction.