30-day morbidity and mortality after transoral robotic surgery for human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma: A retrospective analysis of two prospective adjuvant de-escalation trials (MC1273 & MC1675).

OBJECTIVE: Dose de-escalation of adjuvant therapy (DART) in patients with HPV(+)OPSCC was investigated in two prospective Phase II and III clinical trials (MC1273 and MC1675). We report the 30-day morbidity and mortality associated with primary TORS resection in patients enrolled in these trials. MATERIALS AND METHODS: Patients with HPV(+)OPSCC, who underwent TORS resection between 2013 and 2020 were considered in this analysis. The severity of postoperative transoral bleeding was graded using both the Hinni Grade (HG) transoral surgery bleeding scale and the Common Terminology for Adverse Events (CTCAE) v5.0. Post-surgical complications within 30 days of surgery, as well as rates of tracheostomy, PEG and nasogastric tube placement. RESULTS: 219 patients were included. A total of 7 (3.2 %) patients had a tracheostomy placed at the time of surgery, and all were decannulated within 26 days (median: 5, range: 2-26). There were 33 (15.1 %) returns to the emergency department (ED) with 10 (4.6 %) patients requiring readmission. Using the HG scale, 10 (4.6 %) patients experienced ≥ Grade 3 bleeding with no Grade 5 or 6 bleeds. In contrast, using the CTCAE scale, 15 patients (6.8 %) experienced ≥ Grade 3 bleeding with no Grade 5 bleeds. There was one post-operative death in a patient withdrawn from the trial, and no deaths related to hemorrhage. CONCLUSION AND RELEVANCE: TORS for HPV(+)OPSCC in carefully selected patients at a high volume center was associated with low morbidity and mortality.

Non-opioid analgesics and post-operative pain following transoral robotic surgery for oropharyngeal cancer.

OBJECTIVE: To investigate associations between multimodal analgesia and post-operative pain among patients undergoing transoral robotic surgery for oropharyngeal squamous cell carcinoma. METHODS: Records of patients who underwent surgery from 5 September 2012 to 30 November 2016 were abstracted. Associations were assessed using multivariable analysis. RESULTS: A total of 216 patients (mean age of 59.1 years, 89.4 per cent male) underwent transoral robotic surgery (92.6 per cent were human papilloma virus positive, 87.5 per cent had stage T1-T2 tumours, and 82.9 per cent had stage N0-N1 nodes). Gabapentin (n = 86) was not associated with a reduction in severe pain. Ibuprofen (n = 72) was administered less often in patients with severe pain. Gabapentin was not associated with increased post-operative sedation (p = 0.624) and ibuprofen was not associated with increased bleeding (p = 0.221). Post-operative opioid usage was not associated with surgical duration, pharyngotomy, bilateral neck dissections, tumour stage, tumour size, subsite or gabapentin. CONCLUSION: Scheduled low-dose gabapentin was not associated with improved pain control or increased respiratory depression. Ibuprofen was not associated with an increased risk of bleeding and may be under-utilised.

QTc interval in survivors of out of hospital cardiac arrest.

BACKGROUND: QTc interval (QTc) prolongation is seen on the post-arrest electrocardiogram (ECG) of many out of hospital cardiac arrest (OHCA) survivors. It remains unclear whether this is a transient phenomenon or a manifestation of an underlying arrhythmic substrate. This observational study assessed the trend of QTc in an unselected group of patients presenting with OHCA. We sought to identify any relationship between QTc, gender and aetiology of arrest. We observed whether targeted temperature management (TTM) is associated with malignant arrhythmia. METHOD: We analysed 60 patients presenting with OHCA to the Bristol Heart Institute during a 20-month period. We measured QTc on admission and assessed for persistence, development and resolution of prolongation at up to 5 time points post-OHCA. Aetiology of arrest was divided into coronary, non-coronary or primary arrhythmic to investigate for patterns in QTc behaviour. RESULTS: 81.7% (49/60) of arrests were attributed to an acute coronary event. 55% (33/60) had QTc prolongation on admission, of which 79% resolved. There were no significant differences in QTc behaviour by aetiology. One patient presenting with a normal QTc, developed prolongation during admission and received a genetic diagnosis of Long QT Syndrome. TTM was employed in 57/60, with no increased incidence of malignant arrhythmia. CONCLUSIONS: Prolonged QTc on admission does not imply a primary arrhythmic aetiology and resolves in the majority pre-discharge. However, an initial normal QTc post-OHCA does not preclude a diagnosis of Long QT syndrome, highlighting the importance of thorough investigations in these patients. TTM appears safe from a cardiac perspective.

The clinical effects of a low dose dexmedetomidine constant rate infusion in isoflurane anesthetized cats.

The aim of this study was to evaluate the effects of a low dose dexmedetomidine constant rate infusion (CRI) on cardiopulmonary function, inhalant anesthetic concentration and recovery in isoflurane anesthetized cats. In a prospective, randomized, blinded, controlled design, 12 cats undergoing anesthesia for ovariohysterectomy were administered hydromorphone (0.1mg/kg) intramuscularly, propofol (4.3-7.8mg/kg) intravenously and maintained with isoflurane. During isoflurane anesthesia, the cats were administered either a dexmedetomidine loading dose (0.5µg/kg) followed by a dexmedetomidine CRI (0.5µg/kg/h) (group LDD), or a saline loading dose followed by a saline CRI (group SAL). Heart rate (HR), respiratory rate, blood pressure, temperature, oxygen saturation (SpO2), end tidal carbon dioxide concentration (ETCO2), end tidal isoflurane concentration (ETISO) and anesthetic depth were recorded at nine time points (T0-T8). Overall effects (T1-8) and individual time point results were compared between groups. There were no significant differences in baseline variables (T0), age, weight, propofol dose, anesthesia and surgery time, time to extubation or recovery score between groups. Among the physiological variables measured, significant differences were observed in respiratory rate, ETCO2, and mean and diastolic blood pressure, between groups at individual time points. Systolic blood pressure, HR, SpO2, ETISO and temperature were not significantly different between groups at individual time points. Overall, ETCO2 and ETISO were significantly lower and respiratory rate was significantly higher for LDD compared to SAL. At the doses administered, a CRI of dexmedetomidine reduced isoflurane requirements in anesthetized cats undergoing ovariohysterectomy. The utility of a low dose dexmedetomidine CRI in the perioperative setting requires further investigation, since intraoperative cardiopulmonary values during dexmedetomidine infusion were not different from those receiving saline.

Looking behind the bars: emerging health issues for people in prison.

Introduction: There are more than 10 million people imprisoned worldwide. These individuals experience a higher burden of communicable and non-communicable disease, mental health and substance misuse problems than the general population and often come from marginalized and underserved groups in the community. Prisons offer an important opportunity for tackling health problems in a way that can deliver benefits to the individual and to the community. This paper focuses specifically on emerging health issues for prisons across the world. Sources of data: This paper uses sources of international data from published systematic reviews and research studies, the Ministry of Justice for England and Wales, the Prisons and Probations Ombudsmen Review and other United Kingdom government briefing papers. Areas of agreement: Deaths in custody are a key concern for the justice system as well as the health system. Areas of controversy: Suicide is the leading cause of mortality in prisons worldwide but non-communicable diseases, such as cardiovascular disease, are increasing in importance in high-income countries and are now the leading cause of mortality in prisons in England and Wales. Growing points: The prison population is ageing in most high-income countries. Older people in prison typically have multiple and complex medical and social care needs including reduced mobility and personal care needs as well as poor health. Areas timely for developing research: Further research is needed to understand the complex relationship between sentencing patterns, the ageing prison population and deaths in custody; to model its impact on prisons and healthcare provision in the future and to determine effective and cost-effective models of care. Research into the health of prisoners is important in improving the health of prisoners but there is considerable variation in quantity and quality between countries. Recent innovations seek to address this disparity and facilitate the sharing of good practice.

Pathology-based staging for HPV-positive squamous carcinoma of the oropharynx.

OBJECTIVE: The rapid worldwide rise in incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) has generated studies confirming this disease as an entity distinct from traditional OPSCC. Based on pathology, surgical studies have revealed prognosticators specific to HPV-positive OPSCC. The current AJCC/UICC staging and pathologic nodal (pN)-classification do not differentiate for survival, demonstrating the need for new, HPV-specific OPSCC staging. The objective of this study was to define a pathologic staging system specific to HPV-positive OPSCC. METHODS: Data were assembled from a surgically-managed, p16-positive OPSCC cohort (any T, any N, M0) of 704 patients from five cancer centers. Analysis was performed for (a) the AJCC/UICC pathologic staging, (b) newly published clinical staging for non-surgically managed HPV-positive OPSCC, and (c) a novel, pathology-based, "HPVpath" staging system that combines features of the primary tumor and nodal metastases. RESULTS: A combination of AJCC/UICC pT-classification and pathology-confirmed metastatic node count (⩽4 versus ⩾5) yielded three groups: stages I (pT1-T2, ⩽4 nodes), II (pT1-T2, ⩾5 nodes; pT3-T4, ⩽4 nodes), and III (pT3-T4, ⩾5 nodes), with incrementally worse prognosis (Kaplan-Meier overall survival of 90%, 84% and 48% respectively). Existing AJCC/UICC pathologic staging lacked prognostic definition. Newly published HPV-specific clinical stagings from non-surgically managed patients, although prognostic, showed lower precision for this surgically managed cohort. CONCLUSIONS: Three loco-regional "HPVpath" stages are identifiable for HPV-positive OPSCC, based on a combination of AJCC/UICC primary tumor pT-classification and metastatic node count. A workable, pathologic staging system is feasible to establish prognosis and guide adjuvant therapy decisions in surgically-managed HPV-positive OPSCC.

Epigenomic profiling of preterm infants reveals DNA methylation differences at sites associated with neural function.

DNA methylation (DNAm) plays a determining role in neural cell fate and provides a molecular link between early-life stress and neuropsychiatric disease. Preterm birth is a profound environmental stressor that is closely associated with alterations in connectivity of neural systems and long-term neuropsychiatric impairment. The aims of this study were to examine the relationship between preterm birth and DNAm, and to investigate factors that contribute to variance in DNAm. DNA was collected from preterm infants (birth<33 weeks gestation) and healthy controls (birth>37 weeks), and a genome-wide analysis of DNAm was performed; diffusion magnetic resonance imaging (dMRI) data were acquired from the preterm group. The major fasciculi were segmented, and fractional anisotropy, mean diffusivity and tract shape were calculated. Principal components (PC) analysis was used to investigate the contribution of MRI features and clinical variables to variance in DNAm. Differential methylation was found within 25 gene bodies and 58 promoters of protein-coding genes in preterm infants compared with controls; 10 of these have neural functions. Differences detected in the array were validated with pyrosequencing. Ninety-five percent of the variance in DNAm in preterm infants was explained by 23 PCs; corticospinal tract shape associated with 6th PC, and gender and early nutritional exposure associated with the 7th PC. Preterm birth is associated with alterations in the methylome at sites that influence neural development and function. Differential methylation analysis has identified several promising candidate genes for understanding the genetic/epigenetic basis of preterm brain injury.

Differential loss of expression of common fragile site genes between oral tongue and oropharyngeal squamous cell carcinomas.

The common fragile sites (CFSs) are large regions of profound genomic instability found in all individuals. A number of the CFSs have been found to span genes that extend over large genomic regions (>700 kb). The expression of these genes is frequently abrogated in a number of different cancers and several of them have already been shown to function as tumor suppressor genes, both in vitro and in vivo. We analyzed the expression of 14 large CFS genes in two distinct groups of head and neck cancers using real-time RT-PCR. The first were oral tongue squamous cell carcinomas (SCCs) and the second were base of tongue/tonsillar (oropharyngeal) SCCs. These two groups were previously examined for the presence of human papillomavirus (HPV) and while 46% of the oropharyngeal cancers were positive for HPV16 only one of 52 oral cancers contained HPV16 sequences. We observed a distinct pattern of loss of expression of the large CFS genes in the two groups of head and neck cancers. In addition, there was no correlation between the relative instability in different CFS regions and which genes were inactivated. Thus, this report demonstrates another distinction between these two groups of head and neck cancer. In addition, it suggests that there is selection for loss of expression of specific CFS genes in these cancers.

Effective hand hygiene education with the use of flipcharts in a hospital in El Salvador.

In developing countries, continuing education for healthcare staff may be limited by staff shortages and lack of sophisticated means of delivery. These limitations have implications for compliance with an important infection control practice, namely good hand hygiene. A comparison was made between the efficacy of two educational tools commonly used in healthcare and practical sanitation settings in developing countries, i.e. videotapes and flipcharts, in delivering hand hygiene education to 67 nurses in a paediatric hospital in El Salvador. Efficacy was measured on the basis of scores obtained in pre- and post-training tests consisting of 10 multiple-choice questions. Half of the nurses received video-based instruction and half received instruction via flipcharts. Both methods of instruction increased participants' knowledge of good hand hygiene, and the extent of knowledge acquisition by the two methods was similar. Feedback obtained from flipchart users six months after training indicated that most of the respondents used the flipchart to teach hand hygiene to patients' families (62.5%), patients (50%) and healthcare workers (43.8%). Flipchart users ranked flipcharts as their favourite educational tool. Flipcharts offer an economical, easy-to-use, non-technological yet effective alternative to videotapes for delivering education in developing countries. Although the use of flipcharts requires a skilled and well-trained instructor, flipcharts could be used more widely to deliver education in resource-poor settings.

Lead (Pb2+) modulation of potassium currents of guinea pig outer hair cells.

Outer hair cells (OHC) are mechanosensitive sensory cells of the inner ear cochlea and are involved in modulating the activity of inner hair cells in the transduction of an acoustic stimulus. Potassium (K(+)) currents play an important role in the sensory transduction process. K(+) currents were recorded from acutely dissociated OHC obtained from the guinea pig organ of Corti. The whole-cell patch clamp technique was employed. We identified a channel that exhibited outward current of the delayed rectifier type (Kv). Kv channels mediating inward currents carried by potassium ions were also identified and took on the appearance of a previously described inwardly rectifying current. Lead (Pb(2+)) acetate at concentrations of 0.1, 1.0, 10, and 100 microM was bath applied. Time to activation for outward-going current was not affected by Pb(2+). The time course of Pb(2+) effects was seen as a dose-dependent reduction of K(+) current over time, with very little or no recovery after washout. Pb(2+) inhibited the outward Kv relative current with values of 0.10, 0.14, 0.18, and 0.30 at 0.1, 1.0, 10, and 100 microM, respectively. Pb(2+) did not modulate time to activation, peak current, or inactivation of inward I(K). The effects of Pb(2+) on the potassium currents of OHC are not remarkable and therefore OHC are probably not a major cause of purported peripheral hearing loss observed in Pb(2+)-exposed animals and humans.

Insulin lispro: a potential role in preventing nocturnal hypoglycaemia in young children with diabetes mellitus.

AIMS: The long duration of action of soluble insulin given in the evening could contribute to the high prevalence of nocturnal hypoglycaemia seen in young children with Type 1 diabetes mellitus (T1DM). We examined whether replacing soluble insulin with insulin lispro reduced this risk in children on a three times daily insulin regimen. METHODS: Open crossover study comparing insulin lispro vs. soluble insulin in 23 (16 boys) prepubertal children (age 7-11 years) with T1DM on three injections/day; long-acting isophane insulin remained identical. At the end of each 4-month treatment arm, an overnight 15-min venous sampled blood glucose profile was performed. RESULTS: Despite similar blood glucose levels pre-evening meal (lispro vs. soluble: mean +/- se 6.5 +/- 1.0 vs. 7.1 +/- 1.1 mmol/l, P = 0.5), post-meal (18.00-22.00 h) blood glucose levels were lower on insulin lispro (area under curve 138 +/- 12 vs. 170 +/- 13 mmol min-1 l-1, P = 0.03). In contrast, in the early night (22.00-04.00 h) the prevalence of low blood glucose levels (< 3.5 mmol/l) was lower on lispro (8% of blood glucose levels) than on soluble insulin (13%, P = 0.01). In the early morning (04.00-07.00 h) mean blood glucose and prevalence of low levels were no different between the two treatment groups, and fasting (07.00 h) blood glucose levels were similar (6.1 +/- 0.8 vs. 6.3 +/- 0.9 mmol/l, P = 0.8). At the end of each treatment arm there were no differences in HbA1c (lispro vs. soluble 8.6% vs. 8.4%, P = 0.3), or in insulin doses (mean, range 0.97, 0.68-1.26 vs. 0.96, 0.53-1.22 U/kg per day, P = 0.2). CONCLUSIONS: The shorter duration of action of insulin lispro given before the evening meal may reduce the prevalence of early nocturnal hypoglycaemia without compromising HbA1c in young children with T1DM.

Mercury (Hg2+) suppression of potassium currents of outer hair cells.

The heavy metal mercury (Hg(2+)) is an insidious environmental pollutant that causes toxic effects on sensory systems. It is well known that the group IIB divalent cation Hg(2+) is an inhibitor of the group I monovalent potassium (K(+)) cation pore-forming channel in several biological preparations. Here, we used the whole cell patch clamp technique on freshly isolated outer hair cells (OHCs) of the guinea pig cochlea to record outward K(+) currents and inward K(+) currents treated with mercuric chloride (HgCl(2)). HgCl(2) affected K(+) currents in a voltage- and dose-dependent manner. The effects of HgCl(2) at 1.0-100 microM are more pronounced on onset peak current than on steady-state end current. HgCl(2) depolarized also the resting membrane potential. Although the effect of HgCl(2) at 1.0 microM was partially washed out over several minutes, the effects at 10 and 100 microM were irreversible to washout. Since K(+) channels of OHCs are targets for HgCl(2) ototoxicity, this may lead to auditory transduction problems, including a loss in hearing sensitivity. A better understanding of fundamental mechanisms underlying K(+) channelopathies in OHCs due to HgCl(2) poisoning may lead to better preventive or therapeutic agents.

Prospective analysis of the efficacy of continuous intraoperative nerve monitoring during thyroidectomy, parathyroidectomy, and parotidectomy.

OBJECTIVE: Continuous intraoperative electromyographic monitoring was prospectively performed in all parotidectomies, thyroidectomies, and parathyroidectomies over approximately 5 years to assess the efficacy of this technology. STUDY DESIGN AND SETTING: Continuous intraoperative nerve monitoring with perioperative nerve assessment was performed. The postresection minimal stimulation level of the nerves was determined to evaluate if this level would predict nerve function postoperatively. RESULTS: Forty-four parotidectomies and 70 thyroid/parathyroid operations were performed with 140 nerves at risk (44 facial, 96 recurrent laryngeal). The incidence of temporary facial paralysis was 15.9% (7 of 44) and the incidence of permanent paralysis was 0%. The incidence of temporary recurrent laryngeal nerve paralysis in terms of nerves at risk was 1.0% (1 of 96), and the incidence of permanent recurrent laryngeal nerve paralysis was 0%. All patients with normally functioning facial and recurrent laryngeal nerves postoperatively had minimal stimulation levels less than or equal to 0.4 mA. CONCLUSION: Continuous intraoperative nerve monitoring was associated with extremely low rates of temporary and permanent nerve paralysis in our series of 140 nerves at risk as compared to the rates documented in the literature.

The I' potential of the human auditory brainstem response to paired click stimuli.

When stimulated with an appropriate stimulus, the hair cells of the organ of Corti depolarize, causing the release of a neurotransmitter substance, which excites afferent VIIIth nerve dendrites. It is reasonable to hypothesize that excitatory postsynaptic potentials (EPSPs) generated by the dendrites of the auditory nerve in turn initiate a compound action potential (CAP). The EPSP is thought to be the generator potential for the CAP, and may be recorded in auditory brainstem responses (ABRs) as the I' potential. Determining the anatomical origin of I' may enhance the sensitivity of the ABR technique in hair cell/dendrite/auditory nerve evaluations. Whether I' is of sensory or of neural origin is equivocal, and therefore I' is not well understood. To investigate this dilemma, ABRs were recorded from human subjects using standard and paired-click stimuli, and using subtraction methods to generate a derived ABR. Two early peaks, designated as I degree and I', occurred before wave I in the derived ABR. It was hypothesized that peaks I degrees and I' represent the summating potential and the generator potential, generated by the cochlea and VIIIth nerve dendrites, respectively.

Atrophic rhinitis: a review of 242 cases.

Atrophic rhinitis is a debilitating nasal mucosal disease of unknown etiology. It is characterized by progressive nasal mucosal atrophy, nasal crusting, fetor, and enlargement of the nasal space with paradoxical nasal congestion. Primary atrophic rhinitis has decreased markedly in incidence in the last century. This probably relates to the increased use of antibiotics for chronic nasal infection. Secondary atrophic rhinitis resulting from trauma, surgery granulomatous diseases, infection, and radiation exposure accounts for the majority of cases encountered by the rhinologist today. Excessive turbinate surgery has been both acquitted and accused in the literature as an etiology for secondary atrophic rhinitis. We saw 242 patients with the diagnosis of atrophic rhinitis between 1982 and 1999. The diagnosis was confirmed by physical examination, biopsy, and imaging studies. Patients were diagnosed with primary atrophic rhinitis if their condition developed in a previously healthy nose and secondary atrophic rhinitis if their condition developed after sinonasal surgery, trauma, or chronic granulomatous disease. Prevention and treatment of the disease is discussed.

Microcystins (cyanobacterial toxins) in drinking water enhance the growth of aberrant crypt foci in the mouse colon.

Microcystis aeruginosa produces toxic cyclic peptides called microcystins, potent hepatotoxins that have been implicated in tumor promotion in skin and liver. The model used in this investigation was the azoxymethane (AOM)-induced aberrant crypt focus (ACF) in the male C57Bl/6J mouse colon. Three intraperitoneal (i.p.) injections of 5 mg/kg AOM were administered at 7-d intervals to mice; 19 d after the last AOM injection, drinking water containing Microcystis extract was commenced and continued for a further 212 d. The content of microcystins in the drinking water was determined by mouse bioassay, high-performance liquid chromatography (HPLC), capillary eletrophoresis, and protein phosphatase inhibition. The doses employed were 0, 382, and 693 micrograms/kg bodyweight/d at the midpoint of the trial. Following postmortem examination blood cells, serum enzymes and organ pathology were investigated. A significant microcystin dose-dependent increase in the area of aberrant crypt foci was observed. There was no marked increase in the number of crypts/colon. Two overt colonic tumors (approximately 30 mm3) were seen in microcystin-treated mice, and one microscopic colonic tumor in an AOM-alone-treated mouse. This investigation provides the first evidence for the stimulation of preneoplastic colon tumor growth by microcystin.

Preoperative and postoperative topical tretinoin on high-tension excisional wounds and full-thickness skin grafts in a porcine model: A pilot study.

BACKGROUND: Tretinoin induces neovascularization and the formation of collagen when applied topically. OBJECTIVE: The goal was to determine whether preoperative and postoperative treatment with tretinoin enhances the healing of high-tension, full-thickness excisional wounds and the survival of full-thickness skin grafts. METHODS: A blinded, randomized, placebo-controlled pilot study involved high-tension excisional wounds and full-thickness skin grafts treated perioperatively with tretinoin in a porcine model. RESULTS: Perioperative treatment of high-tension excisional surgery sites with tretinoin appeared to have no consistent beneficial or adverse effects on wound healing or scar spreading. In the full-thickness skin graft model, a trend toward impaired wound healing was noted. CONCLUSION: The collagen-inducing effects of topical tretinoin do not appear to enhance the healing of high-tension excisional surgery wounds in a porcine model. Tretinoin does not appear to improve the survival of full-thickness skin grafts and, in fact, a detrimental effect was apparent in our model.

Auditory brainstem responses in Golden Syrian hamsters (Mesocricetus auratus) affected with the Wh gene.

BACKGROUND AND PURPOSE: The anophthalmic white (Wh) gene in Golden Syrian hamsters (Mesocricetus auratus) is autosomal semi-dominant and causes several developmental defects, including hearing loss. The Wh mutation is thought to be homologous to Waardenburg syndrome in humans, apparently affecting similar developmental processes. The purpose of this study was to assess the hearing of hamsters in the AN/As-Wh strain. METHODS: Using auditory brainstem responses, electrophysiologic activity was determined in 20 hamsters of the AN/As-Wh strain, with the aim of elucidating hearing status. Hamsters were classified into five genotypes and were evaluated by use of click stimuli. RESULTS AND CONCLUSION: Hamsters assigned to the genotypes differed in their hearing sensitivity and could be classified into categories of normal hearing, moderate hearing loss, and profound hearing loss.