Human Papilloma Virus Positive Oropharyngeal Squamous Cell Carcinoma and the Immune System: Pathogenesis, Immunotherapy and Future Perspectives.

Oropharyngeal squamous cell carcinoma (OPSCC), a subset of head and neck squamous cell carcinoma (HNSCC), involves the palatine tonsils, soft palate, base of tongue, and uvula, with the ability to spread to adjacent subsites. Personalized treatment strategies for Human Papillomavirus-associated squamous cell carcinoma of the oropharynx (HPV+OPSCC) are yet to be established. In this article, we summarise our current understanding of the pathogenesis of HPV+OPSCC, the intrinsic role of the immune system, current ICI clinical trials, and the potential role of small molecule immunotherapy in HPV+OPSCC.

Variation in health service use by veterans with an accepted disability of post-traumatic stress disorder who had a service record post 1975: a cluster analysis.

BACKGROUND: The use of health services is likely to vary among veterans with an accepted disability of post-traumatic stress disorder (PTSD), however, the extent of variation is not known. We aimed to determine the extent and type of health services used by veterans with an accepted disability of PTSD. METHODS: The cohort included veterans who served post 1975, were eligible for all Australian Government Department of Veterans' Affairs funded health services, had PTSD as an accepted disability prior to July 2015 and were alive at the 30 June 2016. Veterans were assigned to groups based on their use of health services using K-means cluster analysis. RESULTS: The cohort comprised five clusters involving 2286 veterans. The largest cluster (43%) were a younger, general practitioner (GP) managed cluster who saw their GP quarterly and the psychiatrist twice a year. The second GP cluster (30%) had higher levels of physical comorbidity. The psychiatrist managed cluster (14%) had a mean of 12 psychiatrist visits and one PTSD hospitalisation in the year. The remaining two clusters involved GP and allied healthcare, but no psychologist care. High levels of antidepressant use occurred in all clusters, ranging from 44% up to 69%. The psychiatrist managed cluster had 47% on antipsychotics and 58% on anxiolytics. CONCLUSION: Our study highlights the heterogeneity in health service use. These results identify the significant health utilisation required for up to one-sixth of veterans with PTSD and the significant role of primary care physicians in supporting veterans with PTSD.

Two weeks of repetitive gut-challenge reduce exercise-associated gastrointestinal symptoms and malabsorption.

Debilitating gastrointestinal symptoms is a common feature of endurance running and may be exacerbated by and/or limit the ability to tolerate carbohydrate intake during exercise. The study aimed to determine whether two weeks of repetitive gut-challenge during running can reduce exercise-associated gastrointestinal symptoms and carbohydrate malabsorption. Endurance runners (n=18) performed an initial gut-challenge trial (GC1) comprising 2-hour running exercise at 60% VO2max (steady state) while consuming a formulated gel-disk containing 30 g carbohydrates (2:1 glucose-fructose, 10% w/v) every 20 minutes, followed by a 1-hour running effort bout. Gastrointestinal symptoms, feeding tolerance, and breath hydrogen (H2 ) were determined along the gut-challenge trial. After GC1, participants were randomly assigned to a blinded carbohydrate (CHO, 90 gCHO hour-1 ) or placebo (PLA, 0 gCHO hour-1 ) gut-training group. This comprised of consuming the group-specific feeding intervention during 1-hour running exercise at 60% VO2max equivalent, daily over a period of two weeks. Participants then repeated the gut-challenge trial (GC2). In GC2, a reduced gut discomfort (P=.012), total (P=.009), upper- (P=.015), and lower-gastrointestinal (P=.008) symptoms, and nausea (P=.05) were observed on CHO, but not PLA. Feeding tolerance did not differ between GC1 and GC2 on CHO and PLA. H2 peak was attenuated in GC2 (6±3 ppm) compared to GC1 (13±6 ppm) on CHO (P=.004), but not on PLA (GC1 11±7 ppm, and GC2 10±10 ppm). The effort bout distance was greater in GC2 (12.3±1.3 km) compared with GC1 (11.7±1.5 km) on CHO (P=.035) only. Two weeks of repetitive gut-challenge improve gastrointestinal symptoms and reduce carbohydrate malabsorption during endurance running, which may have performance implications.

How long will I have my ACE? The natural history of the antegrade continence enema stoma in idiopathic constipation.

PURPOSE: We aim to determine the natural history of the ACE in idiopathic constipation and factors predictive of closure. METHODS: A retrospective case-note review of all patients undergo ACE formation for idiopathic constipation Jan 2003-Mar 2016. Kaplan-Meier analysis was used to determine ACE survival and Cox's proportional hazard models to examine potential predictors of closure. RESULTS: 29/84 (35%) ACEs were closed: 21/84 due to success and 8/84 due to failure. Median age of closure was 15.5 years (3.5-23.6). Median ACE survival was 77.0 months (95% CI 58.0-96.0). An ACE survival curve was derived from which we estimate that 5-year post-ACE, one-third of patients can expect to have had their ACE closed. Younger age at ACE was predictive of earlier closure (p = 0.023) and closure for success (p < 0.001). Neither patient sex (p = 0.546) nor presence of psychological comorbidities (p = 0.769) predicted likelihood of closure. Incontinence 6-week post-ACE was also associated with increased likelihood of closure (p = 0.042). CONCLUSION: The ACE survival curve estimates the proportion of patients with idiopathic constipation who can expect closure (either due to success or failure) at certain timepoints. This may be useful for patient counseling. Younger age at ACE was associated with earlier closure (for success).

Gold nanotriangles: scale up and X-ray radiosensitization effects in mice.

In the past decade, there has been considerable interest in radiosensitization using gold nanoparticles that accumulate specifically in cancerous tissue while sparing normal tissues. Despite this interest, it remains unclear which nanoparticle morphologies, cellular uptake, or cytoplasmic distribution elicit optimal radiosensitization. We introduce gold nanotriangles (AuNTs) as a possible X-ray radiotherapy sensitizer. In this study, we first explored a large-scale synthetic method for the production of high quality monodisperse AuNTs. Second, we conducted in vitro and in vivo experiments to evaluate the effect of PEGylated AuNTs (pAuNTs) on cellular uptake, cytotoxicity, bio-distribution, and radiosensitization on radiation-resistant human Glioblastoma Multiforme (GBM) cells. Our results suggest that the new scale up synthesis methodology consistently produced high quality AuNTs and pAuNTs which had nonspecific cellular uptake without any obvious cytotoxicity and exhibited excellent radiosensitization.

Contemporary pediatric surgical training in the UK.

INTRODUCTION: Pediatric surgical trainees worldwide face pressures from expansion of programs and training positions, subspecialization, regionalization, restrictions of working hours, and rigid training criteria. The era of apprenticeship training has long gone, and surgical education needs to be responsive and adapt to newer challenges. The aim of this study was to examine the teaching provision component of pediatric surgical training in the UK. METHOD: A national teaching survey was sent to UK pediatric surgery trainees in 2010 and compared to results of a repeat survey in 2015. Analysis was carried out to compare type of teaching, trends in teaching delivery, quality, and attendance over time. RESULTS: Regional variability was noted in teaching programs. Both provision of educational activities and ability to attend teaching improved between 2010 and 2015. Despite this, overall trainee satisfaction remained low, with 50% and 52% of respondents describing their teaching as "good" or "excellent" in 2010 and 2015, respectively (P=0.84). Seventy-five percent of centers provided simulation training, and 25% of respondents had regional teaching provided. Survey response rate was comparable between 2010 and 2015. CONCLUSION: Variability in national educational provision was observed. We suggest regular national audit of educational activity and responsive adaption to external pressures on training if competent surgeons are to be the product of contemporary pediatric surgery training programs.

Free tissue transfer in head and neck reconstruction: 100 consecutive cases.

OBJECTIVES: Free flap reconstruction of head and neck defects is a rapidly changing field. We present a case series in this field in which we critically assess our survival rates and complications, and we highlight specific technical variables that may be associated with improved outcomes. METHODOLOGY: This case series from a tertiary medical centre comprises 100 consecutive head and neck microvascular free flap reconstructions. Medical notes were reviewed specifically for indications, adjuvant and neoadjuvant chemoradiotherapy, complications, and outcome of the free flap. RESULTS: The overall flap survival rate was 99%, with a 6% return-to-theatre rate. Three cases had a general complication in the form of a non-flap compromising haematoma that necessitated a return to theatre for an evacuation. Specific microvascular anastomosis-related complication rate was 2% requiring salvage revision. One flap was lost due to infection. Of the 100 cases, 87% were fasciocutaneous free flaps, 7% were musculocutaneous, 5% were osseocutaneous, and one was a skin/cartilage free flap. With regard to indications for reconstruction, oncological resection accounted for 86% of cases; a total of 12% had mandibular bone involvement that required osseocutaneous reconstruction. CONCLUSIONS: We have highlighted specific technical steps we used that may have contributed to our positive results. Moreover, we encourage the use of standardised postoperative monitoring guidelines for all multidisciplinary surgical teams involved in head and neck patients; they facilitate communication and increase early detection of complications, permitting timely intervention, which may be critical for flap survival.

The importance of a medical chaperone: a quality improvement study exploring the use of a note stamp in a tertiary breast surgery unit.

OBJECTIVES: The project aim was to determine current use and documentation of medical chaperones within a major breast service unit. It explored ways of improving adherence to professional guidelines concerning chaperones. SETTING: The single centre quality improvement project was completed in a tertiary breast service unit in North West London. It was a three-stage project with initial audit in October 2013, 1st postintervention cycle in November 2013 and 2nd postintervention cycle in October 2014. PARTICIPANTS: In each study cycle, data were collected from entries in clinic notes until at least 155 encounters with documented clinical examination were analysed. All notes were of female patients. INTERVENTIONS: (1) Intervention 1st cycle: presentation and discussion of chaperone guidelines alongside reminder posters and introduction of note stamp. (2) Intervention 2nd cycle: note stamp alone. PRIMARY AND SECONDARY OUTCOME MEASURES: Documentation of chaperone offer, documentation of patient preference regarding chaperone, identifier (name or signature) of chaperone present and gender of examining clinician. RESULTS: In the 1st postintervention cycle, 69.95% documentation of chaperone offer was recorded, p<0.001, CI (59.04% to 80.76%). This result was replicated in the 2nd postintervention cycle a year later with 74.86% documentation of chaperone offer recorded, p<0.001, CI (66.41% to 83.31%). The 4.91% difference was insignificant; p=0.294, CI (14.03% to 4.21%). CONCLUSIONS: The authors suggest that a proforma approach to medical chaperones is an effective means of ensuring adherence to best practice guidelines. A stamp, or similar, that can be embedded into documentation structure is an effective example of such an approach. Improved documentation allows any problems with adherence to guidelines to be more easily identified, helping to ensure the safeguarding of patients and staff involved in intimate examinations.

Meta-analysis of the effectiveness of esomeprazole in gastroesophageal reflux disease and Helicobacter pylori infection.

WHAT IS KNOWN AND OBJECTIVE: Proton pump inhibitors (PPIs) are one of the most widely used classes of drugs. However, the quantum clinical benefit of newer and more expensive PPIs over the older generation PPIs remains uncertain. This meta-analysis sought to assess the clinical and safety profiles of esomeprazole versus omeprazole at pharmacologically equivalent doses in healing gastroesophageal reflux disease (GERD), peptic ulcer disease and eradicating Helicobacter pylori (H. pylori) infection. METHODS: PubMed and the Cochrane Library were searched for randomized controlled trials comparing esomeprazole with omeprazole at all doses up to February 2015. Trials were assessed by two reviewers for eligibility according to predefined study inclusion criteria. Meta-analysis was conducted using a random effects model, and heterogeneity in the estimated effects was investigated using meta-regression. Sensitivity analysis was performed to test the robustness of the findings. RESULTS AND DISCUSSION: Fifteen trials were included and none of which compared esomeprazole with omeprazole in peptic ulcer disease. The included studies had not evaluated esomeprazole 20 mg versus omeprazole 40 mg. In GERD, esomeprazole 40 mg (relative risk (RR) = 1·07; 95% confidence interval (CI) 1·02 to 1·12) and 20 mg (RR=1·04; 95% CI 1·01 to 1·08) significantly improved esophagitis healing when compared with omeprazole 20 mg at week 8. The corresponding numbers needed to treat were 17 and 30, respectively. No significant difference was observed between esomeprazole 20 mg and omeprazole 20 mg at week 4. In H. pylori eradication, there was no difference in the treatment effects between esomeprazole 20 mg and omeprazole 20 mg (RR = 1·01;95% CI 0·96 to 1·05). Their safety profiles were comparable. WHAT IS NEW AND CONCLUSION: Esomeprazole demonstrated better esophagitis healing rate in patients with GERD than omeprazole at week 8. However, this clinical advantage diminished when both drugs were given at the same doses at week 4. Superiority of esomeprazole was not observed in the H. pylori eradication rates.

Ileal atresia secondary to antenatal strangulation of Littre's hernia in an exomphalos minor.

We describe an unusual case of ileal atresia, resulting from antenatal strangulation of a Meckel's diverticulum in an exomphalos minor. This is a rare antenatal complication of Littre's hernia, which has not been previously described. A small exomphalos minor at the base of umbilical cord and late onset vascular accident at the narrow defect leading to ileal atresia may be missed in the prenatal diagnosis. The triad of exomphalos minor, Meckel's diverticulum and terminal ileal atresia secondary to antenatal strangulation of Littre's hernia is very rare to find in the same patient. A small exomphalos minor at the base of the umbilical cord can be missed even in the postnatal period. Our case lends direct evidence of vascular accident as a cause of ileal atresia and supports vascular theory. Whenever possible umbilicus should be preserved naturally and exomphalos sac should be opened higher up for excellent cosmetic results.

Mutational characterization of congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Malaysia.

BACKGROUND AND AIM: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is a common autosomal recessive disorder. Our objective was to identify the 21-hydroxylase active gene, CYP21A2 mutations in Malaysian 21-OHD patients using different techniques. MATERIALS AND METHODS: Blood samples were obtained from 97 Malaysian 21-OHD patients, which included 40 siblings from 19 families. We used various techniques which include restriction enzyme digestion, Southern blot, multiple ligation-dependent probe amplification (MLPA) and sequencing to elucidate CYP21A2 mutations. RESULTS: Homozygous and compound heterozygous mutations were identified in 95 of the 97 patients (98%). Deletions of CYP21A2 were found in 43 patients (44.3%). Deletions identified in CYP21A2 gene were the usual 30-kb deletion comprising 3'UTR CYP21A1P, C4B and 5'CYP21A2, complete deletion of CYP21A2 gene, deletion in exons 1-3, exons 1-6 and exons 1-8 of CYP21A2. The common mutations identified in CYP21A2 gene were deletion/conversion (22.6%), p.R356W (22%), IVS2-13A/C>G (21.3%), p.I172N (5.3%), p.Q318X (5.3%), and p.P30L (1.03%). This is the first report of the mutation frequency in CYP21A2 gene among the Malay ethnic group. Two novel mutations, c.Y97insT and p.L345P were identified in our patients. Our results show good phenotype-genotype correlation in most of the cases, although clinical variations were identified in some patients. CONCLUSIONS: The study has found various mutations including deletions in CYP21A2 gene in Malaysian patients with 21-hydroxylase deficiency using the MLPA technique that is being widely used in present laboratory settings.

Pressure necrosis secondary to negative pressure dressing.

Wound complications in patients with significant co-morbidities is common; however, in our patient the problem was compounded by the inappropriate placement of negative pressure dressing.

Invasive fungal infection in an elderly patient with defective inflammatory macrophage function.

Macrophages are known to be involved in pathogen recognition and mediate host immune responses, but, in the clinical setting, their purported central role in opportunistic fungal infections has not been demonstrated to date. Herein, we describe a patient with invasive testicular aspergillosis in whom we found, for the first time, a defect in macrophage function.

Outcomes of diverting jejunostomy for severe necrotizing enterocolitis.

BACKGROUND/PURPOSE: A diverting jejunostomy without bowel resection is an option for surgical management of extensive necrotizing enterocolitis (NEC). We aimed to determine outcomes of infants who underwent this operation. METHODS: We collected clinical and outcome data on infants undergoing a diverting jejunostomy with no bowel resection as a primary procedure for extensive NEC. Data are median (range). RESULTS: Seventeen neonates underwent a diverting jejunostomy. Eleven (65%) had multifocal disease, whereas 6 (35%) had pan-intestinal involvement. Perforation was seen in 7 (41%), all with multifocal disease. The stoma was placed 12 cm (8-45) from the duodenojejunal flexure. Six infants (35%) died, 4 of these within a day of operation, owing to persisting instability. Intestinal continuity was achieved in all survivors after 52 (17-83) days, and only 1 infant (9%) had a colonic stricture. Seven infants recovered without the need for further intestinal resection distal to the jejunostomy. In those that survived, parenteral nutrition was needed for 2.2 months (1.3-18.0). A single patient had short bowel syndrome. CONCLUSIONS: A diverting jejunostomy is a useful surgical procedure that allows high survival and enteral autonomy in the treatment of extensive NEC. In most patients, the affected intestine recovers without further intestinal resection.

Regulation of cytokine responses by seasonality of vitamin D status in healthy individuals.

The immune modulating capacity of vitamin D(3) is well-recognized. Ultra-violet (UV) exposure determines production of vitamin D(3) in vivo and varies through the course of the year, especially in temperate regions. However, it is not known whether the human innate immune response differs due to seasonality. To validate the seasonal effects of vitamin D(3) , the effect of 1,25(OH)(2) D(3) on peripheral blood mononuclear cells (PBMC) cytokine response was first determined in vitro. 1,25(OH)(2) D(3) decreased interleukin (IL)-6 and tumour necrosis factor (TNF)-α release by PBMC stimulated with tripalmitoyl-S-glycerylcysteine (Pam3Cys) or lipopolysaccharide (LPS). Subsequently, ex-vivo stimulation studies were performed in 15 healthy volunteers through the course of the four seasons of the year. PBMC were isolated and stimulated with Toll-like receptor (TLR)-2 and TLR-4 ligands Pam3Cys and LPS, respectively. Circulating concentrations of 25(OH)D(3) and 1,25(OH)(2) D(3) were higher during summer (P<0·05) and a down-regulation of TLR-4-mediated IL-1ß, IL-6, TNF-α, interferon (IFN)-γ and IL-10 production in summer was observed compared to winter (P<0·05). The variation in cytokine response upon TLR-2 (Pam3Cys) stimulation was moderate throughout the four seasons. The repressed cytokine production during the summer months could be explained partly by the reduced cell-membrane expression of TLRs. Physiological variation in vitamin D(3) status through the four seasons of the year can lead to alteration in the innate immune responses. Elevated vitamin D(3) level in vivo is associated with down-regulation of cytokine response through diminished surface expression of pattern recognition receptors.

Chlorhexidine impregnated central venous catheter inducing an anaphylatic shock in the intensive care unit.

Chlorhexidine, a bisbiguanide, is widely used as an antiseptic agent in medical practice as it has the greatest residual antimicrobial activity. Central venous catheters coated extraluminally with chlorhexidine have been made to reduce extraluminal contamination. By using both the chlorhexidine-alchohol skin preparation and antimicrobial-coated catheters during vascular cannulation, it can reduce catheter related bloodstream significantly [1]. The reduction in infection rate is especially vital in critically ill patients who require long-term vascular access. Adverse reactions to chlorhexidine are rare and uncommon, and have been under-recognised as a cause of anaphylaxis. There are several reports of allergic reactions following exposure to chlorhexidine. We report of a case of anaphylaxis shock requiring cardiopulmonary resuscitation during the placement of a chlorhexidine impregnated central venous catheters.