The UK Divide: Does Having a Pembrolizumab-Chemotherapy Option in Head and Neck Cancer Matter? Real-world Experience of First-line Palliative Pembrolizumab Monotherapy and Pembrolizumab-Chemotherapy Combination in Scotland.

AIMS: The Scottish Medical Consortium recently approved first-line pembrolizumab monotherapy or in combination with chemotherapy for head and neck squamous cell carcinoma in the palliative setting, contrasting with the decision made by the National Institute for Health and Care Excellence, who approved monotherapy alone in England and Wales. The aim of this study was to provide real-world performance data for first-line pembrolizumab-containing treatments for head and neck squamous cell carcinoma in the palliative setting in Scotland. MATERIALS AND METHODS: We analysed the electronic records of patients who started pembrolizumab-containing treatment between 1 March 2020 and 30 September 2021. Outcomes included overall survival, progression-free survival (PFS), the duration of response and the disease control rate. Data were compared with the KEYNOTE-048 study and clinical factors were evaluated for association with survival. RESULTS: Our cohort included 91 patients (median follow-up 10.8 months). Patient characteristics were similar to those in the KEYNOTE-048 study, although our cohort had a higher proportion of patients with newly diagnosed, non-metastatic disease. For patients receiving monotherapy (n = 76), 12- and 24-month overall survival were 45% and 27%, respectively. For patients receiving pembrolizumab-chemotherapy (n = 15), 12-month overall survival was 60% (24-month overall survival had not yet been reached). Experiencing one or more immune-related adverse event (irAE; versus no irAEs), of any grade, was associated with favourable overall survival and PFS for patients receiving monotherapy in both univariable Log-rank analysis (median overall survival 17.4 months versus 8.6 months, respectively, P = 0.0033; median PFS 10.9 months versus 3.0 months, respectively, P < 0.0001) and multivariable analysis (Cox proportional hazards regression: overall survival hazard ratio 0.31, P = 0.0009; PFS hazard ratio 0.17, P < 0.0001). CONCLUSION: Our real-world data support the KEYNOTE-048 study findings and the value of combination treatment options. Additionally, our data show that irAEs of any grade, as reported in routine clinical records, are associated with better outcomes in this patient group, adding to the growing body of evidence showing that irAEs are generally a positive marker of programmed death-ligand 1 (PD-L1) inhibitor response.

Is there a role for modified probiotics as beneficial microbes: a systematic review of the literature.

Our objective was to conduct a systematic review and meta-analysis for the use of modified (heat-killed or sonicated) probiotics for the efficacy and safety to prevent and treat various diseases. Recent clinical research has focused on living strains of probiotics, but use in high-risk patients and potential adverse reactions including bacteremia has focused interest on alternatives to the use of live probiotics. We searched MEDLINE/PubMed, Embase, Cochrane Central Register of Controlled Trials, CINAHL, Alt Health Watch, Web of Science, Scopus, PubMed, from inception to February 14, 2017 for randomised controlled trials involving modified probiotic strains. The primary outcome was efficacy to prevent or treat disease and the secondary outcome was incidence of adverse events. A total of 40 trials were included (n=3,913): 14 trials (15 arms with modified probiotics and 20 control arms) for the prevention of diseases and 26 trials (29 arms with modified probiotics and 32 control arms) for treatment of various diseases. Modified microbes were compared to either placebo (44%), or the same living probiotic strain (39%) or to only standard therapies (17%). Modified microbes were not significantly more or less effective than the living probiotic in 86% of the preventive trials and 69% of the treatment trials. Modified probiotic strains were significantly more effective in 15% of the treatment trials. Incidence rates of adverse events were similar for modified and living probiotics and other control groups, but many trials did not collect adequate safety data. Although several types of modified probiotics showed significant efficacy over living strains of probiotics, firm conclusions could not be reached due to the limited number of trials using the same type of modified microbe (strain, daily dose and duration) for a specific disease indication. Further research may illuminate other strains of modified probiotics that may have potential as clinical biotherapeutics.

Blue Rubber Bleb Nevus Syndrome with Musculo-skeletal Involvement and Pulmonary Stenosis.

BACKGROUND: Blue rubber bleb nevus syndrome is a rare clinical entity. CASE CHARACTERISTICS: A 13-year-old Indian boy presented with characteristic cutaneous lesions, gastrointestinal malformations, skeletal involvement and pulmonary stenosis. OBSERVATIONS: Diagnosis was confirmed on skin biopsy, radiographic evaluation, colonoscopy and echocardiography. Echocardiography revealed pulmonary stenosis, an association hitherto undescribed. MESSAGE: Detailed evaluation in a patient of blue rubber bleb nerves syndrome is mandatory.

Comparison of the utility of Cocaine- and Amphetamine-Regulated Transcript (CART), chromogranin A, and chromogranin B in neuroendocrine tumor diagnosis and assessment of disease progression.

CONTEXT: Prognosis in patients with neuroendocrine tumors (NETs) is often poor, frequently reflecting delayed diagnosis. Hence, accurate and practical NET markers are needed. Cocaine- and amphetamine-regulated transcript (CART) peptide is a potential novel NET marker. DESIGN AND PARTICIPANTS: Circulating levels of CART peptide and the established NET markers chromogranin A (CgA) and chromogranin B (CgB) were measured using RIA in 353 patients with NET (normal renal function) and in controls. Clinical data were collected retrospectively. MAIN OUTCOME MEASURE(S): The comparative and combined utility of CART, CgA, and CgB for diagnosis and assessment of disease progression was measured in different NET subtypes. RESULTS: CgA and CgB in combination improved diagnostic accuracy in patients with gut NETs, nongastroenteropancreatic NETs, and NETs with an unknown primary origin compared with each biomarker alone. Measuring CART did not further improve diagnosis in these NET subtypes. For pancreatic NETs, CgB was superior to CgA and CART in detecting stable disease (P < .007), whereas CgA and CART in combination were most effective in identifying progressive disease. In phaeochromocytomas/paragangliomas (PCC/PGL), CART was the most useful biomarker for identifying stable (P < .001) and progressive (P = .001) disease. Consistent with this, plasma CART decreased following PCC/PGL tumor resection, remaining low in all patients in remission, but increasing in those with progressive disease. CONCLUSIONS: CART is a useful marker for identifying progressive pancreatic NETs. CART is superior to CgA and CgB in detecting stable and progressive PCC/PGLs, and may have a role as a surveillance marker for PCC/PGL patients.

Selection of natural health products for clinical trials: a preclinical template.

In preparation for a clinical trial on the efficacy of Echinacea products with a pediatric population, a rational method for selection of test products was developed, based on phytochemical and bioassay evaluation. Ten currently available commercial products of Echinacea angustifolia (EA) or Echinacea purpurea (EP) were selected, and 3 bottles of each of 2 different lots were purchased for each product. Investigators were blinded to product identity before phytochemical analysis. Lot-to-lot variation was small, but product variation due to species and formulation was large. Products derived from ethanol extracts had low polysaccharide content and high levels of alkamides (EA), echinacoside (EA), cynarin (EA), cichoric acid (EP), and caftaric acid (EP). These products possessed high antiviral activities that differed between EA and EP products, but limited immune activation properties. In contrast, products derived without ethanol extraction had higher polysaccharide levels, but low levels of other components. These aqueous compounds showed immunostimulant activity as measured in a mouse macrophage model and a somewhat different antiviral profile. The choice of Echinacea product for clinical trial must therefore consider the impact of immune enhancement, the specific viral infection targeted, and the potential to reduce symptoms via antiinflammatory activity. Product selection may also depend on whether the intent of the trial is prophylaxis or treatment.

Vitamin D status is not associated with the risk of hospitalization for acute bronchiolitis in early childhood.

The association between vitamin D status and susceptibility to acute lower respiratory tract infection (ALRI) was studied in young Canadian children. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were measured in patients aged 1-25 months admitted to hospital with uncomplicated ALRI (primarily viral bronchiolitis) as well as in healthy, similarly aged patients without a history of hospitalization for ALRI (controls). Serum 25(OH)D concentrations were similar among cases and controls (77.0 versus 77.2 nmol l(-1); P=0.960), and there was no case-control difference in the prevalence of vitamin D insufficiency using two thresholds (<40 nmol l(-1): 4.7 versus 1.5%, P=0.365; <80 nmol l(-1): 51.6 versus 56.9%, P=0.598). Vitamin D status was not associated with the risk of hospitalization for ALRI in this population.

Subjective visual perceptions during vitreoretinal surgery under local anaesthesia.

PURPOSE: To evaluate the visual experiences of patients during vitreoretinal surgery under local anaesthesia (LA). METHODS: Prospective questionnaire survey of 80 patients within 30 min of completion of vitreoretinal surgery under LA. Preoperative visual acuity, surgical procedure and its duration, efficacy of the local block, as well as intraoperative perceptions of flashes, colours, movements, and seeing instruments were documented. RESULTS: A sub-Tenon's block was performed in 62/80 (77.5%) and a peribulbar block in the remainder. Overall, 72 (90%) of patients perceived light at some stage during their surgery. Of these, 51 (70.83%) observed movements, 45 (62.5%) saw colours, 38 (52.77%) saw instruments, and 24 (33.33%) saw flashes. The commonest observations were colourful swirls, black pipes, and the colour red. Most patients found these experiences pleasant or bearable; two found them frightening, and four would like to have been warned preoperatively about them. Preoperative visual acuity, diagnosis, gender of the patient, degree of akinesia, and the duration of surgery did not associate with visual perceptions. Logistic regression analysis showed that younger people were more likely to experience flashing lights (P=0.03) and to see instruments (P=0.04), patients having a sub-Tenon's block to perceive light (P=0.005), and those who did not receive awake sedation were more likely to see instruments (P=0.04). CONCLUSIONS: Visual experiences are common during vitreoretinal surgery undertaken under LA. Where appropriate, patients should be forewarned about these experiences and reassured that they are not normally frightening.

Epidemiology of NHP-drug interactions: identification and evaluation.

Increasing numbers of adults and children around the world are using natural health products (NHPs) to promote wellbeing or alleviate illness. Although often considered safe due to their natural origin, NHPs are potentially pharmacologically active and, therefore may cause harm. Limited data suggest that NHPs can interact with other NHPs as well as with prescription medication and foods. Although some common NHP-drug interactions have been identified and studied, in general, the epidemiology of NHP-drug interactions is not well-understood, in part because these harms are often underreported. Users rarely disclose NHP use to their physicians, and physicians rarely enquire about such use. Even if physicians become aware of a potential NHP-drug interaction, passive surveillance systems mean that it is left to the physician's discretion whether or not to report it to the proper authority. It is likely that active surveillance of NHP-drug interactions would result in increased reporting of NHP-related harms as well as better quality reports. Subsequent lab investigation would determine if adulteration, contamination, species misidentification, or misuse was responsible for the harm, or if a pharmacokinetic or pharmacodynamic NHP-drug interaction occurred. This kind of thorough detection and investigation of potential NHP-drug interactions is necessary to ensure the safe use of NHPs.

Interventions to prevent hypothermia at birth in preterm and/or low birthweight infants.

BACKGROUND: Hypothermia incurred during routine postnatal resuscitation is a world-wide issue (across all climates), associated with morbidity and mortality. Keeping vulnerable preterm infants warm is problematic even when recommended routine thermal care guidelines are followed in the delivery suite. OBJECTIVES: To assess efficacy and safety of interventions designed for prevention of hypothermia in preterm and/or low birthweight infants applied within ten minutes after birth in the delivery suite compared with routine thermal care. SEARCH STRATEGY: The standard search strategy of The Cochrane Collaboration was followed. Electronic databases were searched: MEDLINE (1966 to July Week 4 2007 ), CINAHL (1982 to July Week 4 2007), EMBASE (1974 to 01/08/2007), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2007), Database of Abstracts of Reviews of Effects (DARE 1994 to July 2007), conference/symposia proceedings using ZETOC (1993 to 17/08/2007), ISI proceedings (1990 to 17/08/2007) and OCLC WorldCat (July 2007). Identified articles were cross-referenced. No language restrictions were imposed. SELECTION CRITERIA: All trials using randomised or quasi-randomised allocations to test a specific intervention designed to prevent hypothermia, (apart from 'routine' thermal care) applied within 10 minutes after birth in the delivery suite to infants of < 37 weeks' gestational age or birthweight

Computational studies of Family A and Family B GPCRs.

A full picture of the similarities between Family A and Family B GPCRs (G-protein coupled receptors) has been frustrated by the lack of clear homology between the respective sequences. Here, we review previous computational studies on GPCR dimerization in which the putative dimerization interfaces have been analysed using entropy, the ET (evolutionary trace) method and related methods. The results derived from multiple sequence alignments of Family A subfamilies have been mapped on to the rhodopsin crystal structure using standard alignments. Similarly, the results for the Family B alignments have been mapped on to the rhodopsin crystal structure using the 'cold-spot' alignment. For both Family A and Family B GPCRs, the sequence analysis indicates that there are functional sites on essentially all transmembrane helices, consistent with the parallel daisy chain model of GPCR oligomerization in which each GPCR makes interactions with a number of neighbouring GPCRs. The results are not too sensitive to the quality of the alignment. Molecular Dynamics simulations of the activation process within a single transmembrane bundle of the rhodopsin and the beta(2)-adrenergic receptor have been reviewed; the key observation, which is consistent with other computational studies, is that there is a translation and bending of helix 6, which contributes to a significant opening out of the intracellular face of the receptor, as shown in the accompanying movies. The simulations required the application of specific experiment-derived harmonic and half-harmonic distance restraints and so the application of such simulations to Family B GPCRs requires considerable care because of the alignment problem. Thus, in order to address the alignment problem, we have exploited the observation that GCR1, a plant GPCR, has homology with Family A, Family B and Family E GPCRs. The resulting alignment for transmembrane helix 3 is presented.

Cercarial dermatitis in central India: an emerging health problem among tribal communities.

Although cercarial dermatitis is an emerging disease world-wide, cases of such dermatitis may often go undiagnosed, especially in communities that are affected by various skin infections. Between August 2001 and July 2002, 1336 individuals from tribal villages in central India were examined for dermatitis. Skin scrapings were collected and examined for Sarcoptes scabiei and each subject's response to antiscabies treatment was recorded. Freshwater snails were collected from the local ponds used for bathing, and examined for cercariae. The recorded prevalence of dermatitis ranged between 2.1% and 12.5% during the study year, peaking at the end of winter (February-March) and during the rainy season (August-October). Snail positivity for cercariae peaked in the rainy season. The prevalence and the severity of dermatitis were both higher in children than in adults. As most recorded cases of dermatitis were associated with a rash that developed soon after bathing in the local pond, all the skin scrapings were negative for itch mites, and the response to antiscabies treatment was poor, most if not all of the dermatitis observed was probably cercarial. Cercarial dermatitis therefore appears to be a significant health problem among the tribal populations of central India.

Probiotics for the prevention of pediatric antibiotic-associated diarrhea.

BACKGROUND: Antibiotics alter the microbial balance within the gastrointestinal tract. Probiotics may prevent antibiotic-associated diarrhea (AAD) via restoration of the gut microflora. Antibiotics are prescribed frequently in children and AAD is common in this population. OBJECTIVES: To assess the efficacy and adverse effects of probiotics (any specified strain or dose) for the prevention of antibiotic-associated diarrhea in children. To assess adverse events associated with the use of probiotics when co-administered with antibiotics in children. SEARCH STRATEGY: MEDLINE, EMBASE, CENTRAL, CINAHL , AMED, and the Web of Science (inception to August 2006) were searched along with specialized registers including the Cochrane IBD/FBD Review Group, CISCOM, Chalmers PedCAM Research Register and trial registries from inception to 2005. Letters were sent to authors of included trials, nutra/pharmaceutical companies, and experts in the field requesting additional information on ongoing or unpublished trials. Conference proceedings, dissertation abstracts, and reference lists from included and relevant articles were hand searched. SELECTION CRITERIA: Randomized, parallel, controlled (placebo, active, or no treatment) trials comparing co-administered probiotics with antibiotics for the prevention of diarrhea secondary to antibiotic use in children (0 to 18 years). DATA COLLECTION AND ANALYSIS: Methodological quality assessment and data extraction were conducted independently by two authors (BCJ, AS). Dichotomous data (incidence of diarrhea, adverse events) were combined using pooled relative risks, and continuous data (mean duration of diarrhea, mean daily stool frequency) as weighted mean differences, along with their corresponding 95% confidence intervals. Adverse events were summarized using risk difference. For overall pooled results on the incidence of diarrhea, a priori sensitivity analyses included per protocol versus intention to treat, random versus fixed effects, and methodological quality criterion. Subgroup analysis were conducted on probiotic strain, dose, definition of antibiotic-associated diarrhea, and antibiotic agent. MAIN RESULTS: Ten studies met the inclusion criteria. Trials included treatment with either Lactobacilli spp., Bifidobacterium spp., Streptococcus spp., or Saccharomyces boulardii alone or in combination. Six studies used a single strain probiotic agent and four combined two probiotic strains. The per protocol analysis for 9/10 trials reporting on the incidence of diarrhea show statistically significant results favouring probiotics over active/non active controls (RR 0.49; 95% CI 0.32 to 0.74). However, intention to treat analysis showed non-significant results overall (RR 0.90; 95% CI 0.50 to 1.63). Five of ten trials monitored for adverse events (n = 647); none reported a serious adverse event. AUTHORS' CONCLUSIONS: Probiotics show promise for the prevention of pediatric AAD. While per protocol analysis yields treatment effect estimates that are both statistically and clinically significant, as does analysis of high quality studies, the estimate from the intention to treat analysis was not statistically significant. Future studies should involve probiotic strains and doses with the most promising evidence (e.g., Lactobacillus GG, Lactobacillus sporogenes, Saccharomyces boulardii at 5 to 40 billion colony forming units/day). Research done to date does not permit determination of the effect of age (e.g., infant versus older children) or antibiotic duration (e.g., 5 days versus 10 days). Future trials would benefit from a validated primary outcome measure for antibiotic-associated diarrhea that is sensitive to change and reflects what treatment effect clinicians, parents, and children consider important. The current data are promising, but it is premature to routinely recommend probiotics for the prevention of pediatric AAD.

Interventions to prevent hypothermia at birth in preterm and/or low birthweight babies.

BACKGROUND: Hypothermia incurred during routine postnatal resuscitation is a world-wide issue (across all climates), with associated morbidity and mortality. Keeping vulnerable preterm infants warm is problematic even when recommended routine thermal care guidelines are followed in the delivery suite. OBJECTIVES: To assess efficacy and safety of interventions, designed for prevention of hypothermia in preterm and/or low birthweight infants, applied within 10 minutes after birth in the delivery suite compared with routine thermal care. SEARCH STRATEGY: The standard search strategy of The Cochrane Collaboration was followed. Electronic databases were searched: MEDLINE (1966 to May Week 4 2004 ), CINAHL (1982 to May Week 4 2004), EMBASE (1974 to 09/07/04), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2004), Database of Abstracts of Reviews of Effects (DARE 1994 to July 2004), conference/symposia proceedings using ZETOC (1993 to July 2004), ISI proceedings (1990 to 09/07/2004) and OCLC WorldCat (July 2004). Identified articles were cross-referenced. No language restrictions were imposed. SELECTION CRITERIA: All trials using randomised or quasi-randomised allocations to test a specific intervention designed to prevent hypothermia, (apart from 'routine' thermal care) applied within 10 minutes after birth in the delivery suite to infants of < 37 weeks' gestational age or birthweight