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.

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

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.

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.

Accelerating effect of ascorbic acid on N-nitrosamine formation and nitrosation by oxyhyponitrite.

The reaction of nitrite ion with ascorbic acid and its effect on the rate of nitrosation of secondary amines have been investigated by differential pulse polarography in aqueous acidic solution. Ascorbic acid shows nonuniform behavior: it accelerates the nitrosation of N-methylaniline between pH 1.00 and 1.95, allows the nitrosation of diphenylamine and iminodiacetonitrile, but inhibits the nitrosation of secondary amines, such as dimethylamine, diethylamine, proline, hydroxyproline, N-methylaminoacetonitrile, N-methylaminopropionitrile, and sarcosine. The nitrosating agent generated by the reaction between ascorbic acid and nitrite ion appears to be oxyhyponitrite ion (N2O3-2).

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.

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

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.

Influence of stressors on the rewarding effects of alcohol in Wistar rats: studies with alcohol deprivation and place conditioning.

RATIONALE AND OBJECTIVES: Studies on laboratory animals have provided conflicting results regarding the actions of stressors on the rewarding effects of alcohol. In the present study, we first examined the effects of footshock or social defeat, given during deprivation, on the alcohol deprivation effect (ADE). We then tested the effects of stressors on place conditioning to alcohol, another technique used to measure drug reward. METHODS: Male Wistar rats were trained to drink 10% alcohol in a 24 h access, free-choice design and received intermittent footshock or defeat 5 times during a 2-week alcohol deprivation period, followed by 2 weeks of free access to alcohol. There were three such cycles. In the place conditioning studies, animals received footshock, defeat, or no stress immediately prior to conditioning sessions where they received alcohol (0.6 or 1.0 g/kg, i.p.) or vehicle injections. RESULTS: Alcohol intake of footshock-treated animals was significantly higher than that of controls following the first and second, but not the third period of alcohol deprivation and stress exposure. Defeat caused a smaller increase in alcohol intake that was significant only after the first deprivation and stress cycle. In the place conditioning studies, we found that either stressor blocked the place aversion induced by 1.0 g/kg alcohol. CONCLUSIONS: These results demonstrate that stressors can modify the rewarding and aversive properties of alcohol, measured using two different paradigms. Footshock and defeat produced transient, but significant increases in the magnitude of ADE, while exposure to either stressor reduced the aversive effects of a high dose of alcohol measured using the place conditioning paradigm.

Transitional cell carcinoma arising in a pyelocaliceal cyst. An unusual cystic renal lesion with cytologic and imaging findings.

The differentiation between benign and malignant cystic lesions of the kidney is a diagnostic challenge. Medical imaging aids in this task, but many cystic renal lesions require further work-up, frequently by computed tomography-guided fine needle aspiration. We report on the pathological findings in a case of moderately differentiated papillary transitional carcinoma, which arose in a pre-existing pyelocaliceal cyst in a 53-year-old man. In the case of this lesion, the distinction between a benign and a malignant renal cyst is blurred. To our knowledge, this is the third such occurrence to be reported and the first to be diagnosed by fine needle aspiration biopsy.

Balanitis and balanoposthitis.

Balanitis is an inflammation of the glans penis. There are several etiologic agents, including bacterial and yeast infections, parasitic infestations, and trauma or irritants. Plasma-cell balanitis and balanitis xerotica obliterans are two distinct clinical entities. The authors review the clinical and pathologic features and the treatment options for these conditions.

Practical limitations of the Deltatrac indirect calorimeter.

Indirect calorimetry is used to assess energy requirements. The Deltatrac Metabolic Monitor is a relatively inexpensive indirect calorimeter which uses a 'fixed' flow of ambient air to collect expired air. Only oxygen and carbon dioxide concentrations are measured and the 'fixed flow' is assumed in the calculation of oxygen consumption ((.)VO(2)) and carbon dioxide production ((.)VCO(2)). Using inert gas dilution we have studied the effect on (.)VO(2), and on the variability in (.)VO(2), of changing and lengthening the 1.77 m length of 35 mm tubing supplied with the instrument to collect expired air, and of using a mask to collect expired air instead of the manufacturer's hood. One would anticipate that changing the tubing could cause a change in resistance to gas flow and thus affect the true flow rate. This would alter the gas concentrations seen by the analysers, but the 'fixed flow' would still be assumed so the results would be in error. Adding extra lengths of manufacturers tubing caused an apparent rise in (.)VO(2) of 0.36%/m of tubing added, and using 22 mm tubing instead of the manufacturer's 35 mm tubing increased (.)VO(2) by 0.42% for each 10 cm of tubing added. Using the mask to collect expired air instead of the canopy (.)VO(2) was higher, possibly due to the energy cost of holding the mask, and was more variable, probably because of poorer mixing of the expired air. To measure (.)VO(2) using a mask with the same precision as a 10 min measurement made with the hood would entail measuring (.)VO(2) for 14.5 min. The methods used to collect expired air (mask or canopy, length and type of tubing) when measuring metabolic rate with the Deltatrac do affect the results obtained but these effects are small and predictable.

Hypothetical framework for a relationship between maternal thyroid function, nausea and vomiting of pregnancy, and congenital heart disease.

Our objective was to investigate whether a relationship exists among maternal thyroid function, nausea and vomiting of pregnancy, and congenital heart disease. A Medline search from 1966 to the present was conducted to look for reports on the existence of this relationship. The results were supplemented by abstract searches and personal communication with relevant authors. Our search found independent evidence that maternal hyperthyroidism is related to increased rates of nausea and vomiting of pregnancy, which in turn is significantly related to a decrease in the incidence of congenital heart disease. Early evidence indicates that the converse may be true: maternal hypothyroidism and thyroid replacement therapy are associated with an increase in congenital heart disease in children. The potential relationship between maternal thyroid function, nausea and vomiting of pregnancy, and thyroid replacement therapy needs further study. We propose a case-control study of children presenting for echocardiography to elicit specific information regarding the pregnancy.

Effect of wrist position on power grip and key pinch strength following carpal tunnel decompression.

Power grip and thumb key pinch strength were measured pre- and immediately postoperatively in 30 patients with carpal tunnel syndrome while the wrist was in flexion and extension. The carpal tunnel decompression was performed under local infiltration with 1% lignocaine. Grip strength decreased more in wrist flexion than in wrist extension. No difference was found in thumb pinch strength. The authors conclude that some of the immediate postoperative loss of grip strength in wrist flexion can be attributed to prolapse of flexor tendons out of the carpal tunnel in this position.

Neonatal outcome: correlation with Goodwin's High Risk Score.

PIP: 500 pregnant women in labor were studied to assess the efficacy of the Goodwin High Risk Scoring System for prediction of neonatal outcome. Goodwin scores ranged from 0-10 with babies at greater risk receiving higher scores. Offspring of these mothers were followed till the time of discharge from the hospital or until death. A total of 433 babies were discharged in apparently good condition while 67 babies expired. The mean resk scores for the babies who were discharged and babies who expired were 2.47 and 5.8 respectively. It was observed that the incidence of low birthweights also increased with increasing risk score. In asphyxiated babies (Apgar score 5 at 1 minute) who had risk scores of 6 or more were almost 8 times more prone to a fatal outcome than those with a lower risk score of 3 or less. This simple scoring system which can be easily applied by even paramedical workers can go a long way not only in selection of patients for referral to well-equipped centers but also in screening of patients needing special care in the overcrowded central hospitals.^ieng