Tracheal tube size in adults undergoing elective surgery - a narrative review.

Tracheal tubes are routinely used in adults undergoing elective surgery. The size of the tracheal tube, defined by its internal diameter, is often generically selected according to sex, with 7-7.5 mm and 8-8.5 mm tubes recommended in women and men, respectively. Tracheal diameter in adults is highly variable, being narrowest at the subglottis, and is affected by height and sex. The outer diameter of routinely used tracheal tubes may exceed these dimensions, traumatise the airway and increase the risk of postoperative sore throat and hoarseness. These complications disproportionately affect women and may be mitigated by using smaller tracheal tubes (6-6.5 mm). Patient safety concerns about using small tracheal tubes are based on critical care populations undergoing prolonged periods of tracheal intubation and not patients undergoing elective surgery. The internal diameter of the tube corresponds to its clinical utility. Tracheal tubes as small as 6.0 mm will accommodate routinely used intubation aids, suction devices and slim-line fibreoptic bronchoscopes. Positive pressure ventilation may be performed without increasing the risk of ventilator-induced lung injury or air trapping, even when high minute volumes are required. There is also no demonstrable increased risk of aspiration or cuff pressure damage when using smaller tracheal tubes. Small tracheal tubes may not be safe in all patients, such as those with high secretion loads and airflow limitation. A balanced view of risks and benefits should be taken appropriate to the clinical context, to select the smallest tracheal tube that permits safe peri-operative management.

Analgesic benefits and clinical role of the posterior suprascapular nerve block in shoulder surgery: a systematic review, meta-analysis and trial sequential analysis.

The posterior suprascapular nerve block has been proposed as an analgesic alternative for shoulder surgery based on the publication of several comparisons with interscalene block that failed to detect differences in analgesic outcomes. However, quantification of the absolute treatment effect of suprascapular nerve block on its own, in comparison with no block (control), to corroborate the aforementioned conclusions has been lacking. This study examines the absolute analgesic efficacy of suprascapular nerve block compared with control for shoulder surgery. We systematically sought electronic databases for studies comparing suprascapular nerve block with control. The primary outcomes included postoperative 24-h cumulative oral morphine consumption and the difference in area under the curve for 24-h pooled pain scores. Secondary outcomes included the incidence of opioid-related side-effects (postoperative nausea and vomiting) and patient satisfaction. Data were pooled using random-effects modelling. Ten studies (700 patients) were analysed; all studies examined landmark-guided posterior suprascapular nerve block performed in the suprascapular fossa. Suprascapular nerve block was statistically but not clinically superior to control for postoperative 24-h cumulative oral morphine consumption, with a weighted mean difference (99%CI) of 11.41 mg (-21.28 to -1.54; p = 0.003). Suprascapular nerve block was also statistically but not clinically superior to control for area under the curve of pain scores, with a mean difference of 1.01 cm.h. Nonetheless, suprascapular nerve block reduced the odds of postoperative nausea and vomiting and improved patient satisfaction. This review suggests that the landmark-guided posterior suprascapular nerve block does not provide clinically important analgesic benefits for shoulder surgery. Investigation of other interscalene block alternatives is warranted.

Proliferating pilomatricoma in a 9-year-old girl.

Proliferating pilomatricoma is a rare, benign tumor of hair matrix origin that rarely occurs in children. We report the case of a 9-year-old girl with a rapidly growing, proliferating pilomatricoma located on the glabella. The lesion was embolized and surgically excised, with histopathological examination of the tissue confirming the diagnosis of proliferating pilomatricoma.

Discovery of a Chiral DNA-Targeted Platinum-Acridine Agent with Potent Enantioselective Anticancer Activity.

A structure-activity relationship study was performed for a set of rigidified platinum-acridine anticancer agents containing linkers derived from chiral pyrrolidine and piperidine scaffolds. Screening a library of microscale reactions and selected resynthesized compounds in non-small-cell lung cancer (NSCLC) cells showed that cytotoxicities varied by more than three orders of magnitude. A potent hit compound was discovered containing a (R)-N-(piperidin-3-yl) linker (P2-6R), which killed NCI-H460 and A549 lung cancer cells 100 times more effectively than the S enantiomer (P2-6S). P2-6R accumulated in A549 cells significantly faster and produced 50-fold higher DNA adduct levels than P2-6S. Ligand similarity analysis suggests that only module 6R may be compatible with strainless monofunctional intercalative binding. NCI-60 screening and COMPARE analysis highlights the spectrum of activity and potential utility of P2-6R for treating NSCLC and other solid tumors.

Distribution pattern and multivariate analyses for anthropogenic apportionment of selected coastal water in Macajalar Bay, Philippines.

Macajalar Bay in the southern Philippines has become an attractive thoroughfare with recent developments, rendering anthropogenic input to the coastal waters. Expediting coastal resource management strategies necessitates the present study on coastal water characteristics. This was aided with distribution pattern and multivariate analyses for apportioning possible anthropogenic inputs. A total of 15 biophysicochemical characteristics were studied covering two municipalities (Opol and Jasaan) with six subcoastal communities in 2017. Data were all processed for Q test to eliminate outliers before distribution analyses using univariate (descriptive), inferential (t test, one-way ANOVA, Pearson correlation), and multivariate statistics (hierarchal cluster analysis (HCA) and principal component analysis (PCA)). Overall, higher concentrations were determined in the ecotourism site (Opol) than in the industrial site (Jasaan) as sampling months progressed except for oil and grease. Results for total coliform, fecal coliform, heterotrophic plate count (HPC), total suspended solids (TSS), chemical oxygen demand (COD), and oil and grease regardless of spatial-temporal variations exceeded the standards. Distribution pattern revealed variations selectively for pH, temperature, dissolved oxygen (DO), and oil and grease, indicating site-specific distribution. HCA and PCA results corroborated correlation matrices showing elevated concentrations in an ecotourism site (Opol) apportioned anthropogenic input mainly due to rural development and ecotourism. Likewise, in the industrial site (Jasaan), HCA and PCA results reflected possible anthropogenic input from rural development and industries. Overall, anthropogenic apportionment in the bay was influenced by rural development, ecotourism, and industries.

Characterization of a recombinant humanized anti-cocaine monoclonal antibody produced from multiple clones for the selection of a master cell bank candidate.

We have generated a humanized anti-cocaine monoclonal antibody (mAb), which is at an advanced stage of pre-clinical development. We report here in vitro binding affinity studies, and in vivo pharmacokinetic and efficacy studies of the recombinant mAb. The overall aim was to characterize the recombinant antibody from each of the three highest producing transfected clones and to select one to establish a master cell bank. In mAb pharmacokinetic studies, after injection with h2E2 (120 mg/kg iv) blood was collected from the tail tip of mice over 28 days. Antibody concentrations were quantified using ELISA. The h2E2 concentration as a function of time was fit using a two-compartment pharmacokinetic model. To test in vivo efficacy, mice were injected with h2E2 (120 mg/kg iv), then one hour later injected with an equimolar dose of cocaine. Blood and brain were collected 5 min after cocaine administration. Cocaine concentrations were quantified using LC/MS. The affinity of the antibody for cocaine was determined using a [3H] cocaine binding assay. All three antibodies had long elimination half-lives, 2-5 nM Kd for cocaine, and prevented cocaine's entry into the brain by sequestering it in the plasma. Pharmacokinetic and radioligand binding assays supported designation of the highest producing clone 85 as the master cell bank candidate. Overall, the recombinant h2E2 showed favorable binding properties, pharmacokinetics, and in vivo efficacy.

Miniaturized implantable sensors for in vivo localized temperature measurements in mice during cold exposure.

We report on in vivo temperature measurements performed in mice at two specific sites of interest in the animal body over a period of several hours. In particular, the aim of this work was to monitor mouse metabolism during cold exposure, and to record possible temperature differences between the body temperature measured in the abdomen and the temperature of the brown adipose tissue (BAT) situated in the interscapular area. This approach is of biological interest as it may help unravelling the question whether biochemical activation of BAT is associated with local increase in metabolic heat production. For that purpose, miniaturized thermistor sensors have been accurately calibrated and implanted in the BAT and in the abdominal tissue of mice. After 1 week of recovery from surgery, mice were exposed to cold (6 °C) for a maximum duration of 6 h and the temperature was acquired continuously from the two sensors. Control measurements with a conventional rectal probe confirmed good performance of both sensors. Moreover, two different mouse phenotypes could be identified, distinguishable in terms of their metabolic resistance to cold exposure. This difference was analyzed from the thermal point of view by computational simulations. Our simple physical model of the mouse body allowed to reproduce the global evolution of hypothermia and also to explain qualitatively the temperature difference between abdomen and BAT locations. While with our approach, we have demonstrated the importance and feasibility of localized temperature measurements on mice, further optimization of this technique may help better identify local metabolism variations.

A qualitative study of cancer survivors' responses to information on the long-term and late effects of pelvic radiotherapy 1-11 years post treatment.

As more patients survive cancer for longer term, the long-term and late effects of treatments become increasingly important issues for cancer survivors and providing information to enable survivors to recognise and manage them becomes an increasingly pressing challenge for health care professionals. The aim of this study was to explore the experiences of cancer survivors regarding information given on potential long-term and late effects of pelvic radiotherapy. Semi-structured interviews were conducted with 28 cancer survivors who had had radiotherapy to the pelvic area for a range of cancers 1-11 years previously. Participants were recruited using maximum variation sampling from a larger questionnaire survey of patients treated at one hospital. Interviews were recorded, transcribed and analysed using Framework. Participants recognised the value of information to reassure and to inform action but also its potentially undesirable effects to frighten or raise anxieties about future problems and its inherent limitations in meeting their wider needs. They identified the timing, amount of information and context in which it was given as of particular importance. Information based on personal experience was also valued. These findings highlight the importance of appropriate, individualised information during treatment, at hospital discharge and subsequently in primary care.

Pharmacokinetics, safety and tolerability of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with hepatic impairment.

AIMS: This open-label, parallel-group study investigated the effect of various degrees of hepatic impairment on the pharmacokinetics, safety and tolerability of the sodium glucose cotransporter 2 inhibitor empagliflozin. METHODS: Thirty-six subjects [8 each with mild, moderate or severe hepatic impairment (Child-Pugh classification), and 12 matched controls with normal hepatic function] received a single 50 mg dose of empagliflozin. RESULTS: Empagliflozin was rapidly absorbed. After reaching peak levels, plasma drug concentrations declined in a biphasic fashion. Compared with subjects with normal hepatic function, geometric mean ratios (90% confidence interval) of AUC(0-∞) and C(max) were 123.15% (98.89-153.36) and 103.81% (82.29-130.95), respectively, in patients with mild hepatic impairment, 146.97% (118.02-183.02) and 123.31% (97.74-155.55), respectively, in patients with moderate hepatic impairment, and 174.70% (140.29-217.55) and 148.41% (117.65-187.23), respectively, in patients with severe hepatic impairment. Adverse events, all mild or moderate in intensity, were reported in three subjects with moderate hepatic impairment, two subjects with severe hepatic impairment and six subjects with normal hepatic function. CONCLUSIONS: Empagliflozin was well tolerated in subjects with hepatic impairment. Increases in empagliflozin exposure were less than twofold in patients with hepatic impairment; therefore no dose adjustment of empagliflozin is required in patients with hepatic impairment.

Oral Structural Dysphagia in Children.

Oral causes of dysphagia in infancy may involve the lips, the tongue, or the palate. Whereas ankyloglossia is commonly diagnosed in infants with dysphagia, assessment of the need for surgical intervention may be less straightforward. Tongue size (macroglossia) may be associated with dysphagia as it may cause limitation of movement of the food or milk bolus by the lips or cheeks. Congenital conditions such as cleft lip and palate, micrognathia, or craniofacial microsomia may also be associated with dysphagia. Diagnosis and treatment of these conditions can be improved with the engagement of lactation and feeding experts as well as multidisciplinary craniofacial teams.

Antioxidants green tea extract and nordihydroguaiaretic acid confer species and strain-specific lifespan and health effects in Caenorhabditis nematodes.

The Caenorhabditis Intervention Testing Program (CITP) is an NIH-funded research consortium of investigators who conduct analyses at three independent sites to identify chemical interventions that reproducibly promote health and lifespan in a robust manner. The founding principle of the CITP is that compounds with positive effects across a genetically diverse panel of Caenorhabditis species and strains are likely engaging conserved biochemical pathways to exert their effects. As such, interventions that are broadly efficacious might be considered prominent compounds for translation for pre-clinical research and human clinical applications. Here, we report results generated using a recently streamlined pipeline approach for the evaluation of the effects of chemical compounds on lifespan and health. We studied five compounds previously shown to extend C. elegans lifespan or thought to promote mammalian health: 17α-estradiol, acarbose, green tea extract, nordihydroguaiaretic acid, and rapamycin. We found that green tea extract and nordihydroguaiaretic acid extend Caenorhabditis lifespan in a species-specific manner. Additionally, these two antioxidants conferred assay-specific effects in some studies-for example, decreasing survival for certain genetic backgrounds in manual survival assays in contrast with extended lifespan as assayed using automated C. elegans Lifespan Machines. We also observed that GTE and NDGA impact on older adult mobility capacity is dependent on genetic background, and that GTE reduces oxidative stress resistance in some Caenorhabditis strains. Overall, our analysis of the five compounds supports the general idea that genetic background and assay type can influence lifespan and health effects of compounds, and underscores that lifespan and health can be uncoupled by chemical interventions.

Blood-stage malaria vaccine candidate RH5.1/Matrix-M in healthy Tanzanian adults and children; an open-label, non-randomised, first-in-human, single-centre, phase 1b trial.

BACKGROUND: A blood-stage Plasmodium falciparum malaria vaccine would provide a second line of defence to complement partially effective or waning immunity conferred by the approved pre-erythrocytic vaccines. RH5.1 is a soluble protein vaccine candidate for blood-stage P falciparum, formulated with Matrix-M adjuvant to assess safety and immunogenicity in a malaria-endemic adult and paediatric population for the first time. METHODS: We did a non-randomised, phase 1b, single-centre, dose-escalation, age de-escalation, first-in-human trial of RH5.1/Matrix-M in Bagamoyo, Tanzania. We recruited healthy adults (aged 18-45 years) and children (aged 5-17 months) to receive the RH5.1/Matrix-M vaccine candidate in the following three-dose regimens: 10 µg RH5.1 at 0, 1, and 2 months (Adults 10M), and the higher dose of 50 µg RH5.1 at 0 and 1 month and 10 µg RH5.1 at 6 months (delayed-fractional third dose regimen; Adults DFx). Children received either 10 µg RH5.1 at 0, 1, and 2 months (Children 10M) or 10 µg RH5.1 at 0, 1, and 6 months (delayed third dose regimen; Children 10D), and were recruited in parallel, followed by children who received the dose-escalation regimen (Children DFx) and children with higher malaria pre-exposure who also received the dose-escalation regimen (High Children DFx). All RH5.1 doses were formulated with 50 µg Matrix-M adjuvant. Primary outcomes for vaccine safety were solicited and unsolicited adverse events after each vaccination, along with any serious adverse events during the study period. The secondary outcome measures for immunogenicity were the concentration and avidity of anti-RH5.1 serum IgG antibodies and their percentage growth inhibition activity (GIA) in vitro, as well as cellular immunogenicity to RH5.1. All participants receiving at least one dose of vaccine were included in the primary analyses. This trial is registered at ClinicalTrials.gov, NCT04318002, and is now complete. FINDINGS: Between Jan 25, 2021, and April 15, 2021, we recruited 12 adults (six [50%] in the Adults 10M group and six [50%] in the Adults DFx group) and 48 children (12 each in the Children 10M, Children 10D, Children DFx, and High Children DFx groups). 57 (95%) of 60 participants completed the vaccination series and 55 (92%) completed 22 months of follow-up following the third vaccination. Vaccinations were well-tolerated across both age groups. There were five serious adverse events involving four child participants during the trial, none of which were deemed related to vaccination. RH5-specific T cell and serum IgG antibody responses were induced by vaccination and purified total IgG showed in vitro GIA against P falciparum. We found similar functional quality (ie, GIA per µg RH5-specific IgG) across all age groups and dosing regimens at 14 days after the final vaccination; the concentration of RH5.1-specific polyclonal IgG required to give 50% GIA was 14·3 µg/mL (95% CI 13·4-15·2). 11 children were vaccinated with the delayed third dose regimen and showed the highest median anti-RH5 serum IgG concentration 14 days following the third vaccination (723 µg/mL [IQR 511-1000]), resulting in all 11 who received the full series showing greater than 60% GIA following dilution of total IgG to 2·5 mg/mL (median 88% [IQR 81-94]). INTERPRETATION: The RH5.1/Matrix-M vaccine candidate shows an acceptable safety and reactogenicity profile in both adults and 5-17-month-old children residing in a malaria-endemic area, with all children in the delayed third dose regimen reaching a level of GIA previously associated with protective outcome against blood-stage P falciparum challenge in non-human primates. These data support onward efficacy assessment of this vaccine candidate against clinical malaria in young African children. FUNDING: The European and Developing Countries Clinical Trials Partnership; the UK Medical Research Council; the UK Department for International Development; the National Institute for Health and Care Research Oxford Biomedical Research Centre; the Division of Intramural Research, National Institute of Allergy and Infectious Diseases; the US Agency for International Development; and the Wellcome Trust.

The risk of a subsequent cancer diagnosis after herpes zoster infection: primary care database study.

BACKGROUND: Herpes zoster and cancer are associated with immunosuppression. Zoster occurs more often in patients with an established cancer diagnosis. Current evidence suggests some risk of cancer after zoster but is inconclusive. We aimed to assess the risk of cancer following zoster and the impact of prior zoster on cancer survival. METHODS: A primary care database retrospective cohort study was undertaken. Subjects with zoster were matched to patients without zoster. Risk of cancer following zoster was assessed by generating hazard ratios using Cox regression. Time to cancer was generated from the index date of zoster diagnosis. RESULTS: In total, 2054 cancers were identified in 74,029 patients (13,428 zoster, 60,601 matches). The hazard ratio for cancer diagnosis after zoster was 2.42 (95% confidence interval 2.21, 2.66) and the median time to cancer diagnosis was 815 days. Hazard ratios varied between cancers, and were highest in younger patients. There were more cancers in patients with zoster than those without for all age groups and both genders. Prior immunosuppression was not associated with change in risk, and diagnosis of zoster before cancer did not affect survival. CONCLUSION: This study establishes an association between zoster and future diagnosis of cancer having implications for cancer case finding after zoster diagnosis.

The risk of oesophago-gastric cancer in symptomatic patients in primary care: a large case-control study using electronic records.

BACKGROUND: Over 15 000 new oesophago-gastric cancers are diagnosed annually in the United Kingdom, with most being advanced disease. We identified and quantified features of this cancer in primary care. METHODS: Case-control study using electronic primary-care records of the UK patients aged ≥40 years was performed. Cases with primary oesophago-gastric cancer were matched to controls on age, sex and practice. Putative features of cancer were identified in the year before diagnosis. Odds ratios (ORs) were calculated for these features using conditional logistic regression, and positive predictive values (PPVs) were calculated. RESULTS: A total of 7471 cases and 32 877 controls were studied. Sixteen features were independently associated with oesophago-gastric cancer (all P<0.001): dysphagia, OR 139 (95% confidence interval 112-173); reflux, 5.7 (4.8-6.8); abdominal pain, 2.6 (2.3-3.0); epigastric pain, 8.8 (7.0-11.0); dyspepsia, 6 (5.1-7.1); nausea and/or vomiting, 4.9 (4.0-6.0); constipation, 1.5 (1.2-1.7); chest pain, 1.6 (1.4-1.9); weight loss, 8.9 (7.1-11.2); thrombocytosis, 2.4 (2.0-2.9); low haemoglobin, 2.4 (2.1-2.7); low MCV, 5.2 (4.2-6.4); high inflammatory markers, 1.7 (1.4-2.0); raised hepatic enzymes, 1.3 (1.2-1.5); high white cell count, 1.4 (1.2-1.7); and high cholesterol, 0.8 (0.7-0.8). The only PPV >5% in patients ≥55 years was for dysphagia. In patients <55 years, all PPVs were <1%. CONCLUSION: Symptoms of oesophago-gastric cancer reported in secondary care were also important in primary care. The results should inform guidance and commissioning policy for upper GI endoscopy.

Lack of drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and warfarin in healthy volunteers.

AIM: To investigate potential drug-drug interactions between empagliflozin and warfarin. METHODS: Healthy subjects (n = 18) received empagliflozin 25 mg qd for 5 days (treatment A), followed by empagliflozin 25 mg qd for 7 days (days 6-12) with a single 25 mg dose of warfarin on day 6 (treatment B), and a single 25 mg dose of warfarin alone (treatment C), in an open-label, crossover study. Subjects received treatments in sequence AB_C or C_AB with a washout period of ≥14 days between AB and C or C and AB. RESULTS: Warfarin had no effect on empagliflozin area under concentration-time curve or maximum plasma concentration at steady-state (AUC(τ,ss) or C(max,ss)): geometric mean ratios (GMRs) (90% confidence intervals [CI]) were 100.89% (96.86, 105.10) and 100.64% (89.79, 112.80), respectively. Empagliflozin had no effect on AUC from 0 h to infinity (AUC(0-∞)) or C(max) for R- or S-warfarin (GMRs [90% CI] for AUC(0-∞): 98.49% [95.29, 101.80] and 95.88% [93.40, 98.43], respectively; C(max): 97.89% [91.12, 105.15] and 98.88% [91.84, 106.47], respectively). Empagliflozin had no clinically relevant effects on warfarin's anticoagulant activity (international normalised ratio [INR]) (GMR [95% CI] for peak INR: 0.87 [0.73, 1.04]; area under the effect-time curve from 0 to 168 h: 0.88 [0.79, 0.98]. No drug-related adverse events were reported for empagliflozin after monotherapy or combined administration. The combination of empagliflozin and warfarin was well tolerated. CONCLUSIONS: No drug-drug interactions were observed between empagliflozin and warfarin, indicating that empagliflozin and warfarin can be co-administered without dosage adjustments of either drug.

Toxicokinetics of a humanized anti-cocaine monoclonal antibody in male and female rats and lack of cross-reactivity.

A humanized monoclonal antibody h2E2 designed to bind cocaine with high affinity, specificity, and a long half-life (~7 d in rats) is being developed as a treatment for cocaine use disorder. We report here a pharmacokinetic (PK) study of h2E2 using male and female rats conducted under a Good Laboratory Practice (GLP) protocol over a dose range of 40 to 1200 mg/kg. The maximum concentration measured in rat plasma (Cmax) varied proportionately to the dose administered in both male and female rats. The terminal elimination half-lives (t1/2ß) were not significantly different in male and female rats at all doses tested. Importantly, this study reports pharmacokinetics for a humanized monoclonal antibody at a dose never tested before. h2E2 has a high affinity for cocaine, whereas low or no affinity was demonstrated for cocaine metabolites (all except cocaethylene), endogenous monoamines, and methamphetamine. This demonstrates its specificity and a potential lack of interactions with physiological and endocrine systems. A review of the clinical signs in single-dose toxicity studies in rats revealed no effects on the central nervous, respiratory, or cardiovascular systems following single intravenous doses of 40 to 1200 mg/kg. This study predicts that this monoclonal antibody may be safe and effective in humans.

C-Terminal Arginine-Selective Cleavage of Peptides as a Method for Mimicking Carboxypeptidase B.

C-Terminal residues play a pivotal role in dictating the structure and functions of proteins. Herein, we report a mild, efficient, chemoselective, and site-selective chemical method that allows for precise chemical proteolysis at C-terminal arginine dictated by 9,10-phenanthrenequinone independent of the remaining sequence. This biomimetic approach also exhibits the potential to synthesize C-terminal methyl ester (-CO2Me) peptides.

Dendrite-derived supernumerary axons on adult axotomized motor neurons possess proteins that are essential for the initiation and propagation of action potentials and synaptic vesicle release.

Axotomy can trigger profound alterations in the neuronal polarity of adult neurons in vivo. This can manifest itself in the development of new axon-like processes emanating from the tips of distal dendrites. Previously, these processes have been defined as axonal based on their axonal morphology. This study extends this definition to determine whether, more importantly, these processes possess the prerequisite molecular machinery to function as axons. Using a combination of intracellular labeling and immunohistochemistry, we demonstrate that the distribution of voltage-gated sodium channels on these processes matches the arrangement of these channels that is necessary for the initiation and conduction of action potentials. At terminal bouton-like structures they possess key proteins necessary for the release of synaptic vesicles (SV2 and synaptophysin). Thus, axon-like processes emanating from the tips of distal dendrites represent a rearrangement of neuronal polarity whereby axotomized neurons can develop additional functional axons in vivo.

Cancer outcomes and all-cause mortality in adults allocated to metformin: systematic review and collaborative meta-analysis of randomised clinical trials.

AIMS/HYPOTHESIS: Observational studies suggest that metformin may reduce cancer risk by approximately one-third. We examined cancer outcomes and all-cause mortality in published randomised controlled trials (RCTs). METHODS: RCTs comparing metformin with active glucose-lowering therapy or placebo/usual care, with minimum 500 participants and 1-year follow-up, were identified by systematic review. Data on cancer incidence and all-cause mortality were obtained from publications or by contacting investigators. For two trials, cancer incidence data were not available; cancer mortality was used as a surrogate. Summary RRs, 95% CIs and I (2)statistics for heterogeneity were calculated by fixed effects meta-analysis. RESULTS: Of 4,039 abstracts identified, 94 publications described 14 eligible studies. RRs for cancer were available from 11 RCTs with 398 cancers during 51,681 person-years. RRs for all-cause mortality were available from 13 RCTs with 552 deaths during 66,447 person-years. Summary RRs for cancer outcomes in people randomised to metformin compared with any comparator were 1.02 (95% CI 0.82, 1.26) across all trials, 0.98 (95% CI 0.77, 1.23) in a subgroup analysis of active-comparator trials and 1.36 (95% CI 0.74, 2.49) in a subgroup analysis of placebo/usual care comparator trials. The summary RR for all-cause mortality was 0.94 (95% CI 0.79, 1.12) across all trials. CONCLUSIONS/INTERPRETATION: Meta-analysis of currently available RCT data does not support the hypothesis that metformin lowers cancer risk by one-third. Eligible trials also showed no significant effect of metformin on all-cause mortality. However, limitations include heterogeneous comparator types, absent cancer data from two trials, and short follow-up, especially for mortality.

The risk of pancreatic cancer in symptomatic patients in primary care: a large case-control study using electronic records.

BACKGROUND: Over 8000 new pancreatic cancers are diagnosed annually in the UK; most at an advanced stage, with only 3% 5-year survival. We aimed to identify and quantify the risk of pancreatic cancer for features in primary care. METHODS: A case-control study using electronic primary care records identified and quantified the features of pancreatic cancer. Cases, aged ≥40 in the General Practice Research Database, UK, with primary pancreatic cancer were matched with controls on age, sex and practice. Putative features of pancreatic cancer were identified in the year before diagnosis. Odds ratios (OR) were calculated for features of cancer using conditional logistic regression. Positive predictive values (PPV) were calculated for consulting patients. RESULTS: In all, 3635 cases and 16,459 controls were studied. Nine features were associated with pancreatic cancer (all P<0.001 except for back pain, P=0.004); jaundice, OR 1000 (95% confidence interval (CI) 4,302,500); abdominal pain, 5 (4.4, 5.6); nausea/vomiting, 4.5 (3.5, 5.7); back pain, 1.4 (1.1, 1.7); constipation, 2.2 (1.7, 2.8); diarrhoea, 1.9 (1.5, 2.5); weight loss, 15 (11, 22); malaise, 2.4 (1.6, 3.5); new-onset diabetes 2.1 (1.7, 2.5). Positive predictive values for patients aged ≥60 were <1%, apart from jaundice at 22% (95% CI 14, 52), though several pairs of symptoms had PPVs >1%. CONCLUSION: Most previously reported symptoms of pancreatic cancer were also relevant in primary care. Although predictive values were small - apart from jaundice - they provide a basis for selection of patients for investigation, especially with multiple symptoms.