Likelihood Ratio Test and the Evidential Approach for 2 × 2 Tables.

Categorical data analysis of 2 × 2 contingency tables is extremely common, not least because they provide risk difference, risk ratio, odds ratio, and log odds statistics in medical research. A χ2 test analysis is most often used, although some researchers use likelihood ratio test (LRT) analysis. Does it matter which test is used? A review of the literature, examination of the theoretical foundations, and analyses of simulations and empirical data are used by this paper to argue that only the LRT should be used when we are interested in testing whether the binomial proportions are equal. This so-called test of independence is by far the most popular, meaning the χ2 test is widely misused. By contrast, the χ2 test should be reserved for where the data appear to match too closely a particular hypothesis (e.g., the null hypothesis), where the variance is of interest, and is less than expected. Low variance can be of interest in various scenarios, particularly in investigations of data integrity. Finally, it is argued that the evidential approach provides a consistent and coherent method that avoids the difficulties posed by significance testing. The approach facilitates the calculation of appropriate log likelihood ratios to suit our research aims, whether this is to test the proportions or to test the variance. The conclusions from this paper apply to larger contingency tables, including multi-way tables.

Does Hyaluronidase Enhance Drug Penetration to Mechanoreceptors?

BACKGROUND: The pharmacological study of mechanoreceptors embedded within tissue is hampered by tissue barriers to applied research drugs. METHODS: Hyaluronidase increases the permeability of tissues and is used clinically to facilitate the distribution of injected drugs. An in vitro rat sinus hair preparation was used to determine whether hyaluronidase (1,500 or 3,000 IU/10 mL) had an effect on drug access to receptor sites on slowly adapting St I and St II mechanoreceptors. Electrical recordings were made from single mechanoreceptor units that were activated by trapezoid ramp stimuli. Cinnamaldehyde (500-1,500 µM) and capsazepine (100 µM) were used as test drugs. Changes in onset time and degree of depression of firing due to test drugs were compared to control experiments not employing hyaluronidase. RESULTS: There were no statistical effects on any of the observed measures. Often the effects were opposite to those predicted. Using a likelihood approach, it was calculated that there was strong evidence (log-likelihood ratios from -0.5 to -6.5) to support a null effect over a facilitatory effect. There was no evidence of loss of integrity of mechanoreceptor mechanotransduction mechanisms following hyaluronidase applications. Comparison with Existing Method: The use of hyaluronidase does not facilitate drug access to receptors. CONCLUSIONS: In the in vitro sinus hair preparation, the addition of hyaluronidase does not allow easier access to slowly adapting mechanoreceptors within the follicle.

Use of beta blockers is associated with hearing loss.

OBJECTIVE: This study was conducted to investigate the hypothesis that patients using ß-blockers will develop hearing loss. DESIGN: A cross-sectional study. STUDY SAMPLE: A total of 125 patients completed the study. A total of 63 patients were on ß-blockers and 62 were not on ß-blockers. RESULTS: Carvedilol was significantly associated with hearing loss. Other beta-blockers including metoprolol and atenolol showed no association with hearing loss. Linear multiple regression analysis was run including variables of gender, age, ischaemic heart disease, cardiac failure/dilated cardiomyopathy, frusemide and carvedilol use as predictors for total hearing loss severity at all frequencies. Age and gender, as well as carvedilol, were found to be the only statistically significant predictors for hearing loss severity. CONCLUSION: Chronic use of carvedilol was associated with significant hearing loss. This may need to be taken into account when prescribing the drug. Further randomised controlled studies with baseline audiometric hearing tests before starting treatment, and periodic follow-up tests, would provide a better assessment of the effect of carvedilol on hearing.

Suspected appendicitis in pregnancy.

AIM: Acute appendicitis is one of the most common acute surgical presentations. However investigation and management is sometimes confounded in a pregnant patient. Appendicitis in pregnancy is often managed jointly by both the surgical and obstetric teams, which can lead to discrepant pathways, which may be detrimental to the patient. This review sets out to identify the normal physiological changes of pregnancy that pose diagnostic and therapeutic difficulties to the clinician, assess the more common differential diagnoses and review the current evidence to assist achieving a swift diagnosis and appropriate treatment. METHODS: A literature review of the investigation and management of suspected appendicitis in pregnancy was undertaken. Guidelines by the relevant surgical, obstetric and radiological societies were also reviewed. RESULTS: There remains no consensus on the best diagnostic pathway for appendicitis in pregnancy; which is unsurprising given that appendicitis in non-pregnant patients can yield diagnostic conundrums. However this review identifies a role for MRI scanning as a useful adjunct in these patients. The increasing role of laparoscopy in these patients is also becoming more apparent. CONCLUSION: Appendicitis in pregnancy remains a complex problem necessitating a close working relationship between various specialties to achieve the best outcome for mother and fetus.

Glutamatergic modulation of synaptic-like vesicle recycling in mechanosensory lanceolate nerve terminals of mammalian hair follicles.

Our aim in the present study was to determine whether a glutamatergic modulatory system involving synaptic-like vesicles (SLVs) is present in the lanceolate ending of the mouse and rat hair follicle and, if so, to assess its similarity to that of the rat muscle spindle annulospiral ending we have described previously. Both types of endings are formed by the peripheral sensory terminals of primary mechanosensory dorsal root ganglion cells, so the presence of such a system in the lanceolate ending would provide support for our hypothesis that it is a general property of fundamental importance to the regulation of the responsiveness of the broad class of primary mechanosensory endings. We show not only that an SLV-based system is present in lanceolate endings, but also that there are clear parallels between its operation in the two types of mechanosensory endings. In particular, we demonstrate that, as in the muscle spindle: (i) FM1-43 labels the sensory terminals of the lanceolate ending, rather than the closely associated accessory (glial) cells; (ii) the dye enters and leaves the terminals primarily by SLV recycling; (iii) the dye does not block the electrical response to mechanical stimulation, in contrast to its effect on the hair cell and dorsal root ganglion cells in culture; (iv) SLV recycling is Ca(2+) sensitive; and (v) the sensory terminals are enriched in glutamate. Thus, in the lanceolate sensory ending SLV recycling is itself regulated, at least in part, by glutamate acting through a phospholipase D-coupled metabotropic glutamate receptor.

Cardiovascular adverse events of antineoplastic monoclonal antibodies among cancer patients: real-world evidence from a tertiary healthcare system.

BACKGROUND: Antineoplastic monoclonal antibodies (mAbs), such as trastuzumab, bevacizumab, and pertuzumab have been the mainstay of therapy in cancer patients. Despite proven efficacy of the monoclonal antibodies, cardiovascular-induced adverse events such as heart failure, hypertension, ischemic heart disease, arrhythmias, thromboembolic events, and hemorrhage remain a major complication. The European society of cardiology address that concern with antineoplastic monoclonal antibodies issuing a guideline to manage and monitor chemotherapy-induced cardiotoxicity. There is limited evidence of the real-world prevalence of cardiovascular (CV) events induced by monoclonal antibodies among patients with cancer in Saudi Arabia. OBJECTIVE: To evaluate the prevalence of cardiovascular adverse events among patients with cancer treated with monoclonal antibodies in Saudi Arabia. METHODS: This is a retrospective study conducted in a tertiary care hospital, Riyadh, Saudi Arabia. Data were obtained from an electronic medical record of patients with cancer treated with one of the selected monoclonal antibodies, who met the inclusion criteria between January 2005 until June 2015 and have been followed up for at least one year. Patients were stratified into groups according to monoclonal antibodies treatment: trastuzumab, bevacizumab, pertuzumab, and combined mAbs. RESULTS: A total of 1067 patient were included in the study, within the pre-determined study period. The prevalence of cardiovascular disease among patients with cancer treated with monoclonal antibodies was 16.3%. The prevalence of heart failure was relatively higher in the trastuzumab group (46/626 patients, 7.3%). Among 418 patients treated with bevacizumab, hypertension was the most frequent adverse event, reported in 38 patients (9.1%), followed by thromboembolism reported in 27 patients (6.5%). Treatment discontinuation owing to cardiovascular adverse events was reported in 42/1,067 patients (3.9%). CONCLUSION AND RELEVANCE: Prevalence of antineoplastic monoclonal antibody induced cardiovascular adverse events among patients with cancer is substantially high in Saudi Arabia. There is an urgent need to streamline the practice for identifying high risk patients and flexible referral system for cardio-oncology care.

Palliative excisional surgery for primary colorectal cancer in patients with incurable metastatic disease. Is there a survival benefit? A systematic review.

AIM: Patients with stage IV colorectal cancer with unresectable metastases can either receive chemotherapy or palliative resection of the primary lesion. In the absence of any randomized data the choice of initial treatment in stage IV colorectal cancer is not based on firm evidence. METHOD: A search of MEDLINE, Pubmed, Embase and the Cochrane Library database was performed from 1980 to 2010 for studies comparing palliative resection in stage IV colorectal cancer with other treatment modalities. Audits and observational studies were excluded. Median survival was the primary outcome measure. The morbidity and mortality of surgical and nonsurgical treatments were compared. RESULTS: Twenty-one studies (no randomized controlled trials) were identified. Most demonstrated a survival benefit for patients who underwent palliative resection. Multivariate analysis indicates that tumour burden and performance status are both major independent prognostic variables. Selection bias, incomplete follow up and nonstandardized reporting of complications make the data difficult to interpret. CONCLUSION: The studies indicate that there may be a survival benefit for primary resection of colorectal cancer in stage IV disease. The findings suggest that resection of the primary tumour should be based on tumour burden and performance status rather than on the presence or absence of symptoms alone.

Effects of camphor and related compounds on slowly adapting mechanoreceptors in the rat sinus hair follicle.

Introduction: Camphor is a popular compound for therapeutic and cosmetic use with a distinctive odour, and somatosensory warming and cooling properties. The mechanisms for its action remain unclear. Objective: The current study examined the effects of two enantiomers of camphor and related monoterpenoid compounds on mechanoreceptors. Methods: Extracellular recordings were made in an in vitro bath preparation. Camphor, borneol, eugenol, carveol, and thymol were tested on the neural activity of St I and St II slowly adapting mechanoreceptors in the rat vibrissal hair follicle preparation. Results: All compounds tested (0.5 - 2 mM bath concentrations) resulted in dose-dependent depression of spontaneous and mechanically evoked firing (dynamic and static phases). The mean latency of responses also increased. Both St I and St II were similarly affected, although (-)-camphor had a greater depressant effect on St II than on St I units. Differences were found across the different compounds for their effect on the dynamic and static phases. Thymol was found to have the greatest depressant effect on these phases. The broad spectrum TRP blocker ruthenium red did not reverse the depressant effects of camphor. The depressant effects of the compounds appeared similar to those obtained using the local anaesthetic lignocaine. The depressant effects of camphor and of lignocaine were partially reversed by the K+ channel blocker tetraethylammonium. Conclusions: The results question whether the depressant effects of camphor and related compounds act through TRP channels. Perhaps the use of more selective blockers may reveal the molecular mechanisms through which these compounds act.

Effects of potassium channel modulators on the responses of mammalian slowly adapting mechanoreceptors.

Introduction: slowly adapting mechanoreceptors in the skin provide vital tactile information to animals. The ionic channels that underlie their functioning is the subject of intense research. Previous work suggests that potassium channels may play particular roles in the activation and firing of these mechanoreceptors. Objective: We used a range of potassium channel blockers and openers to observe their effects on different phases of mechanoreceptor responses. Methods: Extracellular recording of neural activity of slowly adapting mechanoreceptors was carried out in an in vitro preparation of the sinus hair follicles taken from rat whisker pads. A range of potassium (K+) channel modulators were tested on these mechanoreceptor responses. The channel blockers tested were: tetraethylammonium (TEA), barium chloride (BaCl2), dequalinium, 4-aminopyridine (4-AP), paxilline, XE 991, apamin, and charybdotoxin. Results: Except for charybdotoxin and apamin, these drugs increased the activity of both types of slowly adapting units, St I and St II. Generally, both spontaneous and evoked (dynamic and static) activities increased. The channel opener NS1619 was also tested. NS1619 clearly decreased evoked activity (both dynamic and static) while leaving spontaneous activity relatively unaffected, with no clear discrimination of effects on the two types of St receptor. Conclusion: These findings are consistent with the targets of the drugs suggesting that K+ channels play an important role in the maintenance of spontaneous firing and in the production of and persistence of mechanoreceptor activity.

Evaluation of COVID-19 myths in Saudi Arabia.

OBJECTIVES: To examine the awareness level of COVID-19 and to highlight the frequency of myths and misconceptions among Saudi Arabia's population. METHODS: We conducted a cross-sectional study from June 13 to 20, 2020 by distributing a 16-item online Google forms questionnaire among adults (18-65 years old) living in Saudi Arabia. We utilized the convenience sampling. Data analysis was performed using Chi-square and multiple regression analysis on Jamovi. RESULTS: A total of 1436 responses were analyzed with 43.5% males and 56.5% females. Most respondents (89.1%) thought that only the elderly above 60 years old are considered at high risk of contracting COVID-19. Most respondents (86.5%) agreed that people with other health conditions could be more affected by COVID-19. Approximately 97.2% agreed that wearing a mask and avoiding touching eyes, nose, and mouth with unwashed hands was the leading preventive action. Most participants (99.4%) chose fever as an associated symptom. Respondents from the healthcare sector presented statistically higher scores than those in non-healthcare sectors (p<0.001). Higher education and higher salary were important predictors of better COVID-19 knowledge. CONCLUSION: Public health officials need to increase awareness measures on COVID-19 to limit myths and misconceptions and reduce psychological distress associated with it.

Comparative Analysis of Prescription Drug Prices in South Asian Association for Regional Cooperation Countries.

OBJECTIVES: The SAARC (South Asian Association for Regional Cooperation) is a geopolitical organization composed of 8 neighboring countries: Afghanistan, Bangladesh, Bhutan, India, the Maldives, Nepal, Pakistan, and Sri Lanka. The objective of this study was to compare the prices of some selected drugs in SAARC countries. METHODS: A list of 24 drugs was prepared based on certain inclusion and exclusion criteria. The retail prices of the drugs were determined from different sources and verified manually in the open market. The prices obtained in local currencies were converted into US dollars for comparison purposes. In another analysis, the gross domestic product (GDP) of each country was factored for comparative analysis. RESULTS: Out of the 23 drugs, 17 comparisons across countries were statistically different at P < .05. These analyses revealed large differences in drug prices among SAARC countries. The GDP-adjusted median drug prices revealed a more polarized picture, with Nepal generally having the highest prices (19 out of 24 drugs) and Sri Lanka having the lowest (19 out of 24 drugs). For example, the widely used antipsychotic drug risperidone was 7 times more expensive in Pakistan ($0.316) compared with Sri Lanka ($0.045). Adjusting for GDP made risperidone more than 18 times more expensive ($21.90 and $1.20) across the same 2 countries. CONCLUSION: Prices of selected drugs varied markedly in SAARC countries. After adjusting for GDP, drug prices became more polarized across countries, with Nepal featuring the highest prices. In determining drug prices, the country's GDP and the population's purchasing power need to be taken into account.

Combined analysis of eIF4E and 4E-binding protein expression predicts breast cancer survival and estimates eIF4E activity.

Increased eukaryotic translation initiation factor 4E (eIF4E) expression occurs in many cancers, and makes fundamental contributions to carcinogenesis by stimulating the expression of cancer-related genes at post-transcriptional levels. This key role is highlighted by the facts that eIF4E levels can predict prognosis, and that eIF4E is an established therapeutic target. However, eIF4E activity is a complex function of expression levels and phosphorylation statuses of eIF4E and eIF4E-binding proteins (4E-BPs). Our hypothesis was that the combined analyses of these pathway components would allow insights into eIF4E activity and its influence on cancer. We have determined expression levels of eIF4E, 4E-BP1, 4E-BP2 and phosphorylated 4E-BP1 within 424 breast tumours, and have carried out analyses to combine these and relate the product to patient survival, in order to estimate eIF4E activity. We show that this analysis gives greater prognostic insights than that of eIF4E alone. We show that eIF4E and 4E-BP expression are positively associated, and that 4E-BP2 has a stronger influence on cancer behaviour than 4E-BP1. Finally, we examine eIF4E, estimated eIF4E activity, and phosphorylated 4E-BP1 as potential predictive biomarkers for eIF4E-targeted therapies, and show that each determines selection of different patient groups. We conclude that eIF4E's influence on cancer survival is modulated substantially by 4E-BPs, and that combined pathway analyses can estimate functional eIF4E.

Practical advice on clinical decision making during neoadjuvant chemotherapy for primary breast cancer.

Neoadjuvant chemotherapy (NACT) is a useful approach in the treatment of many breast cancers. One of the main advantages of NACT is the possibility of breast conservation surgery in patients who would otherwise require a mastectomy. Most literature on NACT focuses on the effectiveness of different chemotherapy regimen and subsequent mastectomy rates. There is little guidance in the literature on aspects of individual patient management and decision making during NACT. This paper considers practical management advice where NACT is considered and adopted.

Effects of transient receptor potential (TRP) channel agonists and antagonists on slowly adapting type II mechanoreceptors in the rat sinus hair follicle.

The possible functional role of transient receptor potential (TRP) channels was investigated by testing various TRP agonists and antagonists in an isolated rat sinus hair follicle preparation. Extracellular recordings from slowly adapting type II mechanoreceptor units were made. The antagonist capsazepine depressed spontaneous and mechanically evoked activity, with an IC(50) of 82 microM. In one-third of units, capsazepine caused a selective depression of mechanically evoked firing, such that the existing spontaneous firing was interrupted by an absence of activity during the mechanical stimulus. The broad spectrum TRP blocker ruthenium red (30 microM) had inconsistent effects, although in some units a delayed onset (following wash) bursting and paroxysmal firing ensued. The agonist icilin (50-100 microM) had an excitatory effect on spontaneous firing, and (-)-menthol (200 microM) had inconsistent effects. Cinnamaldehyde (1-2 mM) depressed all types of activity equally, mechanically evoked and spontaneous. Camphor (0.5-2 mM) also depressed all types of activity, although it had a preferential effect on spontaneous activity. Capsaicin (1-10 microM) and allyl isothiocyanate (50-100 microM) had no clear effects. These results rule out any role for TRPA1 and TRPV1 channels in mechanotransduction processes of slowly adapting type II mechanoreceptors.

The potential role of ER beta isoforms in the clinical management of breast cancer.

The discovery of a second oestrogen receptor, ER beta, was a subject of much interest, as this suggested a means to improve the prognostic stratification of invasive breast cancer, better predict response to endocrine therapy, develop new chemotherapeutic/chemopreventative drugs and perhaps prevent inappropriate treatment. However, this has not proved to be straightforward with the discovery of five ER beta isoforms and numerous exon deletion variants. This review sets out to identify the present state of knowledge regarding the clinicopathological role of ER beta isoforms and discusses possible reasons for conflicting results arising from recent research findings.

Selective decline in the prevalence of slowly adapting type I mechanoreceptors during development.

Merkel nerve endings are identified physiologically as slowly adapting type I mechanoreceptor units. They are important for fine acuity tactile perception. We examined the effect of age on the electrophysiological availability of different types of slowly adapting mechanoreceptor units. Using 6-50 week old rats, we observed an obvious decline with age in the probability of recording from St I units of the deep vibrissal nerve. The precipitous decline occurred between ages 6-14 weeks and then stabilized. By contrast, the prevalence of St II units, the other type of slowly adapting mechanoreceptor, remained constant over the age range studied. These observations correlate with anatomical findings reported elsewhere.

Enhanced short-latency responses in the ventral posterior medial (VPM) thalamic nucleus following whisker trimming in the adult rat.

This study examined the effects of whisker trimming on the functional organization of the adult somatosensory thalamus. In vivo extracellular unit recordings were made on ventral posterior medial (VPM) thalamic neurons in urethane anaesthetised adult rats. Neuronal response properties to controlled whisker deflection were recorded in untrimmed control animals and in animals where one row of whiskers had been trimmed for a median of 18 days. Trimming significantly increased short-latency responses to stimulation of the centre receptive field whisker (mean increase of 36%, p<.001). Longer latency responses to surround receptive field whiskers were unaffected. Spontaneous firing was significantly decreased in trimmed animals. A condition-test paradigm indicated that thalamic inhibition was reduced following whisker trimming, although this effect failed to reach statistical significance. These results demonstrate a capacity of the adult somatosensory thalamus to undergo functional reorganization in response to non-traumatic and innocuous whisker trimming.

Behavioural lateralization of tactile performance in the rat.

Ten rats were assessed for behavioural lateralization using two different tests: paw preference and tail-suspension test. It was found that animals, at an individual level, tended to have a behavioural preference which was polarized either to the left side or the right side. Animals were then randomly assigned to two groups. One group had whiskers trimmed ipsilateral, and the other group had whisker trimmed contralateral, to their lateralized behavioural preference. Over 10 days the rats were trained on a roughness discrimination task. It was found that animals with whiskers trimmed on the contralateral side performed better (p<.05) than those with whiskers trimmed on the ipsilateral side. This finding was associated with a large effect size (partial eta(2)) of .474. The side of whisker trimming (right versus left) per se had no effect on performance (p=.26). These results indicate that motor lateralization at the individual level is associated with lateralization in the efficacy of whisker use.

Clinicians' guide to microarrays.

Cancer is a heterogeneous disease with wide-ranging subsets of patients who have different prognoses and who respond differently to treatments. Accordingly, deciding the best treatment strategy has become a priority in cancer care. The development of microarray technology over the last decade has caused great excitement, with the promise that these new tools may provide molecular signatures to help predict patient outcome and direct therapeutic approaches. Here, we describe the different types of microarrays available and discuss their pros and cons from a clinical perspective, with respect to breast cancer.