A case of melanoma in situ of the central forehead repair by V-Y advancement flap and Burow graft.

Large defects on the face after Mohs surgery have posed significant reconstructive challenges. A 90-year-old man presented with melanoma in situ of the central forehead, which resulted in a 4.5cmx4.3cm defect after multiple stages of Mohs surgery. Although different approaches for forehead repair with nasal root involvement are possible, we demonstrate that the V-Y advancement flap and subsequent Burrow graft for nasal root repair represents a viable closure technique for large circular defects of the central forehead.

Bilateral eccrine angiomatous hamartomas of the proximal interphalangeal joints.

Eccrine angiomatous hamartoma is an uncommon, benign clinical entity constituting a nodular proliferation of eccrine glands and vascular structures localized to the dermis that typically present as unilateral, flesh-colored, erythematous, or violaceous papules on the extremities. These hamartomas may be associated with pain, hyperhidrosis, joint deformity, or functional impairment depending on the severity of the disease process. We present a case of bilaterally symmetric, asymptomatic eccrine angiomatous hamartomas involving all proximal interphalangeal joints of both hands. To date, there are only four prior cases of bilaterally symmetric eccrine angiomatous hamartomas reported in the literature, suggesting that the distribution experienced by our patient may represent a previously undescribed syndrome.

Updated assessment of occupational safety and health hazards of climate change.

Workers, particularly outdoor workers, are among the populations most disproportionately affected by climate-related hazards. However, scientific research and control actions to comprehensively address these hazards are notably absent. To assess this absence, a seven-category framework was developed in 2009 to characterize the scientific literature published from 1988-2008. Using this framework, a second assessment examined the literature published through 2014, and the current one examines literature from 2014-2021. The objectives were to present literature that updates the framework and related topics and increases awareness of the role of climate change in occupational safety and health. In general, there is substantial literature on worker hazards related to ambient temperatures, biological hazards, and extreme weather but less on air pollution, ultraviolet radiation, industrial transitions, and the built environment. There is growing literature on mental health and health equity issues related to climate change, but much more research is needed. The socioeconomic impacts of climate change also require more research. This study illustrates that workers are experiencing increased morbidity and mortality related to climate change. In all areas of climate-related worker risk, including geoengineering, research is needed on the causality and prevalence of hazards, along with surveillance to identify, and interventions for hazard prevention and control.

Clinicopathologic Characteristics of Melanoma in Patients with Parkinson Disease.

Patients with Parkinson disease (PD) are at high risk for developing melanoma, although current literature lacks details on the associated clinicopathologic characteristics. Our retrospective case-control study aimed to guide skin cancer surveillance recommendations for patients with PD, focusing on tumor sites. Our study included 70 adults with concurrent diagnoses of PD and melanoma from January 1, 2007 to January 1, 2020 at Duke University and 102 age-, sex-, and race-matched controls. The head/neck region accounted for 39.5% of invasive melanomas in the case group compared with 25.3% in the control group as well as 48.7% of noninvasive melanomas in the case group compared with 39.1% in the control group. Of note, 50% of metastatic melanomas in patients with PD originated on the head and neck (n = 3). Logistic regression showed 2.09 times higher odds of having a head/neck melanoma in our case group compared with that in the control group (OR = 2.09, 95% confidence interval = 1.13‒3.86; P = 0.020). Our study is limited by small sample size, and our case cohort lacked diversity regarding race, ethnicity, sex, and geography. Validation of the reported trends could provide more robust guidance for melanoma surveillance in patients with PD.

The Sloop family: Addressing rural health disparities through service and education.

Dr Mary T. Martin Sloop and Dr Eustace Henry Sloop shaped the landscape of healthcare and education for the small town of Crossnore in the mountains of Western North Carolina throughout the early- to mid-twentieth century. The duo of general practitioners founded the Crossnore School and the Garrett Memorial Hospital, later renamed Sloop Memorial Hospital before its closure in 1999. The Sloops provided medical care to an underserved Appalachian population and sought advice and assistance from key community stakeholders with every project they undertook, demonstrating their commitment to cultural assimilation. While the story of the Sloop family is one of success, patients in rural America are currently facing a dual crisis of healthcare access. Rural healthcare professional shortages contribute to difficulties establishing longitudinal relationships with primary care providers, which in turn decreases access to preventative medicine services. With over 106 rural hospitals closing since 2010, patients may face travel barriers to reach inpatient facilities with associated emergency services, and access to specialty services such as surgery is diminished. It is paramount to reflect on and learn from the stories of the past, highlighting the personal and professional fulfillment that can be found in embracing rurality through service and community integration.

Quality and Perceived Usefulness of Patient-Submitted Store-and-Forward Teledermatology Images.

Importance: Patient-submitted images vary considerably in quality and usefulness. Studies that characterize patient-submitted images in a real-life setting are lacking. Objective: To evaluate the quality and perceived usefulness of patient-submitted images as determined by dermatologists and characterize agreement of their responses. Design, Setting, and Participants: This survey study included patient images submitted to the Department of Dermatology at Duke University (Durham, North Carolina) between August 1, 2018, and December 31, 2019. From a total pool of 1200 images, 10 dermatologists evaluated 200 or 400 images each, with every image being evaluated by 3 dermatologists. Data analysis occurred during the year leading up to the article being written. Main Outcomes and Measures: The primary outcomes were the responses to 2 questions and were analyzed using frequency counts and interrater agreement (Fleiss κ) to assess image quality and perceived usefulness. We performed a random-effects logistic regression model to investigate factors associated with evaluators' decision-making comfort. We hypothesized that most images would be of low quality and perceived usefulness, and that interrater agreement would be poor. Results: A total of 259 of 2915 patient-submitted images (8.9%) did not depict a skin condition at all. The final analysis comprised 3600 unique image evaluations. Dermatologist evaluators indicated that 1985 images (55.1%) were useful for medical decision-making and 2239 (62.2%) were of sufficient quality. Interrater agreement for a given image's diagnostic categorization was fair to substantial (κ range, 0.36-0.64), while agreement on image quality (κ range, 0.35-0.47) and perceived usefulness (κ range, 0.29-0.38) were fair to moderate. Senior faculty had higher odds of feeling comfortable with medical decision-making than junior faculty (odds ratio [OR], 3.68; 95% CI, 2.9-4.66; P < .001) and residents (OR, 5.55; 95% CI, 4.38-7.04; P < .001). Images depicting wounds (OR, 1.75; 95% CI, 1.18-2.58; P = .01) compared with inflammatory skin conditions and that were in focus (OR, 5.56; 95% CI, 4.63-6.67; P < .001) had higher odds of being considered useful for decision-making. Conclusions and Relevance: In this survey study including 10 dermatologists, a slight majority of patient-submitted images were judged to be of adequate quality and perceived usefulness. Fair agreement between dermatologists was found regarding image quality and perceived usefulness, suggesting that store-and-forward teledermatology initiatives should consider a physician's individual experiences and comfort level. The study results suggest that images are most likely to be useful when they are in focus and reviewed by experienced attending physicians for wound surveillance, but dermatologists may be burdened by irrelevant or unsuitable images.

Neuromodulation and Eating Disorders.

PURPOSE OF REVIEW: We review recent evidence on the use of neuromodulation for treating eating disorders (EDs), including anorexia nervosa, bulimia nervosa and binge eating disorder. We evaluate studies on (a) modern non-invasive methods of brain stimulation, such as transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), (b) electroconvulsive therapy (ECT) and (c) more invasive techniques, including deep brain stimulation (DBS). RECENT FINDINGS: Most reports on the clinical applications of neuromodulation in EDs are limited to case studies, case series and small clinical trials. The majority have focused on severe, enduring and hard-to-treat cases of AN. In this population, data suggest that both rTMS and DBS have therapeutic potential and are safe and acceptable. High-quality clinical trials in different ED populations are needed which investigate different stimulation methods, sites and parameters, the use of neuromodulation as stand-alone and/or adjunctive treatment, as well as the mechanisms of action.

Panlobular emphysema is associated with COPD disease severity: A study of emphysema subtype by computed tomography.

BACKGROUND: Computed tomography has the potential to inform COPD prognosis. We sought to determine associations of emphysema phenotype with clinical parameters including lung function, inflammatory markers, and quality of life. METHODS: Participants of this single-center observational cohort (n = 83) were 40-80 years old, had ≥10 pack-year smoking, and a diagnosis of COPD confirmed by spirometry. All participants had available historic chest CT scans which were systematically reviewed by a single expert radiologist and scored for emphysema subtype, extent, and distribution. Associations between radiographic findings and clinical parameters were determined. RESULTS: Median age of participants was 72 years, median smoking 40 pack-years, and median FEV1 59% predicted. 84% of the participants had radiographic emphysema. Of those, 26% had panlobular emphysema (PLE), 68% centrilobular emphysema (CLE), and 6% paraseptal emphysema (PSE). As compared to the participants with no radiographic emphysema, the presence of PLE-dominant emphysema was associated with a lower BMI (P = 0.012) and greater extent of emphysema (P = 0.014). After adjusting for age, sex, and pack-years smoking history, PLE was associated with greater airflow obstruction by FEV1% (48% vs 71%, P = 0.005), greater symptom burden by CAT score (18 vs 9, P = 0.015), worse quality of life by SGRQ score (43 vs 22, P = 0.025), and more systemic inflammation by erythrocyte sedimentation rate (P = 0.001). CLE- or PSE-dominant emphysema were not similarly associated with clinical features or symptom burden. CONCLUSIONS: The presence of PLE-dominant emphysema was associated with greater extent of emphysema, greater airflow obstruction, increased respiratory symptoms, worse quality of life, and systemic inflammation. Further investigation is indicated to explore the pathogenesis of the PLE phenotype and the prognostic and treatment implications of PLE.

A Multicentre Retrospective Study of Fulvestrant Use and Efficacy in Advanced/Metastatic Breast Cancer.

AIMS: Fulvestrant is a selective oestrogen receptor (ER) degrader used in postmenopausal women with hormone receptor-positive advanced breast cancer. The study aim was to analyse demographics and outcomes of UK patients treated with fulvestrant monotherapy at nine representative centres. MATERIALS AND METHODS: Medical records of 459 patients with locally advanced or metastatic ER-positive, HER2-negative breast cancer treated with fulvestrant between August 2011 and November 2018 at nine UK centres were reviewed. Data were collated on demographics, progression-free survival, overall survival and disease response at first radiological assessment following fulvestrant initiation. Patients still alive by December 2018 were censored. RESULTS: Data from 429 of the 459 patients identified were eligible for inclusion in the analysis. The median age was 69 (range 21-95) and 64% (n = 275) had Eastern Cooperative Oncology Group performance status 0-1. Bone was the most commonly involved metastatic site (72%, n = 306). However, 295 (69%) patients had visceral involvement. Patients had received a median 2 (range 0-5) prior lines of endocrine therapy and median 0 (range 0-6) prior chemotherapies. Fulvestrant was first-line therapy in 43 patients (10%). The median duration of treatment was 5 months (range 1-88). The median progression-free survival was 5.5 months. In 51% of 350 patients radiologically assessed, there was evidence of disease response to fulvestrant. Fifteen per cent of these had a complete/partial response. Fulvestrant was discontinued predominantly due to disease progression, with 3% discontinued solely due to adverse events. The median overall survival for the whole cohort was 22.5 months (range 0-88). CONCLUSIONS: This is one of the largest studied cohorts of breast cancer patients treated with fulvestrant. This heavily endocrine-pretreated population reflects real-life use in the UK. Within this context, our retrospective data show that patients can experience maintained disease response when treated with fulvestrant, supporting the importance of equitable availability for all UK patients.

Trainee-trainer outcomes in mastoid surgery: a comparative study.

BACKGROUND: Mastoid exploration remains an advanced, mainstay operation within ENT, in which the surgical trainees' role has been debated. This audit compares mastoid exploration outcomes between trainees and consultants. METHODS: Cortical mastoidectomy, atticotomy, atticoantrostomy, modified radical mastoidectomy, combined-approach tympanoplasty and revision mastoidectomy operations performed between 2009 and 2020 were reviewed. Complications assessed were: facial palsy, labyrinth injury, dead ear, disease recurrence and time to recurrence. The chi-square test was used to determine significant associations. RESULTS: A total of 118 operations were surveyed. Thirty-five per cent of procedures (n = 41) were performed by trainees under supervision, and 65 per cent (n = 77) were carried out solely by consultants. Patients from 5 per cent of trainees' operations (n = 2) developed recurrence, compared with 7.8 per cent of consultants' (n = 6) (p = 0.55). No other complications developed in either group. CONCLUSION: The results corroborate those of other studies, indicating no significant increase in complication rate from consultants to trainees. Trainees likely completed less complicated cases. The stepwise incorporation of trainees did not compromise patient safety.

Early weight gain trajectories in first episode anorexia: predictors of outcome for emerging adults in outpatient treatment.

BACKGROUND: Early response to treatment has been shown to be a predictor of later clinical outcomes in eating disorders (EDs). Specifically, early weight gain trajectories in anorexia nervosa (AN) have been shown to predict higher rates of later remission in inpatient treatment. However, no study has, as of yet, examined this phenomenon within outpatient treatment of first episode cases of AN or in emerging adults. METHODS: One hundred seven patients with AN, all between the ages of 16 and 25 and with an illness duration of < 3 years, received treatment via the first episode rapid early intervention in eating disorders (FREED) service pathway. Weight was recorded routinely across early treatment sessions and recovery outcomes (BMI > 18.5 kg/m2 and eating psychopathology) were assessed up to 1 year later. Early weight gain across the first 12 treatment sessions was investigated using latent growth mixture modelling to determine distinct classes of change. Follow-up clinical outcomes and remission rates were compared between classes, and individual and clinical characteristics at baseline (treatment start) were tested as potential predictors. RESULTS: Four classes of early treatment trajectory were identified. Three of these classes (n = 95), though differing in their early change trajectories, showed substantial improvement in clinical outcomes at final follow-up. One smaller class (n = 12), characterised by a 'higher' start BMI (> 17) and no early weight gain, showed negligible improvement 1 year later. Of the three treatment responding groups, levels of purging, depression, and patient reported carer expressed emotion (in the form of high expectations and low tolerance of the patient) determined class membership, although these findings were not significant after correcting for multiple testing. A higher BMI at treatment start was not sufficient to predict optimal clinical outcomes. CONCLUSION: First episode cases of AN treated via FREED fit into four distinct early response trajectory classes. These may represent subtypes of first episode AN patients. Three of these four trajectories included patients with substantial improvements 1 year later. For those in the non-response trajectory class, treatment adjustments or augmentations could be considered earlier, i.e., at treatment session 12.

A key feature of anorexia nervosa (AN) is an unhealthily low body weight. Previous studies show that more weight gained early in inpatient treatment leads to better outcomes. This study tried to see if this was also true for outpatients receiving treatment for the first time. All participants were emerging adults between the ages of 16 and 25 who had been ill for less than 3 years. Weight was recorded across the first 12 weekly treatment sessions. Statistics showed that the patients fit roughly into four different groups in early treatment, each with different starting weights and rates of weight gain in the first 12 treatment sessions. The group a patient belonged to could sometimes be predicted by vomiting behaviours, level of depression, and patients' perception of parental tolerance and expectations at the start of treatment. Out of the four groups, three did relatively well 1 year later, but one small group of patients did not. This small group had a higher starting weight than many of the other groups but did not gain any weight across the first 12 sessions. These patients could benefit from a change or increase in the amount or intensity of treatment after the first 12 treatment sessions.

Adam Brown Kelly and his operating chair.

BACKGROUND: Adam Brown Kelly, well known for lending his name to Paterson-Brown Kelly syndrome, is steeped in the early history of otolaryngology. To date, little light has been shone on his contributions to the specialty in that exciting period and to his home town of Glasgow. METHOD: A historical review of his life and times was undertaken based on surviving accounts of his life, published work and archived memoirs. RESULTS: This article summarises his life and connections, with particular reference to his unique chair that has survived to this day. CONCLUSION: Brown Kelly remains a pioneer of modern otolaryngology, and deserving of prominence within the medical history of Glasgow.

The effect of the visual exercise environment on the response to psychological stress: a pilot study.

Background: Performing physical activity whilst exposed to nature can improve health. However, there is little evidence of its impact on stress outcomes. The aim of this study was to examine the influence of the visual exercise environment on the response to a psychosocial stressor. Methods: Eighteen participants were randomized to one of three conditions: i. nature; ii. built or; iii. control condition. Participants exercised for 30 min on a treadmill at 50% of their VO2max whilst viewing a video of either a natural or built environment or a blank screen. Following the exercise, participants completed the Trier Social Stress Test (TSST), a standardized laboratory stressor. Salivary samples were collected before, during and after the TSST to calculate cortisol reactivity and recovery. Results: One-way ANOVA revealed a significant effect of viewing condition on cortisol reactivity [F(2, 11) = 4.686, p = .034; n2p = .460]; with significantly lower reactivity in the built compared to the nature condition (p = .027, d = 1.73). There was no effect of condition on cortisol recovery (p = .137; n2p = .257). Conclusions: In the context of the adverse health impact of lower (i.e., blunted) cortisol responding, these findings could indicate a negative impact of the built environment on stress responses.

Clinical Outcomes of Soft Tissue Preservation Surgery With Hydroxyapatite-Coated Abutments Compared to Traditional Percutaneous Bone Conduction Hearing Implant Surgery-A Pragmatic Multi-Center Randomized Controlled Trial.

Background: Soft tissue preservation using a hydroxyapatite-coated abutment in bone conduction hearing implant surgery may lead to improved clinical outcomes over the short (1 year) and long term (3 years). Methods: In this open multi-center, randomized (1:1), controlled clinical trial, subjects with conductive, mixed hearing loss or single-sided sensorineural deafness were randomly assigned to receive the conventional intervention, a titanium abutment with soft tissue reduction surgery (control), or a new intervention, a hydroxyapatite-coated abutment with soft tissue preservation surgery (test). The primary efficacy outcome was the combined endpoint of numbness, pain, peri-abutment dermatitis, and soft tissue thickening/overgrowth after 1 and 3 years. Results: The Intention-to-treat (ITT) population consisted of 52 control subjects and 51 test subjects. The difference between the groups after 1 year of follow-up as measured by the primary efficacy outcome was not statistically significant (p = 0.12) in the ITT population (n = 103), but did reach statistical significance (p = 0.03) in the per-protocol (PP) population (n = 96). It showed an advantage for the test group, with over twice as many subjects (29%) without these medical events during the first year compared to the control group (13%). After 3 years, the difference between the two groups had declined and did not reach statistical significance (24 vs. 10%, ITT p = 0.45). Secondary outcome measures which showed a statistical significant difference during the first year, such as surgical time (15 vs. 25 minutes, p < 0.0001), numbness (90 vs. 69% of subjects experienced no numbness at 1 year, p < 0.01), neuropathic pain at 3 months (p = 0.0087) and the overall opinion of the esthetic outcome (observer POSAS scale at 3 months, p < 0.01) were favorable for the test group. More soft tissue thickening/overgrowth was observed at 3 weeks for the test group (p = 0.016). Similar results were achieved for the long term follow up. Conclusions: Soft tissue preservation with a hydroxyapatite-coated abutment leads to a reduction in the combined occurrence of complications over the first year which is not statistically significant in the ITT population but is in the PP population. This effect decreased for the long-term study follow up of 3 years and did also not reach statistical significance.

A phase 2, double-blind, placebo-controlled study of NSI-189 phosphate, a neurogenic compound, among outpatients with major depressive disorder.

NSI-189 is a novel neurogenic compound independent of monoamine reuptake pathways. This trial evaluated oral NSI-189 as monotherapy in major depressive disorder. To improve signal detection, the sequential-parallel comparison design (SPCD) was chosen. Two hundred and twenty subjects were randomized to NSI-189 40 mg daily, 80 mg daily, or placebo for 12 weeks. The primary outcome measure was the Montogmery Asberg Depression Rating Scale (MADRS). Secondary subject-rated measures included the Symptoms of Depression Questionnaire (SDQ), the Cognitive and Physical Functioning Scale (CPFQ), the patient-rated version of the Quick Inventory of Depressive Symptomatology Scale (QIDS-SR), and subtests from the CogScreen and Cogstate cognitive tests. MADRS score reduction versus placebo did not reach significance for either dose (40 mg pooled mean difference -1.8, p = 0.22, 80 mg pooled mean difference -1.4, p = 0.34, respectively). However, the 40 mg dose showed greater overall reduction in SDQ (pooled mean difference -8.2; Cohen's d for Stages 1 and 2 = -0.11 and -0.64, p = 0.04), and CPFQ scores (pooled mean difference -1.9; Cohen's d for Stages 1 and 2 = -0.28 and -0.47, p = 0.03) versus placebo, as well as QIDS-SR scores in Stage 2 of SPCD (-2.5; Cohen's d Stages 1 and 2 = -0.03 and -0.68, p = 0.04). The 40 mg dose also showed advantages on some objective cognitive measures of the CogScreen (absolute Cohen's d ranged between 0.12 and 1.12 in favor of NSI-189, p values between 0.002 and 0.048 for those with overall significance), but not the Cogstate test. Both doses were well tolerated. These findings replicate those of phase 1b study, and warrant further exploration of the antidepressant and pro-cognitive effects of NSI-189.

Attenuated cortisol reactivity to psychosocial stress is associated with greater visual dependency in postural control.

Despite known anatomical links between the hypothalamic-pituitary-adrenal (HPA) axis and the vestibular system, there are no studies on the relationship between postural control and HPA axis function. Visual dependence in postural control, often measured by increased postural sway on exposure to visual motion, is an indication of altered visual-vestibular integration with greater weighting towards visual cues for balance. Visual dependence is more common in older age and a range of vestibular and non-vestibular health conditions. The relationship between visual dependence in postural control was investigated in relation to cortisol reactivity to psychosocial stress (using the Trier Social Stress Test for groups: TSST-G), as an index of HPA axis function, in healthy young females. In those who exhibited a cortisol response (>2 nmol/l), a negative relationship between stress-induced cortisol reactivity and visual dependence in postural control was observed, since those with the largest cortisol response showed less visual motion induced postural sway (measured by force platform). This finding in healthy females indicates that subtle non-clinical differences in vestibular function are associated with dysregulated HPA axis activity as indicated by lower cortisol reactivity to psychosocial stress. It adds to the growing body of evidence linking blunted cortisol reactivity to stress to poor homeostatic regulation and potential negative health and behavioural outcomes.

Repressors exhibit lower cortisol reactivity to group psychosocial stress.

Repressors are well-known to monitor potential psychosocial threats to their self-esteem and self-concept. In research, repressors are traditionally categorised as those scoring low on trait anxiety and high on defensiveness (as measured by social desirability scales). Examining repressors' cortisol reactivity to a group socio-evaluative laboratory stressor could be an important way to extend work on the classic 'repressor dissociation', which proposes that this group experience higher levels of physiological stress, but lower levels of subjective affect, during stressful situations. Research however has focused mainly on repressors' higher, more risk-prone levels of autonomic, rather than hypothalamic-pituitary-adrenal (HPA), reactivity to stressful stimuli. We assessed cortisol reactivity using a group-based acute psychosocial stressor, the Trier Social Stress Test for groups (TSST-G), which required participants to individually perform public speaking and mental arithmetic tasks in front of up to six other group members, as well as an evaluative panel of judges. Seventy-seven healthy young females (mean age ± SD: 20.2 ± 3.2 years) took part, of which 64 met the conventional criterion for a response to the TSST-G (<15.5% increase from baseline sample). The Stress-Arousal Checklist was completed pre- and post-TSST-G. Participants also completed the Perceived Stress Scale, the Trait Anxiety Inventory and the Marlow-Crowne Social Desirability Scale. The latter two measures were used to provide a categorisation of repressive coping style. Participants identified as repressive copers exhibited significantly lower cortisol reactivity during the TSST-G. Repressors also self-reported less subjective stress. These findings provide some evidence against the notion of the repressor dissociation and are discussed in terms of how cortisol hyporeactivity may be a pathway through which repressive coping adversely affects health.

An extended phase Ib study of epertinib, an orally active reversible dual EGFR/HER2 tyrosine kinase inhibitor, in patients with solid tumours.

BACKGROUND: Dose-escalation of epertinib (S-222611), a new potent oral EGFR/HER2 inhibitor, has established a recommended daily dose of 800 mg in patients with solid tumours. In this study, we have recruited a larger number of patients to assess further the safety, tolerability, pharmacokinetics (PKs) and antitumour activity. PATIENTS AND METHODS: Patients with solid tumours expressing EGFR or HER2 received a single dose of epertinib at 800 mg on Day 1 to assess PK over 7 days, followed by continuous once-daily dosing from Day 8. RESULTS: We treated 76 patients with breast (n = 27), upper gastrointestinal (GI; n = 30), head and neck (n = 12) or renal cancers (n = 7). Epertinib was well-tolerated with mostly grade I and II adverse events (AEs). The most frequent AE was diarrhoea, which was generally manageable with loperamide. The objective response rate (ORR) in patients with heavily pretreated breast and upper GI cancers was 16.0% (4 PRs) and 8.3% (1CR, 1PR), respectively. All six responding patients had HER2-positive tumours; the ORR for HER2-positive breast and upper GI cancer populations was 19.0% and 20.0%. Partial response in the brain disease of one breast cancer patient lasted 7.5 months. CONCLUSION: Once-daily dosing of epertinib at 800 mg was well-tolerated and demonstrated promising antitumour activity in patients with heavily pretreated HER2-positive breast and upper GI cancer, including those with brain metastases. EUDRACT NUMBER: 2009-017817-31.

Folic acid supplementation during the preconception period: A systematic review and meta-analysis.

Guidelines recommend that women take folic acid supplements in the preconception period to prevent neural tube defects (NTDs) in their offspring. Estimates of adherence to this recommendation across different countries worldwide have not been synthesized. Medline, CINAHL, and EMBASE were systematically searched to identify studies reporting the prevalence of preconception folic acid supplementation. Pooled prevalence estimates for each country (where data were available) were calculated; and differences based on demographic, methodological, and study quality characteristics were examined. Of 3372 titles and abstracts screened, 722 full-texts were reviewed and 105 articles that reported 106 estimates of preconception folic acid supplementation in 34 countries were included. Pooled prevalence estimates were 32-51% in North America, 9-78% in Europe, 21-46% in Asia, 4-34% in the Middle East, 32-39% in Australia/New Zealand, and 0% in Africa. No South American studies were identified. Higher supplementation prevalence was observed in studies that had more highly educated samples, were conducted in fertility clinics, and assessed folic acid use via self-report. Of note, only 32% and 28% of studies reported timing of folic acid use and adherence to folic acid, respectively. Preconception folic acid supplementation is highly variable worldwide and many women may not achieve sufficient folate levels to prevent NTDs. To better understand non-adherence, recommendations for future research include: more explicit reporting of methodology, more detailed assessment of folic acid use, assessment of variables potentially relevant to folic acid use, and surveillance of folic acid use in a greater diversity of countries, especially in the developing world.