Secular Trends in Severe Idiosyncratic Drug-Induced Liver Injury in North America: An Update From the Acute Liver Failure Study Group Registry.

INTRODUCTION: Idiosyncratic drug-induced liver injury (DILI) is the second leading cause of acute liver failure (ALF) in the United States. Our study aims were to characterize secular trends in the implicated agents, clinical features, and outcomes of adults with DILI ALF over a 20-year period. METHODS: Among 2,332 patients with ALF enrolled in the ALF Study Group registry, 277 (11.9%) were adjudicated as idiosyncratic DILI ALF (INR ≥ 1.5 and hepatic encephalopathy) through expert opinion. The 155 cases in era 1 (January 20, 1998-January 20, 2008) were compared with the 122 cases in era 2 (January 21, 2008-January 20, 2018). RESULTS: Among 277 cases of DILI ALF, 97 different agents, alone or in combination, were implicated: antimicrobials, n = 118 (43%); herbal/dietary supplements (HDS), n = 42 (15%); central nervous system agents/illicit substances, n = 37 (13%); oncologic/biologic agents, n = 29 (10%); and other, n = 51 (18%). Significant trends over time included (i) an increase in HDS DILI ALF (9.7% vs 22%, P < 0.01) and decrease in antimicrobial-induced DILI ALF (45.8% vs. 38.5%, P = 0.03) and (ii) improved overall transplant-free survival (23.5%-38.7%, P < 0.01) while the number of patients transplanted declined (46.4% vs 33.6%, P < 0.03). DISCUSSION: DILI ALF in North America is evolving, with HDS cases rising and other categories of suspect drugs declining. The reasons for a significant increase in transplant-free survival and reduced need for liver transplantation over time remain unclear but may be due to improvements in critical care, increased NAC utilization, and improved patient prognostication.

The Effects of Sleep Quality and Resilience on Perceived Stress, Dietary Behaviors, and Alcohol Misuse: A Mediation-Moderation Analysis of Higher Education Students from Asia, Europe, and North America during the COVID-19 Pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has increased the already high levels of stress that higher education students experience. Stress influences health behaviors, including those related to dietary behaviors, alcohol, and sleep; yet the effects of stress can be mitigated by resilience. To date, past research studying the connections between dietary behaviors, alcohol misuse, sleep, and resilience commonly investigated singular relationships between two of the constructs. The aim of the current study was to explore the relationships between these constructs in a more holistic manner using mediation and moderation analyses. METHODS: Higher education students from China, Ireland, Malaysia, South Korea, Taiwan, the Netherlands, and the United States were enrolled in a cross-sectional study from April to May 2020, which was during the beginning of the COVID-19 pandemic for most participants. An online survey, using validated tools, was distributed to assess perceived stress, dietary behaviors, alcohol misuse, sleep quality and duration, and resilience. RESULTS: 2254 students completed the study. Results indicated that sleep quality mediated the relationship between perceived stress and dietary behaviors as well as the relationship between perceived stress and alcohol misuse. Further, increased resilience reduced the strength of the relationship between perceived stress and dietary behaviors but not alcohol misuse. CONCLUSION: Based on these results, higher education students are likely to benefit from sleep education and resilience training, especially during stressful events.

Allergy to oak pollen in North America.

Background: Oak pollen is an important allergen in North America. The genus Quercus (oak) belongs to the family Fagaceae under the order Fagales. Objective: The objective of this article was to narratively review the oak pollen season, clinical and epidemiologic aspects of allergy to oak pollen, oak taxonomy, and oak allergen cross-reactivity, with a focus on the North American perspective. Methods: A PubMed literature review (no limits) was conducted. Publications related to oak pollen, oak-related allergic rhinitis with or without conjunctivitis, and oak-related allergic asthma were selected for review. Results: Oak species are common throughout the United States and contribute up to 50% to overall atmospheric pollen loads. Mean peak oak pollen counts can reach >2000 grains/m³. The start of the oak pollen season generally corresponds to the seasonal shift from winter to spring based on latitude and elevation, and may begin as early as mid February. The duration of the season can last > 100 days and, in general, is longer at lower latitudes. In the United States, ∼30% of individuals with allergy are sensitized to oak. The oak pollen season correlates with increased allergic rhinitis symptom-relieving medication use and asthma-related emergency department visits or hospitalizations. Oak falls within the birch homologous group. Extensive immunologic cross-reactivity has been demonstrated between oak pollen and birch pollen allergens, and, more specifically, their major allergens Que a 1 and Bet v 1. The cross-reactivity between oak and birch has implications for allergy immunotherapy (AIT) because guidelines suggest selecting one representative allergen within a homologous group for AIT, a principle that would apply to oak. Conclusion: Allergy to oak pollen is common in North America and has a substantial clinical impact. Oak pollen allergens are cross-reactive with birch pollen allergens, which may have implications for AIT.

Mortality among uranium miners in North America and Europe: the Pooled Uranium Miners Analysis (PUMA).

BACKGROUND: The Pooled Uranium Miners Analysis (PUMA) study draws together information from cohorts of uranium miners from Canada, the Czech Republic, France, Germany and the USA. METHODS: Vital status and cause of death were ascertained and compared with expectations based upon national mortality rates by computing standardized mortality ratios (SMRs) overall and by categories of time since first hire, calendar period of first employment and duration of employment as a miner. RESULTS: There were 51 787 deaths observed among 118 329 male miners [SMR = 1.05; 95% confidence interval (CI): 1.04, 1.06]. The SMR was elevated for all cancers (n = 16 633, SMR = 1.23; 95% CI: 1.21, 1.25), due primarily to excess mortality from cancers of the lung (n = 7756, SMR = 1.90; 95% CI: 1.86, 1.94), liver and gallbladder (n = 549, SMR = 1.15; 95% CI: 1.06, 1.25), larynx (n = 229, SMR = 1.10; 95% CI: 0.97, 1.26), stomach (n = 1058, SMR = 1.08; 95% CI: 1.02, 1.15) and pleura (n = 39, SMR = 1.06; 95% CI: 0.75, 1.44). Lung-cancer SMRs increased with duration of employment, decreased with calendar period and persisted with time since first hire. Among non-malignant causes, the SMR was elevated for external causes (n = 3362, SMR = 1.41; 95% CI: 1.36, 1.46) and respiratory diseases (n = 4508, SMR = 1.32; 95% CI: 1.28, 1.36), most notably silicosis (n = 814, SMR = 13.56; 95% CI: 12.64, 14.52), but not chronic obstructive pulmonary disease (n = 1729, SMR = 0.98; 95% CI: 0.93, 1.02). CONCLUSIONS: Whereas there are important obstacles to the ability to detect adverse effects of occupational exposures via SMR analyses, PUMA provides evidence of excess mortality among uranium miners due to a range of categories of cause of death. The persistent elevation of SMRs with time since first hire as a uranium miner underscores the importance of long-term follow-up of these workers.

Lyme borreliosis: diagnosis and management.

Lyme borreliosis is the most common vectorborne disease in the northern hemisphere. It usually begins with erythema migrans; early disseminated infection particularly causes multiple erythema migrans or neurologic disease, and late manifestations predominantly include arthritis in North America, and acrodermatitis chronica atrophicans (ACA) in Europe. Diagnosis of Lyme borreliosis is based on characteristic clinical signs and symptoms, complemented by serological confirmation of infection once an antibody response has been mounted. Manifestations usually respond to appropriate antibiotic regimens, but the disease can be followed by sequelae, such as immune arthritis or residual damage to affected tissues. A subset of individuals reports persistent symptoms, including fatigue, pain, arthralgia, and neurocognitive symptoms, which in some people are severe enough to fulfil the criteria for post-treatment Lyme disease syndrome. The reported prevalence of such persistent symptoms following antimicrobial treatment varies considerably, and its pathophysiology is unclear. Persistent active infection in humans has not been identified as a cause of this syndrome, and randomized treatment trials have invariably failed to show any benefit of prolonged antibiotic treatment. For prevention of Lyme borreliosis, post-exposure prophylaxis may be indicated in specific cases, and novel vaccine strategies are under development.

Food insecurity and mental health: a systematic review and meta-analysis.

OBJECTIVE: Food security has been suggested to be a risk factor for depression, stress and anxiety. We therefore undertook a systematic review and meta-analysis of available publications to examine these associations further. DESIGN: Relevant studies were identified by searching Web of Science, Embase, Scopus and PubMed databases up to January 2019. SETTING: OR was pooled using a random-effects model. Standard methods were used for assessment of heterogeneity and publication bias. PARTICIPANTS: Data were available from nineteen studies with 372 143 individual participants from ten different countries that were pooled for the meta-analysis. RESULTS: The results showed there was a positive relationship between food insecurity (FI) and risk of depression (OR = 1·40; 95 % CI: 1·30, 1·58) and stress (OR = 1·34; 95 % CI: 1·24, 1·44) but not anxiety. Subgroup analysis by age showed that subjects older than ≥65 years exhibited a higher risk of depression (OR = 1·75; 95 % CI: 1·20, 2·56) than younger participants (OR = 1·34; 95 % CI: 1·20, 1·50), as well as a greater risk of depression in men (OR = 1·42; 95 % CI: 1·17, 1·72) than women (OR = 1·30; 95 % CI: 1·16, 1·46). Finally, subgroup analysis according to geographical location illustrated that food insecure households living in North America had the highest risk of stress and anxiety. CONCLUSIONS: The evidence from this meta-analysis suggests that FI has a significant effect on the likelihood of being stressed or depressed. This indicates that health care services, which alleviate FI, would also promote holistic well-being in adults.

PUMA - pooled uranium miners analysis: cohort profile.

OBJECTIVES: Epidemiological studies of underground miners have provided clear evidence that inhalation of radon decay products causes lung cancer. Moreover, these studies have served as a quantitative basis for estimation of radon-associated excess lung cancer risk. However, questions remain regarding the effects of exposure to the low levels of radon decay products typically encountered in contemporary occupational and environmental settings on the risk of lung cancer and other diseases, and on the modifiers of these associations. These issues are of central importance for estimation of risks associated with residential and occupational radon exposures. METHODS: The Pooled Uranium Miner Analysis (PUMA) assembles information on cohorts of uranium miners in North America and Europe. Data available include individual annual estimates of exposure to radon decay products, demographic and employment history information on each worker and information on vital status, date of death and cause of death. Some, but not all, cohorts also have individual information on cigarette smoking, external gamma radiation exposure and non-radiological occupational exposures. RESULTS: The PUMA study represents the largest study of uranium miners conducted to date, encompassing 124 507 miners, 4.51 million person-years at risk and 54 462 deaths, including 7825 deaths due to lung cancer. Planned research topics include analyses of associations between radon exposure and mortality due to lung cancer, cancers other than lung, non-malignant disease, modifiers of these associations and characterisation of overall relative mortality excesses and lifetime risks. CONCLUSION: PUMA provides opportunities to evaluate new research questions and to conduct analyses to assess potential health risks associated with uranium mining that have greater statistical power than can be achieved with any single cohort.

Clinical burden and healthcare resource utilization among patients with chronic hypoparathyroidism, overall and by adequately vs not adequately controlled disease: a multi-country chart review.

Aims: To assess the real-world clinical burden and healthcare resource utilization (HRU) among patients with chronic hypoparathyroidism, overall and by adequately controlled (AC) vs not adequately controlled (NAC) disease, informed by guideline-recommended clinical management targets, including biochemistry and symptoms. Materials and methods: In this retrospective online chart review, endocrinologists in the US, Canada, the UK, France, Germany, Italy, and Spain were randomly selected to review the medical charts of adult patients with chronic hypoparathyroidism receiving calcium and activated vitamin D. Patients' demographics, disease characteristics, symptoms, comorbidities, and hypoparathyroidism-related HRU during the 1 year before the review date were assessed. Clinical burden and HRU were compared between patients with NAC and AC hypoparathyroidism. Results: Of 614 patients with hypoparathyroidism (AC, N = 442; NAC, N = 172), the mean age was 43.6 years, and the majority were female (61.6%), Caucasian (78.8%), and had post-surgical hypoparathyroidism (74.4%). Mean duration of hypoparathyroidism was 46.0 months. Hypoparathyroidism-related symptoms and comorbidities were reported in 59.4% and 46.7% of patients, respectively; 90.7% of patients had ≥1 hypoparathyroidism-related HRU event. More patients with NAC (57.6%) vs AC (42.5%) hypoparathyroidism experienced ≥1 comorbidity including calcium/phosphate imbalances, and brain, cardiovascular, metabolic, and renal disorders (all p < 0.01). More patients with NAC vs AC hypoparathyroidism incurred ≥1 hypoparathyroidism-related hospitalization (27.9% vs 16.3%) and emergency room visits (47.7% vs 38.5%), and patients with NAC vs AC hypoparathyroidism had a higher number of outpatient visits (3.6 vs 2.6; all p < 0.05), in the 1-year observation period. Limitations and conclusions: Limitations of this online chart review include possible under-estimation of disease burden, limited sample size, and the inability to rule out selection bias. Findings indicate that patients with chronic hypoparathyroidism experience substantial symptomatic and comorbid burdens resulting in frequent HRU, suggesting an unmet need, particularly in NAC disease.

Treatment of psychiatric comorbidities in patients with epilepsy and intellectual disabilities: Is there a role for the neurologist?

This paper will explore the nature of psychiatric co-morbidities in people with an intellectual disability (ID) who have epilepsy. The complexity of clinical presentations and associated co-morbidities require thorough assessment utilising both neurological and psychiatric skills. The neurologist plays a central role in the management of epilepsy in people with ID and therefore requires basic competencies in the assessment of neuropsychiatric co-morbidities. This is key to liaison with other specialist services to ensure individuals receive holistic person-centred care. This article is part of the Special Issue "Obstacles of Treatment of Psychiatric Comorbidities in Epilepsy".

Italian and North American dietary intake after ivacaftor treatment for Cystic Fibrosis Gating Mutations.

BACKGROUND: In patients with cystic fibrosis (CF), ivacaftor treatment results in significant weight gain and the impact on diet has not been explored. METHODS: A study in 22 subjects (6.1-61.6 years) compared diet, energy balance, weight gain, and body composition, before and after three months of treatment in Italians and North Americans with CFTR gating mutations. RESULTS: With no differences between groups in energy or macronutrient intake at baseline, fat intake increased in all subjects, and both fat and energy intake increased in Italians. Height, weight, BMI, lean and fat mass, and % body fat increased and resting energy expenditure decreased after treatment. Weight gain was associated with energy and fat intake. CONCLUSIONS: Fat intake increased with treatment, possibly due to the recommendation to take ivacaftor with high fat meals. Increased energy and fat intake correlated with weight gain. Regional dietary patterns differed.

Geographic and demographic variations of inhalant allergen sensitization in Koreans and non-Koreans.

BACKGROUND: To diagnose and treat respiratory allergic diseases, it is important to identify the specific allergens involved. Many differences exist between common inhalant allergens depending on the residential environment and demographic factors. This study aimed to compare common inhalant allergens between Koreans and non-Koreans according to their residential region, age, and sex. METHODS: This study evaluated 15,334 individuals who underwent serum tests for multiple allergen-specific immunoglobulin E at a tertiary academic medical center between January 2010 and December 2016. The individuals included 14,786 Koreans and 548 non-Koreans. The AdvanSure™ Allostation assay (LG Life Science, Korea) was used to test for 33 inhalant allergens. RESULTS: The house dust mite (HDM) was the most common allergen in both Koreans and non-Koreans, although the proportion of individuals with HDM sensitization was greater among Koreans. High sensitization rates for various pollen types were detected among Koreans in Gangwon region, whereas Japanese cedar pollen was unique among Koreans in Jeju region. Grass pollen and animal dander were relatively common among individuals from the Americas, whereas weed and grass pollen accounted for the 10 most common allergens for individuals from Central Asia. The total sensitization rate, sensitization to HDM, and sensitization to animal dander peaked among adolescents and young adults, then subsequently decreased with age. CONCLUSIONS: This large-scale study demonstrates that various regional and age-related differences exist in the allergen sensitization rates of Koreans and non-Koreans. These data could be useful for development of avoidance measures, immunotherapy for causative allergens, and policymaking regarding allergic diseases.

Well differentiated papillary peritoneal mesothelioma treated by cytoreduction and hyperthermic intraperitoneal chemotherapy-the experience of the PSOGI registry.

BACKGROUND: Well differentiated papillary peritoneal mesothelioma (WDPPM) is a rare variant of mesothelioma which affects mainly women in the reproductive age. The disease may present multifocally and recur after primary resection. Our aim was to describe the outcomes of cytoreduction (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in this disease. METHODS: Patients with histological diagnosis of WDPPM were retrieved from the PSOGI registry. Demographical and clinical data were extracted as well as outcomes data (overall survival (OS) and recurrence free survival (RFS)). RESULTS: We analyzed 45 patients for whom complete data was available. The majority of patients were women (n = 33, 73%) with a median age of 44 years. Preoperative chemotherapy (CT) was administered in 8 patients (18%). Median peritoneal carcinomatosis index was 9 (1-30), and complete cytoreduction was achieved in 69% of patients. There was one case (2%) of postoperative mortality, and 24% rate of severe morbidity. Overall, there were 4 deaths and 5 years OS was 80%. 8 patients (18%) had disease recurrence, all within 5 years from operation. On univariate analysis preoperative CT, high PCI and severe morbidity were associated with reduced RFS. On multivariate analysis, only preoperative CT (HR = 32.6, 95% CI: 2.39-446.2, p = 0.009) and high PCI (HR = 21.7, 95% CI: 1.11-425.7, p = 0.04) remained significant risk factors. CONCLUSIONS: WDPPM can be a lethal disease with substantial recurrence even after aggressive treatment. Patients presenting with extensive disease or disease recurrence after surgical excision are at increased risk for relapse. CRS + HIPEC can be safely applied to WDPPM in specialized centers.

A comprehensive review and update on Crohn's disease.

The term inflammatory bowel disease (IBD) refers principally to two major categories of chronic relapsing inflammatory intestinal disorders: Crohn's disease (CD) and ulcerative colitis (UC). In the United States, it is currently estimated that about 1.5 million people suffer from IBD, causing considerable suffering, mortality and economic loss every year. Yet the cause of IBD is unknown, and until we understand more, prevention or cure will not be possible. There is a lot of variation in the incidence and prevalence of CD based on geographic region, environment, immigrant population, and ethnic groups. The annual incidence of CD in North America is reported to be 3.1-20.2 per 100,000 with a prevalence of 201 per 100,000 population. Based on the epidemiological, genetic and immunological data, CD is considered to be a heterogeneous disorder with multifactorial etiology in which genetics and environment interact to manifest the disease. Several genes have been studied so for with respect to CD, but thus far the strong and replicated associations have been identified with NOD2, IL23R and ATG16L1 genes. The risk factors implicated with CD include smoking, low fiber- high carbohydrate diet, altered microbiome and medications such as non-steroidal anti-inflammatory drugs. CD is typically characterized by transmural inflammation of the intestine and could affect any part of the gastrointestinal tract from mouth to perianal area. In terms of distribution of the disease 25% of the patients have colitis only, 25% is ileitis only and 50% have ileocolitis. The Montreal classification is based on the age at diagnosis (<16, 17-40, > 40), disease location (Ileal, colonic, Ileocolonic) and the disease behavior (nonstricturing/nonpenetrating, stricturing, penetrating). The key features for diagnosing CD comprises a combination of radiographic, endoscopic and pathological findings demonstrating focal, asymmetric, transmural or granulomatous features. Abdominal Computed tomography (CT) enterography is the most preferred first-line radiologic study used in the assessment of small bowel CD. The diagnostic accuracy of magnetic resonance enterography/enteroclysis is similar to that of CT scans and also prevents exposure to ionizing radiation. Endoscopic scores are considered to be the gold standard tool to measure the activity of CD and they are used more commonly in the clinical trials to measure the efficacy of various drugs on inducing and maintaining mucosal healing. The most common scoring systems used to measure clinical disease activity include Crohn's Disease Activity Index (CDAI), HBI- Harvey-Bradshaw index (HBI), short inflammatory bowel disease questionnaire (SIBDQ) and Lehmann score. Management of Crohn's disease has been seen as an evolving challenge owing to its widely heterogeneous manifestations, overlapping characteristics with other inflammatory disorders, often elusive extraintestinal manifestations and uncertain etiology. Therapeutic interventions are tailored to address symptomatic response and subsequent tolerance of the intervention. Chronology of treatment should favor treatment dose acute disease or "induction therapy", followed by maintenance of adequate response or remission, i.e. "maintenance therapy". The medications which are highly effective in inducing remission include steroids and Tumor Necrosis Factor (TNF) inhibitors. Medications used to maintain remission include 5-aminosalicyclic acid products, immunomodulators (Azathioprine, 6-mercaptopurine, methotrexate) and TNF inhibitors (infliximab, adalimumab, certolizumab and golimumab). Surgical interventions like bowel resection, stricturoplasty or drainage of abscess is required in up to two thirds of CD patients during their lifetime. The most common indications for surgical resection are medically refractory disease, perforation, persisting or recurrent obstruction, abscess not amenable to percutaneous drainage, intractable hemorrhage, dysplasia or cancer. Endoscopic recurrence in postoperative CD patients, as defined by Rutgeers score i2-i4 occur in 30-90% of the patients at the neoterminal ileum within 12 months of surgery and almost universally by 5 years. Treating CD requires a comprehensive care team including the patient, primary care provider, and gastroenterologist. In summary CD is a chronic inflammatory condition with a remitting and relapsing course primarily affecting relatively younger population with significant socioeconomic effects.

Exploring the East-West Divide in Prevalence of Affective Disorder: A Case for Cultural Differences in Coping With Negative Emotion.

Lifetime rates of clinical depression and anxiety in the West tend to be approximately 4 to 10 times greater than rates in Asia. In this review, we explore one possible reason for this cross-cultural difference, that Asian cultures think differently about emotion than do Western cultures and that these different systems of thought help explain why negative affect does not escalate into clinical disorder at the same rate. We review research from multiple disciplines-including cross-cultural psychology, social cognition, clinical psychology, and psychiatry-to make the case that the Eastern holistic principles of contradiction (each experience is associated with its opposite), change (the world exists in a state of constant flux), and context (the interconnectedness of all things) fundamentally shape people's experience of emotions in different cultures. We then review evidence for how these cultural differences influence how successfully people use common emotion regulation strategies such as rumination and suppression.

North American Population-Based Validation of the National Comprehensive Cancer Network Practice Guideline Recommendation of Pelvic Lymphadenectomy in Contemporary Prostate Cancer.

BACKGROUND: National Comprehensive Cancer Network (NCCN) guidelines recommend a pelvic lymph node dissection (PLND) in prostate cancer (PCa) patients treated with radical prostatectomy (RP) if a nomogram predicted risk of lymph node invasion (LNI) is ≥2%. We examined this and other thresholds, including nomogram validation. METHODS: We examined records of 26,713 patients treated with RP and PLND between 2010 and 2013, within the Surveillance, Epidemiology, and End Results database. Nomogram thresholds of 2-5% were tested and external validation was performed. RESULTS: LNI was recorded in 4.7% of patients. Nomogram accuracy was 80.4% and maintained minimum accuracy of 75.6% in subgroup analyses, according to age, race, and nodal yield >10. With the NCCN recommended 2% nomogram threshold, PLND could be avoided in 22.3% of patients at the expense of missing 3.0% of individuals with LNI. Alternative thresholds of 3%, 4%, and 5% yielded respective PLND avoidance rates of 60.4%, 71.0%, and 79.8% at the expense of missing 17.8%, 27.2%, and 36.6% of patients with LNI. NCCN cut-off recommendation was best satisfied with a threshold of <2.6%, at which PLND could be avoided in 13,234 patients (49.5%) versus missing 141 patients with LNI (11.2%). CONCLUSION: NCCN LNI nomogram remains accurate in contemporary patients. However, the 2% threshold appears to be too strict, since only 22.3% of PLNDs can be avoided, instead of the stipulated 47.7%. The optimal 2.6% threshold allows a higher rate of PLND avoidance (49.5%), at the cost of 11.2% missed instances of LNI, as recommended by NCCN guidelines. PATIENT SUMMARY. External validation in contemporary SEER prostate cancer patients showed that the NCCN nomogram remains accurate for predicting lymph node invasion and seems to be optimal at an alternative 2.6% threshold, with best ratio of avoided pelvic lymph node dissections (49.5%) and missed LNIs (11.2%), as recommended by NCCN guideline. Prostate 77:542-548, 2017. © 2017 Wiley Periodicals, Inc.

Cannabis and epilepsy: An ancient treatment returns to the fore.

Cannabis has been associated with the treatment of epilepsy throughout history, and if ancient Assyrian sources referring to "hand of ghost" are considered credible, this relationship may span four millennia. A tradition of usage continued in Arabic medicine and Ayurvedic practice in India, which led, in turn, to early experiments in Europe and North America with "Indian hemp." Lack of standardization, bioavailability issues, and ultimately prohibition were all factors in cannabis-based medicines failing to maintain mainstream usage in seizure treatment, but investigation was resumed in the 1970s with interesting signals noted in both laboratory and clinical settings. Early case studies showed promise, but lacked sufficient rigor. Resumption of research coupled with mass experimentation by families of epilepsy patients has led to intense interest in cannabis-based medicines for its treatment once more, with greatest focus on cannabidiol, but additional investigation of tetrahydrocannabinol, tetrahydrocannabinolic acid, and other phytocannabinoids. This article is part of a Special Issue entitled "Cannabinoids and Epilepsy".

TRANSLATING ECOLOGY, PHYSIOLOGY, BIOCHEMISTRY, AND POPULATION GENETICS RESEARCH TO MEET THE CHALLENGE OF TICK AND TICK-BORNE DISEASES IN NORTH AMERICA.

Emerging and re-emerging tick-borne diseases threaten public health and the wellbeing of domestic animals and wildlife globally. The adoption of an evolutionary ecology framework aimed to diminish the impact of tick-borne diseases needs to be part of strategies to protect human and animal populations. We present a review of current knowledge on the adaptation of ticks to their environment, and the impact that global change could have on their geographic distribution in North America. Environmental pressures will affect tick population genetics by selecting genotypes able to withstand new and changing environments and by altering the connectivity and isolation of several tick populations. Research in these areas is particularly lacking in the southern United States and most of Mexico with knowledge gaps on the ecology of these diseases, including a void in the identity of reservoir hosts for several tick-borne pathogens. Additionally, the way in which anthropogenic changes to landscapes may influence tick-borne disease ecology remains to be fully understood. Enhanced knowledge in these areas is needed in order to implement effective and sustainable integrated tick management strategies. We propose to refocus ecology studies with emphasis on metacommunity-based approaches to enable a holistic perspective addressing whole pathogen and host assemblages. Network analyses could be used to develop mechanistic models involving multihost-pathogen communities. An increase in our understanding of the ecology of tick-borne diseases across their geographic distribution will aid in the design of effective area-wide tick control strategies aimed to diminish the burden of pathogens transmitted by ticks.

Relevance of a 5-grass sublingual tablet for immunotherapy of patients with grass pollen allergy in North America.

Grass pollen allergy is common and clinically consequential in North America. While it is frequently treated with subcutaneous or sublingual immunotherapy, debate remains regarding whether allergen immunotherapy is best carried out using a single representative or multiple cross-reactive allergen(s). Patients are commonly exposed to pollens from multiple allergenic grass species belonging to the Pooideæ subfamily. Beyond the known IgE cross-reactivity, considerable molecular heterogeneity exists with respect to allergen content among grass species, with further evidence that these molecular variants can be detected by the patients' immune system. These observations provide a compelling scientific rationale for the use of mixed pollen allergen extracts to broaden the allergen repertoire, with the aim of reorienting inappropriate immune responses in allergic patients.