Analysis of intestinal epithelial cell responses to Cryptosporidium highlights the temporal effects of IFN-γ on parasite restriction.

The production of IFN-γ is crucial for control of multiple enteric infections, but its impact on intestinal epithelial cells (IEC) is not well understood. Cryptosporidium parasites exclusively infect epithelial cells and the ability of interferons to activate the transcription factor STAT1 in IEC is required for parasite clearance. Here, the use of single cell RNA sequencing to profile IEC during infection revealed an increased proportion of mid-villus enterocytes during infection and induction of IFN-γ-dependent gene signatures that was comparable between uninfected and infected cells. These analyses were complemented by in vivo studies, which demonstrated that IEC expression of the IFN-γ receptor was required for parasite control. Unexpectedly, treatment of Ifng-/- mice with IFN-γ showed the IEC response to this cytokine correlates with a delayed reduction in parasite burden but did not affect parasite development. These data sets provide insight into the impact of IFN-γ on IEC and suggest a model in which IFN-γ signalling to uninfected enterocytes is important for control of Cryptosporidium.

The inhibitory effect of a recent distractor: singleton vs. multiple distractors.

In the complex interplay between sensory and cognitive processes, the brain must sift through a flood of sensory data to pinpoint relevant signals. This selective mechanism is crucial for the effective control of behaviour, by allowing organisms to focus on important tasks and blocking out distractions. The Inhibition of a Recent Distractor (IRD) Task examines this selection process by exploring how inhibiting distractors influences subsequent eye movements towards an object in the visual environment. In a series of experiments, research by Crawford et al. (2005a) demonstrated a delayed response to a target appearing at the location that was previously occupied by a distractor, demonstrating a legacy inhibition exerted by the distractor on the spatial location of the upcoming target. This study aimed to replicate this effect and to investigate any potential constraints when multiple distractors are presented. Exploring whether the effect is observed in more ecologically relevant scenarios with multiple distractors is crucial for assessing the extent to which it can be applied to a broader range of environments. Experiment 1 successfully replicated the effect, showing a significant IRD effect only with a single distractor. Experiments 2-5 explored a number of possible explanations for this phenomenon.

Validation of an open source, remote web-based eye-tracking method (WebGazer) for research in early childhood.

Measuring eye movements remotely via the participant's webcam promises to be an attractive methodological addition to in-person eye-tracking in the lab. However, there is a lack of systematic research comparing remote web-based eye-tracking with in-lab eye-tracking in young children. We report a multi-lab study that compared these two measures in an anticipatory looking task with toddlers using WebGazer.js and jsPsych. Results of our remotely tested sample of 18-27-month-old toddlers (N = 125) revealed that web-based eye-tracking successfully captured goal-based action predictions, although the proportion of the goal-directed anticipatory looking was lower compared to the in-lab sample (N = 70). As expected, attrition rate was substantially higher in the web-based (42%) than the in-lab sample (10%). Excluding trials based on visual inspection of the match of time-locked gaze coordinates and the participant's webcam video overlayed on the stimuli was an important preprocessing step to reduce noise in the data. We discuss the use of this remote web-based method in comparison with other current methodological innovations. Our study demonstrates that remote web-based eye-tracking can be a useful tool for testing toddlers, facilitating recruitment of larger and more diverse samples; a caveat to consider is the larger drop-out rate.

Staff resilience and innovation essential to New York City diabetes prevention programs going virtual during COVID-19 pandemic lockdowns.

BACKGROUND: COVID-19 lockdowns in March 2020 forced National Diabetes Prevention Programs (DPPs) to pause, cancel or reformulate. This qualitative study sought to (a) document if/how New York City(NYC) DPPs adapted and served participants during lockdowns, and (b) identify successes and challenges to operating programs during the lockdowns and restrictions on social gathering. METHODS: Researchers contacted 47 CDC-registered DPPs in NYC. Eleven DPP directors, lifestyle coaches, and coordinators involved in program implementation completed 1-hour semi-structured virtual interviews and received a $50 gift card. Interviews were recorded, transcribed, and analyzed using Grounded Theory (Dedoose, Version 9). RESULTS: Interviewees represented 7 organization types: public hospitals, weight loss programs, healthcare centers, community-based organizations, health insurance companies, faith-based DPPs, and federally qualified health centers. DPPs served participants in 4 of 5 NYC boroughs. Six organizations provided DPP services during lockdowns by going virtual. Successes and challenges related to staffing, resource allocation, virtual data tracking, and participant engagement. Most programs were successful due to resilient, dedicated, and extraordinarily innovative staff. CONCLUSION: The pandemic highlighted opportunities for successful virtual DPPs in urban settings, and the need for more robust funding, staff support, and technical assistance for sustainability and scalability of the DPP.

Surface Reconstruction of Fluoropolymers in Liquid Media.

Surface reconstruction is the rearrangement of atoms or molecules at an interface in response to a stimulus, driven by lowering the overall free energy of the system. Perfluoroalkyl acrylate polymers with short side chains undergo reconstruction at room temperature when exposed to water. Here, we use contact angle aging to examine the liquid- and temperature- dependency of surface reconstruction of plasma polymerized perfluoroalkyl acrylates. We use a first order kinetic model to examine the dynamics of reconstructive processes. Our results show that, above the bulk melting point of the polymers, the contact angles of both polar and nonpolar (hydrocarbon) liquids show a time dependency well fit by the model. We conclude that surface reconstruction can be driven by the preferential segregation of hydrocarbon and fluorocarbon moieties as well as by polar interactions. This has implications in terms of using fluorocarbons to design oleophobic surfaces (and vice versa) and in terms of designing fluorocarbon and/or hydrocarbon surfaces with switchable wettability.

A high-volume ERCP service led by surgeons is associated with good outcomes and meets national key performance indicators: results from a British district general hospital.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is a common, but technically challenging procedure used in the management of hepatopancreaticobiliary (HPB) disease. It is traditionally performed by medical gastroenterologists. In 2014, the British Society of Gastroenterology (BSG) proposed key performance indicators to evaluate and set standards of ERCP practice. This study aimed to compare our ERCP outcomes against these targets, in a centre where ERCP is exclusively performed by surgeons. METHODS: A retrospective analysis of all ERCPs undertaken over a 38 months in a District General Hospital in the United Kingdom (UK), by three Upper Gastrointestinal Surgeons. Study outcomes were based upon, and compared against, BSG key performance indicators, including number of ERCPs per annum, proportion of successful cannulations of bile duct and stone clearance, ERCP-specific complications and mortality. RESULTS: The unit's caseload over this period was 1324, equating to approximately 418 per annum (BSG minimum 200 per unit). Management of bile duct stones was the commonest indication for ERCP. Overall, 95% (1253/1324) of bile ducts were cannulated and 92% (645/698) for those undergoing their first ERCP. Bile duct clearance was achieved in 80% of patients (BSG recommend > 75%) and the successful stenting of extra-hepatic strictures in 94% (BSG recommend > 80%). The overall complication rate was 4.3% (BSG standard < 6%). Procedure-specific mortality was 0.3% (4/1324) where death was either caused by pancreatitis or sepsis. CONCLUSION: A high-volume ERCP service led and performed exclusively by surgeons meets all BSG performance indicators, with good procedural and patient outcomes. Formal training pathways should be developed to encourage more surgical centres to provide an ERCP service and deal with what are common surgical pathologies.

Resting skeletal muscle PNPLA2 (ATGL) and CPT1B are associated with peak fat oxidation rates in men and women but do not explain observed sex differences.

NEW FINDINGS: What is the central question of this study? What is the relationship between proteins in skeletal muscle and adipose tissue determined at rest and at peak rates of fat oxidation in men and women? What is the main finding and its importance? The resting contents of proteins in skeletal muscle involved in triglyceride hydrolysis and mitochondrial lipid transport were more strongly associated with peak fat oxidation rates than proteins related to lipid transport or hydrolysis in adipose tissue. Although females displayed higher relative rates of fat oxidation than males, this was not explained by the proteins measured in this study, suggesting that other factors determine sex differences in fat metabolism. ABSTRACT: We explored key proteins involved in fat metabolism that might be associated with peak fat oxidation (PFO) and account for sexual dimorphism in fuel metabolism during exercise. Thirty-six healthy adults [15 women; 40 ± 11 years of age; peak oxygen consumption 42.5 ± 9.5 ml (kg body mass)-1  min-1 ; mean ± SD] completed two exercise tests to determine PFO via indirect calorimetry. Resting adipose tissue and/or skeletal muscle biopsies were obtained to determine the adipose tissue protein content of PLIN1, ABHD5 (CGI-58), LIPE (HSL), PNPLA2 (ATGL), ACSL1, CPT1B and oestrogen receptor α (ERα) and the skeletal muscle protein content of FABP 3 (FABPpm), PNPLA2 (ATGL), ACSL1, CTP1B and ESR1 (ERα). Moderate strength correlations were found between PFO [in milligrams per kilogram of fat-free mass (FFM) per minute] and the protein content of PNPLA2 (ATGL) [rs  = 0.41 (0.03-0.68), P < 0.05] and CPT1B [rs  = 0.45 (0.09-0.71), P < 0.05] in skeletal muscle. No other statistically significant bivariate correlations were found consistently. Females had a greater relative PFO than males [7.1 ± 1.9 vs. 4.5 ± 1.3 and 7.3 ± 1.7 vs. 4.8 ± 1.2 mg (kg FFM)-1  min-1 in the adipose tissue (n = 14) and skeletal muscle (n = 12) subgroups, respectively (P < 0.05)]. No statistically significant sex differences were found in the content of these proteins. The regulation of PFO might involve processes relating to intramyocellular triglyceride hydrolysis and mitochondrial fatty acid transport, and adipose tissue is likely to play a more minor role than muscle. Sex differences in fat metabolism are likely to be attributable to factors other than the resting content of proteins in skeletal muscle and adipose tissue relating to triglyceride hydrolysis and fatty acid transport.

Nocturnal whey protein ingestion impairs post-prandial glucose tolerance at breakfast.

Poor post-prandial glucose control is a risk factor for multiple health conditions. The second-meal effect refers to the progressively improved glycaemic control with repeated feedings, an effect which is achievable with protein ingestion at the initial eating occasion. The most pronounced glycaemic response each day therefore typically occurs following breakfast, so the present study investigated whether ingesting protein during the night could improve glucose control at the first meal of the day. In a randomised crossover design, fifteen adults (seven males, eight females; age, 22 (sd 3) years; BMI, 24·0 (sd 2·8) kg/m2; fasting blood glucose, 4·9 (sd 0·5) mmol/l) woke at 04.00 (sd 1) hours to ingest 300 ml water with or without 63 g whey protein. Participants then completed a mixed-macronutrient meal tolerance test (1 g carbohydrate/kg body mass, 2356 (sd 435) kJ), 5 h 39 min following the nocturnal feeding. Nocturnal protein ingestion increased the glycaemic response (incremental AUC) to breakfast by 43·5 (sd 55·5) mmol × 120 min/l (P = 0·009, d = 0·94). Consistent with this effect, individual peak blood glucose concentrations were 0·6 (sd 1·0) mmol/l higher following breakfast when protein had been ingested (P = 0·049, d = 0·50). Immediately prior to breakfast, rates of lipid oxidation were 0·02 (sd 0·03) g/min higher (P = 0·045) in the protein condition, followed by an elevated post-prandial energy expenditure (0·38 (sd 0·50) kJ/min, P = 0·018). Post-prandial appetite and energy intake were similar between conditions. The present study reveals a paradoxical second-meal phenomenon whereby nocturnal whey protein feeding impaired subsequent glucose tolerance, whilst increasing post-prandial energy expenditure.

Pertussis: Common Questions and Answers.

Pertussis, also known as whooping cough, remains a public health concern despite expanded immunization recommendations over the past three decades. The presentation of pertussis, which is variable and evolves over the course of the disease, includes nonspecific symptoms in the catarrhal stage, coughing with the classic whooping in the paroxysmal stage, and persistent cough in the convalescent stage. When there is clinical suspicion for pertussis, the diagnosis should be confirmed using polymerase chain reaction testing, which has replaced culture as the preferred confirmatory test. Recent evidence has confirmed a waning of acquired immunity following pertussis immunization or infection, leading to changes in tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) immunization recommendations. Patients 11 years or older should receive at least one dose of Tdap, although Tdap may replace any dose of the tetanus and diphtheria toxoids (Td) vaccine. All pregnant patients should receive Tdap between 27 and 36 weeks' gestation with each pregnancy to convey immunity to the newborn. Cocooning (vaccinating close contacts of high-risk individuals) is no longer recommended because immunized patients can still contract and transmit pertussis. A history of seizure or hypotonic-hyporesponsive episodes after a prior pertussis vaccination is no longer a contraindication to immunization. Antibiotic treatment is intended to prevent transmission of pertussis to others and does not shorten the disease course or improve symptoms. Antibiotic prophylaxis is recommended for household contacts of someone with pertussis and for those exposed to pertussis who are at high risk of severe illness (e.g., infants, people who are immunocompromised or in the third trimester of pregnancy) or in close contact with someone at high risk. Azithromycin is the preferred antibiotic for treatment or prophylaxis.

The impact of age on approach-related complications with navigated lateral lumbar interbody fusion.

OBJECTIVE: Age is known to be a risk factor for increased complications due to surgery. However, elderly patients can gain significant quality-of-life benefits from surgery. Lateral lumbar interbody fusion (LLIF) is a minimally invasive procedure that is commonly used to treat degenerative spine disease. Recently, 3D navigation has been applied to LLIF. The purpose of this study was to determine whether there is an increased complication risk in the elderly with navigated LLIF. METHODS: Patients who underwent 3D-navigated LLIF for degenerative disease from 2014 to 2019 were included in the analysis. Patients were divided into elderly and nonelderly groups, with those 65 years and older categorized as elderly. Ninety-day medical and surgical complications were recorded. Patient and surgical characteristics were compared between groups, and multivariate regression analysis was used to determine independent risk factors for complication. RESULTS: Of the 115 patients included, 56 were elderly and 59 were nonelderly. There were 15 complications (25.4%) in the nonelderly group and 10 (17.9%) in the elderly group, which was not significantly different (p = 0.44). On multivariable analysis, age was not a risk factor for complication (p = 0.52). However, multiple-level LLIF was associated with an increased risk of approach-related complication (OR 3.58, p = 0.02). CONCLUSIONS: Elderly patients do not appear to experience higher rates of approach-related complications compared with nonelderly patients undergoing 3D navigated LLIF. Rather, multilevel surgery is a predictor for approach-related complication.

Is schizotypic maternal personality linked to sensory gating abilities during infancy?

Schizotypy is a personality dimension within the general population elevated among schizophrenia-spectrum patients and their first-degree relatives. Sensory gating is the pre-attentional habituation of responses distinguishing between important and irrelevant information. This is measured by event-related potentials, which have been found to display abnormalities in schizophrenic disorders. The current study investigated whether 6-month-old infants of mothers with schizotypic traits display sensory gating abnormalities. The paired-tone paradigm: two identical auditory tones (stimulus 1 and stimulus 2) played 500 ms apart, was used to probe the selective activation of the brain during 15-minutes of sleep. Their mothers completed the Oxford and Liverpool Inventory of Feelings and Experiences-Short Form as an index of schizotypy dimensionality, categorized into: infants of control, and infants of schizotypic, mothers. The findings revealed that although the infants' P50 components displayed significant differences between stimulus 1 and stimulus 2 in the paired-tone paradigm, there was no clear difference between infants of schizotypic and infants of control mothers. In contrast, all mothers displayed significant differences between stimulus 1 and stimulus 2, as observed in the infants, but also significant differences between their sensory gating ability correlated with schizotypy dimensionality. These findings are consistent with sensory processes, such as sensory gating, evidencing impairment in schizophrenia-spectrum disorders. The present research supports the idea that first-degree relatives of individuals who identify on this spectrum, within the sub-clinical category, do not display the same deficit at 6 postnatal months of age.

History of cerebral localization and the emigration plight of three neuroscience giants from Nazi Germany: Josef Gerstmann, Adolf Wallenberg, and Franz Josef Kallmann.

The Nazi regime held power for well over a decade in Germany and were steadfast in their anti-Semitic agenda. Among the massive cohort of immigrants to America were approximately 5056 Jewish physicians, including several highly esteemed neurologists and neuroscientists of the time. Emigrating to a new world proved difficult and provided new challenges by way of language barriers, roadblocks in medical careers, and problems integrating into an alien system of medical training and clinical practice. In this article, the authors examine the tumultuous and accomplished lives of three Jewish German and Austrian neurologists and neuroscientists during the time of the Third Reich who shaped the foundations of neuroanatomy and neuropsychology: Josef Gerstmann, Adolf Wallenberg, and Franz Josef Kallmann. The authors first examine the successful careers of these individuals in Germany and Austria prior to the Third Reich, followed by their journeys to and lives in the United States, to demonstrate the challenges an émigré physician faces for career opportunities and a chance at a new life. This account culminates in a description of these scientists' eponymous syndromes.Although their stories are a testimony to the struggles in Nazi Germany, there are intriguing and notable differences in their ages, ideologies, and religious beliefs, which highlight a spectrum of unique circumstances that impacted their success in the United States. Furthermore, in this account the authors bring to light the original syndromic descriptions: Gerstmann discovered contralateral agraphia and acalculia, right-left confusion, and finger agnosia in patients with dominant angular gyrus damage; Wallenberg described a constellation of symptoms in a patient with stenosis of the posterior inferior cerebellar artery; and Kallmann identified an association between hypogonadotropic hypogonadism and anosmia based on family studies. The article also highlights the unresolved confusions and international controversies about these syndromic descriptions. Still, these unique cerebral syndromes continue to fascinate neurologists and neurosurgeons across the world, from residents in training to practicing clinicians and neuroscientists alike.

A meta-analysis of cognitive flexibility in autism spectrum disorder.

Cognitive flexibility is a fundamental process that underlies adaptive behaviour in response to environmental change. Studies examining the profile of cognitive flexibility in autism spectrum disorder (ASD) have reported inconsistent findings. To address whether difficulties with cognitive flexibility are characteristic of autism, we conducted a random-effects meta-analysis and employed subgroup analyses and meta-regression to assess the impact of relevant moderator variables such as task, outcomes, and age. Fifty-nine studies were included and comprised of 2122 autistic individuals without intellectual disabilities and 2036 neurotypical controls, with an age range of 4 to 85 years. The results showed that autistic individuals have greater difficulties with cognitive flexibility, with an overall statistically significant small to moderate effect size. Subgroup analyses revealed a significant difference between task outcomes, with perseverative errors obtaining the largest effect size. In summary, the present meta-analysis highlights the existence of cognitive flexibility difficulties in autistic people, in the absence of learning disabilities, but also that this profile is characterised by substantial heterogeneity. Potential contributing factors are discussed.

Fueling the future of neurosurgery: increasing trends in female enrollment expanding the neurosurgical workforce from 2010 to 2019.

OBJECTIVE: Regular reporting on recruitment of women into neurosurgery is a mechanism to track the progress of minority inclusion and diversity. For more than 20 years, half of US medical students have been women, yet a disproportionate minority pursue a career in neurosurgery. The authors previously published data tracking women in neurosurgery for the prior decade from 2000 to 2009, which showed an increasing match rate of women over time, from 18 women matched at the beginning of the decade to 36 matched at the end. They now present updated data on the matriculation of women into neurosurgical residencies across the most recent decade, from 2010 to 2019. METHODS: Public databases from the Association of American Medical Colleges were analyzed for applicants to neurosurgical residency from 2010 to 2019. Demographic data for those matched was obtained from the American Medical Association Masterfile and analyzed for year of match and gender. Secondary outcomes included program location, age, and gap year(s) between medical school and residency. RESULTS: Women made up 18.8% (394/2094) of residents matched into neurosurgery from 2010 to 2019, compared to 12% during the previous decade. There was an increase in overall match rate of 2.2% per year (male + female) from 2010 to 2019, representing the predicted need for expansion of the neurosurgical workforce to meet national needs. Women made up the majority of this expansion, rising by 5.5% over the time period (p = 0.002), compared to men increasing by 1.4% over the time period (p = 0.096). The percentage of women applicants who matched was 34.4%, compared to men at 38.6% (p = 0.009). There was no significant difference in gender with regard to age, number of gap years, or program location. CONCLUSIONS: The number of women matching into neurosurgery has continued to increase across the last 2 decades. Despite this, there remains significant disparity between the number of men and women matching into neurosurgery. Ongoing mitigation of barriers to recruitment of women into neurosurgery is critical. The authors' data highlight the fact that women are important to fueling the expansion of the neurosurgical workforce.

Assessing clinicians' and trainees' knowledge and practice of the IDSA guidelines for asymptomatic bacteriuria in older adults.

A survey of advanced practice clinicians (APCs), physicians, residents, and medical students at an academic medical center and community practices in southeastern Texas revealed a gap in knowledge and practice related to testing and treatment for asymptomatic bacteriuria (ASB) in older adults.

Alterations in attentional processing in youth with misophonia: A phenotypical cross-comparison with anxiety patients.

BACKGROUND: Misophonia is a complex condition characterized by extreme emotional distress in response to specific sounds or specific visual stimuli. Despite a growing body of clinical and neuroscientific literature, the etiology of this condition remains unclear. Hyperarousal, that is, a state of heightened alertness and disinhibition, as a core feature of misophonia is supported by behavioral and neuroimaging literature and might represent a viable clinical target for the development of both behavioral and pharmacological interventions. The aim of this study was to investigate how hyperarousal might be linked to neurocognitive processes associated with vigilance and stimulus discrimination in youth with misophonia. METHODS: We compared 72 children and adolescents with misophonia (13.74 ± 2.44 years) (64 % female) and 89 children and adolescents with anxiety (12.35 ± 2.57 years) (58.4 % female) on behavioral and signal detection performance of the immediate memory task (IMT). Anxiety patients were used as a clinical control group to distinguish attentional processes specific for misophonia. RESULTS: Both groups demonstrated similar behavioral performance, including response rate and reaction time. However, misophonia was associated with elevated stimulus discrimination (d prime), which in turn was positively correlated with the severity of misophonia trigger reports. CONCLUSIONS: Our findings are in line with previous cognitive and neuroimaging studies, and support an arousal-based model of misophonia, where individuals with misophonia experience a state of heightened vigilance, being more aware of stimuli in the environment. Our findings provide a neurocognitive basis for future study of neurochemical imaging that might further progress towards clinical targets.

Family Accommodation in Children and Adolescents With Misophonia.

Family accommodation (e.g., reassurance, modifying routines, assisting avoidance) has not been explored among youth with misophonia but may have important clinical and intervention implications. We examined family accommodation in 102 children and adolescents with interview-confirmed misophonia and compared its frequency and content to family accommodation in 95 children and adolescents with anxiety disorders. Findings showed that family accommodation was ubiquitous in pediatric misophonia and may be even more frequent than in youth with anxiety disorders. Assisting the child, participating in misophonia-related behaviors, and modifying family routines were endorsed by more than 70% of parents of children with misophonia. Further, compared to parents of children with anxiety disorders, parents of children with misophonia more frequently reported child distress and anger when they did not accommodate. Family accommodation was moderately to strongly associated with misophonia severity even when accounting for co-occurring internalizing and externalizing symptoms and sociodemographic factors. This first study of family accommodation in pediatric misophonia suggests accommodation may be an important clinical feature. A notable study limitation is that the measure of misophonia did not delineate between adaptive versus maladaptive accommodations. Excessive and maladaptive accommodation may be one potential candidate to target in interventions when considered within a broader treatment plan. Importantly, adaptive accommodations should also be considered in day-to-day management if they improve functioning and quality of life.

Dendritic cell-mediated responses to secreted Cryptosporidium effectors promote parasite-specific CD8+ T cell responses.

Cryptosporidium causes debilitating diarrheal disease in patients with primary and acquired defects in T cell function. However, it has been a challenge to understand how this infection generates T cell responses and how they mediate parasite control. Here, Cryptosporidium was engineered to express a parasite effector protein (MEDLE-2) that contains the major histocompatibility complex-I restricted SIINFEKL epitope which is recognized by T cell receptor transgenic OT-I(OVA-TCR-I) clusters of differentiation (CD)8+ T cells. These modified parasites induced expansion of endogenous SIINFEKL-specific and OT-I CD8+ T cells that were a source of interferon-gamma (IFN-γ) that could restrict growth of Cryptosporidium. This T cell response was dependent on the translocation of the effector and similar results were observed with another secreted parasite effector (rhoptry protein 1). Although infection and these translocated effector proteins are restricted to intestinal epithelial cells, type 1 conventional dendritic cells were required to generate CD8+ T cell responses to these model antigens. These data sets highlight Cryptosporidium effectors as potential targets of the immune system and suggest that crosstalk between enterocytes and type 1 conventional dendritic cells is crucial for CD8+ T cell responses to Cryptosporidium.

Study protocol for the randomised controlled trial: antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study).

BACKGROUND: Some patients with depression do not respond to first and second line conventional antidepressants and are therefore characterised as suffering from treatment refractory depression (TRD). On-going psychosocial stress and dysfunction of the hypothalamic-pituitary-adrenal axis are both associated with an attenuated clinical response to antidepressants. Preclinical data shows that co-administration of corticosteroids leads to a reduction in the ability of selective serotonin reuptake inhibitors to increase forebrain 5-hydroxytryptamine, while co-administration of antiglucocorticoids has the opposite effect. A Cochrane review suggests that antiglucocorticoid augmentation of antidepressants may be effective in treating TRD and includes a pilot study of the cortisol synthesis inhibitor, metyrapone. The Antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study) is a multicentre randomised placebo controlled trial of metyrapone augmentation of serotonergic antidepressants in a large population of patients with TRD in the UK National Health Service. METHODS/DESIGN: Patients with moderate to severe treatment refractory Major Depression aged 18 to 65 will be randomised to metyrapone 500 mg twice daily or placebo for three weeks, in addition to on-going conventional serotonergic antidepressants. The primary outcome will be improvement in Montgomery-Åsberg Depression Rating Scale score five weeks after randomisation (i.e. two weeks after trial medication discontinuation). Secondary outcomes will include the degree of persistence of treatment effect for up to 6 months, improvements in quality of life and also safety and tolerability of metyrapone. The ADD Study will also include a range of sub-studies investigating the potential mechanism of action of metyrapone. DISCUSSION: Strengths of the ADD study include broad inclusion criteria meaning that the sample will be representative of patients with TRD treated within the UK National Health Service, longer follow up, which to our knowledge is longer than any previous study of antiglucocorticoid treatments in depression, and the range of mechanistic investigations being carried out. The data set acquired will be a rich resource for a range of research questions relating to both refractory depression and the use of antiglucocorticoid treatments. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN45338259; EudraCT Number: 2009-015165-31.

Pertussis: a reemerging infection.

Pertussis, also known as whooping cough, is an acute respiratory tract infection that has increased in incidence in recent years. The initial catarrhal stage presents with nonspecific symptoms of malaise, rhinorrhea, sneezing, lacrimation, and mild cough. During the paroxysmal stage, severe outbreaks of coughing often lead to the classic high-pitched whooping sound patients make when gasping for breath. The paroxysmal stage is followed by the convalescent stage and resolution of symptoms. Complications vary by age, with infants more likely to experience severe complications such as apnea, pneumonia, seizures, or death. In adolescents and adults, complications are the result of chronic cough. The diagnosis depends on clinical signs and laboratory testing. Both culture and polymerase chain reaction testing can be used to confirm the diagnosis; serologic testing is not standardized or routinely recommended. Although antibiotics have not shown clear effectiveness in the treatment of pertussis, they eradicate nasal bacterial carriage and may reduce transmission rates. Macrolide antibiotics such as azithromycin are first-line treatments to prevent transmission; trimethoprim/sulfamethoxazole is an alternative in cases of allergy or intolerance to macrolides. Immunization against pertussis is essential for disease prevention. Current recommendations in the United States consist of administering five doses of the diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine to children before seven years of age, and administering a tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) booster between 11 and 18 years of age. Recent efforts have focused on the vaccination of adolescents and adults, with new recommendations for a single dose of the Tdap booster if it has not been previously administered.