Remote Fluorination of α,ß-Unsaturated Carbonyls via Silyl Dienol Ethers.

We report a general, regioselective, and metal free γ-fluorination of α,ß-unsaturated carbonyls via silyl dienol ethers that are readily prepared from simple ketones and aldehydes. The transformation displays broad scope including 27 cyclic and acyclic siloxydienes providing γ-fluoro compounds in 28-91 % yield. Notably, the reported conditions are also suitable for the synthesis of challenging tertiary fluorides. The regioselectivity of the reaction was studied on a series of acyclic siloxydienes and was observed to be sensitive to the conformational flexibility of the substrate. Diversification of the γ-fluorocarbonyls demonstrates the promise of fluorine as a stereocontrol element.

Two Clinical Prediction Tools to Inform Rapid Tuberculosis Treatment Decision-making in Children.

Background: In the absence of bacteriologic confirmation to diagnose tuberculosis (TB) in children, it is suggested that treatment should be initiated when sufficient clinical evidence of disease is available. However, it is unclear what clinical evidence is sufficient to make this decision. To identify children who would benefit from rapid initiation of TB treatment, we developed 2 clinical prediction tools. Methods: We conducted a secondary analysis of a prospective intensified TB patient-finding intervention conducted in Pakistan in 2014-2016. TB disease was determined through either bacteriologic confirmation or a clinical diagnosis. We derived 2 tools: 1 uses classification and regression tree (CART) analysis to develop decision trees, while the second uses multivariable logistic regression to calculate a risk score. Results: Of the 5162 and 5074 children included in the CART and prediction score, respectively, 1417 (27.5%) and 1365 (26.9%) were eligible for TB treatment. CART identified abnormal chest radiographs and family history of TB as the most important predictors (area under the receiver operating characteristic curve [AUC], 0.949). The final prediction score model included age group (0-4, 5-9, 10-14), weight <5th percentile, cough, fever, weight loss, chest radiograph suggestive of TB disease, and family history of TB; the identified best cutoff score was 9 (AUC, 0.985%). Conclusions: Use of clinical evidence was sufficient to accurately identify children who would benefit from treatment initiation. Our tools performed well compared with existing algorithms, though these results need to be externally validated before operationalization.

Development of treatment-decision algorithms for children evaluated for pulmonary tuberculosis: an individual participant data meta-analysis.

BACKGROUND: Many children with pulmonary tuberculosis remain undiagnosed and untreated with related high morbidity and mortality. Recent advances in childhood tuberculosis algorithm development have incorporated prediction modelling, but studies so far have been small and localised, with limited generalisability. We aimed to evaluate the performance of currently used diagnostic algorithms and to use prediction modelling to develop evidence-based algorithms to assist in tuberculosis treatment decision making for children presenting to primary health-care centres. METHODS: For this meta-analysis, we identified individual participant data from a WHO public call for data on the management of tuberculosis in children and adolescents and referral from childhood tuberculosis experts. We included studies that prospectively recruited consecutive participants younger than 10 years attending health-care centres in countries with a high tuberculosis incidence for clinical evaluation of pulmonary tuberculosis. We collated individual participant data including clinical, bacteriological, and radiological information and a standardised reference classification of pulmonary tuberculosis. Using this dataset, we first retrospectively evaluated the performance of several existing treatment-decision algorithms. We then used the data to develop two multivariable prediction models that included features used in clinical evaluation of pulmonary tuberculosis-one with chest x-ray features and one without-and we investigated each model's generalisability using internal-external cross-validation. The parameter coefficient estimates of the two models were scaled into two scoring systems to classify tuberculosis with a prespecified sensitivity target. The two scoring systems were used to develop two pragmatic, treatment-decision algorithms for use in primary health-care settings. FINDINGS: Of 4718 children from 13 studies from 12 countries, 1811 (38·4%) were classified as having pulmonary tuberculosis: 541 (29·9%) bacteriologically confirmed and 1270 (70·1%) unconfirmed. Existing treatment-decision algorithms had highly variable diagnostic performance. The scoring system derived from the prediction model that included clinical features and features from chest x-ray had a combined sensitivity of 0·86 [95% CI 0·68-0·94] and specificity of 0·37 [0·15-0·66] against a composite reference standard. The scoring system derived from the model that included only clinical features had a combined sensitivity of 0·84 [95% CI 0·66-0·93] and specificity of 0·30 [0·13-0·56] against a composite reference standard. The scoring system from each model was placed after triage steps, including assessment of illness acuity and risk of poor tuberculosis-related outcomes, to develop treatment-decision algorithms. INTERPRETATION: We adopted an evidence-based approach to develop pragmatic algorithms to guide tuberculosis treatment decisions in children, irrespective of the resources locally available. This approach will empower health workers in primary health-care settings with high tuberculosis incidence and limited resources to initiate tuberculosis treatment in children to improve access to care and reduce tuberculosis-related mortality. These algorithms have been included in the operational handbook accompanying the latest WHO guidelines on the management of tuberculosis in children and adolescents. Future prospective evaluation of algorithms, including those developed in this work, is necessary to investigate clinical performance. FUNDING: WHO, US National Institutes of Health.

Factors related to recruitment and retention of patients into diabetes group visits in Federally Qualified Health Centers.

RATIONALE, AIMS AND OBJECTIVES: To examine factors related to recruitment of eligible patients and retention of enrolled patients in diabetes group visits (GVs). METHOD: As part of a cluster randomized trial, 272 eligible patients were contacted and 75 patients were eventually enrolled in GVs at six community health centers (CHC). Fisher's exact tests and χ2 tests were used to compare enrolled and nonenrolled patients by patient recruitment method, gender and preferred language. Linear mixed models were used to evaluate characteristics associated with GV attendance such as diabetes self-empowerment and diabetes-associated distress. Content analysis was used to analyse patients' open-ended survey responses, and template analysis was used to analyse CHC staff interviews. RESULTS: In terms of recruitment and enrollment analysis, patients who received in-person contact only and both phone and in-person contact comprised a greater fraction of the enrolled than unenrolled group, while those who received phone only and both phone and mail comprised a smaller fraction of the enrolled than unenrolled group (p = 0.004). In terms of retention analysis, 70 of the 75 enrolled patients attended at least one GV (93%). The average number of GVs was 3.2 out of 6 visits. Higher GV attendance was associated with lower baseline diabetes empowerment (p = 0.03). Patients' most common self-reported motivating factors to attend GVs were to learn more about diabetes, gain improved blood glucose control and find support from peers. CONCLUSION: In-person recruitment for GVs at CHCs was more effective than recruitment by telephone/mail. Patients who felt less empowered to manage their diabetes were most motivated to attend GVs. These findings could help clinicians implement targeted recruitment of patient populations who are more likely to attend diabetes GVs and tailor self-management education interventions to their patient populations, particularly for underserved patients who face disparate clinical outcomes.

Age-specific Clinical Presentation and Risk Factors for Extrapulmonary Tuberculosis Disease in Children.

BACKGROUND: Clinical presentation for extrapulmonary tuberculosis (EPTB) in children can be variable and nonspecific, leading to delayed diagnosis, disease and death. We describe the age-specific clinical presentation and identify risk factors for EPTB among children in Pakistan. METHODS: In 2015-2016 in 4 facilities in Sindh, Pakistan, children were diagnosed with TB either through bacteriologic confirmation or clinical-radiologic criteria. EPTB comprised any form of TB disease that did not involve the lungs. Among children with TB disease, we report demographics, clinical characteristics and symptoms, family medical history and diagnostic test results for children with and without EPTB. We conduct age-specific regression analyses to identify factors associated with an EPTB diagnosis among children age 0-4, 5-9 and 10-14 years. RESULTS: A total of 1163 children were diagnosed with TB disease, of which 157 (13.5%) had EPTB. Of those, 46 (29.3%) were 0-4, 53 (33.8%) were 5-9 and 58 (36.9%) were 10-14 years old. Of children with EPTB, the most frequently reported sites were lymph node (113, 72.4%) and abdominal (31, 19.9%). Weight loss was associated with an increased risk of EPTB in the 0-4-year-old (adjusted odds ratio: 2.80, 95% confidence interval: 1.05-7.47) and 10-14-year-old (adjusted odds ratio: 2.79, 95% confidence interval: 1.28-6.07) groups, and the presence of cough was associated with a decreased risk of EPTB. CONCLUSIONS: This study provides new knowledge about age-specific clinical presentation and risk factors of EPTB in children in Pakistan. Our results can help to optimize clinical algorithms designed to achieve a timely diagnosis in children with EPTB along with improved treatment outcomes.

Age-specific effectiveness of a tuberculosis screening intervention in children.

OBJECTIVE: To apply a cascade-of-care framework to evaluate the effectiveness-by age of the child-of an intensified tuberculosis patient-finding intervention. DESIGN: From a prospective screening program at four hospitals in Pakistan (2014-2016) we constructed a care cascade comprising six steps: screened, positive screen, evaluated, diagnosed, started treatment, and successful outcome. We evaluated the cascade by each year of age from 0 to 14 and report the age-specific mean proportion and standard deviation. RESULTS: On average across all ages, only 12.5% (standard deviation: 2.0%) of children with a positive screen were not evaluated. Among children who had a complete evaluation, the highest percentages of children diagnosed with tuberculosis were observed in children 0-4 (mean: 31.9%; standard deviation: 4.8%), followed by lower percentages in children 5-9 (mean: 22.4%; standard deviation: 2.2%), and 10-14 (mean: 26.0%; standard deviation:5.4%). Nearly all children diagnosed with tuberculosis initiated treatment, and an average of 93.3% (standard deviation: 3.3%) across all ages had successful treatment outcomes. CONCLUSIONS: This intervention was highly effective across ages 0-14 years. Our study illustrates the utility of applying operational analyses of age-stratified cascades to identify age-specific gaps in pediatric tuberculosis care that can guide future, novel interventions to close these gaps.

Cost-effectiveness of household contact investigation for detection of tuberculosis in Pakistan.

OBJECTIVES: Despite WHO guidelines recommending household contact investigation, and studies showing the impact of active screening, most tuberculosis (TB) programmes in resource-limited settings only carry out passive contact investigation. The cost of such strategies is often cited as barriers to their implementation. However, little data are available for the additional costs required to implement this strategy. We aimed to estimate the cost and cost-effectiveness of active contact investigation as compared with passive contact investigation in urban Pakistan. METHODS: We estimated the cost-effectiveness of 'enhanced' (passive with follow-up) and 'active' (household visit) contact investigations compared with standard 'passive' contact investigation from providers and the programme's perspective using a simple decision tree. Costs were collected in Pakistan from a TB clinic performing passive contact investigation and from studies of active contact tracing interventions conducted. The effectiveness was based on the number of patients with TB identified among household contacts screened. RESULTS: The addition of enhanced contact investigation to the existing passive mode detected 3.8 times more cases of TB per index patient compared with passive contact investigation alone. The incremental cost was US$30 per index patient, which yielded an incremental cost of US$120 per incremental patient identified with TB. The active contact investigation was 1.5 times more effective than enhanced contact investigation with an incremental cost of US$238 per incremental patient with TB identified. CONCLUSION: Our results show that enhanced and active approaches to contact investigation effectively identify additional patients with TB among household contacts at a relatively modest cost. These strategies can be added to the passive contact investigation in a high burden setting to find the people with TB who are missed and meet the End TB strategy goals.

Restricting the Sale of Electronic Nicotine Delivery System Flavors.

Electronic nicotine delivery system use contributes to the epidemic of youth vaping. Regulations to curtail or prohibit the sale of flavored nicotine products aim to disrupt initiation of child nicotine use by reducing access to enticing nicotine flavorings. A total of 6 states and >300 localities have restricted or banned flavored nicotine product sales. In this case study, we outline the use of a localized town-based strategy, which offered 2 potential bills to incrementally restrict or prohibit sale of flavored vape products when county or state legislation was not politically feasible. Over the course of 18 months, these bills reduced the number of municipalities where these products could be sold or advertised until county, city, and statewide bans were effectively in place, ultimately making the passage of a bill in the statehouse palatable. Strong partnerships with officials who had expertise in local town government, local American Academy of Pediatrics chapter physician champions, and a diverse coalition were instrumental in motivating smaller governments, which often pass legislation faster than larger legislatures, to create child-protective tobacco policies.

Quantified TB Exposure Can Predict Prevalent TB Disease in Child Contacts.

In a matched case-control study in Pakistan, we found that quantified tuberculosis (TB) exposure using a 10-point score is associated with prevalent TB disease in pediatric household contacts. A 1 unit increase in TB exposure score increased the odds of TB disease by 44% (conditional odds ratio: 1.44, 95% confidence interval: 1.33-1.56). Collecting well-documented exposure history can help TB diagnosis in resource-limited settings.

Predictors of unsuccessful tuberculosis treatment outcomes in children from a prospective cohort study in Pakistan.

BACKGROUND: Every year, about 239 000 children die from tuberculosis (TB), despite availability of highly effective regimens. Few studies have evaluated predictors for poor treatment outcomes in children treated for TB. METHODS: We assessed predictors of unsuccessful TB treatment outcomes in a prospective cohort of children diagnosed by an intensified TB patient-finding intervention at four facilities in Pakistan between 2014 and 2016. A case of TB disease was determined through either bacteriologic confirmation of disease or a clinical diagnosis. To estimate characteristics predictive of experiencing an unsuccessful treatment outcome, we used a multi-level model with a modified Poisson approach, accounting for clustering at the facility level. We report estimated relative risks (RR) and 95% confidence intervals (CI). RESULTS: During the study period, 1404 children less than 15 years old were initiated on treatment for drug-susceptible TB. In total, 709 (50.5%) were 0-4, 406 (28.9%) were 5-9 years, and 289 (20.6%) were 10-14 years old; 614 (43.7%) were female; and of the 1377 children assessed for malnourishment, 1161 (84.3%) were malnourished. A total of 1322 (94.2%) children experienced a successful treatment outcome, 14 (1.0%) children transferred out to a different facility, and 68 (4.8%) children experienced an unsuccessful treatment outcome: 14 (1.0%) died, 20 (1.4%) failed treatment, and 34 (2.4%) were lost to follow-up. After adjustment for age group, sex, and malnutrition status, we identified increased risk of unsuccessful treatment outcome in children presenting with fever (RR = 2.56, 95% CI = 1.02-6.44; P = 0.05) or an abdominal examination suggestive of TB disease (RR = 2.34, 95% CI = 1.20-4.58; P = 0.01), and a decreased risk in children who initiated treatment at a rural facility (RR = 0.05, 95% CI = 0.00-0.74; P = 0.03). CONCLUSIONS: More than 94% of children experienced successful treatment outcomes. We identified individual-, facility-, and clinical-factors predictive of experiencing unsuccessful treatment outcomes. Children with fevers and abdominal findings suggestive of TB disease should be tested for TB and followed closely throughout treatment to ensure necessary support for successful completion of treatment.

Risk Factors for Adverse Events in Household Contacts Prescribed Preventive Treatment for Drug-resistant Tuberculosis Exposure.

BACKGROUND: Completion of tuberculosis (TB) preventive treatment is important to optimize efficacy; treatment-related adverse events (AEs) sometimes result in discontinuation. This study describes the occurrence of AEs and their risk factors during a 6-month, 2-drug, fluoroquinolone-based preventive treatment for household contacts of patients with drug-resistant TB in Karachi, Pakistan. METHODS: The primary outcome was development of any clinical AE during preventive treatment. Adverse events were categorized using the AE grading tables of the National Institutes of Health. Time-to-event analysis with Kaplan-Meier curves and Cox proportional hazards models accounting for recurrence were used to analyze associated risk factors. RESULTS: Of the 172 household contacts on preventive treatment, 36 (21%) developed 64 AEs during 813 months of treatment. The incidence of AEs over 6 months of treatment was 7.9 per 100 person-months; 16 per 100 person-months with a fluoroquinolone and ethionamide, and 4.4 per 100 person-months with a fluoroquinolone and ethambutol. There were 53 (83%) grade 1 and 11 grade 2 AEs, with no grade 3 or 4 AEs. In multivariable analysis, the risk of AEs was higher in contacts prescribed ethionamide as compared to ethambutol adjusting for age, sex, and body mass index (adjusted hazard ratio, 2.1 [95% confidence interval {CI}, 1.2-3.6]). Overall, there was no notable difference in treatment completion among the contacts who experienced an AE and those who did not (crude odds ratio, 1.1 [95% CI, .52-2.5]). CONCLUSIONS: A fluoroquinolone-based preventive treatment regimen for drug-resistant TB exposure is well tolerated. Regimens with ethionamide are more likely to result in AEs.

Too Much of a Good Thing? Cerebral Sinovenous Thrombosis Due to Excessive Milk Intake Associated Anemia.

INTRODUCTION: In young children, excessive cow's milk intake causes iron-deficiency anemia, which is associated with hypercoagulable states. We present a case series of 4 toddlers with excessive milk intake iron-deficiency anemia and cerebral sinovenous thrombosis. METHODS: Retrospective chart review of 4 patients was performed for patients with cerebral sinovenous thrombosis and iron-deficiency anemia secondary to excessive milk intake. Iron-deficiency anemia was defined as hemoglobin <11 mg/dL, mean corpuscular volume <70 fL, and serum ferritin <12 µg/L. Excessive milk intake was defined as consumption of >24 oz daily. Clinical, laboratory, and radiographic features were reviewed. RESULTS: Age ranged from 12 to 24 months. Average hemoglobin, hematocrit, mean corpuscular volume, and ferritin levels were 6.1 g/dL, 22.7 g/dL, 52.7 fL, and 3.2 ng/mL, respectively. Daily milk consumption ranged from 40 to 60 oz. All patients presented with focal neurologic deficits, including seizures in 3. The location of cerebral sinovenous thrombosis varied, and 3 patients had venous infarcts, one of them hemorrhagic. All patients had a limited diet and were described as "picky eaters" by their parents, and only 1 had transitioned of a bottle. All patients were treated with anticoagulation, iron supplementation, and extensive dietary counseling to reduce cow's milk intake. CONCLUSION: Iron-deficiency anemia due to excessive milk intake is an important and preventable etiology of pediatric cerebral sinovenous thrombosis. Focused anticipatory guidance is necessary for at-risk groups to prevent this neurologic emergency.

Tuberculosis Preventive Therapy for Individuals Exposed to Drug-resistant Tuberculosis: Feasibility and Safety of a Community-based Delivery of Fluoroquinolone-containing Preventive Regimen.

BACKGROUND: Observational studies have demonstrated the effectiveness of a fluoroquinolone-based regimen to treat individuals presumed to be infected with drug-resistant tuberculosis (DR-TB). We sought to assess the feasibility of this approach in an urban setting in South Asia. METHODS: From February 2016 until March 2017, all household contacts of DR-TB patients enrolled at the Indus Hospital were screened for TB symptoms at home. Children aged 0-17 years, symptomatic adults, and those with an immunocompromising condition (human immunodeficiency virus, diabetes, or malnutrition) were evaluated for TB disease. Contacts diagnosed with TB disease were started on treatment. Contacts without TB disease aged <5 years, contacts aged between 5 and 17 years with either a positive tuberculin skin test or an immunocompromising condition, or contacts aged ≥18 years with an immunocompromising condition were offered 6 months of treatment with a fluoroquinolone. RESULTS: One hundred households with 800 contacts were enrolled: 353 (44.1%) individuals aged ≤17 years with a median age of 19 years (interquartile range, 10-32); 423 (52.9%) were males. In total, 737 (92.1%) individuals were screened, of which 8 were already on treatment for TB (1.1%); another 3 (0.4%) contacts were diagnosed with TB disease and started on treatment. Of 215 eligible for infection treatment, 172 (80.0%) contacts initiated and 121 (70.3%) completed treatment. No TB disease or significant adverse events were observed during 12 months of follow-up. CONCLUSIONS: Fluoroquinolone-based treatment for contacts with presumed DR-TB infection is feasible and well tolerated in a high TB burden setting.

Breast Abcess and Tuberculosis and its Diagnostic Challenges: A Two-Year Prospective Study in Karachi, Pakistan.

Breast tuberculosis (TB) is rare among extrapulmonary tuberculosis cases, and the diagnosis is usually preceded by a high index of suspicion and findings of granulomatous lesions. We conducted this study to evaluate different clinical presentations of breast TB, including its diagnosis and association with lactation. We also examined the association of breast TB with TB elsewhere in the body and contact history. This prospective, descriptive study was conducted at a tertiary care hospital in Karachi, Pakistan from March 2017 to March 2019. The study population consisted of 100 women of age ranging from 30 to 39 years after 10 patients were lost to follow-up. After providing informed written consent and a histopathology or culture report, participants completed a proforma. We used IBM SPSS Statistics for Windows, Version 22.0 (IBM Corp., Armonk, NY) to analyze the data, which were kept confidential. Twenty-four patients had diabetes, while 36 patients had no comorbidities. The most consistent symptoms were breast pain (98%), breast lump (89%), fever (83%), and discharge (45%). Of the 100 women, 34 were diagnosed with TB, while 66 women had nonspecific inflammation. Sixty-nine women were lactating, and 31 were nonlactating. Of the 69 lactating women, 21 had been diagnosed with TB while 48 had nonspecific inflammation. TB represents a great burden in underdeveloped countries like Pakistan. Therefore, concerned departments must take necessary action to facilitate early diagnosis and prompt treatment.

The Impact of Funding on Childhood TB Case Detection in Pakistan.

This study is a review of routine programmatically collected data to describe the 5-year trend in childhood case notification in Jamshoro district, Pakistan from January 2013 to June 2018 and review of financial data for the two active case finding projects implemented during this period. The average case notification in the district was 86 per quarter before the start of active case finding project in October 2014. The average case notification rose to 322 per quarter during the implementation period (October 2014 to March 2016) and plateaued at 245 per quarter during the post-implementation period (April 2016 to June 2018). In a specialized chest center located in the district, where active case finding was re-introduced during the post implementation period (October 2016), the average case notification was 218 per quarter in the implementation period and 172 per quarter in the post implementation period. In the rest of the district, the average case notification was 160 per quarter in the implementation period and 78 during the post implementation period. The cost per additional child with TB found ranged from USD 28 to USD 42 during the interventions. A continuous stream of resources is necessary to sustain high notifications of childhood TB.

Evaluation of GenoType MTBDRplus for the detection of drug-resistant Mycobacterium tuberculosis on isolates from Karachi, Pakistan.

OBJECTIVE: To compare the diagnostic performance of the GenoType MRBDRplus assay with the gold standard phenotypic drug susceptibility testing in the detection of drug resistance among culture isolates obtained from patients in Karachi, Pakistan. DESIGN: Mycobacterium tuberculosis isolates were obtained from 96 consecutive tuberculosis patients found to have resistance to isoniazid from two health centers in Karachi (January-November 2017). Isolates were tested for drug resistance against rifampin and isoniazid using the MTBDRplus assay. Results were compared with conventional drug-susceptibility testing and the frequency of specific mutations were reported. RESULTS: The MTBDRplus assay had a sensitivity for rifampin resistance of 98.8% (95% CI: 93.4-100) and for isoniazid resistance of 90.6% (95% CI: 83.0-95.6). The MTBDRplus assay showed mutations in rpoB in 81 of the 96 (84.4%) isolates. Of the 87 isolates showing resistance to isoniazid via the MTBDRplus assay, 71 (74.0%) isolates had mutations in the katG gene only, 15 (15.6%) isolates had mutations in the inhA promoter region, and 1 (1.0%) showed mutations in both genes. CONCLUSION: The GenoType MTBDRplus assay in Pakistan can identify subgroups at high-risk of having isolates with mutations in the katG and/or inhA genes. Understanding the local burden of these mutations have implications for local diagnostic and treatment guidelines.

Modulative effect of a new hydrazide derivative on wheat-induced pulmonary inflammation in rats.

NEW FINDINGS: What is the central question of this study? What is the mechanism of wheat-induced pulmonary inflammation and how does a hydrazide derivative modulate it? What is the main finding and its importance? A hydrazide derivative significantly reduced wheat-induced pulmonary inflammation in a rat model mainly by down-regulating inflammatory cell infiltration, pathological lesions in the lungs and the level of pro-inflammatory cytokines, COX-1, COX-2 and T-cell proliferation. ABSTRACT: We investigated the ameliorative anti-inflammatory effect of a previously synthesized hydrazide derivative (N'-(4-methoxybenzylidene)-6-(4-chlorophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carbohydrazide; MD) as an immunomodulator in a newly developed allergen-induced pulmonary inflammation (AIPI) rat model. Wheat and thresher dust were used as allergens to induce pulmonary inflammation while MD was used to reverse the inflammatory response. Blood and bronchoalveolar lavage fluid (BALF) were collected after killing the rats and inflammatory cells were counted. Histological analysis of lung airways was carried out by haematoxylin and eosin and periodic acid-Schiff staining while the level of total serum IgE, interleukin (IL)-4, IL-5 and cyclooxygenase (COX)-1 in BALF and in vitro T-cell proliferation in spleen were measured through enzyme-linked immunosorbent assay. mRNA expression level of IL-4, IL-5, IL-13, transforming growth factor ß (TGF-ß), interferon-γ, tumour necrosis factor α, COX-1 and COX-2 was evaluated by qRT-PCR. A liver and kidney function test was used to observe any toxic impact of MD. The results indicated that 2 mg of wheat and thresher dust led to higher levels of inflammatory cytokines in the blood, BALF and lung airways of rats. MD potentially down-regulated the inflammatory cell infiltration in BALF and pathological lesions in the lung airways of AIPI rats. MD significantly suppressed the elevated total serum IgE, along with IL-4, IL-5, IL-13, TGF-ß, COX-1 and COX-2 mRNA expression and T-cell proliferation in spleen. In conclusion, MD at 10 mg kg-1 exhibited a significant reduction in all the markers in both wheat- and thresher dust-induced pulmonary inflammation mainly by inhibiting pro-inflammatory cytokine production and T-cell proliferation. The data suggest that inhibition of the T-cell response may be responsible for the modulative effect of MD in an AIPI rat model.

Pharmacokinetics of Levofloxacin in Children Treated for Exposure to Drug-Resistant Tuberculosis.

Levofloxacin is used to treat and prevent drug-resistant tuberculosis in children. We assessed levofloxacin serum drug concentrations in 24 children aged 2 to 10 years who received levofloxacin-based tuberculosis preventive therapy in Karachi, Pakistan. Only 9 children (37.5%) achieved adequate drug exposure. Target serum drug concentration was met in 4 (26.7%) of 15 children dosed consistently with World Health Organization recommendations and 4 (80.0%) of 5 who received higher-than-recommended doses. Levofloxacin dosing recommendations may require reevaluation.

Staff perceptions of borderline personality disorder and recovery: A Q-sort method approach.

OBJECTIVES: This study was the first to explore how staff that work with people diagnosed with borderline personality disorder (BPD) perceive recovery in this client group. These views are important because of the crucial role that staff play in the care of people with BPD, and the challenges that staff experience with these clients. DESIGN: A Q methodology design was used, containing 58 statements about recovery. METHODS: Twenty-nine mental health staff sorted recovery statements according to perceived importance to recovery in BPD. RESULTS: There were two different viewpoints about recovery in BPD. A medically oriented group viewed coping with symptoms and behaviours specific to BPD as being most important to recovery, whereas participants who were more well-being oriented viewed achieving overall well-being that was universally valued regardless of diagnosis as more important. Both groups reported that engaging in socially valued activities such as work and education was not an important aspect of recovery and that people with BPD could be considered to have recovered despite continued impairments in everyday functioning. CONCLUSIONS: Staff perceptions of recovery in BPD can differ, which poses risks for consistent team working, a particularly important issue in this client group due to the relational difficulties associated with the diagnosis. Multidisciplinary teams working with people diagnosed with BPD therefore need to find a forum to promote a shared understanding of each patient's needs and support plans. We advocate that team formulation is a promising approach to achieve more consistent ways of working within teams. PRACTITIONER POINTS: Findings Multidisciplinary teams working with people with borderline personality disorder should use team formulations to create a shared understanding of individual patient's needs and goals for recovery, so they can deliver a consistent approach to care. Recovery questionnaires should be used to develop an understanding of a patient's individual recovery goals. Limitations Opportunity sampling was utilized in recruitment, and the sample was not representative of the general population of staff working with borderline personality disorder. Although views from a wide range of professions were sampled in this research, the views of psychiatrists were not represented.