Surgery as an Adjunctive Treatment for Multidrug-Resistant Tuberculosis: An Individual Patient Data Metaanalysis.

BACKGROUND: Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual patient data metaanalysis to evaluate the effectiveness of surgery as adjunctive therapy for MDR-tuberculosis. METHODS: Individual patient data, was obtained from the authors of 26 cohort studies, identified from 3 systematic reviews of MDR-tuberculosis treatment. Data included the clinical characteristics and medical and surgical therapy of each patient. Primary analyses compared treatment success (cure and completion) to a combined outcome of failure, relapse, or death. The effects of all forms of resection surgery, pneumonectomy, and partial lung resection were evaluated. RESULTS: A total of 4238 patients from 18 surgical studies and 2193 patients from 8 nonsurgical studies were included. Pulmonary resection surgery was performed on 478 patients. Partial lung resection surgery was associated with improved treatment success (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.5-5.9; I(2)R, 11.8%), but pneumonectomy was not (aOR, 1.1; 95% CI, .6-2.3; I(2)R, 13.2%). Treatment success was more likely when surgery was performed after culture conversion than before conversion (aOR, 2.6; 95% CI, 0.9-7.1; I(2)R, 0.2%). CONCLUSIONS: Partial lung resection, but not pneumonectomy, was associated with improved treatment success among patients with MDR-tuberculosis. Although improved outcomes may reflect patient selection, partial lung resection surgery after culture conversion may improve treatment outcomes in patients who receive optimal medical therapy.

Assessing the impact of a nurse-delivered home dried blood spot service on uptake of testing for household contacts of hepatitis B-infected pregnant women across two London trusts.

Despite national guidance recommending testing and vaccination of household contacts of hepatitis B-infected pregnant women, provision and uptake of this is sub-optimal. The aim of this study was to evaluate the use of in-home dried blood spot (DBS) testing to increase testing and vaccination of household contacts of hepatitis B-infected pregnant women as an alternative approach to conventional primary-care follow-up. The study was conducted across two London maternity trusts (North Middlesex and Newham). All hepatitis B surface antigen-positive pregnant women identified through these trusts were eligible for inclusion. The intervention of in-home DBS testing for household contacts was introduced at North Middlesex Trust from November 2010 to December 2011. Data on testing and vaccination uptake from GP records across the two trusts were compared between baseline (2009) and intervention (2010-2011) periods. In-home DBS service increased testing uptake for all ages (P < 0·001) with the biggest impact seen in partners, where testing increased from 30·3% during the baseline period to 96·6% during the intervention period in North Middlesex Trust. Although impact on vaccine uptake was less marked, improvements were observed for adults. The provision of nurse-led home-based DBS may be useful in areas of high prevalence.

Allele specific inactivation of insulin 1 and 2, in the mouse yolk sac, indicates imprinting.

Genomic imprinting, gene inactivation during gametogenesis, causes maternal and paternal alleles of some genes to function unequally. We examined the possibility of imprinting in insulin genes because the human insulin gene (ins) and its mouse homologue (ins2) are adjacent to the known imprinted genes, igf2 and H19, and because imprinting has been implicated in the transmission of an ins linked risk for Type I diabetes. We show, by single strand conformational polymorphism (SSCP) analysis of cDNAs from parents and progeny of interspecies mouse crosses, that insulin genes are imprinted. While both alleles of the two mouse insulin genes were active in embryonic pancreas, only paternal alleles for both genes were active in the yolk sac.

There is more to this fever than meets the eye: A case of neuroleptic malignant-like syndrome (NMLS) secondary to withdrawal of procyclidine and L-dopa on a background of long-standing flupenthixol depot use.

This case report highlights the risk of development of Neuroleptic Malignant-Like Syndrome secondary to withdrawal of procyclidine with brief withdrawal of L-dopa and long-term typical antipsychotic depot. The patient responded to reintroduction of procyclidine, sedation and supportive treatment. The mechanism and management of NMS and NMLS is also reviewed. This case emphasises that any changes in antipsychotic and antiparkinsonian medications should be undertaken with extreme caution and patient should be closely monitored for development of NMLS after alteration in these medications.

The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission.

Striking differences in Kaposi's sarcoma (KS) risk for AIDS patients who acquire HIV via homosexual activity and those whose HIV infections derive from blood product exposure suggest the presence of a sexually transmitted agent other than HIV in the development of KS. Using an immunofluorescence assay, we examined serum samples from 913 patients for the presence of antibody specific for infection by human herpesvirus 8 (HHV8), an agent whose genome is regularly found in KS tissue. The distribution of HHV8 seropositivity conforms to that expected for a sexually transmitted pathogen and tracks closely with the risk for KS development. Our data support the inference that this virus is the etiologic cofactor predicted by the epidemiology of KS.

Hospitalizations with TB, California, 2009-2017.

BACKGROUND: Hospitalization is a costly event that affects more than half of all TB patients in the United States. State-level hospitalization data are crucial in estimating the cost of TB disease and the financial impact of preventing TB.METHODS: We used California administrative hospital discharge data from 2009 to 2017 to characterize TB hospitalizations in comparison with non-neonatal, non-maternal hospitalizations. TB hospitalization was defined as a hospitalization with a TB ICD-9/10 code as the primary diagnosis. We estimated hospitalization costs in 2017 dollars from reported charges using cost-to-charge ratios.RESULTS: In comparison to persons hospitalized for other conditions, persons hospitalized for TB in 2017 were more likely to be male, of working age, and Asian/Pacific Islander. The median cost for TB hospitalizations was US$22,807 vs. US$11,568 for other hospitalizations. The median length of stay for TB hospitalizations was 12 days compared to 3 days for other hospitalizations. Medicaid was expected to pay for 50% of TB hospitalizations costing US$21,438,208.CONCLUSIONS: Societal cost estimates of TB hospitalization should be updated to reflect long hospital stays and the disproportionate burden on working age persons. This analysis enhances our understanding of the high cost of TB care and underscores the costs averted if TB cases are prevented.

Linezolid in the treatment of multidrug-resistant tuberculosis.

BACKGROUND: Linezolid is a new antibiotic with activity against Mycobacterium tuberculosis in vitro and in animal studies. Several small case series suggest that linezolid is poorly tolerated because of the side effects of anemia/thrombocytopenia and peripheral neuropathy. To characterize our clinical experience with linezolid, the California Department of Public Health Tuberculosis Control Branch's Multidrug-Resistant Tuberculosis (MDR-TB) Service reviewed cases in which the MDR-TB treatment regimens included linezolid therapy. METHODS: Record review was performed for 30 patients treated with linezolid as part of an MDR-TB regimen. Data were collected on clinical and microbiological characteristics, linezolid tolerability, and treatment outcomes. The dosage of linezolid was 600 mg daily. Vitamin B6 at a dosage of 50-100 mg daily was used to mitigate hematologic toxicity. RESULTS: During 2003-2007, 30 patients received linezolid for the treatment of MDR-TB. Patients had isolates resistant to a median of 5 drugs (range, 2-13 drugs). Of the 30 cases, 29 (97%) were pulmonary; of these 29, 21 (72%) had positive results of acid-fast bacilli smear, and 16 (55%) were cavitary. Culture conversion occurred in all pulmonary cases at a median of 7 weeks. At data censure (31 December 2008), 22 (73%) of 30 patients had successfully completed treatment. Five continued to receive treatment. There were no deaths. Three patients had a poor outcome, including 2 defaults and 1 treatment failure. Side effects occurred in 9 patients, including peripheral and optic neuropathy, anemia/thrombocytopenia, rash, and diarrhea. However, only 3 patients stopped linezolid treatment because of side effects. CONCLUSIONS: Linezolid was well tolerated, had low rates of discontinuation, and may have efficacy in the treatment of MDR-TB.

Modulation of memory processing by cholecystokinin: dependence on the vagus nerve.

Allowing mice access to food immediately after an aversive training session enhances memory retention. Cholecystokinin-octapeptide (CCK-8), which is a gastrointestinal hormone released during feeding, also enhances memory retention when administered intraperitoneally. This memory-enhancing effect of CCK-8 is blocked when the vagus nerve is cut, indicating that CCK-8 may produce its effect on memory retention by activating ascending fibers in the vagus nerve. Thus, CCK-8, a peripherally acting peptide, may mediate the memory-enhancing effects of feeding.

Memory: modification of anisomycin-induced amnesia by stimulants and depressants.

Mice were trained in a passive (foot shock)avoidance task. When administered after training, the stimulants caffeine or nicotine blocked amnesia for the task that had been produced by injections of the protein synthesis inhibitor anisomycin given prior to training. With foot shock at a higher intensity, anisomycin did not produce amnesia by itself, but the administration of the depressants chloral hydrate or sodium phenobarbital after training did cause amnesia. Stimulants and depressants did not have an appreciable influence on the overall degree of protein synthesis inhibition produced by anisomycin. The results support the hypothesis that arousal after training is an important factor in the conversion of short-term to long-term memory.

Increased tuberculosis risk among immigrants arriving in California with abnormal domestic chest radiographs.

SETTING: Tuberculosis (TB) cases in California, USA, occur predominantly among foreign-born persons, many of whom have abnormal chest radiographs (CXRs) on overseas medical examination. These persons are recommended for follow-up TB evaluation upon arrival in the United States. OBJECTIVE: To estimate the increased TB risk associated with abnormal vs. normal domestic CXRs among individuals arriving with abnormal overseas CXRs. DESIGN: Cox regression analyses of 35 633 foreign-born persons aged 15 years who arrived in California during 1999-2012 with abnormal overseas CXRs and were free of imported active TB. Domestic CXRs were conducted during post-arrival evaluation. Subsequent cases through 2014 were identified from California's TB registry. RESULTS: A total of 121 (0.3%) arrivers developed TB disease. Progression rates were respectively 63.6 (95%CI 50.8-76.4) and 25.4 (95% CI 15.7-35.2) cases/100 000 person-years among persons with abnormal and normal domestic CXRs. Relative to arrivers with normal domestic CXRs, those with abnormal domestic CXRs had an elevated disease risk during the first 4 years after immigration; this increased risk was greatest during the first year (hazard ratio 2.9, 95%CI 1.8-4.8). CONCLUSION: Among arrivers with abnormal overseas CXRs, those with abnormal CXRs upon domestic evaluation have an elevated disease risk and represent an important target group for preventive treatment.

The California Multidrug-Resistant Tuberculosis Consult Service: a partnership of state and local programs.

Background: The US Centers for Disease Control and Prevention recommend expert consultation for multi-drug-resistant tuberculosis (MDR-TB) cases. In 2002, the California MDR-TB Service was created to provide expert MDR-TB consultations. We describe the characteristics, treatment outcomes and management of patients referred to the Service. Methods: Surveillance data were used for descriptive analysis of cases, with consultation during July 2002-December 2012. Clinical consultation data and modified World Health Organization indicators were used to assess the care and management of cases, with consultation from January 2009 to December 2012. Results: Of 339 MDR-TB patients, 140 received a consultation. The proportion of patients receiving a consultation increased from 12% in 2002 to 63% in 2012. There were 24 pre-extensively drug-resistant TB and 5 patients with extensively drug-resistant TB. The majority (n = 123, 88%) completed treatment, 5 (4%) died, 7 (5%) moved before treatment completion, 4 (3%) stopped treatment due to an adverse event and 1 (1%) had an unknown outcome. Indicator data showed that 86% underwent rapid molecular drug susceptibility testing, 98% received at least four drugs to which they had known or presumed susceptibility, and 93% culture converted within 6 months. Conclusions: Consultations with the MDR-TB Service increased over time. Results highlight successful treatment and indicator outcomes.

Contexte : Les Centers for Disease Control and Prevention des Etats Unis recommandent de consulter un expert en cas de tuberculose multirésistante (TB-MDR). En 2002, le California MDR-TB Service a été créé afin de fournir une consultation d'experts en TB-MDR. Nous décrivons les caractéristiques, les résultats du traitement et la prise en charge des patients référés vers ce service.Méthode : Les données de surveillance ont été utilisées pour une analyse descriptive des cas ayant eu une consultation entre juillet 2002 et décembre 2012. Les données de consultation clinique et les indicateurs modifiés de l'Organisation Mondiale de la Santé ont été utilisés afin d'évaluer la prise en charge des cas qui ont bénéficié d'une consultation entre janvier 2009 et décembre 2012.Résultats : Sur 339 patients TB-MDR, 140 ont bénéficié d'une consultation. Cette proportion est passée de 12% en 2002 à 63% en 2012. Il y a eu 24 patients TB pré-ultrarésistante et 5 patients TB ultrarésistante. La majorité (n = 123 ; 88%) a achevé le traitement, 5 (4%) sont décédés, 7 (5%) ont déménagé avant la fin du traitement, 4 (3%) ont arrêté le traitement à cause d'un effet secondaire et 1 (1%) a eu un résultat inconnu. Les indicateurs ont montré que 86% avaient bénéficié d'un test de pharmacosensibilité moléculaire rapide, que 98% avaient reçu au moins quatre médicaments avec une sensibilité connue ou présumée et que 93% ont eu une conversion de culture dans les 6 mois.Conclusion : Les consultations au service de TB-MDR ont augmenté dans le temps. Nous avons mis en lumière les bons résultats du traitement et des indicateurs.

Marco de referencia: Los Centros para el Control y la Prevención de Enfermedades de los Estados Unidos recomiendan que se recurra a la consulta con expertos en los casos de tuberculosis multirresistente (TB-MDR). En el 2002, se creó el California MDR-TB Service en California, con el objeto de proveer consultas de expertos en la materia. En el presente estudio se describen las características, los desenlaces terapéuticos y el tratamiento de los pacientes remitidos a este servicio.Métodos: Se utilizaron los datos de la vigilancia en el análisis descriptivo de los casos que consultaron el Servicio de julio del 2002 a diciembre del 2012. A partir de la base de datos de la consulta y los indicadores modificados de la Organización Mundial de la Salud se evaluó la atención y el tratamiento de los casos que consultaron de enero del 2009 a diciembre del 2012.Resultados: De los 339 pacientes con diagnóstico de TB-MDR, 140 obtuvieron la consulta de expertos. La proporción de pacientes con una consulta aumentó de un 12% en el 2002 al 63% en el 2012. Se atendieron 24 pacientes con TB pre-ultrarresistente y cinco pacientes con TB ultrarresistente. La mayoría completó el tratamiento (n = 123; 88%), 5 pacientes fallecieron (4%), 7 se mudaron antes de haber completado el tratamiento (5%), 4 interrumpieron el tratamiento debido a una reacción adversa (3%) y se desconoció el desenlace de 1 paciente (1%). Según los datos de los indicadores, en 86% de los casos se practicaron pruebas moleculares rápidas de sensibilidad a los medicamentos, el 98% de pacientes recibió como mínimo cuatro fármacos con sensibilidad confirmada o supuesta y el 93% de los pacientes había convertido el cultivo en un lapso de 6 meses.Conclusión: Las consultas al Servicio de expertos en TB-MDR han aumentado con el transcurso del tiempo. Los resultados del estudio ponen de manifiesto la eficacia del tratamiento y revelan indicadores de evolución muy favorables.

Clinical and bacteriological characteristics associated with clustering of multidrug-resistant tuberculosis.

SETTING: The impact of the genetic characteristics of Mycobacterium tuberculosis on the clustering of multidrug-resistant tuberculosis (MDR-TB) has not been analyzed together with clinical and demographic characteristics. OBJECTIVE: To determine factors associated with genotypic clustering of MDR-TB in a community-based study. DESIGN: We measured the proportion of clustered cases among MDR-TB patients and determined the impact of clinical and demographic characteristics and that of three M. tuberculosis genetic characteristics: lineage, drug resistance-associated mutations, and rpoA and rpoC compensatory mutations. RESULTS: Of 174 patients from California and Texas included in the study, the number infected by East-Asian, Euro-American, Indo-Oceanic and East-African-Indian M. tuberculosis lineages were respectively 70 (40.2%), 69 (39.7%), 33 (19.0%) and 2 (1.1%). The most common mutations associated with isoniazid and rifampin resistance were respectively katG S315T and rpoB S531L. Potential compensatory mutations in rpoA and rpoC were found in 35 isolates (20.1%). Hispanic ethnicity (OR 26.50, 95%CI 3.73-386.80), infection with an East-Asian M. tuberculosis lineage (OR 30.00, 95%CI 4.20-462.40) and rpoB mutation S531L (OR 4.03, 95%CI 1.05-23.10) were independent factors associated with genotypic clustering. CONCLUSION: Among the bacterial factors studied, East-Asian lineage and rpoB S531L mutation were independently associated with genotypic clustering, suggesting that bacterial factors have an impact on the ability of M. tuberculosis to cause secondary cases.

Characteristics and costs of multidrug-resistant tuberculosis in-patient care in the United States, 2005-2007.

OBJECTIVE: A population-based study of 135 multidrug-resistant tuberculosis (MDR-TB) patients reported to the Centers for Disease Control and Prevention (CDC) during 2005-2007 found 73% were hospitalized. We analyzed factors associated with hospitalization. METHODS: We assessed statistically significant multivariable associations with US in-patient TB diagnosis, frequency of hospitalization, length of hospital stay, and in-patient direct costs to the health care system. RESULTS: Of 98 hospitalized patients, 83 (85%) were foreign-born. Blacks, diabetics, or smokers were more likely, and patients with disseminated disease less likely, to receive their TB diagnosis while hospitalized. Patients aged ⩾65 years, those with the acquired immune-deficiency syndrome (AIDS), or with private insurance, were hospitalized more frequently. Excluding deaths, length of stay was greater for patients aged ⩾65 years, those with extensively drug-resistant TB (XDR-TB), those residing in Texas, those with AIDS, those who were unemployed, or those who had TB resistant to all first-line medications vs. others. Average hospitalization cost per XDR-TB patient (US$285 000) was 3.5 times that per MDR-TB patient (US$81 000), in 2010 dollars. Hospitalization episode costs for MDR-TB rank third highest and those for XDR-TB highest among the principal diagnoses. CONCLUSIONS: Hospitalization was common and remains a critical care component for patients who were older, had comorbidities, or required complex management due to XDR-TB. MDR-TB in-patient costs are among the highest for any disease.

Characteristics of learning and memory in streptozocin-induced diabetic mice.

We demonstrated that mice with streptozocin-induced diabetes mellitus have normal acquisition for relatively simple tasks but show problems in learning more complex tasks such as shuttle box avoidance. Enhanced learning previously reported in simple passive avoidance tasks appears to be due to increased foot shock sensitivity. Diabetic mice show a marked memory retention deficit after learning an active avoidance T-maze task. This retention deficit was reversed by a single injection of insulin, suggesting that it may be related to hyperglycemia per se. Diabetic mice have a shift to the left in the inverted U-shaped dose-response curve for memory retention produced by the acetylcholine agonist arecoline. Based on a preliminary screening, responses to several other pharmacological memory enhancers are probably altered in diabetic mice. These studies suggest that this mouse model of diabetes mellitus demonstrates a deficit in memory retention and retrieval similar to that seen in humans with diabetes mellitus.

Investigation of human contacts: a Mycobacterium bovis outbreak among cattle at a California dairy.

BACKGROUND: In May 2002, a Mycobacterium bovis outbreak occurred among cattle at a California dairy. We investigated to determine whether persons were infected after working with the cattle or drinking their raw milk. METHODS: We identified persons with potential contact with infected cattle, including dairy workers, their family members, and slaughterhouse workers. Persons were given a tuberculin skin test (TST), and their occupational and milk-drinking habits were recorded. RESULTS: Of 88 potential contacts, 78 (90%) were given a TST; 33 (43%) had positive TST results, of whom 32 were Mexican-born (RR 15.8, 95%CI 2.3-108.8). No persons had active tuberculosis. Eighteen (72%) dairy workers, 11 (27%) family members, and four (33%) slaughterhouse workers had positive TST results. After adjusting for Mexican-birth and age, dairy workers were no more likely to have positive TST results than others (adjusted RR 1.2, 95%CI 0.6-2.1). Forty-one (62%) dairy staff and their family members drank raw milk from the dairy; 21 (51%) had positive TST results and were Mexican-born. All 13 US-born raw milk drinkers had negative TST results. CONCLUSION: A high prevalence of positive TST results was documented among workers at the affected dairy, although results were not independently associated with contact with infected cattle or milk products. Further assessment of California dairy workers should be considered.

Erythromycin-induced clozapine toxic reaction.

Clozapine, used in the treatment of patients with schizophrenia resistant to other neuroleptic medication, is metabolized by the hepatic microsomal system to demethyl-clozapine and clozapine-N-oxide. Changes in clozapine serum concentrations have been documented after initiation of therapy with medications known to induce or inhibit liver microsomal enzymes. These interactions are of clinical importance when diminished efficacy or increased toxic effects of clozapine therapy occur. A 34-year-old schizophrenic man had increased clozapine serum concentrations, leukocytosis, and adverse effects as a result of concomitant erythromycin therapy given for suspected lower respiratory tract infection. Symptoms included somnolence, difficulty in coordination and ambulation, slurred speech, disorientation, and incontinence. The symptoms resolved after treatment with clozapine and erythromycin were discontinued, and treatment with clozapine was gradually resumed.

Learning and memory in the SAMP8 mouse.

The SAMP8 (P8) mouse strain develops deficits in learning and memory relatively early in its lifespan. This review provides an overview of the age-related changes that occur in P8 mice. Behavioral studies with P8 mice show impaired acquisition and retention as early as 4 months of age. Deficits in acquisition and retention occur with both aversive and appetitive training tasks. Anatomical studies have detected a number of age-related changes that occur in the central nervous system of P8 mice. The age-related increase in amyloid beta protein is well correlated with the age-related decline in learning and memory. Antibody to amyloid beta protein injected prior to training alleviated impaired acquisition and retention, whereas post-training injections alleviated retention deficits in older P8 mice. Biochemical studies have detected numerous age-related changes with reduced NMDA receptor activity most closely related to impaired learning and memory in P8 mice. Pharmacological studies have found age-related functional changes in the ability of drugs to improve memory processing in P8 mice in the septum and the hippocampus. The specific pattern of pharmacological changes and the inferred change in neurotransmitter activity suggest that age-related impairment in memory processing may be due to impaired septohippocampal interactions. The proposal that P8 mice may be a useful model for studying the early phases of age-related dementia of the Alzheimer type, while still requiring considerable study, seems reasonable.

Age-related changes in footshock avoidance acquisition and retention in senescence accelerated mouse (SAM).

An inbred strain has been developed which exhibits some characteristics of aging in mice as young 6 months of age. The strain was designated "Senescence Accelerated Mouse" (SAM). A subline of the SAM strain, P/8, has an early onset of impaired learning in appetitive and aversive training tasks. Simple aversive and appetitive tasks were learned normally up to 12 months of age, whereas more difficult tasks detected impairment as early as 6 months of age while the mice still had good general health. Comparable impairment of learning and memory in C57BL/6Nnia mice was not detected until about 24 months of age which is near the end of the strain's lifespan when general health declines. In the present study, we report age-dependent impairment of acquisition and retention for footshock avoidance conditioning. Long-term (1 week) but not short-term (1 h) retention was adversely effected by aging. In 12-month-old P/8 mice, practicing the avoidance response (overtraining) did not alleviate the impairment of long-term memory processing.

Effect of acute arecoline, tacrine and arecoline + tacrine post-training administration on retention in old mice.

The amnesias characteristic of Alzheimer's disease and other age-related dementias are refractory to conventional pharmacotherapy. A recent treatment strategy is to combine drugs to improve their memory enhancing effect. We previously reported that in young weakly trained mice, the combination of arecoline and tacrine was more effective on a mg/kg basis than either drug administered alone. This was true whether the route of administration was intracerebroventricular, subcutaneous or oral. We now report that 24 month old mice trained to avoid footshock in a T-maze show poor retention when tested one week later. Subcutaneous administration of arecoline, tacrine (also referred to as tetrahydroaminoacridine, THA) and arecoline plus tacrine administered immediately after T-maze footshock avoidance training enhanced retention of 24 month old mice compared to the saline-injected control. Since the combination was as effective as the single drug treatments even though 96% less arecoline and 99.7% less tacrine was administered, the combination showed marked potentiation of drug action of memory processing.