WHO target product profiles for TB preventive treatment.

BACKGROUND: The WHO has developed target product profiles (TPPs) describing the most appropriate qualities for future TPT regimens to assist developers in aligning the characteristics of new treatments with programmatic requirements.METHODS: A technical consultation group was convened by the WHO to determine regimen attributes with greatest potential impact for patients (i.e., improved risk/benefit profile) and populations (i.e., reduction in transmission and TB prevalence). The group categorised regimen attributes as 'priority´ or 'desirable´; and defined for each attribute the minimum requirements and optimal targets.RESULTS: Nine priority attributes were defined, including efficacy, treatment duration, safety, drug-drug interactions, barrier to emergence of drug resistance, target population, formulation, dosage, frequency and route of administration, stability and shelf life. Regimens meeting optimal targets were characterised, for example, as having superior efficacy, treatment duration of ≤2 weeks, and improved tolerability and safety profile compared with current regimens. The four desirable attributes included regimen cost, safety in special populations, treatment adherence and need for drug susceptibility testing in the index patient.DISCUSSION: It may be difficult for a single regimen to satisfy all characteristics so regimen developers may have to consider trade-offs. Additional operational aspects may be relevant to the feasibility and public health impact of new TPT regimens.

Interventions to reduce losses in the cascade of care for latent tuberculosis: a systematic review and meta-analysis.

BACKGROUND: Losses can occur throughout the latent tuberculosis infection (LTBI) cascade of care. This can result in suboptimal rates of effective treatment for LTBI. We conducted a systematic review and meta-analysis to estimate the effect of different interventions to reduce losses in the LTBI cascade before treatment completion.METHODS: We searched several databases for articles reporting outcomes for interventions designed to strengthen the LTBI cascade. We included papers published in English from January 1990 until February 2018. Where possible, estimates were pooled using random-effects meta-analysis.RESULTS: We identified 30 studies that evaluated 32 different interventions aimed at reducing losses in the LTBI cascade. In pooled analysis, interventions that improved completion of cascade steps included patient incentives (respectively 42 [95% CI 34-51] and 48 [95% CI 15-81] additional patients completing initial assessment and medical evaluation per 100 starting); health care worker education (28 [95% CI 4-52] additional patients initiating initial assessment per 100 identified; home visits (additional 13 [95% CI 4-21] patients completing initial assessment per 100 starting); digital solutions (additional 11 [95% CI 4-21] patients initiating initial assessment per 100 identified); and patient reminders (additional 7 [95% CI 0.3-13] patients completing initial assessment per 100 starting). Several other interventions reduced losses at specific cascade steps, but evidence for these interventions came from single studies and could not be pooled.CONCLUSIONS: Although there is limited evidence that any single intervention significantly improves the LTBI cascade, many studies provide information about effective ways to strengthen it.

Management practices associated with stress in cattle on western Canadian cow-calf operations: A mixed methods study.

Handling, weaning, and euthanasia are some of the most stressful practices performed on cow-calf operations. Although strategies to minimize stress exist, their use on western Canadian cow-calf operations is unknown. The objectives were to describe current stress-associated practices on western Canadian cow-calf operations, describe producer and operation demographics associated with the use of nonabrupt weaning methods, and explore producer perceptions toward these practices. A questionnaire focusing on stressful management practices was delivered to 109 cow-calf producers in western Canada. Fifteen respondents were purposively selected for individual interviews. The majority of producers reported calves less than 1 wk of age were handled by manual restraint (87%) and those older than 1 wk of age were handled using a cattle squeeze or table. Most producers performed abrupt weaning (70%). Interviewees often mentioned that cost and logistics were major factors in deciding on a weaning strategy. Pasture availability and facilities were viewed as constraints toward the adoption of a nonabrupt weaning method. Animal stress was considered, as producers expressed concern that nonabrupt weaning methods may cause increased stress because of the additional handling required. Producers conveyed that animal age was a major factor that impacted weaning stress and that improved animal performance might motivate them to adopt a nonabrupt weaning strategy. Producers also expressed reluctance to change previously successful traditional approaches. Of respondents, 13% did not euthanize cattle on farm and 8% did not confirm death. Producers interviewed reported that the decision to euthanize cattle on farm was difficult and that veterinary advice was often considered. Factors that influenced their decision to euthanize included the animal's likelihood of recovery and degree of pain and distress. Finally, producers explained that they considered whether the animal was salvageable and able to be transported. Identification of common methods of handling provides focus for future research to determine optimal handling strategies. Identified barriers to nonabrupt weaning may be addressed through research, extension, or policy to encourage the adoption of weaning methods that could improve animal welfare. Confirmation of death after euthanasia was identified as an area that needs to be addressed by producer education to minimize animal stress during on-farm euthanasia.

Management practices associated with pain in cattle on western Canadian cow-calf operations: A mixed methods study.

The implementation of on-farm pain mitigation strategies is dependent on feasibility and importance to producers. Currently, there is a lack of information regarding adoption of management practices associated with pain in cattle within the Canadian beef industry. The objective of this mixed methods study was to describe pain-associated practices implemented on farm and producer perceptions toward pain mitigation strategies. A questionnaire about calving management and calf processing was delivered to 109 cow-calf producers in western Canada. In addition, 15 respondents were purposively selected based on questionnaire responses to participate in individual semistructured, on-farm interviews. The prevalence of pain mitigation strategies used for dystocia and cesarean section by respondents were 46 and 100%, respectively. The majority of operations reported castrating and dehorning calves before 3 mo of age (95 and 89%, respectively). The majority of operations did not use pain mitigation strategies for castration and dehorning (90 and 85%, respectively). Branding was practiced by 57% of respondents, 4% of which used pain mitigation. Thematic content analysis revealed that producers' perception of pain were influenced by what they referred to as "common sense," relatability to cattle, visual evidence of pain, and age of the animal. Factors that influenced participant rationale for the implementation of pain mitigation practices included access to information and resources, age of the animal, benefit to the operation, cost and logistics, market demands, and personal conscience. Overall, management practices were generally in compliance with published Canadian guidelines. Results of this study may provide direction for future policy making, research, and extension efforts to encourage the adoption of pain mitigation strategies.

Latent tuberculosis diagnostic tests to predict longitudinal tuberculosis during dialysis: a meta-analysis.

SETTING: Tuberculosis (TB) rates in dialysis patients are more than 10 times greater than in the general population. Recent recommendations advise the use of interferon-gamma release assays (IGRAs) over the tuberculin skin test (TST) to aid in the diagnosis of latent tuberculous infection (LTBI); however, their longitudinal predictive ability for TB development has not been assessed. OBJECTIVE: To determine whether the TST or IGRA are able to predict longitudinal TB development in dialysis patients. DESIGN: We performed a systematic review to determine the longitudinal risk of TB in dialysis patients. Random-effects meta-analysis was used to determine the incidence rate ratio (IRR) of longitudinal TB development and the predictive value of such tests. RESULTS: Eight studies were included. An IRR of 2.59 (95%CI 1.20-5.57) for longitudinal TB was seen in patients with a TST ⩾ 10 mm compared to patients with a TST < 10 mm. The positive predictive value (PPV) of a TST ⩾ 10 mm was 11.93% and the negative predictive value was 94.03%. We were unable to analyse the studies that used IGRAs, as only one study had TB events. CONCLUSION: A TST with a 10 mm cut-off point appears to offer the capability to distinguish long-term risk of TB, with a modest PPV. The predictive value of IGRAs could not be quantified.

Therapeutic drug monitoring in anti-tuberculosis treatment: a systematic review and meta-analysis.

BACKGROUND: Therapeutic drug monitoring (TDM) may improve tuberculosis (TB) treatment outcomes, but there is little evidence to guide TDM in clinical practice. DESIGN: We performed a systematic review and meta-analysis to summarise existing literature on TDM in first-line drugs. RESULTS: We identified 41 studies that reported 2 h post-dose drug concentrations (C2h) for first-line drugs and 12 studies that reported clinical outcomes. We pooled data by study quality, design, region, dosing modality and patient characteristics. The pooled proportion of subjects with low isoniazid C2h was 0.43 (95%CI 0.32-0.55), 0.67 (95%CI 0.60-0.74) had low rifampicin C2h, 0.27 (95%CI 0.17-0.38) had low ethambutol C2h, and 0.12 (95%CI 0.07-0.19) had low pyrazinamide C2h. Patients with diabetes had a non-significant increase in the proportion of subjects with low C2h levels across all four drugs. Only three of 12 studies that examined clinical outcomes demonstrated an association between low C2h and unsuccessful treatment outcomes. CONCLUSION: Across a wide variety of studies, a high proportion of patients undergoing first-line anti-tuberculosis treatment had 2 h drug concentrations below the accepted normal threshold. These findings point to a discrepancy between accepted 2 h TDM thresholds and TB drug dosing recommendations.

Distinguishing true coagulase-negative Staphylococcus infections from contaminants in the neonatal intensive care unit.

OBJECTIVE: To characterize true coagulase-negative Staphylococcus (CoNS) infections in infants receiving neonatal intensive care. STUDY DESIGN: Retrospective cohort study of neonatal intensive care unit (NICU) infants with clinical sepsis and CoNS isolated from ≥ 2 blood cultures (BCs) or one BC and a sterile site (proved infection) or CoNS isolated from one BC and deemed significant after blinded data review (probable infection). RESULT: In all, 98% of 40 proved and 96% of 55 probable infections occurred in infants with birth weight (BW) <2000 g and gestation <34 weeks. Total central lines (CLs) placed, but not CL duration or presence in situ, predicted proved (odds ratio (OR) 3.5, 95% confidence interval (CI) 1.4 to 8.3; P=0.005) and probable infection (OR 2.7, 95% CI 1.3 to 5.6; P=0.007) by multivariate analysis as did lethargy and gastric residuals. CONCLUSION: True CoNS infection is unlikely in infants with BW >2000 g and gestation >34 weeks. Total CL required for care, lethargy and gastric residuals predicted true CoNS infection.

Agreement between three serological tests for Neospora caninum in beef cattle.

During 1999, serum samples were collected from beef cows on pastures in western Canada. Some of the herds had a history of confirmed abortions associated with Neospora caninum infection. All these samples were initially analyzed using a single application of 1 common commercial enzyme-linked immunosorbent assay (ELISA) for antibodies to N. caninum. From these initial results, 239 positive and 250 negative samples were randomly selected for further testing. This group of samples was retested using the 3 commercially available ELISA tests for N. caninum as per the manufacturer's recommendations. The agreement between 2 of the ELISAs was good (K = 0.76); agreement of these 2 tests with the third test was much lower (K = 0.46 and 0.60). Quantitative agreement between tests measured by intraclass correlation coefficients was also acceptable between the first 2 tests but was almost zero when the first 2 tests were compared with the third. This information is necessary to understand the differences in seroprevalence reported in different regions from laboratories using different methods.

Prevalence of enterotoxigenic Escherichia coli (ETEC) in hospitalized acute diarrhea patients in Denpasar, Bali, Indonesia.

The relationship between enterotoxigenic Escherichia coli (ETEC) and hospitalized patients with acute diarrhea was examined in a study conducted in two hospitals from June 2000 to May 2001 in Denpasar, Bali, Indonesia. A total of 489 hospitalized patients with acute diarrhea were enrolled, and their rectal swabs were screened for enteric bacterial pathogens. Toxins, colonization factor antigens (CFAs), in vitro antimicrobial susceptibility and seasonal distribution patterns associated with ETEC were ascertained. The diagnosis of ETEC infection and CFAs association were performed with GM-1 ELISA and Dot blot immunoassays. Enterotoxigenic Escherichia coli was isolated from the rectal swabs of 14.9% of the patients. The distribution of toxins among the ETEC strains found was ST in 51 (69.9%), while LT and ST/LT were found in 28.8% and 1.3% respectively. The highest isolation rate for ETEC was found among children between the ages of 1 and 15 years. Colonization factor antigens were identified in 28.8% of the ETEC strains. A high prevalence of CFA was found among the rectal swabs of patients with ST isolates. High frequency of resistance to ampicillin, trimethoprim/sulfamethoxazole, chloramphenicol, tetracycline and cephalothin was displayed among the ETEC strains. All ETEC strains were susceptible to norfloxacin, ciprofloxacin and nalidixic acid. The results of this study document the prevalence of ETEC in hospitalized patients with acute diarrhea in Denpasar, Bali, Indonesia. Data generated in this study depicts the prevalence of ETEC diarrhea and CFA types among diarrhea patients in the tourist city of Denpasar, Bali, Indonesia.

First documented outbreak of hepatitis E virus transmission in Java, Indonesia.

A suspected hepatitis outbreak occurred in Bondowoso District, East Java Province, Indonesia, in March-May 1998. An investigation was initiated in April 1998, involving a retrospective review of hospital records, a community-based cross-sectional study, and a health service-based case detection and household follow-up. Sera and epidemiological information were collected from 962 individuals: 235 from 3 outbreak-affected communities along the same rural stretch of river, 101 from community controls living distant from the river, 151 cases detected in health centres, 141 family members of the cases, and 334 subjects from neighbouring families. The prevalence of acute hepatitis E virus (HEV), based on anti-HEV IgM, total antibody (Ig) to HEV and polymerase chain reaction (PCR), was significantly (P < 0.00001) higher (52.4%) among the outbreak communities than among the community controls (3%). The background prevalence of HEV, based on anti-HEV IgG, was also significantly (P < 0.00001) higher (47%) among the outbreak communities than among the community controls (3%). None of the 476 sera screened for anti-HAV (hepatitis A virus) IgM was positive. These results indicate that HEV was the aetiological agent responsible for the outbreak. The overall attack rate (AR) for the 3 outbreak-affected communities surveyed was 19%, with AR determined on the basis of clinically recognized, acute jaundice illness. The usage of river water as primary source for bathing, human-waste disposal, and drinking purposes differed significantly (P < 0.00001) between the communities in outbreak areas and those in non-outbreak areas. There is no significant influence attributed to 'boiling water' on acute HEV. No climatic influences (flooding or drought) predisposed this instance of epidemic HEV transmission. This outbreak represents the first documented evidence of epidemic HEV transmission in Java, Indonesia.

Characterization of Norwalk-like virus associated with gastroenteritis in Indonesia.

Norwalk Virus and Norwalk-like viruses (NLVs) are reportedly responsible for 2.5-4.0% of nonbacterial acute gastroenteritis (NBAG) worldwide. To help clarify the impact of NLVs on NBAG in Indonesia, stool specimens from 102 patients, 74 with NBAG and 28 with BAG, were screened for the presence of NLVs, using a reverse transcription-polymerase chain reaction (RT-PCR) assay. The specimens were subtyped using prototype-specific oligonucleotide probes and were sequenced and compared with published NLV sequences. Of the 102 specimens examined, 31 (30%) were found to be positive for NLVs. Type-specific probe analysis of the RT-PCR products indicated that 31 isolates hybridized to UK1 (Taunton agent) and UK3/4 (Hawaii agent/Snow Mountain agent) prototype strains. The results of this study indicate that prototype strains of NV or NLVs co-circulate in Indonesia and contribute to the overall level of acute gastroenteritis throughout the region.

Incidence of Norwalk-like viruses, rotavirus and adenovirus infection in patients with acute gastroenteritis in Jakarta, Indonesia.

Norwalk-like viruses (NLVs), rotavirus and adenovirus are reportedly responsible from 4 to 42% of non-bacterial acute sporadic gastroenteritis. The incidence of NLVs, adenovirus and rotavirus infections in Indonesia is unclear. A total of 402 symptomatic cases from Indonesian patients with acute gastroenteritis and 102 asymptomatic controls that tested negative for bacteria and parasites were screened for the presence of NLVs, rotavirus and adenovirus using the reverse transcriptase-polymerase chain reaction (RT-PCR), Rotaclone kits and Adenoclone kits. Specific prototype probes were used to ascertain which NLV prototypes were present in the area. NLVs were detected in 45/218 (21%), rotavirus was detected in 170/402 (42%) and adenovirus was detected in 11/273 (4%) samples examined. Genetic analysis of the RT-PCR products using specific prototype probes for NLVs indicated that the prototypes were 42% Taunton agent and 58% Hawaii/Snow Mountain agent. Comparative data on patients showed that the incidence of rotavirus infections was two times greater than the NLVs infections, and that adenovirus infections were the least prevalent. All of the control samples tested were negative for NLVs and adenoviruses, however 8/70 (11%) of the samples were positive for rotaviruses. The high incidence of enteric viral-related infections is a threat among acute diarrheic patients in Jakarta, Indonesia.

Experimental infection of Macaca nemestrina with a Toronto Norwalk-like virus of epidemic viral gastroenteritis.

Norwalk virus (NV) and Norwalk-like viruses (NLVs) are common etiologic agents of viral gastroenteritis. Viral gastroenteritis is a common disease that is highly transmissible, spreading rapidly through families, institutions, and communities. Because methods for in vitro cultivation of Norwalk etiologic agents are not available, information regarding this syndrome has come largely from studies in human volunteers. Sequential passaging of an NLV through an immunoincompetent newborn pigtail macaque (Macaca nemestrina) may allow for the adaptation of a human NLV to a primate host, thus providing an animal model for investigating this disease. A fecal filtrate of human origin containing NLV, Toronto virus P2-A, was obtained from a patient during an epidemic of viral gastroenteritis. The filtrate was administered via nasogastric tube to three newborn pigtailed macaques. Clinical illness, which was characterized by diarrhea, dehydration, and vomiting, occurred in three monkeys. Reverse transcription-polymerase chain reaction (RT-PCR) and oligonucleotide probe analysis of RNA extracted from the stool samples following infection revealed viral RNA in all inoculated monkeys. Infection was also transmitted experimentally by feeding two additional newborn macaques a fecal filtrate prepared from the three previously infected animals. Detection of viral RNA in the stools of animals that received the fecal filtrate indicates that viral replication occurred in association with clinical illness. The susceptibility of Macaca nemestrina to infection with a Norwalk-like agent will facilitate the study of the mechanisms of the pathogenesis of NLV. This system may also have the potential to serve as a vaccine test model for human epidemic viral gastroenteritis.

Semantic features of an enterprise interface terminology for SNOMED RT.

OBJECTIVE: To evaluate the utility of SNOMED RT in support of a natural language interface for encoding of clinical assessments. METHOD: Using a random sample of clinical terms from the UNMC Lexicon, I mapped the terminology into canonical data entries using SNOMED RT. Working from the source term language, I evaluated lexical mapping to the SNOMED term set, and the function of the SNOMED RT semantic network in support of a language-based clinical coding interface. RESULTS: Ambiguity in the source terms was low at 0.3%. Lexical (language-based) mapping could account for only 48.8% of meaning from the source terms. The RT semantic network accounted for 39.5% of meaning, and supplementing the lexical map this led to 80.2% capture of source content. Error rates in the segment of RT which I reviewed were low at 0.6%. 97.6% of source content could be accurately captured in SNOMED RT. CONCLUSION: SNOMED RT supported an accurate and reliable representation of clinical assessment data in this sample. The semantic network of RT substantially enhanced the encoding of concepts relative to lexical mapping. However these data suggest that natural language encoding with SNOMED RT in an enterprise environment is unlikely at this time.

Toxins and colonization factor antigens of enterotoxigenic Escherichia coli among residents of Jakarta, Indonesia.

Infection caused by enterotoxigenic Escherichia coli (ETEC) poses a serious health problem among children and adults in developing countries. Colonization of the small intestinal mucosa by ETEC strains is mediated by antigenically specific fimbriae, also known as colonization factor antigens (CFA). The significance of this study arises from reports that active and passive immunization with ETEC strains harboring CFAs has previously been shown to induce protective immunity against diarrhea in animal models. The aim of this study was to determine toxin-associated CFAs of ETEC isolated from a diarrheal disease case-control study in Jakarta, Indonesia. Thirteen hundred and twenty-three diarrheic and control patients with lactose-fermenting colonies were screened by ganglioside GM1-enzyme-linked immunosorbent assay (GM1-ELISA) for heat-labile (LT) and heat-stable (ST) toxins. Two hundred and forty-six (19%) ETEC isolates identified by GM1-ELISA for the LT/ST toxins were screened for CFAs by Dot blot assay using monoclonal antibodies against CFA/I, II, and IV and against the putative colonization antigens (PCF) PCFO159, PCFO166, CS7, and CS17. Of the 246 ETEC isolates, 177 (72%) elaborated ST, 56 (23%) produced LT, while 13 (5%) elicited both the ST and LT toxins. CFA testing of the 246 ETEC isolates showed that 21 (8%) expressed CFA/I, 3 (1%) exhibited CFA/II, 14 (6%) elaborated CFA/IV, while 7 (3%) expressed PCFO159 and PCFO159 plus CS5. No CFAs or PCFs could be associated with 201 (82%) of the ETEC strains. This report documents the types of CFAs associated with ETEC strains in Jakarta, Indonesia. These data may help current research efforts on the development of CFA-based vaccines for humans against ETEC and provide additional information for future ETEC vaccine trials in Southeast Asia.

Allergic response to metabisulfite in lidocaine anesthetic solution.

True allergies to local anesthetics are rare. It is common for practitioners to misdiagnose a serious adverse event to local anesthetics as an allergic reaction. The most likely causes for an allergic response are the preservative, antioxidant, or metabolites and not the anesthetic itself. This case report illustrates the need for practitioners to understand the many potential allergens in local anesthetics and to correctly diagnose patients that are truly allergic to the local anesthetic.