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.

Antibody-mediated killing of suppressor T lymphocytes as a possible cause of macroglobulinemia in the tropical splenomegaly syndrome.

To investigate the pathogenesis of macroglobulinemia in the tropical splenomegaly syndrome (TSS), we assessed the functional activity of B lymphocytes and T cell subsets in a pokeweed mitogen-driven assay of immunoglobulin synthesis. Mononuclear cells from patients with TSS produced more IgM than cells from village or from distant controls. This appeared to result from a decrease in the number and/or activity of suppressor T cells of the T8+ phenotype. The lack of functional suppressor T lymphocytes was associated with the presence in sera from patients with TSS of IgM antibodies that specifically killed T8+, 9.3-, 60.1+ T cells from normal donors. These results support the hypothesis that macroglobulinemia in TSS results from defective immunoregulatory control of B cell function, and that this may be caused by lysis of suppressor T cells by specific lymphocytotoxic antibodies produced by patients with this syndrome.

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.

Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: a report from the Childrens Cancer Study Group.

The Childrens Cancer Study Group (CCSG) undertook a study (CCG-823F) to test the feasibility of administering continuous infusion doxorubicin (CI DOX) and cisplatin (CDDP) in patients with unresectable or incompletely resected hepatoblastoma (HB) or hepatocellular carcinoma (HCC). Chemotherapy consisted of CI DOX 20 mg/m2/d for days 1 to 4 and CDDP 100 mg/m2 on day 1 followed by a 21-day rest period. Second-look surgery was performed after the administration of four chemotherapy courses. Forty-seven (47) assessable patients were entered on study, 33 with HB and 14 with HCC; of these, 34 (26 HB and eight HCC) completed the initial four courses of chemotherapy. Of the 26 HB patients, 25 were evaluated as responding to chemotherapy before the scheduled second-look procedure and were considered surgically resectable at that time. Surgery was performed on 22 patients; three patients refused the second-look surgery. Nine patients had no evidence of residual malignant disease, seven underwent surgical resection of remaining tumor, four were left with microscopic residual disease, one had a partial resection with gross tumor left behind, and one remained unresectable. Nine HCC patients completed four chemotherapy courses. Eight patients achieved a partial remission and second-look surgery was attempted on seven. Only two had all malignant disease removed at the second procedure. Data from 225 courses of chemotherapy were evaluated for toxicity. Neutropenia (absolute granulocyte count less than 500/mL) was observed in 68 courses, and five of these episodes were associated with sepsis. Severe mucositis was documented in 21 courses, and hypomagnesemia (magnesium less than 1.2 mg) was noted in 30 patients. Two patients developed decreased left ventricular shortening fraction, which resolved when chemotherapy was discontinued. In summary, CI DOX plus CDDP is a well-tolerated and effective regimen in inducing surgical resectability in HB patients who are unresectable at diagnosis and significantly improves survival for this group of patients to 66.6%.

Computerized medical records and preventive health care: success depends on many factors.

OBJECTIVE: To study the effect of a computerized medical record and other practice factors on the delivery of preventive health care. DESIGN: Prospective, controlled trial. SETTING: University general internal medicine teaching clinic. PARTICIPANTS: Forty-five internal medicine residents and their 4 supervising attending physicians. INTERVENTION: The study group used a computerized ambulatory medical record system that included health care maintenance reminders. The control group used a conventional paper record with a health care maintenance flow sheet. MEASUREMENTS AND MAIN RESULTS: The computer reminders significantly increased health care maintenance recommendations made to patients for proctosigmoidoscopy, tetanus vaccination, influenza vaccination, and pneumococcal vaccination, but not for fecal occult blood testing, mammography, Pap smears, or serum thyroxine screening in the elderly. First-year residents were nearly twice as successful as third-year residents in overall health care maintenance. Success scores varied markedly depending on which attending physician was supervising the residents. We found a strong interaction among group assignment, supervising attending, and level of training such that the reminders doubled success scores among first-year residents supervised by two of the attending physicians but had little effect on other subgroups. The time of year and the format of the reminder also had important effects for some of the maneuvers. CONCLUSIONS: Although computerized medical records markedly improved the performance of prevention maneuvers by committed physicians, many physicians using computer systems failed to make use of the resource. The reasons for this were complex. Future work in this area should carefully control for personal behaviors and focus upon administrative changes that more effectively implement these potentially powerful tools.

Non-sequence-specific antimalarial activity of oligodeoxynucleotides.

The effects of exogenously applied oligodeoxynucleotides on Plasmodium falciparum proliferation was investigated. A fluorescence-activated cell sorter assay was employed to measure parasitemia after administration of either phosphodiester or phosphorothioate oligodeoxynucleotides. We report sequence-independent antimalarial activity preferentially with phosphorothioate congeners with IC50 values in the 1-2 microM range. Phosphorothioate oligodeoxynucleotides which were antisense, sense or nonsense to Plasmodium mRNA, as well as homopolymers (30-mers containing all A or T bases) were equally effective inhibitors of parasitemia. The antimalarial activity was dependent upon oligomer length, concentration, and time of addition to the cultures but was independent of the parasite strain tested. Four P. falciparum strains, including a multi-drug-resistant strain (MDR-K), a drug-sensitive strain (FCR-3), a erythrocyte membrane sialic acid-independent strain (7G8) and a strain isolated from a cerebral malaria patient (CM-87) were equally susceptible to treatment with a phosphorothioate oligomer. Inhibition of red cell invasion is primarily responsible for the observed decrease in proliferation as determined by a study of parasite maturation in the presence of a 30-mer nonsense phosphorothioate oligodeoxynucleotide.

Intrauterine torsion of an intra-abdominal testis.

Intra-abdominal torsion of an undescended testis is a rare surgical problem in the neonate. However, one must consider the possibility of intrauterine torsion in a neonate who presents with an undescended testis and an abdominal mass.

Congenital posterolateral defect in the right side of the diaphragm.

The infant born with a posterolateral defect in the right side of the diaphragm may appear normal at birth. His abdominal viscera may be normally located; the right side of the diaphragm may seem to be intact. Later, part of the liver may herniate. As it does, it displaces the lower part of the right lung, and hepatic flexure follows into a high posterior position in the right upper quadrant of the abdomen. Rarely, obstruction of portal and hepatic venous flow at the hernial ring may cause liquid to accumulate in the right side of the chest. At any time the liver may resume its interrupted passage. Increase in herniation will quickly make the patient sicker.

Blood lead screening practices among US pediatricians.

OBJECTIVE: In 1991, the Centers for Disease Control and Prevention (CDC) decreased the blood lead level of concern to 10 micrograms/dL (0.48 mumol/L) and recommended universal screening. Because these guidelines continue to provoke controversy, we conducted a study to: 1) estimate the proportion of pediatricians who are members of the American Academy of Pediatrics (AAP) who report screening for elevated blood lead levels; 2) describe their clinical practices regarding screening for elevated blood lead levels; 3) compare attitudes of universal screeners, selective screeners, and nonscreeners; and 4) identify characteristics of pediatricians who universally screen. DESIGN: Confidential, cross-sectional survey of a nationally representative random sample of 1610 pediatricians conducted through the AAP Periodic Survey. SUBJECTS: The study included 1035 responders (64% response rate). Analysis was limited to the 734 pediatricians who provide well-child care (ie, primary-care pediatricians). RESULTS: Fifty-three percent of pediatricians reported screening all their patients aged 9 to 36 months, 39% reported screening some, and 8% reported screening none. Among those who screen, 96% use a blood lead assay. The primary risk factors for which selective screeners screen are: history of pica (94%); living in an older home with recent renovations (92%); living in an older home with peeling paint (93%); and having a sibling who had an elevated blood lead level (88%). Among primary-care pediatricians, 73% agree that blood lead levels > or = 10 micrograms/dL should be considered elevated, and 16% disagree. However, 89% of primary-care pediatricians believe that epidemiologic studies should be performed to determine which communities have high proportions of children with elevated blood lead levels, and 34% of primary-care pediatricians believe that the costs of screening exceed the benefits. CONCLUSIONS: Three years after the Centers for Disease Control and Prevention issued new guidelines for the management of elevated blood lead levels, a slight majority of primary-care pediatricians in the United States who are members of the AAP report that they universally screen their appropriately aged patients, while most of the remaining pediatricians report screening high-risk patients. Many pediatricians may want additional guidance about circumstances under which selective screening should be considered.

Predicting the outcome of the CaNa2EDTA challenge test in children with moderately elevated blood lead levels.

The Centers for Disease Control and Prevention suggests the challenge test for children whose blood lead levels are 1.21-2.12 micromol/L (25-44 microg/dL). However, the challenge test is difficult to perform. By identifying children who are likely to have a negative challenge test, a medical provider can minimize the number of children undergoing this test. The goal of this study was to identify common tests that are likely to predict the outcome of the challenge test. It was conducted as a clinical descriptive study from a series of patients who underwent a CaNa2EDTA challenge test. Results from 178 challenge tests were eligible for analysis. The mean age of children undergoing the challenge test was 38.2 months, and the mean blood lead level was 1.83 micromol/L (38 microg/dL). Blood lead level, age, erythrocyte protoporphyrin level, and RATE (a measure of the rate of change of the blood lead level) were either not sensitive or not specific in predicting the outcome of a challenge test. However, based on a logistic regression model using blood lead level, age, and RATE, we determined criteria that would have identified all children who would have had a positive challenge test while excluding most children who would have had a negative challenge test. Based on this model, we recommend that the challenge test be conducted on children >=36 months of age who have a blood lead level between 1.45 and 1.64 micromol/L (30-34 microg/dL) and on children who have a blood lead level 1.69-2.12 micromol/L (35-44 microg/dL) regardless of age. This approach would have tested all children who subsequently would have had a positive challenge test while testing only 39% of children who would have had a negative challenge test.

The association between caries and childhood lead exposure.

Epidemiologic studies suggest an association between lead exposure and caries. Our objective was to establish whether children with a higher lead exposure as toddlers had more caries at school age than children with a lower lead exposure. We used a retrospective cohort design. A sample of children who attended second and fifth grades in the Rochester, New York, public schools during the 1995-1996 and 1996-1997 school years were examined for caries through a dental screening program. For each child we assessed the number of decayed, missing, or filled surfaces on permanent teeth (DMFS), and the number of decayed or filled surfaces on deciduous teeth (dfs); the number of surfaces at risk (SAR) was also recorded. Lead exposure was defined as the mean of all blood lead levels collected between 18 and 37 months of age by fingerstick [provided the blood lead level was [less than/equal to] 10 microg/dL)] or venipuncture. A total of 248 children (197 second graders and 51 fifth graders) were examined for caries and had a record of blood lead levels to define lead exposure. The mean dfs was 3.4 (range 0-29); the mean DMFS was 0.5 (range 0-8). Logistic regression was used to examine the association between the proportion of children with DMFS [Greater/equal to] 1, and the proportion with dfs [Greater/equal to] 1, and lead exposure [< 0.48 micromol/L vs. [Greater/equal to] 0.48 micromol/L (< 10 microg/dL vs. [Greater/equal to] 10 microg/dL)] while controlling for SAR, age at examination, and grade in school. For DMFS, the adjusted odds ratio was 0.95 [95% confidence interval (CI), 0.43-2.09; p = 0.89); for dfs, the odds ratio was 1.77 (95% CI, 0.97-3.24; p = 0.07). This study did not demonstrate that lead exposure > 10 microg/dL as a toddler was a strong predictor of caries among school-age children. However, the results should be interpreted cautiously because of limitations in the assessment of lead exposure and limited statistical power.

Influenza A virus outbreak in a neonatal intensive care unit.

BACKGROUND: Nosocomial infections with influenza virus are rarely recognized in neonatal intensive care units (NICU). An outbreak of influenza A virus infection in the NICU of an urban county hospital during the 1997 to 1998 influenza season is reported. METHODS: Clinical and virologic data were recorded in all symptomatic NICU patients after influenza A infection was diagnosed in one infant in October, 1997. RESULTS: Influenza A/H3N2 was isolated from two of four symptomatic infants. The application of rapid diagnostic techniques for the characterization of influenza virus infection allowed the timely institution of basic infection control measures, limiting this outbreak. Resistance to amantadine was documented for the first time in this patient population by reverse transcription-PCR within 48 h of treatment in one case. CONCLUSIONS: Prevention by immunization is a priority in those caring for high risk NICU patients.

Epidemiological analysis defining concurrent outbreaks of Serratia marcescens and methicillin-resistant Staphylococcus aureus in a neonatal intensive-care unit.

OBJECTIVE: To describe the epidemiology, interventions, and molecular typing methods used during the investigation and control of concurrent outbreaks of Serratia marcescens and methicillin-resistant Staphylococcus aureus (MRSA) infections in a neonatal intensive-care unit (NICU). SETTING: A 206-bed women's and infants' hospital with a 48-bed NICU. DESIGN: A 22-week, prospective, descriptive study of all NICU infants with S marcescens or MRSA infection or colonization. Repetitive polymerase chain reaction (rep PCR) and pulsed-field gel electrophoresis (PFGE), respectively, were applied to the typing of S marcescens and MRSA isolates. INTERVENTIONS: Infants with S marcescens or MRSA infection or colonization were placed in isolation; all other infants were cohorted. A multidisciplinary task force implemented education for all hospital and medical staff regarding policies essential for outbreak control. Changes in physical setting and patient contact procedure were required to promote adherence to existing policies. RESULTS: Two premature infants had S marcescens infection, and five were colonized; rep PCR verified that both invasive and three of five colonizing isolates were related genotypically. Five bacteremic and 10 MRSA-colonized infants were identified; PFGE confirmed that 12 of the isolates had similar electrophoretic patterns. S marcescens infection was eliminated from the NICU 3 weeks after interventions were initiated. MRSA infections also were eliminated, and MRSA colonization fell to below pre-outbreak rates within 8 weeks. Despite a 100% increase in NICU patient days per month during the subsequent 2 years, no further clusters of S marcescens or MRSA infection have occurred. CONCLUSIONS: Concurrent outbreaks of S marcescens and MRSA in an NICU were confirmed by genotyping of strains. Control was achieved by isolation and cohorting of patients and strict adherence to NICU policies and procedures.

Lead screening among high-risk urban children. Are the 1991 Centers for Disease Control and Prevention guidelines feasible?

OBJECTIVE: To determine whether the 1991 Centers for Disease Control and Prevention lead poisoning prevention guidelines for biannual screening and retesting are feasible among a high-risk population. METHODS: For 632 urban high-risk children aged 9 to 25 months who used a pediatric primary care center between 1989 and 1991, we assessed physician screening practices and the need to increase utilization to meet guidelines for retesting. Analysis also focused on missed opportunities for lead screening. For 425 urban high-risk children who were long-term utilizers of the center, we assessed the need to increase utilization to meet guidelines for biannual screening. RESULTS: Screening was not up to date in 55%, 34%, and 29% of children at ages 9 to 13 months, 14 to 19 months, and 20 to 25 months, respectively. These children had a mean of 2.3, 2.5, and 2.3 missed opportunities during each age period. Among children who had made well-child visits, in 41%, 36%, and 28% of children screening was not up to date at each age period. Between ages 13 and 37 months, 42% of long-term clinic utilizers made sufficient visits to achieve biannual screening. Sixty-five percent of children who were screened made a subsequent visit within 2 to 5 months, at which time retesting could have been performed. CONCLUSIONS: At this primary care center, many high-risk children, including those who had made well-child visits, were not appropriately screened for lead toxic effects. Children not screened had many missed opportunities at all types of visits, including well-child visits. Many children visited frequently enough to achieve biannual screening and retesting without increased numbers of visits if non-well-child visits had been used as opportunities for retesting.