Timeliness metrics for screening and preventing TB in household contacts of pulmonary TB patients in Kenya.

BACKGROUND: The study assessed whether a "7-1-7" timeliness metric for screening and TB preventive therapy (TPT) could be implemented for household contacts (HHCs) of index patients with bacteriologically confirmed pulmonary TB under routine programmatic settings in Kenya. METHODS: A longitudinal cohort study conducted among index patients and their HHCs in 12 health facilities, Kiambu County, Kenya. RESULTS: Between January and June 2023, 95% of 508 index patients had their HHCs line-listed within 7 days of initiating anti-TB treatment ("First 7"). In 68% of 1,115 HHCs, screening outcomes were ascertained within 1 day of line-listing ("Next 1"). In 65% of 1,105 HHCs eligible for further evaluation, anti-TB treatment, TPT or a decision for no drugs was made within 7 days of screening ("Second 7"). Altogether, 62% of screened HHCs started TPT during the "7-1-7" period compared with 58% in a historical cohort. Main barriers to TPT uptake were HHCs not consulting clinicians, HHCs being unwilling to initiate TPT and drug shortages. Healthcare workers felt that a timeliness metric was valuable for streamlining HHC management and proposed "3-5-7" as a workable alternative. CONCLUSIONS: The national TB programme must generate awareness about TPT, ensure uninterrupted drug supplies and assess whether the "3-5-7" metric can be operationalised.

CONTEXTE: L'étude a évalué si une mesure de rapidité "7-1-7" pour le dépistage et le traitement préventif de la TB (TPT) pouvait être mise en œuvre pour les contacts familiaux des patients index atteints de TB pulmonaire confirmée bactériologiquement dans le cadre d'un programme de routine au Kenya. MÉTHODES: Étude de cohorte longitudinale menée auprès de patients index et de leurs contacts familiaux dans 12 établissements de santé du comté de Kiambu, au Kenya. RÉSULTATS: Entre janvier et juin 2023, 95% des 508 patients index ont eu leur centre de santé inscrit sur la liste dans les 7 jours suivant le début du traitement antituberculeux (« First 7 ¼ ). Dans 68% des 1 115 centres de santé, les résultats du dépistage ont été vérifiés dans le jour suivant l'inscription sur la liste (« Next 1 ¼). Dans 65% des 1 105 centres de santé éligibles pour une évaluation plus approfondie, le traitement antituberculeux, le TPT ou la décision de ne pas prendre de médicaments a été prise dans les 7 jours suivant le dépistage (« Second 7 ¼). Au total, 62% des patients dépistés ont commencé un traitement antituberculeux au cours de la période « 7-1-7 ¼, contre 58% dans une cohorte historique. Les principaux obstacles à l'adoption du TPT étaient les suivants : les centres de santé ne consultaient pas les cliniciens, les centres de santé n'étaient pas disposés à commencer le TPT et les pénuries de médicaments. Les professionnels de la santé ont estimé qu'une mesure de la rapidité d'exécution était utile pour rationaliser la gestion des centres de santé et ont proposé le « 3-5-7 ¼ comme solution de rechange viable. CONCLUSION: Le programme national de lutte contre la TB doit sensibiliser au TPT, garantir un approvisionnement ininterrompu en médicaments et évaluer si la mesure « 3-5-7 ¼ peut être mise en œuvre.

Using timeliness metrics for household contact tracing and TB preventive therapy in the private sector, India.

Although screening of household contacts (HHCs) of TB patients and provision of TB preventive therapy (TPT) is a key intervention to end the TB epidemic, their implementation globally is dismal. We assessed whether introducing a '7-1-7' timeliness metric was workable for implementing HHC screening among index patients with pulmonary TB diagnosed by private providers in Chennai, India, between November 2022 and March 2023.This was an explanatory mixed-methods study (quantitative-cohort and qualitative-descriptive).There were 263 index patients with 556 HHCs. In 90% of index patients, HHCs were line-listed within 7 days of anti-TB treatment initiation. Screening outcomes were ascertained in 48% of HHCs within 1 day of line-listing. Start of anti-TB treatment, TPT or a decision to receive neither was achieved in 57% of HHC within 7 days of screening. Overall, 24% of screened HHCs in the '7-1-7' period started TPT compared with 16% in a historical control (P < 0.01). Barriers to achieving '7-1-7' included HHC reluctance for evaluation or TPT, refusal of private providers to prescribe TPT and reliance on facility-based screening of HHCs instead of home visits by health workers for screening.Introduction of a timeliness metric is a workable intervention that adds structure to HHC screening and timely management..

Quantitative Evaluation of Medial Temporal Lobe Morphology in Children with Febrile Status Epilepticus: Results of the FEBSTAT Study.

BACKGROUND AND PURPOSE: The pathogenesis of febrile status epilepticus is poorly understood, but prior studies have suggested an association with temporal lobe abnormalities, including hippocampal malrotation. We used a quantitative morphometric method to assess the association between temporal lobe morphology and febrile status epilepticus. MATERIALS AND METHODS: Brain MR imaging was performed in children presenting with febrile status epilepticus and control subjects as part of the Consequences of Prolonged Febrile Seizures in Childhood study. Medial temporal lobe morphologic parameters were measured manually, including the distance of the hippocampus from the midline, hippocampal height:width ratio, hippocampal angle, collateral sulcus angle, and width of the temporal horn. RESULTS: Temporal lobe morphologic parameters were correlated with the presence of visual hippocampal malrotation; the strongest association was with left temporal horn width (P < .001; adjusted OR, 10.59). Multiple morphologic parameters correlated with febrile status epilepticus, encompassing both the right and left sides. This association was statistically strongest in the right temporal lobe, whereas hippocampal malrotation was almost exclusively left-sided in this cohort. The association between temporal lobe measurements and febrile status epilepticus persisted when the analysis was restricted to cases with visually normal imaging findings without hippocampal malrotation or other visually apparent abnormalities. CONCLUSIONS: Several component morphologic features of hippocampal malrotation are independently associated with febrile status epilepticus, even when complete hippocampal malrotation is absent. Unexpectedly, this association predominantly involves the right temporal lobe. These findings suggest that a spectrum of bilateral temporal lobe anomalies are associated with febrile status epilepticus in children. Hippocampal malrotation may represent a visually apparent subset of this spectrum.

Trend to better nutrition on Australian hospital menus 1986-2001 and the impact of cook-chill food service systems.

OBJECTIVE: To assess trends in the nutritional quality of hospital menus and examine differences between menus used in hospitals with cook-chill or cook-fresh food services. DESIGN: Standard patient menus were analysed against 28 criteria to assess nutritional standards and compared with results from similar studies in 1986 and 1993. SETTING: Menus were collected from 80 hospitals in New South Wales (NSW), Australia, including 36 using cook-chill food service systems. STATISTICAL ANALYSIS: Chi-squared analysis was used to assess differences between the proportions of hospitals meeting the criteria in 1993 and 2001, and between different types of hospitals. RESULTS: In 2001, compared with 1993, significantly many hospitals offered more than one hot choice at the evening meal, more menus highlighted low fat items and more calcium-rich foods were available. More than 90% of hospitals allowed patients to select their own menu, offered wholemeal breads and high-fibre breakfast cereals, fresh fruit, polyunsaturated margarine, a milk dessert at least once a day and two or more hot options at the midday meal. Hospitals with cook-chill food services had menus that were more likely to meet nutritional recommendations, although they were less likely to offer a choice of serving size. A high proportion of unpopular choices were offered in menus, especially meat dishes and desserts. APPLICATIONS/CONCLUSION: Since 1986, NSW hospital menus have improved to offer choices that conform better to dietary guidelines. Cook-chill food services may have positive and negative impacts on meal choices. The assessment criteria are useful in hospitals to assess their menus.

Development and implementation of computerized clinical guidelines: barriers and solutions.

Research indicates that computerized decision support systems (CDSSs) can improve clinical performance and patient outcomes, and yet CDSSs are not in widespread use. Physician guidelines, in general, face barriers in implementation. Guidelines in a computerized format can overcome some of the barriers to conventional text-form guidelines; however, computerized programs have novel aspects that have to be considered, aspects such as technical problems/support and user interface issues that can act as barriers. Though the literature points out that human, organizational, and technical issues can act as barriers in the implementation of CDSSs, studies clearly indicate that there are methods that can overcome these barriers and improve CDSS acceptance and use. These methods come from lessons learned from a variety of CDSS implementation ventures. Notably, most of the methods that improve acceptance and use of a CDSS require feedback and involvement of end-users. Measuring and addressing physician or user attitudes toward the computerized support system has been shown to be important in the successful implementation of a CDSS. This article discusses: 1) the barriers of implementation of guidelines in general and of CDSSs; 2) the importance of the physician's role in development, implementation, and adherence; 3) methods that can improve CDSS acceptance and use; and 4) the types of tools needed to obtain end-user feedback.

Spinal anaesthesia: comparison of plain ropivacaine 5 mg ml(-1) with bupivacaine 5 mg ml(-1) for major orthopaedic surgery.

BACKGROUND: Ropivacaine provides effective spinal anaesthesia for total hip arthroplasty. This study was designed to compare the efficacy and safety of plain ropivacaine with plain bupivacaine for spinal anaesthesia in patients undergoing total hip arthroplasty. METHODS: Sixty-six patients, ASA I or II, were randomized to receive an intrathecal injection of one of two local anaesthetic solutions. Group R (n=32) received 3.5 ml of ropivacaine 5 mg ml(-1) (17.5 mg). Group B (n=34) received 3.5 ml of bupivacaine 5 mg ml(-1) (17.5 mg). The onset and duration of sensory block at dermatome level T10, maximum upper and lower spread of sensory block and the onset, intensity and duration of motor block were recorded, as were safety data. RESULTS: Onset of motor and sensory block was rapid with no significant differences between the two groups. The median time of onset of sensory block at the T10 dermatome was 2 min (range 2-5 min) in Group R and 2 min in Group B (range 2-9 min). The median duration of sensory block at the T10 dermatome was 3.0 h (range 1.5-4.6 h) in Group R and 3.5 h (2.7-5.2 h) in Group B (P<0.0001). The median duration of complete motor block (modified Bromage Scale 3) was significantly shorter in the ropivacaine group compared with the bupivacaine group (2.1 vs 3.9 h, P<0.001). CONCLUSIONS: Intrathecal administration of either 17.5 mg plain ropivacaine or 17.5 mg plain bupivacaine was well tolerated and an adequate block for total hip arthroplasty was achieved in all patients. A more rapid postoperative recovery of sensory and motor function was seen in Group R compared with Group B.

Intrathecal ropivacaine for total hip arthroplasty: double-blind comparative study with isobaric 7.5 mg ml(-1) and 10 mg ml(-1) solutions.

This study was designed to evaluate the efficacy and safety of two concentrations of intrathecal ropivacaine, 7.5 and 10 mg ml(-1), in patients undergoing total hip arthroplasty. One hundred and four patients, ASA I-III, were randomized to receive an intrathecal injection of one of two concentrations of isobaric ropivacaine. Group 1 (n=51) received 2.5 ml of 7.5 mg ml(-1) ropivacaine (18.75 mg). Group 2 (n=53) received 2.5 ml of 10 mg ml(-1) ropivacaine (25 mg). The onset and offset of sensory block at dermatome level T10, maximum upper and lower spread of sensory block and the onset, intensity and duration of motor block were recorded, as were safety data. Onset of motor and sensory block was rapid with no significant differences between the two groups. The median time of onset of sensory block at the T10 dermatome was 2 min (range 1-25 min) in Group 1 and 2 min (range 1-21 min) in Group 2. The median duration of sensory block at the T10 dermatome was 3.0 h (range 0.5-4.2 h) in Group 1 and 3.4 h (1.1-5.9 h) in Group 2 (P=0.002). The median duration of complete motor block was significantly prolonged (P<0.05) in Group 2 compared with Group 1 (1.9 vs 1.2 h, respectively). Anaesthetic conditions were excellent in all but one patient. Intrathecal ropivacaine, in doses of 18.75 and 25 mg, was well tolerated and provided effective anaesthesia for total hip arthroplasty.

Agreement between troponin T levels from plain and heparinized tubes.

OBJECTIVE: To determine whether there was a clinically significant effect on troponin T measurement when the sample was collected in a heparinized (plasma) blood collection tube compared with a serum tube. METHODS: Prospective cohort study using a convenience sample of 198 patients with undifferentiated illness presenting to an Emergency Department who required troponin T measurement. Samples were collected in both plain (serum) tubes and plasma tubes for comparison. All samples were measured using an Elecsys 2010 Immunoassay system (Roche-Boehringer Mannheim, Germany). RESULTS: There were 35 troponin T measurements > or = 0.03 microg/L (the limit of reproducibility of the test). The negative predictive value for troponin T performed in heparinized tubes compared with plain tubes was 100% (95% confidence interval 96.4-100) at the > or = 0.03 microg/L level and 100% (95% confidence interval 97-100%) at the > or = 0.1 microg/L level. At a cut-off point for risk stratification in acute coronary syndromes (> or = 0.1 microg/L), there was 100% concordance between the two measurements for each sample. CONCLUSION: The use of plasma (heparinized) tubes for the collection of troponin T samples is unlikely to produce clinically significant false-negative results compared with collection of troponin T samples in serum (plain) tubes.

Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector.

Pre-clinical studies in mice and haemophilic dogs have shown that introduction of an adeno-associated viral (AAV) vector encoding blood coagulation factor IX (FIX) into skeletal muscle results in sustained expression of F.IX at levels sufficient to correct the haemophilic phenotype. On the basis of these data and additional pre-clinical studies demonstrating an absence of vector-related toxicity, we initiated a clinical study of intramuscular injection of an AAV vector expressing human F.IX in adults with severe haemophilia B. The study has a dose-escalation design, and all patients have now been enrolled in the initial dose cohort (2 x 10(11) vg/kg). Assessment in the first three patients of safety and gene transfer and expression show no evidence of germline transmission of vector sequences or formation of inhibitory antibodies against F.IX. We found that the vector sequences are present in muscle by PCR and Southern-blot analyses of muscle biopsies and we demonstrated expression of F.IX by immunohistochemistry. We observed modest changes in clinical endpoints including circulating levels of F.IX and frequency of FIX protein infusion. The evidence of gene expression at low doses of vector suggests that dose calculations based on animal data may have overestimated the amount of vector required to achieve therapeutic levels in humans, and that the approach offers the possibility of converting severe haemophilia B to a milder form of the disease.

Decisions concerning the allocation of scarce medical resources.

This paper aimed to determine the criteria participants use to make decisions about scarce medical resources (allocation to use a kidney machine). It varied information about patients on 4 factors (sex, smoking, employment status, community service). It also set out to see if decisions made in groups differed from aggregated decisions of those made alone. In the first study, participants completed a simple questionnaire requiring them to rank-order sixteen hypothetical patients. In the second study, a group discussion (in groups of three participants) preceded the group putting an agreed rating on the identical questionnaire. Participants favoured patients who were employed, non-smokers and participated in community service. This suggests that participants adopted a utilitarian moral ideology. Participants' smoking habits interacted with the hypothetical patients' smoking habits, indicating in-group favouritism. In the second study it was found that when the decision was made in a group of three it amplifies the decision made by an individual. In this sense there was clear evidence of group polarization.

Scaling-up production of recombinant AAV vectors for clinical applications.

Recombinant adeno-associated virus (AAV)-based vectors capable of expressing therapeutic gene products in vivo have shown significant promise for human gene therapy. A major challenge for these applications is the development of processes to enable production of large quantities of AAV vectors and purification of material that is well characterized and appropriate for parenteral administration. Several cell culture systems have been developed for AAV vector production, and a limited number of these demonstrate the potential to generate AAV vectors at concentrations compatible with cost-effective large-scale production. Vector purification protocols, in particular those based on the use of scalable column chromatography, have concurrently been developed that demonstrate the potential to provide highly purified AAV vector preparations with high yield. These advances support the potential for AAV vectors as therapeutic agents for gene therapy.

Adenovirus-mediated expresssion of the murine ecotropic receptor facilitates transduction of human hematopoietic cells with an ecotropic retroviral vector.

One factor limiting the ability to modify human repopulating hematopoietic cells genetically with retroviral vectors is the relatively low expression of the cognate viral receptor. We have tested sequential transduction of human hematopoietic cells with an adenoviral vector encoding the ecotropic retroviral receptor followed by transduction with an ecotropic retroviral vector. Adenoviral transduction of K562 erythroleukemia cells was highly efficiently with >95% of cells expressing the ecotropic receptor at a multiplicity of infection (MOI) of 103with a correspondingly high transduction with a retroviral vector. Ecotropic receptor expression in CD34+ cells following transduction with adenoviral vectors was increased by at least two-fold (from 20 to 48%) by replacing the RSV promoter with the CMV E1a promoter, resulting in a parallel increase in retroviral transduction efficiency. Replacing the head portion of the fiber protein in conventional adenoviral vectors (serotype 5) with the corresponding portion from an adenoviral 3 serotype resulted in ecotropic receptor expression in 60% of CD34+ cells at an MOI of 104 and a retroviral transduction of 60% of hematopoietic clonogenic progenitors. The sequential transduction strategy also resulted in efficient transduction of the primitive CD34+CD38- subset suggesting that it may hold promise for genetic modification of human hematopoietic stem cells.

Expression of tissue inhibitor of matrix metalloproteinases 1 by use of an adenoviral vector inhibits smooth muscle cell migration and reduces neointimal hyperplasia in the rat model of vascular balloon injury.

BACKGROUND: Cell migration is a major contributor to injury-induced neointimal hyperplasia and depends on alteration of the proteolytic balance within the arterial wall toward matrix breakdown. This is partly mediated by the matrix metalloproteinases (MMPs) and their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). METHODS AND RESULTS: An increase in expression of biologically active and immunoreactive TIMP-1 was seen in vitro after infection of rat smooth muscle cells (SMCs) with Av1.TIMP1 (an adenoviral vector containing the human TIMP1 cDNA). Infection of rat SMCs with Av1.TIMP1 reduced migration in vitro by 27% compared with control virus-infected cells (37.6+/-4.34 versus 51+/-5.01 cells per high-power field, P<0.05). The adenoviral vector was delivered to the injured rat carotid artery, and 4 days later, immunoreactive protein was identified and migration of SMCs reduced by 60% (5.2+/-0. 5 versus 12.8+/-1.5 cells per section, P<0.05, n=5). Neointimal area 14 days after injury showed a 30% reduction in the animals receiving the Av1.TIMP1 virus compared with controls (0.09+/-0.01 versus 0. 14+/-0.01 mm2, P=0.02, n=14). CONCLUSIONS: The response to arterial balloon injury involves MMP-dependent SMC migration and can be attenuated in vivo by the transmural expression of TIMP-1 by adenoviral gene transfer.

Enhanced neuroblastoma transduction for an improved antitumor vaccine.

BACKGROUND: A recent clinical trial of an antineuroblastoma vaccine used adenovirus serotype 5 (Ad5) vectors to transduce autologous tumor cells with the gene encoding IL-2. A method to improve transduction efficiency was sought to enable the use of lower viral titers, especially when in situ adenoviral-mediated tumor cell transduction is considered. MATERIALS AND METHODS: A chimeric adenoviral delivery vector was utilized in which the fiber head from adenovirus serotype 3 was incorporated into the backbone of Ad5. Since the fiber head protein is responsible for viral attachment to target cells, a different spectrum and range of infectivity might result. Both the chimeric (Av9LacZ4) and Ad5 (Av1LacZ4) vectors were constructed to carry a beta-galactosidase transgene. The relative transduction efficiency of these two vectors was then evaluated in five tumor-derived short-term neuroblastoma cultures and four established neuroblastoma cell lines. Enzyme activity was assessed using three different methods: in situ staining, flow cytometric analysis, and a quantitative assay. RESULTS: A significant improvement in transduction efficiency of the short-term neuroblastoma cultures with the new chimeric adenovector was demonstrated. A similar improvement in transduction efficiency was not observed in the established cell lines, suggesting that the cell surface receptor for the Ad 3 serotype had been lost in vitro. Increased transduction of tumor cells with N-myc amplification was also observed. CONCLUSIONS: The newly constructed chimeric adenoviral vector transduces short-term neuroblastoma cultures more efficiently than the standard Ad5 vector. This vector will permit the use of lower viral titers and may be useful in other adenoviral-based gene-therapy protocols. Increased transgene expression in N-myc-amplified cells offers possible selectivity for in situ gene delivery.