Resource implications of the latent tuberculosis cascade of care: a time and motion study in five countries.

BACKGROUND: The End TB Strategy calls for global scale-up of preventive treatment for latent tuberculosis infection (LTBI), but little information is available about the associated human resource requirements. Our study aimed to quantify the healthcare worker (HCW) time needed to perform the tasks associated with each step along the LTBI cascade of care for household contacts of TB patients. METHODS: We conducted a time and motion (TAM) study between January 2018 and March 2019, in which consenting HCWs were observed throughout a typical workday. The precise time spent was recorded in pre-specified categories of work activities for each step along the cascade. A linear mixed model was fit to estimate the time at each step. RESULTS: A total of 173 HCWs in Benin, Canada, Ghana, Indonesia, and Vietnam participated. The greatest amount of time was spent for the medical evaluation (median: 11 min; IQR: 6-16), while the least time was spent on reading a tuberculin skin test (TST) (median: 4 min; IQR: 2-9). The greatest variability was seen in the time spent for each medical evaluation, while TST placement and reading showed the least variability. The total time required to complete all steps along the LTBI cascade, from identification of household contacts (HHC) through to treatment initiation ranged from 1.8 h per index TB patient in Vietnam to 5.2 h in Ghana. CONCLUSIONS: Our findings suggest that the time requirements are very modest to perform each step in the latent TB cascade of care, but to achieve full identification and management of all household contacts will require additional human resources in many settings.

Targeting adipose tissue via systemic gene therapy.

Adipose tissue has a critical role in energy and metabolic homeostasis, but it is challenging to adapt techniques to modulate adipose function in vivo. Here we develop an in vivo, systemic method of gene transfer specifically targeting adipose tissue using adeno-associated virus (AAV) vectors. We constructed AAV vectors containing cytomegalovirus promoter-regulated reporter genes, intravenously injected adult mice with vectors using multiple AAV serotypes, and determined that AAV2/8 best targeted adipose tissue. Altering vectors to contain adiponectin promoter/enhancer elements and liver-specific microRNA-122 target sites restricted reporter gene expression to adipose tissue. As proof of efficacy, the leptin gene was incorporated into the adipose-targeted expression vector, package into AAV2/8 and administered intravenously to 9- to 10-week-old ob/ob mice. Phenotypic changes were measured over an 8-week period. Leptin mRNA and protein were expressed in adipose and leptin protein was secreted into plasma. Mice responded with reversal of weight gain, decreased hyperinsulinemia and improved glucose tolerance. AAV2/8-mediated systemic delivery of an adipose-targeted expression vector can replace a gene lacking in adipose tissue and correct a mouse model of human disease, demonstrating experimental application and therapeutic potential in disorders of adipose.

Perspectives from the 2nd International Post-Tuberculosis Symposium: mobilising advocacy and research for improved outcomes.

In 2020, it was estimated that there were 155 million survivors of TB alive, all at risk of possible post TB disability. The 2nd International Post-Tuberculosis Symposium (Stellenbosch, South Africa) was held to increase global awareness and empower TB-affected communities to play an active role in driving the agenda. We aimed to update knowledge on post-TB life and illness, identify research priorities, build research collaborations and highlight the need to embed lung health outcomes in clinical TB trials and programmatic TB care services. The symposium was a multidisciplinary meeting that included clinicians, researchers, TB survivors, funders and policy makers. Ten academic working groups set their own goals and covered the following thematic areas: 1) patient engagement and perspectives; 2) epidemiology and modelling; 3) pathogenesis of post-TB sequelae; 4) post-TB lung disease; 5) cardiovascular and pulmonary vascular complications; 6) neuromuscular & skeletal complications; 7) paediatric complications; 8) economic-social and psychological (ESP) consequences; 9) prevention, treatment and management; 10) advocacy, policy and stakeholder engagement. The working groups provided important updates for their respective fields, highlighted research priorities, and made progress towards the standardisation and alignment of post-TB outcomes and definitions.

En 2020, il est estimé qu'il y a 155 millions de survivants de la TB dans le monde, tous exposés à un risque d'invalidité post-TB. Le deuxième Symposium International Post-Tuberculose (Stellenbosch, Afrique du Sud) a été organisé dans le but de sensibiliser davantage à l'échelle mondiale et de permettre aux communautés touchées par la TB de contribuer activement à la mise en œuvre de l'agenda. De plus, nous avons entrepris de mettre à jour les connaissances sur la vie et les maladies post-TB, de déterminer les domaines de recherche prioritaires, d'établir des partenariats de recherche et de souligner l'importance d'intégrer les résultats sur la santé pulmonaire dans les essais cliniques et les services de soins de la TB. Le symposium était une réunion de travail pluridisciplinaire rassemblant des praticiens, des chercheurs, des personnes ayant survécu à la TB, des donateurs, des décideurs politiques et d'autres acteurs clés. Dix groupes de travail académiques ont établi leurs propres objectifs et ont abordé les sujets thématiques suivants : 1) engagement et perspectives des patients ; 2) épidémiologie et modélisation ; 3) pathogénie des séquelles post-TB ; 4) maladie pulmonaire post-TB (PTLD, pour l'anglais «post-TB lung disease ¼) ; 5) complications cardiovasculaires et vasculaires pulmonaires ; 6) complications neuromusculaires et squelettiques ; 7) complications pédiatriques ; 8) conséquences économiques, sociales et psychologiques (ESP, pour l'anglais «economic-social and psychological¼) ; 9) prévention, traitement et gestion ; 10) plaidoyer, politique et engagement des parties prenantes. Les groupes de travail académiques ont apporté des mises à jour significatives dans leurs domaines respectifs, ont mis en évidence les priorités de recherche et ont avancé vers la normalisation et l'harmonisation des résultats et des définitions de la post-TB.

A randomised controlled trial of ribavirin in Crimean Congo haemorrhagic fever: ethical considerations.

The randomised controlled trial (RCT) constitutes a quantitative, comparative, controlled study of a particular treatment, and provides invaluable evidence regarding its pharmacotherapeutic efficacy. These studies are generally predicated upon the ethical principle of clinical equipoise. However, this may be insufficient to justify withholding treatment from a control group while assessing drug therapy in a potentially fatal disease. Thus, the criteria for randomisation, informed consent methodology and timing, and consideration of treatment options in such a scenario remain the province of medical ethics. This paper addresses the need for an RCT of ribavirin in the treatment of Crimean Congo haemorrhagic fever, and highlights underlying ethical concerns in light of the current medical, virological and ethical literature.

A scoping review of interventions to mitigate common non-communicable diseases among people with TB.

BACKGROUND: Recommendations have been made to integrate screening for common non-communicable diseases (NCDs) within TB programs. However, we must ensure screening is tied to evidence-based interventions before scale-up. We aimed to map the existing evidence regarding interventions that address NCDs that most commonly affect people with TB.METHODS: We systematically searched PubMed, Medline, and Embase for studies that evaluated interventions to mitigate respiratory disease, cardiovascular disease, alcohol and substance use disorder, and mental health disorders among people with TB. We excluded studies that only screened for comorbidity but resulted in no further intervention. We also excluded studies focusing on smoking cessation interventions for which evidence-based guidelines are well established.RESULTS: The search identified 20 studies that met our inclusion criteria. The most commonly evaluated intervention was referral for diabetes care (6 studies). Other interventions included pulmonary rehabilitation (5 studies), care programs for alcohol use disorder (4 studies), and psychosocial support or individual counselling (5 studies).CONCLUSION: There is limited robust evidence to support identified interventions in changing individual outcomes, and a significant knowledge gap remains on the long-term durability of the interventions´ clinical benefit, reach, and effectiveness. Implementation research demonstrating feasibility and effectiveness is needed before scaling up.

Active case-finding in contacts of people with TB.

BACKGROUND: Exposure to people with TB substantially elevates a person's risk of tuberculous infection and TB disease. Systematic screening of TB contacts enables the early detection and treatment of co-prevalent disease, and the opportunity to prevent future TB disease. However, scale-up of contact investigation in high TB transmission settings remains limited.METHODS: We undertook a narrative review to evaluate the evidence for contact investigation and identify strategies that TB programmes may consider when introducing contact investigation and management.RESULTS: Selection of contacts for priority screening depends upon their proximity and duration of exposure, along with their susceptibility to develop TB. Screening algorithms can be tailored to the target population, the availability of diagnostic tests and preventive therapy, and healthcare worker expertise. Contact investigation may be performed in the household or at communal locations. Local contact investigation policies should support vulnerable patients, and ensure that drop-out during screening can be mitigated. Ethical issues should be anticipated and addressed in each setting.CONCLUSION: Contact investigation is an important strategy for TB elimination. While its epidemiological impact will be greatest in lower-transmission settings, the early detection and prevention of TB have important benefits for contacts and their communities.

Perception of letters in words: seek not and ye shall find.

Subjects perceive a letter in a briefly presented word more accurately when they attend to the whole word than when they focus their attention on just the letter they want to see.

Feline immunodeficiency virus vectors persistently transduce nondividing airway epithelia and correct the cystic fibrosis defect.

Several problems limit the application of gene transfer to correct the cystic fibrosis (CF) Cl(-) transport defect in airway epithelia. These include inefficient transduction with vectors applied to the apical surface, a low rate of division by airway epithelial cells, failure of transgene expression to persist, and immune responses to vectors or vector-encoded proteins. To address these issues, we used a feline immunodeficiency virus-based (FIV-based) vector. FIV vector formulated with a calcium chelator transduced fully differentiated, nondividing human airway epithelia when applied to the apical surface. FIV-based vector encoding the cystic fibrosis transmembrane conductance regulator cDNA corrected the Cl(-) transport defect in differentiated CF airway epithelia for the life of the culture (>3 months). When this approach was applied in vivo, FIV vector expressing beta-galactosidase transduced 1-14% of adult rabbit airway epithelia. Transduced cells were present in the conducting airways, bronchioles, and alveoli. Importantly, gene expression persisted, and cells with progenitor capacity were targeted. FIV-based lentiviral vectors may be useful for the treatment of genetic lung diseases such as CF. This article may have been published online in advance of the print edition.

The S387Y mutations of the transforming growth factor-beta receptor type I gene is uncommon in metastases of breast cancer and other common types of adenocarcinoma.

Recently, mutations of the transforming growth factor-beta receptor type I gene have been reported to occur at high frequency in breast cancer metastases, with all mutations being an identical C to A transversion at nucleotide 1160 of the gene (T. Chen et al, Cancer Res., 58: 4805-4810, 1998). This mutation would result in a serine to tyrosine substitution at codon 387 (S387Y) and would reportedly disrupt receptor function. Because this mutation reportedly occurred at high frequency in breast cancer metastases (42%) and much less frequently in primary breast cancer tumors (6%), this would seem to represent a pivotal genetic alteration in breast cancer progression. To further investigate the possible role of this specific genetic alteration in the progression of breast cancer and other forms of adenocarcinoma, we analyzed 20 breast cancer metastases, 15 lung adenocarcinoma metastases, and 13 colorectal cancer metastases for possible mutations at this site. Using both single-strand conformation polymorphism screening and sequencing, we found no mutations of this gene in any of our samples. Our results suggest the S387Y mutation of the transforming growth factor-beta receptor type I gene is not common in these types of human cancers.

Classification of small cell lung cancer and pulmonary carcinoid by gene expression profiles.

Small cell lung cancer is a common type of lung cancer that is generally classified within the spectrum of neuroendocrine lung neoplasms. Using high-density cDNA arrays, we profiled gene expression of small cell lung cancers and compared these expression profiles to those of normal bronchial epithelial cells and pulmonary carcinoids, which are classified as benign neuroendocrine tumors. We found the overall expression profiles of two small cell lung cancer cell lines, two microdissected tissue samples of primary small cell lung cancer, and cultured bronchial epithelial cells to be relatively similar to one another, with an average Pearson correlation coefficient for these comparisons of 0.63. However, we found the expression profiles of small cell lung cancers (and bronchial epithelial cells) to be surprisingly dissimilar to those of two samples of pulmonary carcinoid tumors, with an average correlation coefficient for these comparisons of 0.20. We then compared the pulmonary carcinoid expression profiles to those of two samples of infiltrating astrocytic brain cancers (oligodendroglioma and high-grade astrocytoma) and found similarity of gene expression among these four samples (average correlation coefficient, 0.57). These gene expression profiles suggest that small cell lung cancers are closely related to (and possibly derived from) epithelial cells, and that pulmonary carcinoids are related to neural crest-derived brain tumors. More generally, our results suggest that broad profiles of gene expression may reveal similarities and differences between tumors that are not apparent by traditional morphological criteria.

Introduction of spirometry into clinical practice in Georgetown, Guyana: quality and diagnostic outcomes.

SETTING: Georgetown Public Hospital Corporation (GPHC), a 600-bed publicly funded referral hospital in Georgetown, Guyana. OBJECTIVE: To assess spirometry quality and diagnostic outcomes 2 years after the introduction of spirometry into routine clinical practice at GPHC. DESIGN: We performed a retrospective review of 476 consecutive spirometry assessments performed from November 2013 to November 2015. We assessed the proportion and trend of spirometry tests meeting acceptability criteria, along with diagnostic interpretations and spirometry laboratory referral patterns. RESULTS: Overall, 80.4% of the 454 initial spirometry measurements on unique patients met the acceptability criteria, with no significant change in the proportion of acceptable spirometry over the study period (P = 0.450). Of the 369 (81.3%) first tests considered interpretable, 139 (30.6%) were normal, 151 (33.3%) were obstructive, 54 (11.9%) were suggestive of a restrictive pattern, 25 (5.5%) were suggestive of a mixed disorder and 119 (26.2%) tests met the definition of reversibility. CONCLUSION: Over a 2-year period, high-quality spirometry was performed in GPHC, a publicly funded hospital in a middle-income country with no pre-existing specialised respiratory service.

Spatio-temporal analysis of tuberculous infection risk among clients of a homeless shelter during an outbreak.

SETTING: British Columbia (BC) has a low incidence of tuberculosis (TB), with the burden of endogenously acquired disease concentrated among vulnerable populations, including the homeless. In May 2008, a TB outbreak began in a BC homeless shelter, with a single index case seeding multiple secondary cases within the shelter. OBJECTIVE: To use nightly shelter records to quantify the risk of latent tuberculous infection (LTBI) among shelter clients as a function of their sleeping distance from and duration of exposure to the index case. DESIGN: Distance and duration of exposure were visualised and assessed using logistic regression with LTBI status as outcome. We used a novel machine learning approach to establish exposure thresholds that optimally separated infected and non-infected individuals. RESULTS: Of 161 exposed shelter clients, 58 had a recorded outcome of infected (n = 39) or non-infected (n = 19). Only duration of exposure to the index was associated with increased odds of infection (OR 1.26); stays of ⩾ 5 nights put shelter clients at higher odds of infection (OR 4.97). CONCLUSION: The unique data set and analytical approach suggested that, in a shelter environment, long-term clients are at highest risk of LTBI and should be prioritised for screening during an outbreak investigation.

Repetition effects in word and pseudoword identification: comment on Salasoo, Shiffrin, and Feustel.

Two recent articles by Feustel, Shiffrin, and Salasoo (1983) and Salasoo, Shiffrin, and Feustel (1985) argue that word identification is based on episodic memory as well as semantic (or "permanent, abstract") memory. The earlier article argued for separate processing stages affected by repetition (episodic memory) and lexicality (semantic memory). To account for the new finding that number of repetitions interacts with lexicality, the later article invokes the same two types of memory, operating in parallel rather than serially. We argue that Salasoo et al.'s data are compatible with a wide variety of competing theories, including some that do not involve episodic memory at all. We question the relevance of a complex formal model shown by the authors to account for the main trends in the data, because it makes little use of key properties of episodic memory. Furthermore, we show that two variants of a less complex model inspired by logogen theory fit the data as well or better than the model of Salasoo et al., using fewer free parameters. We argue that what is needed is not an existence proof that one particular complex model can fit a body of data, but experimental manipulations that successfully discriminate between broad classes of competing theories.

Laparoscopic cholecystectomy in the geriatric population.

OBJECTIVE: To assess effectiveness and conversion rates of inpatient laparoscopic cholecystectomy in older people living in the community. SETTING AND SUBJECTS: All acute care hospitals providing cholecystectomy in a single state. Medicare patients who underwent inpatient cholecystectomy in fiscal year 1994 in Arkansas. METHODS: A random sample comprising 449 of 2182 geriatric patients who underwent inpatient cholecystectomy in fiscal year 1994, stratified by hospital bed size, had charts reviewed for type of cholecystectomy performed, occurrence of conversion from a laparoscopic to an open cholecystectomy, surgical complications, and need for transfusion. RESULTS: Eighty-two percent of nonincidental cholecystectomies were initially laparoscopic. Total conversion rate for all inpatient laparoscopic cases was 20%. Forty-two percent of this group suffered acute cholecystitis with male patients exhibiting a higher rate of acute cholecystitis than female patients. Conversion rates for elective cholecystectomy for both sexes was between 13 and 14%. Conversion rate to an open procedures was 28% for patients with acute disease, with male patients again having a higher rate than female patients (40% vs 19%, P < .001). Surgical complications and intraoperative transfusions were rare. Conversion rates did not vary between large and small hospitals or among different age groups within the older population. CONCLUSIONS: Inpatient laparoscopic cholecystectomy is common in older people both for acute and chronic gallbladder conditions. Conversion rates ranged from 13% for elective cholecystectomy to 28% for acute disease. These rates are higher than published literature, which focuses on younger populations undergoing elective procedures. Audit committees need to be aware of this higher conversion rate in older people when assessing surgical proficiency.

Spatial attention to arrays of multidimensional objects.

Encoding briefly displayed arrays of multidimensional objects appears to require selective attention, but this hypothesis is challenged by M. J. Nissen's (1985) finding that properties of an object are reported independently. Selective attention to some objects but not others should produce positive dependence. Theoretical analysis shows that deviations from independence would have been difficult to observe in Nissen's data because of high guessing rates and small sample sizes. Four new experiments showing strong positive dependence in property reports are described. Deviations from independence were highly significant for most Ss. Quantitative modeling shows that selective attention to subsets of objects would produce about the amount of dependence obtained. Rather than challenging attention theories, the amount of dependence in encoding multidimensional objects is consistent with selective attention to either objects or locations.

Perceptual repetition blindness effects.

Repetition blindness (RB) may reveal a new limitation on human perceptual processing. Recently, however, researchers have attributed RB to postperceptual processes. The standard rapid serial visual presentation (RSVP) paradigm used in most RB studies is open to such objections. The "single-frame" paradigm introduced by J. C. Johnston and B. L. Hale (1984) allowed investigation of RB with minimal memory demands. Participants made a judgment about whether 1 masked target word was the same or different than a posttarget probe. Confidence ratings permitted use of signal detection methods. In the critical condition for RB, a precue of the posttarget word was provided prior to the target stimulus so that the required judgment amounted to whether the target did or did not repeat the precue word. In control treatments, the precue was an unrelated word or a dummy. Results showed that perceptual sensitivity was significantly reduced in the RB condition relative to baseline control conditions. The data showed that RB can be obtained under conditions in which memory problems are minimal and perceptual sensitivity is assessed independently of biases. RB therefore can be a perceptual phenomenon.

Close binding of identity and location in visual feature perception.

The binding of identity and location information in disjunctive feature search was studied. Ss searched a heterogeneous display for a color or a form target, and reported both target identity and location. To avoid better than chance guessing of target identity (by choosing the target less likely to have been seen), the difficulty of the two targets was equalized adaptively; a mathematical model was used to quantify residual effects. A spatial layout was used that minimized postperceptual errors in reporting location. Results showed strong binding of identity and location perception. After correction for guessing, no perception of identity without location was found. A weak trend was found for accurate perception of target location without identity. We propose that activated features generate attention-calling "interrupt" signals, specifying only location; attention then retrieves the properties at that location.