Outcomes for people with TB by disease severity at presentation.

There is substantial heterogeneity in disease presentation for individuals with TB disease, which may correlate with disease outcomes. We estimated disease outcomes by disease severity at presentation among individuals with TB during the pre-chemotherapy era.We extracted data on people with TB enrolled between 1917 and 1948 in the USA, stratified by three disease severity categories at presentation using the U.S. National Tuberculosis Association diagnostic criteria. These criteria were based largely on radiographic findings ("minimal", "moderately advanced", and "far advanced"). We used Bayesian parametric survival analysis to model the survival distribution overall, and by disease severity and Bayesian logistic regression to estimate the severity-level specific natural recovery odds within 3 years.People with minimal TB at presentation had a 2% (95% CrI 0-11%) probability of TB death within 5 years vs. 40% (95% CrI 15-68) for those with far advanced disease. Individuals with minimal disease had 13.62 times the odds (95% CrI 9.87-19.10) of natural recovery within 3 years vs. those with far advanced disease.Mortality and natural recovery vary by disease severity at presentation. This supports continued work to evaluate individualized (e.g., shortened or longer) regimens based on disease severity at presentation, identified using radiography..

Survival of people with untreated TB: effects of time, geography and setting.

BACKGROUND: An estimated 40% of people who developed TB in 2021 were not diagnosed or treated. Pre-chemotherapy era data are a rich resource on survival of people with untreated TB. We aimed to identify heterogeneities in these data to inform their more precise use.METHODS: We extracted survival data from pre-chemotherapy era papers reporting TB-specific mortality and/or natural recovery data. We used Bayesian parametric survival analysis to model the survival distribution, stratifying by geography (North America vs. Europe), time (pre-1930 vs. post-1930), and setting (sanitoria vs. non-sanitoria).RESULTS: We found 12 studies with TB-specific mortality data. Ten-year survival was 69% in North America (95% CI 54-81) and 36% in Europe (95% CI 10-71). Only 38% (95% CI 18-63) of non-sanitorium individuals survived to 10 years compared to 69% (95% CI 41-87) of sanitoria/hospitalized patients. There were no significant differences between people diagnosed pre-1930 and post-1930 (5-year survival pre-1930: 65%, 95% CI 44-88 vs. post-1930: 72%, 95% CI 41-94).CONCLUSIONS: Mortality and natural recovery risks vary substantially by location and setting. These heterogeneities need to be considered when using pre-chemotherapy data to make inferences about expected survival of people with undiagnosed TB.

Characteristics and Effectiveness of Interventions That Target the Reporting, Communication, or Clinical Interpretation of Lumbar Imaging Findings: A Systematic Review.

BACKGROUND: Patients and clinicians may misinterpret the clinical importance of imaging findings in patients with low back pain, leading to potential harm related to overdiagnosis. PURPOSE: Our aims were to qualitatively summarize the characteristics of tested interventions that target the reporting, communication, or clinical interpretation of lumbar imaging findings and determine whether interventions are effective in improving low back pain-related health outcomes, health care use, or health care costs. DATA SOURCES: PubMed, MEDLINE, CINAHL, EMBASE, PsycINFO, and the Cochrane Library were searched from inception to October 20, 2021. STUDY SELECTION: The search retrieved 4394 articles, nine articles (seven studies) met the inclusion criteria to summarize intervention characteristics. Five of these studies had an adequate design for evaluating intervention effectiveness. DATA ANALYSES: Intervention characteristics were summarized using the Template for Intervention Description and Replication checklist. Effectiveness data were extracted from short, intermediate, and long-term follow-up points. Studies were assessed for risk of bias, and Grading of Recommendations Assessment, Development and Evaluation methodology was used to determine the certainty of the evidence. DATA SYNTHESIS: Four studies investigated the insertion of prevalence information into imaging reports. Single studies investigated withholding diagnostic information, education, and reassurance. Moderate-quality evidence (from 1 study) suggests that inserting prevalence information into imaging reports probably does not change the overall health care use in the long-term but may reduce opioid prescribing. LIMITATIONS: The available evidence is limited, and a meta-analysis was not possible. CONCLUSIONS: Further work is required to develop and test interventions that target the reporting, communication, and clinical interpretation of lumbar imaging findings that may reduce overdiagnosis and improve the management of low back pain.

Particle Analysis by Scanning Electron Microscopy With Energy Dispersive X-Ray Analysis in Pulmonary Pathology Specimens From U.S. Military Service Members Deployed During the Global War on Terror 2002 to 2015.

INTRODUCTION: Between 2001 and 2015, 2.77 million U.S. military service members completed over 5 million deployments to Southwest Asia. There are concerns that deployment-related environmental exposures may be associated with adverse pulmonary health outcomes. Accurate pulmonary diagnosis often requires histopathological biopsy. These lung biopsies are amenable to chemical analysis of retained particulates using scanning electron microscopy with energy dispersive X-ray analysis (SEM/EDXA). METHOD: A retrospective review of SEM/EDXA data collected in conjunction with pathologic diagnostic consultations at the Joint Pathology Center from 2011 to 2016 was conducted. Sections adjacent to those obtained for pathologic diagnosis were prepared for SEM/EDXA particle analysis, which provides qualitative identification of elements present in each particle and semiquantitative estimations of elemental weight percent. The review includes comparison of the particle analysis data and diagnostic findings, the particle count for the standard field analyzed, and types of particles identified. RESULTS: Nonneoplastic lung biopsy specimens from 25 deployed and 7 nondeployed U.S. service members were analyzed as part of the Joint Pathology Center pathologic consultations. The major exogenous particle types identified in both groups include aluminum silicates, other silicates, silica, and titanium dioxide. Endogenous particle types identified include calcium salts and iron-containing particles consistent with hemosiderin. These particles are present in deployed and nondeployed service members and are particle types commonly identified in lung biopsy specimens from urban dwelling adults. Rare particles containing other elements such as cerium and iron alloys were identified in some cases. Possible sources of these materials include diesel fuel and occupational and other environmental exposures. CONCLUSION: Scanning electron microscopy with energy dispersive X-ray particle analysis of inhaled particulates retained in lung tissue from deployed service members identifies particles commonly present in inhaled dust. In this small case series, we were not able to detect particle profiles that were common and unique to deployed patients only.

Clinical utility of skin cancer and melanoma risk scores for population screening: TRoPICS study.

BACKGROUND: Screening for skin cancer can be cost-effective if focused on high-risk groups. Risk prediction tools have been developed for keratinocyte cancers and melanoma to optimize advice and management. However, few have been validated in a clinical setting over the past few years. OBJECTIVES: To assess the clinical utility of risk assessment tools to identify individuals with prevalent skin cancers in a volunteer-based screening clinic. METHODS: Participants were adults presenting for a skin check at a volunteer-based skin cancer screening facility. We used previously published tools, based on questionnaire responses, to predict melanoma and keratinocyte cancers [KCs; basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] and classified each participant into one of five risk categories. Participants subsequently underwent a full skin examination by a dermatologist. All suspicious lesions were biopsied, and all cancers were histopathologically confirmed. RESULTS: Of 789 people who presented to the clinic, 507 (64%) consented to the study. Twenty-two BCCs, 19 SCCs and eight melanomas were diagnosed. The proportion of keratinocyte cancers diagnosed increased according to risk category from <1% in the lowest to 24% in the highest risk category (P < 0.001). Subtype analysis revealed similar proportionate increases in BCC or SCC prevalence according to risk category. However, a similar proportion of melanoma cases were detected in the low-risk and high-risk groups. CONCLUSION: The risk prediction model for keratinocyte cancers can reliably identify individuals with a significant skin cancer burden prior to a skin examination in the community setting. The prediction tool for melanoma needs to be tested in a larger sample exposed to a wider range of environmental risk factors.

A re-interpretation of the structure of the silver borate, Ag16B4O10, in the light of the extended Zintl-Klemm concept.

The borate Ag16B4O10 was synthesized at high temperature and at elevated oxygen pressures [Kovalevskiy et al. (2020). Chem. Sci. 11, 962-969]. Its structure consists of [B4O10]8- polyanions (isostructural to P4O10) embedded in an Ag matrix. According to the standard valences Ag+, B3+ and O2-, the formula has an excess of eight e- which the above authors proposed were located, pairwise, in four Ag4 tetrahedra within the silver substructure. That conclusion was based on the semiconducting and diamagnetic properties, as well as the very small `attractors' of the Electron Localization Function (ELF) found at the centre of these Ag4 tetrahedra. However, a large overlap of the projected density of states (DOS) of silver and oxygen indicated possible dispersion interactions between both atomic species. In this article, an alternative description is proposed based on the extended Zintl-Klemm concept. The anion [B4O10]8- can be formulated as Ψ-[N4O10] P4O10, if it is assumed that the eight e- are transferred to the four B atoms, so converting them into Ψ-N, this then makes sense of its similarity with P4O10, [N4(CH2)6], adamantane and tetraisopropyladamantane. When the Ag atoms connect to the O atoms, they arrange as the H atoms do in hexamethylenetetramine (HMTA). If the two lone pairs of each of the bridging O atoms in Ψ-[N4O10] are equated to the C-H bonds in HMTA, then, this same equivalence exists between the C-H bonds and the O-Ag bonds in the compound Ag16B4O10. The 24 Ag atoms surrounding each [B4O10]8- group prolong the sphalerite structure of the borate anion by means of Ag-O bonds which also fit the sphalerite structure formed of AgO. The eight excess electrons might then be distributed between the Ag and the O atoms, so making sense of the mixing of the Ag and O states. The Ag atoms bonded to the O atoms of the [B4O10]8- groups form a coat that interconnects the borate anions through Ag-O bonds. To establish the validity of this new proposal, the study needs to be extended to the compound Ag3B5O9.

A prospective study evaluating the integration of a multifaceted evidence-based medicine curriculum into early years in an undergraduate medical school.

BACKGROUND: The importance of ensuring medical students are equipped with the skills to be able to practice evidence-based medicine (EBM) has been increasingly recognized in recent years. However, there is limited information on an effective EBM curriculum for undergraduate medical schools. This study aims to test the feasibility of integrating a multifaceted EBM curriculum in the early years of an undergraduate medical school. This was subsequently evaluated using the validated Fresno test and students' self-reported knowledge and attitudes as they progressed through the curriculum. METHODS: EBM was integrated horizontally and vertically into the curriculum into the first 2 years of undergraduate medical school. First year medical students were recruited to participate in the study. The 212-point Fresno test was administered along with a locally developed questionnaire at baseline before EBM teaching in year one and at the end of EBM teaching in year two. RESULTS: Thirty-one students participated at baseline and 55 students participated at the end of second year EBM teaching. For the 18 students who completed the Fresno at both time points, the average score increased by 38.7 marks (p < 0.001) after EBM teaching. Students felt confident in formulating clinical questions and in critically appraising journal articles after EBM teaching. EBM was perceived to be important to their future practice as a doctor and for improving patient outcomes at both time points. CONCLUSIONS: It has been feasible to integrate a multifaceted, EBM curriculum from the first year of an undergraduate medical program. Early evaluation of the curriculum using the Fresno test has shown a significant increase in students' EBM knowledge. The curriculum also demonstrated an increase in students' perceptions of the clinical relevance of EBM in their developing practice.

Rationalization of the crystal structure of eudidymite Na2Be2[Si[4]6O15]·H2O in light of the extended Zintl-Klemm concept.

The structure of eudidymite is described in light of the extended Zintl-Klemm concept which considers that Na and Be atoms transfer their six valence electrons to the six Si atoms, converting them into Ψ-P which forms a skeleton characteristic of pentels (Group 15 elements) and is similar to that described in the compound (NH4)2Ge[6][Ge[4]6O15] when analysed in the same manner. The Si[4] skeleton is formed of bilayers that are connected through Be2O6 groups which are in fact fragments of the ß-BeO structure which bridge the two contiguous Si-bilayers by sharing O atoms. In this context, the Be atoms play a dual role, i.e. on the one hand converting the Si atoms into Ψ-P, on the other hand replicating fragments of its own ß-BeO structure. The Be atoms partially reproduce their own structure despite it being enclosed in a more complex network such as in Na2Be2[Si[4]6O15]·H2O. Calculations of the ionic strength I considering Si as Ψ-P is energetically more favourable than when I is calculated on the basis of tetravalent Si in the silicate, justifying this new approach of developing the theory of pseudo-structure generation. This approach offers a major new development in the study of crystal structures.

The Joint Pathology Center/Vision Center of Excellence Approach to Analyzing Intra-Ocular "Foreign Bodies".

BACKGROUND: The Military Health System recognizes the importance of analyzing "foreign bodies" removed from US service members through several policy documents. This activity focuses on detecting potentially toxic metals. Intra-ocular "foreign bodies" (IOFBs) represent a small, clinically important subset. The development of ocular metallosis with iron and copper fragments is a specific local reaction to IOFBs. The results of the compositional analysis of removed IOFBs can influence clinical management decisions aimed at optimizing the preservation of sight. METHOD: The Joint Pathology Center (JPC) and Vision Center of Excellence (VCE) have established a pathway for the analysis of IOFBs removed from Department of Defense and Veterans Health Administration patients. The analysis of IOFBs uses analytical methods to provide information about the fragments' surface elemental and molecular composition. RESULTS: Metallic specimens analyzed included iron and copper-containing fragments. Non-metallic IOFBs analyzed include glass, plastic (polyurethane), and nitro-cellulose fragments. CONCLUSION: The JPC/VCE approach to analyzing IOFBs promotes uniform handling and shipping of specimens to minimize contamination. The analytical approach allows for the characterization of IOFBs with a wide variety of compositions. The results support clinical management decisions aimed at optimal treatment for the preservation of patients' visual acuity.

Quantifying TB transmission: a systematic review of reproduction number and serial interval estimates for tuberculosis.

Tuberculosis (TB) is the leading global infectious cause of death. Understanding TB transmission is critical to creating policies and monitoring the disease with the end goal of TB elimination. To our knowledge, there has been no systematic review of key transmission parameters for TB. We carried out a systematic review of the published literature to identify studies estimating either of the two key TB transmission parameters: the serial interval (SI) and the reproductive number. We identified five publications that estimated the SI and 56 publications that estimated the reproductive number. The SI estimates from four studies were: 0.57, 1.42, 1.44 and 1.65 years; the fifth paper presented age-specific estimates ranging from 20 to 30 years (for infants <1 year old) to <5 years (for adults). The reproductive number estimates ranged from 0.24 in the Netherlands (during 1933-2007) to 4.3 in China in 2012. We found a limited number of publications and many high TB burden settings were not represented. Certain features of TB dynamics, such as slow transmission, complicated parameter estimation, require novel methods. Additional efforts to estimate these parameters for TB are needed so that we can monitor and evaluate interventions designed to achieve TB elimination.

Digestive gland inclusion bodies in queen conch (Lobatus gigas) are non-parasitic.

Unusual inclusion bodies occur within the epithelial cells of the digestive gland of queen conch, Lobatus gigas, and have previously been described as apicomplexan parasites. The aim of this study was to investigate the parasitic features of these inclusion bodies in queen conch. L. gigas from St. Kitts (Caribbean Sea) consistently (100% of n = 61) showed large numbers of ovoid to tri-bulbous dark brown inclusion bodies (15 × 30 µm) within vacuolar cells. Histochemical stains demonstrated iron, melanin, and glycoprotein and/or mucopolysaccharide within the inclusion bodies. Microscopic features indicative of a host response to injury were lacking in every case, as were consistent morphological forms to indicate distinct parasitic stages. Transmission electron microscopy failed to reveal cellular organelles of parasitic organisms and DNA extractions of purified inclusion bodies did not yield sufficient concentrations for successful PCR amplification. Scanning electron microscopy with energy dispersive X-ray analysis revealed a number of elements, particularly iron, within the inclusion bodies. We conclude that the inclusion bodies are not an infectious agent, and hypothesize that they represent a storage form for iron, and potentially other elements, within a protein matrix. Similar structures have been described in the digestive glands of other invertebrates, including prosobranchs.

The burden of multidrug-resistant tuberculosis in children.

BACKGROUND: Childhood tuberculosis (TB) has historically been neglected, although in recent years there has been increased focus on this problem. In particular, there have been two efforts to estimate the burden of pediatric multidrug-resistant TB (MDR-TB). METHODS: We review current estimates of the global incidence of pediatric MDR-TB disease. We then combine pediatric MDR-TB treatment data from the World Health Organization and recently published case fatality ratio estimates for children with TB to produce mortality estimates for children with MDR-TB. Finally, we combine treatment data and estimates of household size and disease risk to estimate how many children could be treated for probable or confirmed MDR-TB by carrying out household contact investigations around adult MDR-TB patients. RESULTS: Between 25 000 and 32 000 children develop MDR-TB disease annually, accounting for around 3% of all pediatric TB cases. Only 3-4% of these children are likely to receive MDR-TB treatment. We estimate that around 21% of children who develop MDR-TB disease will die. Carrying out household contact investigations around adult MDR-TB patients could find an estimated 12 times as many pediatric MDR-TB cases as are currently being identified. DISCUSSION: The diagnosis and treatment of children with MDR-TB needs to be prioritized by TB programs.

Estimating the global burden of multidrug-resistant tuberculosis among prevalent cases of tuberculosis.

BACKGROUND: Estimates of the multidrug-resistant tuberculosis (MDR-TB) burden are based on incomplete, infrequently updated data among a limited pool of notified or incident pulmonary TB cases. METHODS: Using World Health Organization data reported by 217 countries/territories in 2014, we calculated the MDR-TB burden among prevalent TB cases and compared these with estimates among incident and notified TB patients. We also compared treatment coverage across estimates. RESULTS: Among prevalent TB patients worldwide in 2014, we estimate that 555 545 (95% credible bounds 499 340-617 391) MDR-TB cases occurred. This is 85% more than the 300 000 estimated among notified cases, and 16% more than the 480 000 among incident cases. Only 20% of MDR-TB cases among prevalent-compared to 37% of MDR-TB among notified-TB patients had access to MDR-TB treatment. Applying prior estimates, only 10% of MDR-TB cases will have successful outcomes. CONCLUSION: Estimates based on likely-to-be-diagnosed cases of MDR-TB overlook a significant proportion of morbidity, mortality, and transmission that occur in undiagnosed, untreated, prevalent TB patients. Even though it may still likely underestimate the true disease burden, MDR-TB among patients with prevalent TB represents a closer approximation of disease burden than currently reported indicators. Progress toward elimination or control depends on policies guided by a more complete representation of the disease burden.

Effect of Therapeutic and Supratherapeutic Doses of Vonoprazan on the QT/QTc Interval in a Phase I Randomized Study in Healthy Subjects.

This phase I, randomized, 4-period, 4-sequence, double-blind, active- and placebo-controlled, crossover study assessed the effects of vonoprazan on the QT/QTc interval in healthy subjects. Subjects received single oral doses of vonoprazan 40 mg, vonoprazan 120 mg, moxifloxacin 400 mg (positive control/open label), and placebo. The primary end point was time-matched, placebo-corrected, baseline-adjusted mean Fridericia-corrected QT interval (ddQTcF). Of 64 subjects (mean age, 37.8 years; 50% male), 63 received all four regimens. One subject discontinued due to nondrug-related adverse event of tonsillitis. Assay sensitivity was established; lower bound of the one-sided 95% confidence interval (CI) for ddQTcF was >5 ms between 1.5 and 12 h following moxifloxacin administration. For both doses of vonoprazan, the one-sided upper 95% CI ddQTcF did not exceed 10 ms. There was no correlation between plasma vonoprazan concentrations and increases in ddQTcF. Vonoprazan was well tolerated. No severe adverse events/deaths were reported. (European Clinical Trials Database Registry: 2011-004003-20.).

Isoniazid-resistant tuberculosis: a cause for concern?

The drug isoniazid (INH) is a key component of global tuberculosis (TB) control programmes. It is estimated, however, that 16.1% of TB disease cases in the former Soviet Union countries and 7.5% of cases outside of these settings have non-multidrug-resistant (MDR) INH resistance. Resistance has been linked to poorer treatment outcomes, post-treatment relapse and death, at least for specific sites of disease. Multiple genetic loci are associated with phenotypic resistance; however, the relationship between genotype and phenotype is complex, and restricts the use of rapid sequencing techniques as part of the diagnostic process to determine the most appropriate treatment regimens for patients. The burden of resistance also influences the usefulness of INH preventive therapy. Despite seven decades of INH use, our knowledge in key areas such as the epidemiology of resistant strains, their clinical consequences, whether tailored treatment regimens are required and the role of INH resistance in fuelling the MDR-TB epidemic is limited. The importance of non-MDR INH resistance needs to be re-evaluated both globally and by national TB control programmes.

Pediatric multidrug-resistant tuberculosis clinical trials: challenges and opportunities.

On June 17, 2016, RESIST-TB, IMPAACT, Vital Strategies, and New Ventures jointly hosted the Pediatric Multidrug Resistant Tuberculosis Clinical Trials Landscape Meeting in Arlington, Virginia, USA. The meeting provided updates on current multidrug-resistant tuberculosis (MDR-TB) trials targeting pediatric populations and adult trials that have included pediatric patients. A series of presentations were given that discussed site capacity needs, community engagement, and additional interventions necessary for clinical trials to improve the treatment of pediatric MDR-TB. This article presents a summary of topics discussed, including the following: current trials ongoing and planned; the global burden of MDR-TB in children; current regimens for MDR-TB treatment in children; pharmacokinetics of second-line anti-tuberculosis medications in children; design, sample size, and statistical considerations for MDR-TB trials in children; selection of study population, design, and treatment arms for a trial of novel pediatric MDR-TB regimens; practical aspects of pediatric MDR-TB treatment trials; and strategies for integrating children into adult tuberculosis trials. These discussions elucidated barriers to pediatric MDR-TB clinical trials and provided insight into necessary next steps for progress in this field. Investigators and funding agencies need to respond to these recommendations so that important studies can be implemented, leading to improved treatment for children with MDR-TB.