Gold Standard Cholera Diagnostics Are Tarnished by Lytic Bacteriophage and Antibiotics.

A fundamental, clinical, and scientific concern is how lytic bacteriophage, as well as antibiotics, impact diagnostic positivity. Cholera was chosen as a model disease to investigate this important question, because cholera outbreaks enable large enrollment, field methods are well established, and the predatory relationship between lytic bacteriophage and the etiologic agent Vibrio cholerae share commonalities across bacterial taxa. Patients with diarrheal disease were enrolled at two remote hospitals in Bangladesh. Diagnostic performance was assessed as a function of lytic bacteriophage detection and exposure to the first-line antibiotic azithromycin, detected in stool samples by mass spectrometry. Among diarrheal samples positive by nanoliter quantitative PCR (qPCR) for V. cholerae (n = 78/849), the odds that a rapid diagnostic test (RDT) or qPCR was positive was reduced by 89% (odds ratio [OR], 0.108; 95% confidence interval [CI], 0.002 to 0.872) and 87% (OR, 0.130; 95% CI, 0.022 to 0.649), respectively, when lytic bacteriophage were detected. The odds that an RDT or qPCR was positive was reduced by more than 99% (OR, 0.00; 95% CI, 0.00 to 0.28) and 89% (OR, 0.11; 95% CI, 0.03 to 0.44), respectively, when azithromycin was detected. Analysis of additional samples from South Sudan found similar phage effects on RDTs; antibiotics were not assayed. Cholera burden estimates may improve by accommodating for the negative effects of lytic bacteriophage and antibiotic exposure on diagnostic positivity. One accommodation is using bacteriophage detection as a proxy for pathogen detection. These findings have relevance for other diagnostic settings where bacterial pathogens are vulnerable to lytic bacteriophage predation.

Risk of self-reported symptoms or diagnosis of active tuberculosis in relationship to low body mass index, diabetes and their co-occurrence.

OBJECTIVE: Globally, tuberculosis prevalence has declined, but its risk factors have varied across place and time - low body mass index (BMI) has persisted while diabetes has increased. Using India's National Family Health Survey (NFHS), wave 3 and World Health Survey (WHS) data, we examined their relationships to support projection of future trends and targeted control efforts. METHODS: Multivariate logistic regressions at the individual level with and without diabetes/BMI interactions assessed the relationship between tuberculosis, diabetes and low BMI and the importance of risk factor co-occurrence. Population-level analyses examined how tuberculosis incidence and prevalence varied with diabetes/low BMI co-occurrence. RESULTS: In NFHS, diabetic individuals had higher predicted tuberculosis risks (diabetic vs. non-diabetic: 2.50% vs. 0.63% at low BMI; 0.81% vs. 0.20% at normal BMI; 0.37% vs. 0.09% at high BMI), which were not significantly different when modelled independently or allowing for risk modification with diabetes/low BMI co-occurrence. WHS findings were generally consistent. Population-level analysis found that diabetes/low BMI co-occurrence may be associated with elevated tuberculosis risk, although its predicted effect on tuberculosis incidence/prevalence was generally ≤0.2 percentage points and not robustly statistically significant. CONCLUSIONS: Concerns about the additional elevation of tuberculosis risk from diabetes/low BMI co-occurrence and hence the need to coordinate tuberculosis control efforts around the nexus of co-occurring diabetes and low BMI may be premature. However, study findings robustly support the importance of individually targeting low BMI and diabetes as part of ongoing tuberculosis control efforts.

[The epidemiological advantage of preferential targeting of tuberculosis control at the poor]. / La ventaja epidemiológica de la orientación preferencial del control de la tuberculosis hacia los pobres.

Tuberculosis (TB) remains disproportionately concentrated among the poor, yet known determinants of TB reactivation may fail to explain observed disparities in disease rates according to wealth. Reviewing data on TB disparities in India and the wealth distribution of known TB risk factors, we describe how social mixing patterns could be contributing to TB disparities. Wealth-assortative mixing, whereby individuals are more likely to be in contact with others from similar socio-economic backgrounds, amplifies smaller differences in risk of TB, resulting in large population-level disparities. As disparities and assortativeness increase, TB becomes more difficult to control, an effect that is obscured by looking at population averages of epidemiological parameters, such as case detection rates. We illustrate how TB control efforts may benefit from preferential targeting toward the poor. In India, an equivalent-scale intervention could have a substantially greater impact if targeted at those living below the poverty line than with a population-wide strategy. In addition to potential efficiencies in targeting higher-risk populations, TB control efforts would lead to a greater reduction in secondary TB cases per primary case diagnosed if they were preferentially targeted at the poor. We highlight the need to collect programmatic data on TB disparities and explicitly incorporate equity considerations into TB control plans.

The impact of sputum quality on Xpert positivity in active case-finding for TB.

BACKGROUND: Studies evaluating sputum quality and Xpert® MTB/RIF positivity in the context of active case finding are scarce. We aimed to determine whether sputum quality is associated with Xpert positivity and whether the association differed according to demographic and clinical characteristics.METHODS: A cross-sectional analysis using data from a mass screening programme in Brazilian prisons was conducted from 2017 to 2021. We administered a standardised questionnaire, obtained a chest X-ray and collected a spot sputum sample for Xpert testing. Sputum quality was classified as 'salivary', 'mucoid/mucopurulent' or 'blood-stained'. We used log binomial regressions to estimate the relationship between sputum quality and Xpert positivity, assessing interactions with participant characteristics.RESULTS: Among 4,368 participants for whom sputum quality was assessed, 957 (21.9%) produced salivary specimens, 3,379 (77.4%) had mucoid/mucopurulent sputum and 32 (0.7%) had blood-stained sputum. Xpert positivity was higher among those with mucoid/mucopurulent sputum than among those with salivary samples (12.0% vs. 3.7%). Mucopurulent sputum independently predicted Xpert positivity among individuals with and without symptoms, current smoking and abnormal chest radiographs on CAD4TB.CONCLUSIONS: In our study, sputum appearance independently predicted Xpert positivity, and could be used together with chest X-ray and symptom screening to inform use of Xpert in individual or pooled testing.

Clinical predictors for the aetiology of peripheral lymphadenopathy in HIV-infected adults.

OBJECTIVES: The aim of the study was to determine the aetiology and clinical predictors of peripheral lymphadenopathy in HIV-infected individuals during the antiretroviral (ARV) era in a nontuberculosis endemic setting. METHODS: A multicentred, retrospective cohort study of peripheral lymph node biopsies in HIV-positive adults was carried out. A total of 107 charts were identified and reviewed for clinical features, lymphadenopathy size, and ARV use and duration. Biopsy results were categorized, and multivariate logistic regression determined independent predictors of lymphadenopathy aetiology. RESULTS: Evaluation of 107 peripheral lymph node biopsies revealed that 42.9% of peripheral lymphadenopathy was attributable to malignancy, 49.5% to reactive changes, and 7.5% to infections, with only 2.8% of all cases secondary to tuberculosis. Fevers, weight loss, ARV use, and lower viral loads are significantly associated with nonreactive lymphadenopathy. CONCLUSIONS: Lymphadenopathy is likely to be reactive or malignant in nontuberculosis endemic regions. Readily available clinical features can aid clinicians in predicting the underlying aetiology, those at risk for malignancy, and who to biopsy.

The effect of incarceration on TB treatment outcomes.

BACKGROUND: TB notifications in Latin American prisons have more than doubled over the past two decades; however, treatment outcomes and their determinants among incarcerated individuals in this region are not well understood.METHODS: Newly diagnosed drug-susceptible TB cases reported to Brazil´s Information System for Notifiable Diseases (Sistema de Informação de Agravos de Notificação, SINAN) between January 2015 and December 2017 were included. Multivariate logistic regression was used to assess socio-economic and clinical factors associated with treatment success among incarcerated individuals.RESULTS: Incarcerated individuals (n = 17,776) had greater treatment success than non-incarcerated individuals (n = 160,728; 82.2% vs. 75.1%; P < 0.0001), including after adjusting for demographic and clinical risk factors (adjusted odds ratio aOR 1.27, 95% CI 1.19-1.34). These differences were partially mediated by increased use of directly observed therapy among incarcerated individuals (DOT) (61% vs. 47%; P < 0.001), which was associated with greater efficacy in the incarcerated population (aOR 2.56 vs. aOR 2.17; P < 0.001). DOT was associated with improved treatment success among incarcerated subpopulations at elevated risk of poor outcomes.CONCLUSION: TB treatment success among incarcerated individuals in Brazil is higher than non-incarcerated individuals, but both fall below WHO targets. Expanding the use of DOT and services for socially and medically vulnerable individuals may improve outcomes in carceral settings.

Seasonal drivers of tuberculosis: evidence from over 100 years of notifications in Cape Town.

BACKGROUND: Tuberculosis incidence varies seasonally in many settings. However, the role of seasonal variation in reactivation vs. transmission is unclear.METHODS: We reviewed data on TB notifications in Cape Town, South Africa, from 1903 to 2017 (exclusive of 1995-2002, which were unavailable). Data from 2003 onward were stratified by HIV status, age and notification status (new vs. retreatment). We performed seasonal decomposition and time-dependent spectral analysis using wavelets to assess periodicity over time. We estimated monthly peak-to-peak seasonal amplitude of notifications as a percentage of the annual notification rate.RESULTS: A seasonal trend was intermittently detected between 1904 and 1994, particularly during periods of high notification rates, but was consistently and strongly evident between 2003 and 2017, with peaks in September through November, following winter. Among young children, a second, higher seasonal peak was observed in March. Seasonal variation was greater in children (<5 years, 54%, 95% CI 47-61; 5-14 years, 63%, 95% CI 58-69) than in adults (36%, 95% CI 33-39).CONCLUSIONS: Stronger seasonal effects were seen in children, in whom progression following recent infection is known to be the predominant driver of disease. These findings may support increased transmission in the winter as an important driver of TB in Cape Town.

Temporal trends in the prevalence of Mycobacterium tuberculosis infection in South African adolescents.

South Africa. 1) To measure changes in the adolescent prevalence of latent tuberculous infection (LTBI) between 2005 and 2015, and 2) to evaluate medium-term impact of TB control measures on LTBI prevalence. We compared baseline data from a cohort study (2005-2007) and a vaccine trial (2014-2015) which enrolled adolescents from the same eight South African high schools. LTBI was defined based on QuantiFERON®-TB Gold In-Tube test positivity. We analysed data from 4880 adolescents between 2005 and 2007, and 1968 adolescents between 2014 and 2015, when the average LTBI prevalence was respectively 43.8% (95%CI 28.4-59.1) vs. 48.5% (95%CI 41.1-55.8). Age-specific LTBI prevalence increased between the ages 12 and 18 years by 13% only in lower socio-economic quintile schools, where the average LTBI prevalence was unchanged between the two periods (54% vs. 53%). In the highest socio-economic quintile schools, LTBI prevalence did not increase with age; however, the average LTBI prevalence increased from 20% to 38% between the two periods. Adolescent LTBI prevalence remained high and constant over a decade, suggesting that Mycobacterium tuberculosis transmission to children was not impacted in the medium term by effective TB control efforts. Trends in adolescent LTBI prevalence should be interpreted in the context of the sociodemographic factors that affect the risk of transmission before and during adolescence. .

Disease ecology, health and the environment: a framework to account for ecological and socio-economic drivers in the control of neglected tropical diseases.

Reducing the burden of neglected tropical diseases (NTDs) is one of the key strategic targets advanced by the Sustainable Development Goals. Despite the unprecedented effort deployed for NTD elimination in the past decade, their control, mainly through drug administration, remains particularly challenging: persistent poverty and repeated exposure to pathogens embedded in the environment limit the efficacy of strategies focused exclusively on human treatment or medical care. Here, we present a simple modelling framework to illustrate the relative role of ecological and socio-economic drivers of environmentally transmitted parasites and pathogens. Through the analysis of system dynamics, we show that periodic drug treatments that lead to the elimination of directly transmitted diseases may fail to do so in the case of human pathogens with an environmental reservoir. Control of environmentally transmitted diseases can be more effective when human treatment is complemented with interventions targeting the environmental reservoir of the pathogen. We present mechanisms through which the environment can influence the dynamics of poverty via disease feedbacks. For illustration, we present the case studies of Buruli ulcer and schistosomiasis, two devastating waterborne NTDs for which control is particularly challenging.This article is part of the themed issue 'Conservation, biodiversity and infectious disease: scientific evidence and policy implications'.

The mass miniature chest radiography programme in Cape Town, South Africa, 1948 - 1994: The impact of active tuberculosis case finding.

BACKGROUND: Tuberculosis (TB) control programmes rely mainly on passive detection of symptomatic individuals. The resurgence of TB has rekindled interest in active case finding. Cape Town (South Africa) had a mass miniature radiography (MMR) screening programme from 1948 to 1994. OBJECTIVE: To evaluate screening coverage, yield and secular trends in TB notifications during the MMR programme. METHODS: We performed an ecological analysis of the MMR programme and TB notification data from the City of Cape Town Medical Officer of Health reports for 1948 - 1994. RESULTS: Between 1948 and 1962, MMR screening increased to 12% of the population per annum with yields of 14 cases per 1 000 X-rays performed, accounting for >20% of total annual TB notifications. Concurrent with increasing coverage (1948 - 1965), TB case notification decreased in the most heavily TB-burdened non-European population from 844/100 000 population to 415/100 000. After 1966, coverage declined and TB notifications that initially remained stable (1967 - 1978) subsequently increased to 525/100 000. MMR yields remained low in the European population but declined rapidly in the non-European population after 1966, coincidental with forced removals from District 6. An inverse relationship between screening coverage and TB notification rates was observed in the non-European adult population. Similar secular trends occurred in infants and young children who were not part of the MMR screening programme. CONCLUSION: MMR of a high-burdened population may have significantly contributed to TB control and was temporally associated with decreased transmission to infants and children. These historical findings emphasise the importance of re-exploring targeted active case finding strategies as part of population TB control.

The epidemiological advantage of preferential targeting of tuberculosis control at the poor.

Tuberculosis (TB) remains disproportionately concentrated among the poor, yet known determinants of TB reactivation may fail to explain observed disparities in disease rates according to wealth. Reviewing data on TB disparities in India and the wealth distribution of known TB risk factors, we describe how social mixing patterns could be contributing to TB disparities. Wealth-assortative mixing, whereby individuals are more likely to be in contact with others from similar socio-economic backgrounds, amplifies smaller differences in risk of TB, resulting in large population-level disparities. As disparities and assortativeness increase, TB becomes more difficult to control, an effect that is obscured by looking at population averages of epidemiological parameters, such as case detection rates. We illustrate how TB control efforts may benefit from preferential targeting toward the poor. In India, an equivalent-scale intervention could have a substantially greater impact if targeted at those living below the poverty line than with a population-wide strategy. In addition to potential efficiencies in targeting higher-risk populations, TB control efforts would lead to a greater reduction in secondary TB cases per primary case diagnosed if they were preferentially targeted at the poor. We highlight the need to collect programmatic data on TB disparities and explicitly incorporate equity considerations into TB control plans.

Benefit, risk, and optimization by ROC analysis in cancer radiotherapy.

The objective of definitive cancer radiation therapy is cure or control. The attainment of that objective is not without risk of treatment-induced radiation injury. The optimum treatment is, therefore, that level of radiotherapeutic effect with the maximum probability of benefit and the minimum associated probability of injury. An objective of radiotherapy research is the formulation of a model of optimization that is independent of a consensus of what constitutes optimization. Receiver operating characteristic (ROC) analysis is such a model, for it can relate probabilities of benefit and injury yielding a graphical determination of the optimum level of radiotherapeutic effect. ROC analysis is explained, an example taken from the contemporary radiotherapy literature is presented, and clinical research requirements for a general application of ROC analysis to the optimization of definitive cancer radiotherapy are developed.

Identification of Trichinella pseudospiralis from a human case using random amplified polymorphic DNA.

A human case of infection by Trichinella pseudospiralis has recently been described. Some morphologic anomalies of the muscle larvae, however, raise the possibility of an incorrect taxonomic attribution. A molecular taxonomic approach has therefore been applied for the identification of the parasite. Random amplified polymorphic DNAs were obtained from a single larva extracted from a muscle biopsy of the suspected case of T. pseudospiralis infection, and compared with those derived from 27 reference strains of Trichinella spp. Nearly identical amplification patterns were obtained from the suspected larva and from reference strains of T. pseudospiralis, thus supporting the original morphology-based identification. An enzyme-linked immunosorbent assay and Western blots carried out on pretreatment and post-treatment sera provided further confirmation.

Trichinella pseudospiralis in humans: description of a case and its treatment.

The first known human case of Trichinella pseudospiralis myositis is described. A 33 years old woman reported 5 years of relatively mild symptoms of tiredness, muscle fatigue and muscle pain after exercise. She had minimal proximal weakness. Creatinine kinase was significantly elevated, and muscle biopsy showed polymyositis and Trichinella larvae. Steroid treatment dramatically worsened the weakness. Treatment with albendazole led to complete resolution of symptoms and laboratory abnormalities. Diagnosis and identification of the parasite were based on the distinctive appearance of the unencapsulated larvae and their movement in fresh muscle, plus clinical and laboratory findings.

Biomechanics of overhand throwing with implications for injuries.

Proper throwing mechanics may enable an athlete to achieve maximum performance with minimum chance of injury. While quantifiable differences do exist in proper mechanics for various sports, certain similarities are found in all overhand throws. One essential property is the utilisation of a kinetic chain to generate and transfer energy from the larger body parts to the smaller, more injury-prone upper extremity. This kinetic chain in throwing includes the following sequence of motions: stride, pelvis rotation, upper torso rotation, elbow extension, shoulder internal rotation and wrist flexion. As each joint rotates forward, the subsequent joint completes its rotation back into a cocked position, allowing the connecting segments and musculature to be stretched and eccentrically loaded. Most notable is the external rotation of the shoulder, which reaches a maximum value of approximately 180 degrees. This biomechanical measurement is a combination of true glenohumeral rotation, trunk hyperextension and scapulothoracic motion. Near the time of maximum shoulder external rotation (ERmax), shoulder and elbow musculature eccentrically contract to produce shoulder internal rotation torque and elbow varus torque. Both the shoulder and the elbow are susceptible to injury at this position. At ball release, significant energy and momentum have been transferred to the ball and throwing arm. After ball release, a kinetic chain is used to decelerate the rapidly moving arm with the entire body. Shoulder and elbow muscles produce large compressive forces to resist joint distraction. Both joints are susceptible to injury during arm deceleration.

Effects of throwing overweight and underweight baseballs on throwing velocity and accuracy.

The purpose of this review is to determine how throwing overweight and underweight baseballs affects baseball throwing velocity and accuracy. Two studies examined how a warm-up with overweight baseballs affected throwing velocity and accuracy of 5 oz regulation baseballs. One of these studies showed significant increases in throwing velocity and accuracy, while the other study found no significant differences. Three training studies (6 to 12 weeks in duration) using overweight baseballs were conducted to determine how they affected ball accuracy while throwing regulation baseballs. No significant differences were found in any study. From these data it is concluded that warming up or training with overweight baseballs does not improve ball accuracy. Seven overweight and 4 underweight training studies (6 to 12 weeks in duration) were conducted to determine how throwing velocity of regulation baseballs was affected due to training with these overweight and underweight baseballs. The overweight baseballs ranged in weight from 5.25 to 17 oz, while the underweight baseballs were between 4 and 4.75 oz. Data from these training studies strongly support the practice of training with overweight and underweight baseballs to increase throwing velocity of regulation baseballs. Since no injuries were reported throughout the training studies, throwing overweight and underweight baseballs may not be more stressful to the throwing arm compared to throwing regulation baseballs. However, since currently there are no injury data related to throwing overweight and underweight baseballs, this should be the focus of subsequent studies. In addition, research should be initiated to determine whether throwing kinematics and kinetics are different between throwing regulation baseballs and throwing overweight and underweight baseballs.

Synthesis of tritium labeled Ac-[Nle4, D-Phe7]-alpha-MSH4-11-NH2: a superpotent melanotropin with prolonged biological activity.

Ac-[Nle4, D-Phe7]-alpha-MSH4-11-NH2 an octapeptide, is a melanotropin analogue (Ac-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-NH2), which is a superpotent agonist of frog and lizard skin melanocytes and mouse S 91 (Cloudman) melanoma cells. This melanotropin possesses ultraprolonged activity on melanocytes, both in vitro and in vivo, and the peptide is resistant to inactivation by serum enzymes. The tritium-labeled congener was prepared by direct incorporation of [3H]-labeled norleucine into the peptide. The melanotropic activity of the labeled peptide is identical to the unlabeled analogue. This labeled peptide should be useful for studies on the localization and characterization of melanotropin receptors.

A three-dimensional biomechanical analysis of the squat during varying stance widths.

PURPOSE: The purpose of this study was to quantify biomechanical parameters employing two-dimensional (2-D) and three-dimensional (3-D) analyses while performing the squat with varying stance widths. METHODS: Two 60-Hz cameras recorded 39 lifters during a national powerlifting championship. Stance width was normalized by shoulder width (SW), and three stance groups were defined: 1) narrow stance squat (NS), 107 +/- 10% SW; 2) medium stance squat (MS), 142 +/- 12% SW; and 3) wide stance squat (WS), 169 +/- 12% SW. RESULTS: Most biomechanical differences among the three stance groups and between 2-D and 3-D analyses occurred between the NS and WS. Compared with the NS at 45 degrees and 90 degrees knee flexion angle (KF), the hips flexed 6-11 degrees more and the thighs were 7-12 degrees more horizontal during the MS and WS. Compared with the NS at 90 degrees and maximum KF, the shanks were 5-9 degrees more vertical and the feet were turned out 6 degrees more during the WS. No significant differences occurred in trunk positions. Hip and thigh angles were 3-13 degrees less in 2-D compared with 3-D analyses. Ankle plantar flexor (10-51 N.m), knee extensor (359-573 N.m), and hip extensor (275-577 N.m) net muscle moments were generated for the NS, whereas ankle dorsiflexor (34-284 N.m), knee extensor (447-756 N.m), and hip extensor (382-628 N.m) net muscle moments were generated for the MS and WS. Significant differences in ankle and knee moment arms between 2-D and 3-D analyses were 7-9 cm during the NS, 12-14 cm during the MS, and 16-18 cm during the WS. CONCLUSIONS: Ankle plantar flexor net muscle moments were generated during the NS, ankle dorsiflexor net muscle moments were produced during the MS and WS, and knee and hip moments were greater during the WS compared with the NS. A 3-D biomechanical analysis of the squat is more accurate than a 2-D biomechanical analysis, especially during the WS.

A three-dimensional biomechanical analysis of sumo and conventional style deadlifts.

PURPOSE: Strength athletes often employ the deadlift in their training or rehabilitation regimens. The purpose of this study was to quantify kinematic and kinetic parameters by employing a three-dimensional analysis during sumo and conventional style deadlifts. METHODS: Two 60-Hz video cameras recorded 12 sumo and 12 conventional style lifters during a national powerlifting championship. Parameters were quantified at barbell liftoff (LO), at the instant the barbell passed the knees (KP), and at lift completion. Unpaired t-tests (P < 0.05) were used to compare all parameters. RESULTS: At LO and KP, thigh position was 11-16 degrees more horizontal for the sumo group, whereas the knees and hips extended approximately 12 degrees more for the conventional group. The sumo group had 5-10 degrees greater vertical trunk and thigh positions, employed a wider stance (70 +/- 11 cm vs 32 +/- 8 cm), turned their feet out more (42 +/- 8 vs 14 +/- 6 degrees). and gripped the bar with their hands closer together (47 +/- 4 cm vs 55 +/- 10 cm). Vertical bar distance, mechanical work, and predicted energy expenditure were approximately 25-40% greater in the conventional group. Hip extensor, knee extensor, and ankle dorsiflexor moments were generated for the sumo group, whereas hip extensor, knee extensor, knee flexor, and ankle plantar flexor moments were generated for the conventional group. Ankle and knee moments and moment arms were significantly different between the sumo and conventional groups, whereas hip moments and moments arms did not show any significantly differences. Three-dimensional calculations were more accurate and significantly different than two-dimensional calculations, especially for the sumo deadlift. CONCLUSIONS: Biomechanical differences between sumo and conventional deadlifts result from technique variations between these exercises. Understanding these differences will aid the strength coach or rehabilitation specialist in determining which deadlift style an athlete or patient should employ.