Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus.

BACKGROUND: The appropriate antibiotic treatment for severe scrub typhus, a neglected but widespread reemerging zoonotic infection, is unclear. METHODS: In this multicenter, double-blind, randomized, controlled trial, we compared the efficacy of intravenous doxycycline, azithromycin, or a combination of both in treating severe scrub typhus. Patients who were 15 years of age or older with severe scrub typhus with at least one organ involvement were enrolled. The patients were assigned to receive a 7-day course of intravenous doxycycline, azithromycin, or both (combination therapy). The primary outcome was a composite of death from any cause at day 28, persistent complications at day 7, and persistent fever at day 5. RESULTS: Among 794 patients (median age, 48 years) who were included in the modified intention-to-treat analysis, complications included those that were respiratory (in 62%), hepatic (in 54%), cardiovascular (in 42%), renal (in 30%), and neurologic (in 20%). The use of combination therapy resulted in a lower incidence of the composite primary outcome than the use of doxycycline (33% and 47%, respectively), for a risk difference of -13.3 percentage points (95% confidence interval [CI], -21.6 to -5.1; P = 0.002). The incidence with combination therapy was also lower than that with azithromycin (48%), for a risk difference of -14.8 percentage points (95% CI, -23.1 to -6.5; P<0.001). No significant difference was seen between the azithromycin and doxycycline groups (risk difference, 1.5 percentage points; 95% CI, -7.0 to 10.0; P = 0.73). The results in the per-protocol analysis were similar to those in the primary analysis. Adverse events and 28-day mortality were similar in the three groups. CONCLUSIONS: Combination therapy with intravenous doxycycline and azithromycin was a better therapeutic option for the treatment of severe scrub typhus than monotherapy with either drug alone. (Funded by the India Alliance and Wellcome Trust; INTREST Clinical Trials Registry-India number, CTRI/2018/08/015159.).

The incidence of Orientia tsutsugamushi infection in rural South India.

Scrub typhus is a common bacterial infection in Asia caused by Orientia tsutsugamushi. This serological cohort study estimated the incidence of infection in a rural population in South India. Participants were enrolled through systematic sampling in 46 villages at baseline, and revisited the following year. Blood samples were tested for IgG antibodies using ELISA, followed by indirect immunofluorescence assays (IFA) in those positive for ELISA at both rounds. A case was defined as sero-conversion (ELISA), or at least a 4-fold titre increase (IFA), between the two time points. In addition to crude incidence rate estimates, we used piecewise linear rates across calendar months, with rates proportional to the monthly incidence of local hospital cases to address seasonality and unequal follow-up times. Of 402 participants, 61.7% were female. The mean age was 46.7 years, (range 13-88). 21 participants showed evidence for serological infection. The estimated incidence was 4.4 per 100 person-years (95% CI 2.8-6.7). The piecewise linear rates approach resulted in a similar estimate of 4.6 per 100 person years (95% CI 2.9-6.9). Considering previous estimates of symptomatic scrub typhus incidence in the same study population, only about 2-5% of infections may result in clinically relevant disease.

The need for adolescents' agency in salutogenic approaches shaping physical activity in schools.

Physical activity (PA) contributes to health throughout life. In particular, young people can benefit from this. Schools can play a key role in providing learning conditions to experience meaningful PAs aimed at inspiring students to lifelong PA. In this article, we argue the need for a salutogenic approach in schools focussing on respecting and enhancing adolescents' agency with regard to their PA. This approach entails listening to adolescents' perspectives and inviting them to participate in actively designing and carrying out PA as a prerequisite for their inclusive engagement. We unpack the concept of agency by drawing on insights from the Capability Approach. This provides input for the integration of agency in health promoting schools and salutogenic approaches, to enhance PA-related agency. Finally, we outline a research agenda to, eventually, create opportunities for students in schools to expand their PA-related agency. Lay Summary Physical activity (PA) contributes to health throughout life. Schools can play a key role in fostering meaningful PA experiences to inspire students to lifelong PA. This requires schools to focus on students' personal aspirations, providing them with the space to develop their autonomy and find opportunities to decide and act upon expanding their agency with respect to the physically active lifestyles they deem meaningful.

Clinical characteristics of and antibody response to spotted fever group rickettsial infections in South India: Case series and serological cohort study.

OBJECTIVE: The clinical and serological characteristics of spotted fever group rickettsial (SFGR) infections in South Asia are poorly understood. We studied the clinical presentation and the IgM/IgG response in cases enrolled at two health care centres in South India. METHOD: We enrolled 77 patients. Fifty-seven of these patients were recruited at a tertiary care centre, the remaining 20 at a community hospital (secondary care level). Diagnostic tests included IgM and IgG enzyme-linked immunosorbent assay and polymerase chain reaction. Over a period of 1 year, 41 cases were followed up for repeated sero-analysis. RESULTS: Median age was 9 years (range 1-79). A rash was present in 74% of cases (57/77). In cases aged <15 years, rash was present in 94% (44/47) vs. 43% (13/30) in cases aged ≥15 years. An eschar was found in two cases (3%). Severe infection or complications occurred in 10 cases (13%). These included central nervous system infection (6/77, 8%), kidney injury (3/77, 4%), shock (3/77, 4%), lung involvement (2/77, 3%) and peripheral gangrene (2/77, 3%). IgM antibody levels increased faster after fever onset than IgG antibodies, peaking at 50 and 60 days, respectively. After the peak, IgM and IgG levels showed a slow decline over one year with less than 50% of cases showing persistent IgG antibody levels. CONCLUSION: Spotted fever group rickettsial infections in South India may be under-diagnosed, as many cases may not develop a rash. The proportion of cases developing severe infection seems lower than for scrub typhus in this region. IgG seroprevalence may substantially underestimate the proportion in a population with past SFGR infection.

Antibody response following scrub typhus infection: clinical cohort study.

OBJECTIVE: Scrub typhus is a common cause of fever in Asia. The antibody response to infection and its effect on subsequent infection are unclear. We studied the IgM and IgG antibody response after infection, accounting for clinical severity. METHOD: We studied 197 scrub typhus patients for up to 2 years post-infection. Overall, 501 blood samples were analysed for scrub typhus antibodies using ELISA. IgM and IgG ELISA optical densities (OD) were analysed using quantile regression. OD values of 1.0 (IgM) and 1.5 (IgG) were used to define seropositivity. RESULTS: IgM OD values fell rapidly from an initial peak after infection. 50% of cases were IgM seronegative after 82 days. About 2 years after fever onset, 50% of cases had fitted IgG OD values of <1.5. Patients with high initial IgG OD values (≥2.5, used as a proxy for probable previous scrub typhus infection) had a more sustained IgG response than those with a low initial IgG OD, and more often presented with complications (18/36 = 50% vs. 28/91 = 30.8%, risk ratio = 1.63, 95% CI 1.04, 2.55, P = 0.035). This association was robust to adjusting for age (risk ratio 1.50, 95% CI 0.96, 2.33, P = 0.072). CONCLUSION: Cross-sectional IgG seroprevalence data substantially underestimate the proportion in a population ever infected with scrub typhus. A high initial IgG as a potential marker for previous scrub typhus infection may be associated with long-term IgG persistence and a higher risk of complicated scrub typhus.

OBJECTIF: Le typhus exfoliant est une cause fréquente de fièvre en Asie. La réponse anticorps à l'infection et son effet sur l'infection ultérieure ne sont pas clairs. Nous avons étudié la réponse des anticorps IgM et IgG après infection, en tenant compte de la sévérité clinique. MÉTHODE: Nous avons étudié 197 patients atteints de typhus exfoliant pendant une période allant jusqu'à deux ans après l'infection. Au total, 501 échantillons de sang ont été analysés pour déterminer la présence d'anticorps anti-typhus à l'aide d'ELISA. Les densités optiques (DO) des ELISA d'IgM et d'IgG ont été analysées par régression quantile. Les valeurs de DO de 1,0 (IgM) et 1,5 (IgG) ont été utilisées pour définir la séropositivité. RÉSULTATS: Les valeurs de DO d'IgM ont rapidement diminué par rapport au pic initial après infection. 50% des cas étaient séronégatifs pour les IgM après 82 jours. Environ 2 ans après le début de la fièvre, 50% des cas avaient des valeurs ajustées de OD d'IgG inférieures à 1,5. Les patients présentant des valeurs initiales de DO d'IgG élevées (≥2,5, utilisés comme proxy d'une infection antérieure probable par le typhus exfoliant) présentaient une réponse IgG plus maintenue que ceux présentant une DO initiale d'IgG faible et présentaient plus souvent des complications (18/36 = 50% vs. 28/91 = 30,8%, rapport de risque: 1,63; IC95%: 1,04-2,55, P = 0,035). Cette association était robuste pour l'ajustement en fonction de l'âge (rapport de risque: 1,50; IC95%: 0,96-2,33, P = 0,072). CONCLUSION: Les données transversales sur la séroprévalence des IgG sous-estiment considérablement la proportion dans une population déjà infectée par le typhus exfoliant. Des IgG initialement élevées en tant que marqueur potentiel d'infection antérieure par le typhus exfoliant peuvent être associées à une persistance à long terme des IgG et à un risque plus élevé de typhus exfoliant compliqué.

The effect of pasture quantity temporal variation on milking robot utilization.

In pasture-based automatic milking systems (AMS), a decrease in robot utilization (RU) often occurs in the early morning hours. Novel feeding strategies that encourage voluntary cow traffic throughout 24 h could help mitigate this problem. We determined the effect of 3 distinct pasture allocation methods on RU patterns throughout a 24-h period. The experiment was conducted at the University of Melbourne's Dookie research farm in northern Victoria, Australia. Three Lely Astronaut A3 robotic milking units (Lely, Maassluis, the Netherlands) milked 133 cows, grazing pasture, with concentrate offered at milking in the robots. The farm operated a system of 3-way grazing, with active access to each pasture allocation: 2030-0400 h (allocation A), 0400-1330 h (allocation B), and 1330-2030 h (allocation C). Treatments varied in the quantity of feed offered per hour of active access to each of the 3 pasture allocations. The control treatment offered the same proportion of feed (corrected for active access time) in all 3 pasture allocations (allocation A = 31.3%, B = 39.6%, and C = 29.2%). The day treatment offered the largest proportion of feed during the day (allocation A = 20%, B = 40%, and C = 40%), following the cows' diurnal pattern of feeding activity. The night treatment offered the largest proportion of feed at night (allocation A = 42%, B = 40%, and C = 18%). Due to the nature of pasture-based AMS, treatments could not be applied simultaneously. Therefore, treatments were applied to the entire herd and repeated twice over 42 d, lasting 7 d/treatment, with the first 3 d for habituation, followed by 4 d of data collection. Robot utilization (milkings/h) varied throughout 24 h between treatments, with the night treatment recording greater RU at 0800, 1800, and 1900 h and lower RU between 2100 to 0100 h, compared with the day treatment. The proportion of the herd milking between 0000 and 0600 h was greater for the control (43.3%) and day (45.3%) treatments compared with the night treatment (25.8%). Herd-average daily pasture intake was similar (10.5 kg of dry matter) for all treatments. This experiment is the first to demonstrate the manipulation of RU by varying the quantity of pasture offered. However, the use of variable allocation alone did not eliminate the decrease in RU between 0000 and 0600 h, with the timing of allocation also likely to play a role. We recommend a further research focus on combining both timing and quantity of pasture allocated to improve RU in pasture-based AMS.

Short communication: The diurnal intake and behavior of dairy cows when access to a feed of consistent nutritive value is restricted.

The diurnal variation in pasture nutritive value adds a confounding factor to studies elucidating the effect of time of day on behavior. Our work separates the effect of time of day on both feeding and lying patterns for cows outdoors to enable the alignment of feeding behavior with feed management. We determined the diurnal intake patterns and behavior of dairy cows when the nutritive value of feed remained constant throughout 24 h in an outdoor environment, and when feed access was restricted. Nine nonlactating Holstein-Friesian cows (live weight 626 ± 53 kg, age 96 ± 33 mo; mean ± SD) were split into 3 groups of 3 and offered lucerne hay cubes (cube volume 32 mm3) ad libitum according to 3 treatments: full access (FA, feed access 24 h), day access (DA, feed access between 0600 and 1800 h), and night access (NA, feed access between 1800 and 0600 h). Treatments were applied to individual cows in a crossover design with 7-d periods. During the last 4 d of each period, data were collected on feed intake, as well as feeding and lying behaviors. Total daily intake was greater for cows on the FA treatment (3.5% of BW) compared with the DA and NA treatments at 3.1 and 2.9% of BW, respectively. The cows with FA consumed 69% of their total intake during the day (0600-1800 h), with the greatest intake (39%) occurring during 1200 to 1800 h and only 12% of intake occurring during 2400 to 0600 h. Cows with DA consumed 56% of feed during 0600 to 1200 h and 44% during 1200 to 1800 h. In contrast, NA cows consumed more feed (74%) during the first 6 h period (1800-2400 h), thus maximizing lying time between 2400 and 0600 h. The time spent lying throughout daylight periods varied between treatments; however, total daily lying time was similar across the 3 treatments. This experiment shows the feeding and lying behaviors of cows when feed quality remains constant throughout 24 h, which will assist the formulation of variable feed allocation strategies for future testing in both robotic and conventional milking systems. Varying the quantity of feed offered throughout 24 h may benefit robot utilization at night in automatic milking systems through increased feeding activity, and as we observed, is likely to have little effect on lying time or DMI, with cows readily adapting to changes in feed management. Conversely, aligning feed on offer with preferred feeding time in conventional milking systems may increase the intake of high quality pasture.

The Relationship Between Polyethylene Wear and Periprosthetic Osteolysis in Total Hip Arthroplasty at 12 Years in a Randomized Controlled Trial Cohort.

BACKGROUND: Polyethylene acetabular components are common in hip arthroplasty. Highly cross-linked polyethylene (HXLPE) has lower wear than ultra-high molecular weight polyethylene (UHMWPE). Evidence suggests that wear particles induce inflammation causing periprosthetic osteolysis contributing to implant loosening with wear rates of 0.05 mm/y were considered safe. We aimed to compare incidence and volume of periacetabular osteolysis between HXLPE and UHMWPE using computed tomography. METHODS: Initially, 54 hips in 53 patients were randomized to HXLPE or UHMWPE acetabular liner. At 10 years, 39 hips in 38 patients remained for the radiostereometric analysis' demonstrating significantly lower wear in the HXLPE group. At 12 years, 14 hips in 13 patients were lost to follow-up leaving 25 hips for computed tomography assessment. Images were reconstructed to detect osteolysis and where identified, areas were segmented and volumized. RESULTS: Osteolysis was observed in 8 patients, 7 from the UHMWPE group and only 1 from the HXLPE group (Fisher exact, P = .042). There was no correlation between the amount of polyethylene wear and osteolysis volume; however, the radiostereometric analysis-measured wear rate in patients with osteolysis from both groups was significantly higher than overall average wear rate. CONCLUSION: This data demonstrates lower incidence of periacetabular osteolysis in the HXLPE group of a small cohort. Although numbers are too low to estimate causation, in the context of lower wear in the HXLPE group, this finding supports the hypothesis that HXLPE may not elevate osteolysis risk, and hence does not suggest that HXLPE wear particles are more biologically active than those generated by earlier generations of polyethylene.

Molecular epidemiology and genetic diversity of Orientia tsutsugamushi from patients with scrub typhus in 3 regions of India.

Scrub typhus, an acute febrile illness that is widespread in the Asia-Pacific region, is caused by the bacterium Orientia tsutsugamushi, which displays high levels of antigenic variation. We conducted an investigation to identify the circulating genotypes of O. tsutsugamushi in 3 scrub typhus-endemic geographic regions of India: South India, Northern India, and Northeast India. Eschar samples collected during September 2010-August 2012 from patients with scrub typhus were subjected to 56-kDa type-specific PCR and sequencing to identify their genotypes. Kato-like strains predominated (61.5%), especially in the South and Northeast, followed by Karp-like strains (27.7%) and Gilliam and Ikeda strains (2.3% each). Neimeng-65 genotype strains were also observed in the Northeast. Clarifying the genotypic diversity of O. tsutsugamushi in India enhances knowledge of the regional diversity among circulating strains and provides potential resources for future region-specific diagnostic studies and vaccine development.

A cross sectional study on molecular prevalence of Orientia tsutsugamushi in household rat population of South India.

This study aimed to assess the molecular prevalence of mite-borne zoonotic pathogen O. tsutsugamushi in household rats of South India through nested polymerase chain reaction amplification of O. tsutsugamushi 47-kDa htrA gene and to determine the most suitable sample type for screening of O. tsutsugamushi in rats. Out of 85 rats trapped in Tamil Nadu, Karnataka, and Puducherry regions, 47 rats were found positive for the O. tsutsugamushi genome with prevalence of 55.29 %. Among different sample types screened, faecal samples exhibited the highest positivity rate, followed by liver, spleen, kidney, and blood samples. Agreement between faecal and spleen samples of rats for the presence of O. tsutsugamushi was the highest. Principal component analysis revealed a positive correlation between the spleen, liver, and faeces and a negative correlation between blood and faeces for the presence of O. tsutsugamushi genome. These findings underscore the varied distribution of O. tsutsugamushi among different samples and indicate that the faecal and liver samples of rats are an ideal choice of samples for epidemiological studies. This is the first study to report a high level of presence of O. tsutsugamushi in faecal samples of rats.

Retail chain pharmacy opioid dispensing practices from 1997 to 2020: A content analysis of internal industry documents.

Context: Lawsuits have determined that community pharmacy chains played a crucial role in the opioid epidemic. However, little research has assessed community pharmacy practices. This study sought to understand the contribution of pharmacies to the opioid epidemic through improper opioid prescription dispensing. Methods: We conducted an observational, retrospective content analysis that assessed the opioid dispensing practices of a retail community pharmacy chain, Walgreens, using pharmaceutical industry documents released in litigation between 1997 and 2020. The documents were retrieved from the Opioids Industry Document Archive (OIDA) at the University of California, San Francisco and reviewed to identify themes and identify organizational practices. Findings: We identified four primary factors that may have contributed to improper opioid dispensing practices: store-level procedures, management pressure, distribution center activities, and pharmaceutical company sponsorship. Stores dispensed opioid prescriptions without resolving red flags, management pressured pharmacists to fill more opioid prescriptions, distribution centers failed to investigate high volume orders, and pharmaceutical companies sponsored pharmacist continuing education advocating for opioid pain management. Conclusions: Our findings suggest that Walgreens may have contributed to the early prescription opioid epidemic through improper opioid dispensing and also identify key practices that could be reformed to reduce the risk of future inappropriate dispensing of addictive and potentially harmful medications.

First hominine remains from a ~1.0 million year old bone bed at Cornelia-Uitzoek, Free State Province, South Africa.

We report here on evidence of early Homo around 1.0 Ma (millions of years ago) in the central plains of southern Africa. The human material, a first upper molar, was discovered during the systematic excavation of a densely-packed bone bed in the basal part of the sedimentary sequence at the Cornelia-Uitzoek fossil vertebrate locality. We dated this sequence by palaeomagnetism and correlated the bone bed to the Jaramillo subchron, between 1.07 and 0.99 Ma. This makes the specimen the oldest southern African hominine remains outside the dolomitic karst landscapes of northern South Africa. Cornelia-Uitzoek is the type locality of the Cornelian Land Mammal Age. The fauna contains an archaic component, reflecting previous biogeographic links with East Africa, and a derived component, suggesting incipient southern endemism. The bone bed is considered to be the result of the bone collecting behaviour of a large predator, possibly spotted hyaenas. Acheulian artefacts are found in small numbers within the bone bed among the fossil vertebrates, reflecting the penecontemporaneous presence of people in the immediate vicinity of the occurrence. The hominine tooth was recovered from the central, deeper part of the bone bed. In size, it clusters with southern African early Homo and it is also morphologically similar. We propose that the early Homo specimen forms part of an archaic component in the fauna, in parallel with the other archaic faunal elements at Uitzoek. This supports an emergent pattern of archaic survivors in the southern landscape at this time, but also demonstrates the presence of early Homo in the central plains of southern Africa, beyond the dolomitic karst areas.

In vitro study of elution kinetics and bio-activity of meropenem-loaded acrylic bone cement.

BACKGROUND: Use of antibiotic-loaded acrylic bone cement to treat orthopaedic infections continues to remain popular, but resistance to routinely used antibiotics has led to the search for alternative, more effective antibiotics. We studied, in vitro, the elution kinetics and bio-activity of different concentrations of meropenem-loaded acrylic bone cement. METHODS: Meropenem-loaded bone cement cylinders of different concentrations were serially immersed in normal saline. Elution kinetics was studied by measuring the drug concentration in the eluate, collected at pre-determined intervals, by high-performance liquid chromatography. Bio-activity of the eluate of two different antibiotic concentrations was tested for a period of 3 weeks against each of the following organisms: Staphylococcus aureus ATCC 2593 (MSSA), Enterococcus faecalis ATCC 29212, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, S. aureus ATCC 43300 (MRSA) and Klebsiella pneumoniae ATCC 700603 (ESBL). RESULTS: Meropenem elutes from acrylic bone cement for a period of 3-27 days depending on the concentration of antibiotic. Higher doses of antibiotic concentration resulted in greater elution of the antibiotic. The eluate was found to be biologically active against S. aureus ATCC 2593 (MSSA), P. aeruginosa ATCC 27853, E. coli ATCC 25922 and K. pneumoniae ATCC 700603 (ESBL) for a period of 3 weeks. CONCLUSIONS: The elution of meropenem is in keeping with typical antibiotic-loaded acrylic bone cement elution characteristics. The use of high-dose meropenem-loaded acrylic bone cement seems to be an attractive option for treatment of resistant Gram-negative orthopaedic infections but needs to be tested in vivo.

The magnitude and importance of perceived health dimensions define effective tailor-made health-promoting interventions per targeted socioeconomic group.

Recent insights and developments on health and society urge a critical look at the positive relationship between socioeconomic status (SES) and health. We challenge the notions that it is sufficient to distinguish only between two groups of SES (low and high) and that only overall health is taken into account. A new grouping of SES was developed based on both income and education, resulting in six SES groups. Health was defined in terms of a new positive health concept, operationalized into six health dimensions generating a measure of total general health (TGH). Next, six socioeconomic and demographic determinants of health were included. Linear regression, T-tests and one-way ANOVA were applied to investigate the relationships in a Dutch sample. A subjective way to measure health was applied: self-rated health (SRH). As a result, four out of six dimensions of health determined TGH: bodily functions, daily functioning, quality of life, and social and societal participation. Three out of six socioeconomic and demographic determinants impacted TGH: housing situation, age, and difficulties meeting financial obligations. While this is the general picture for the entire sample, there were interesting similarities and differences between the six SES groups. The similarities lie in the positive impact of the evaluation of bodily functions and daily functioning on TGH in all SES groups. The other dimensions affected TGH in some groups, and some dimensions only in one SES group. None of the socioeconomic and demographic determinants affected TGH in all SES groups. New insights on health inequalities are provided. It is concluded, first that the well-known positive relationship between SES and health is confirmed in this study. Second, further refining the health concept into six dimensions provides more detailed insights on which dimensions impact health the most. The subjective approach applied offers more refined information to better understand which health issues really matter to people. This yields new insights to develop tailor-made interventions aimed at increasing healthy behaviour in specific societal groups.

Shaping Physical Activity through Facilitating Student Agency in Secondary Schools in the Netherlands.

Schools can enable students' capability for lifelong physical activity (PA) by providing a physical, social and pedagogical context fostering students' agency. This entails allowing them to develop their autonomy and ability to shape PAs according to what they value. This paper explores whether, and, if so, how, school practices provide the conditions for developing and employing PA-related student agency. We followed a multiple case study design, partnering with six secondary schools in the Netherlands. We based our qualitative content analysis on the schools' policy documents and transcripts of interviews and focus groups with school management, teaching staff and supporting sports professionals. First, we analysed the space provided for PA-related student agency using the whole-of-school framework. Next, we used a social practice theory perspective to understand how each school practice allows for student agency. Results suggest that schools offer sufficient and varied PA opportunities but have not embedded deliberation with students on their meaningfulness and transfer to other contexts in their practices. We conclude that for schools to promote lifelong PA for students, there is a need for a pedagogical approach involving students' perspectives, participation and reflections, enabling them to transfer PAs to other (future) life settings.

Rituximab therapy for neuro - inflammatory disorders - Real world experience from South India.

BACKGROUND AND OBJECTIVES: To determine the real-world data regarding the use of Rituximab (RTX) in neuroinflammatory disorders (NIDS) and assess the outcomes following RTX treatment. METHODS: A cohort of consecutive patients with NIDS started on RTX (2018-2020) was included. The outcomes assessed were the proportion with favourable clinical response (FCR) as defined by clinical remission/ improvement using disease specific disability scores, comparative efficacy based on timing of initiation and B cell kinetics. RESULTS: A total of 97 patients with NIDS were included. The mean age was 36.43 (±14.4) years and median duration of follow - up being 15 months (IQR 12-16). Forty patients (41.2%) were initiated on RTX "early" in disease course. Favourable clinical response at last follow-up was seen in 94.9% (n = 92). The mean change in disability score (mRS) was 1.89 (SD 1.30) (p < 0.001). RTX appeared more effective when initiated "early" with higher remission rates (75% vs. 42%, p 0.015). B cell kinetics varied across NIDS, with 73% having adequate depletion at 6 months. Minor adverse events including infusion related reactions were reported in 9%. CONCLUSIONS: RTX has a favourable efficacy and safety profile. Future prospective studies are needed to establish the optimal timing of initiation and need for disease-based dosage regimens.

High initial IgG antibody levels against Orientia tsutsugamushi are associated with an increased risk of severe scrub typhus infection.

BACKGROUND: Scrub typhus is a dominant cause of febrile illness in many parts of Asia. Immunity is limited by the great strain diversity of Orientia tsutsugamushi. It is unclear whether previous infection protects from severe infection or enhances the risk. METHODS/PRINCIPAL FINDINGS: We studied IgG antibody levels against O. tsutsugamushi at presentation in 636 scrub typhus patients using enzyme-linked immunosorbent assays (ELISA). The association between ELISA optical density (OD) and risk of severe infection was modelled using Poisson regression. OD was categorised as low (<1.0), intermediate (1.0 to 2.9), and high (≥3.0). OD was also modelled as a continuous variable (cubic spline). Median age of cases was 41 years (range 0-85), with 37% having severe infection. Compared to the low category, the age-adjusted risk of severe infection was 1.5 times higher in the intermediate category (95%CI 1.2, 1.9), and 1.3 times higher in the high category (95%CI 1.0, 1.7). The effect was stronger in cases <40 years, doubling the risk in the intermediate and high categories compared to the low category. The effect was more pronounced in cases tested within 7 days of fever onset when IgG ODs are more likely to reflect pre-infection levels. CONCLUSIONS/SIGNIFICANCE: Intermediate and high IgG antibody levels at the time of diagnosis are associated with a higher risk of severe scrub typhus infection. The findings may be explained by severe infection eliciting an accelerated IgG response or by previous scrub typhus infection enhancing the severity of subsequent episodes.

Mycophenolate in idiopathic inflammatory myositis: outcome data of a large South Asian cohort.

BACKGROUND: Consensus on treatment of idiopathic inflammatory myositis (IIM), particularly with regard to flares and interstitial lung disease (ILD), does not exist. We studied the long-term outcome and treatment response in our large, retrospective cohort of adult South-Asian patients exclusively with IIM. METHODOLOGY: Electronic records of IIM patients satisfying inclusion and exclusion criteria were studied longitudinally at presentation, at 3, 6, 12, 18 and 24 months and thereafter yearly till their last follow up (F/u) visit. Depending on clinical, imaging, and muscle enzyme profile during the F/u period, patients were categorised as complete (CR) and partial responders (PRs). Parameters favouring CR were assessed using multivariate logistic regression analysis. Outcome parameters and flares on immunosuppressants (IS) were then assessed in patients with/without ILD. RESULTS: Two hundred thirty-two patients with median F/u duration of 44.5 months (25-80.25) were included. ILD was seen in 40.1%. Patients with non-Jo1 anti-synthetase antibodies (n=26) were numerically more than those with Jo-1 antibody (n=24). CR status was attained by 50.9% patients. Absence of pericardial effusion (p=0.042, OR 4.223, 95% CI: 1.05-16.9) and presence of Gottron's rash (p=0.044, OR 1.78, 95% CI 1.017-3.121) at baseline predicted CR by multivariate regression. Majority received mycophenolate during the entire F/u period. Discontinuation of steroids was feasible in 51.7% after a median duration of 24 months (18-42). After excluding patients with ILD, flares were numerically lesser in patients only on mycophenolate compared with those only on methotrexate (p=0.06). Further flares were curtailed when switched from other agents to mycophenolate. CONCLUSION: Mycophenolate is an effective treatment option in IIM patients with and without co-existing ILD. Presence of Gottron's rash and absence of pericardial effusion were found to be predictors of favourable clinical outcome in this largest single-centre study.

Secreted Wnt antagonists in scrub typhus.

BACKGROUND: The mechanisms that control local and systemic inflammation in scrub typhus have only been partially elucidated. The wingless (Wnt) signaling pathways are emerging as important regulators of inflammation and infection, but have not been investigated in scrub typhus. METHODOLOGY/PRINCIPAL FINDINGS: Plasma levels of secreted Wnt antagonists (i.e. DKK-1, sFRP-3, WIF-1 and SOST) were analyzed in patients with scrub typhus (n = 129), patients with similar febrile illness without O. tsutsugamushi infection (n = 31), febrile infectious disease controls, and in healthy controls (n = 31) from the same area of South India, and were correlated to markers of inflammation, immune and endothelial cell activation as well as for their association with organ specific dysfunction and mortality in these patients. We found i) Levels of SOST and in particular sFRP-3 and WIF-1 were markedly increased and DKK-1 decreased in scrub typhus patients at admission to the hospital compared to healthy controls. ii) In recovering scrub typhus patients, SOST, sFRP-3 and WIF-1 decreased and DKK-1 increased. iii) SOST was positively correlated with markers of monocyte/macrophage and endothelial/vascular activation as well as with renal dysfunction and poor outcome iv) Finally, regulation of Wnt pathways by O. tsutsugamushi in vitro in monocytes and ex vivo in mononuclear cells isolated from patients with scrub typhus, as evaluated by gene expression studies available in public repositories, revealed markedly attenuated canonical Wnt signaling. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that scrub typhus is characterized by attenuated Wnt signaling possibly involving dysregulated levels of several secreted pathway antagonists. The secreted Wnt antagonist SOST was strongly associated with renal dysfunction and poor prognosis in these patients.

Enzyme-linked immunosorbent assay (ELISA) versus Venereal Disease Research Laboratory test (VDRL) and rapid plasma reagin test (RPR) for screening of syphilis in pregnant women.

OBJECTIVE: To evaluate a treponemal enzyme-linked immunosorbent assay (ELISA) as an alternative screening test for syphilis in pregnant women. METHODS: A cross-sectional study of diagnostic test accuracy was carried out in a large volume laboratory from a tertiary care center. A total of 416 serum samples, including 102 archived syphilis Treponema pallidum hemagglutination (TPHA)-positive samples and 314 samples from pregnant women, were used to determine the sensitivity and specificity of ELISA. All the samples were subjected to Venereal Disease Research Laboratory (VDRL), rapid plasma reagin (RPR), ELISA, and TPHA tests. Performance characteristics of VDRL, RPR, and ELISA were calculated with TPHA as a reference standard test. RESULTS: VDRL and RPR exhibited higher false positivity of 10.5% and 9.6%, respectively, compared to 2.5% by ELISA. The sensitivity and specificity of ELISA were 98% and 97.5%, of VDRL were 71.6% and 89.5%, and of RPR were 73.5% and 90.5%, respectively. Moreover, ELISA had an excellent agreement (kappa=0.9) with TPHA compared to VDRL/RPR which had a moderate agreement (kappa=0.6) only. CONCLUSION: ELISA has the potential to replace VDRL/RPR as a screening test for syphilis in centers that can perform ELISA, especially for antenatal screening.