The appropriate antibiotic treatment for severe scrub typhus, a neglected but widespread reemerging zoonotic infection, is unclear.
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.
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.
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.).
Segmental duplications at breakpoints (BP4-BP5) of chromosome 15q13.2q13.3 mediate a recurrent genomic imbalance syndrome associated with mental retardation, epilepsy, and/or electroencephalogram ...(EEG) abnormalities.
DNA samples from 1445 unrelated patients submitted consecutively for clinical array comparative genomic hybridisation (CGH) testing at Children's Hospital Boston and DNA samples from 1441 individuals with autism from 751 families in the Autism Genetic Resource Exchange (AGRE) repository.
We report the clinical features of five patients with a BP4-BP5 deletion, three with a BP4-BP5 duplication, and two with an overlapping but smaller duplication identified by whole genome high resolution oligonucleotide array CGH. These BP4-BP5 deletion cases exhibit minor dysmorphic features, significant expressive language deficits, and a spectrum of neuropsychiatric impairments that include autism spectrum disorder, attention deficit hyperactivity disorder, anxiety disorder, and mood disorder. Cognitive impairment varied from moderate mental retardation to normal IQ with learning disability. BP4-BP5 covers approximately 1.5 Mb (chr15:28.719-30.298 Mb) and includes six reference genes and 1 miRNA gene, while the smaller duplications cover approximately 500 kb (chr15:28.902-29.404 Mb) and contain three reference genes and one miRNA gene. The BP4-BP5 deletion and duplication events span CHRNA7, a candidate gene for seizures. However, none of these individuals reported here have epilepsy, although two have an abnormal EEG.
The phenotype of chromosome 15q13.2q13.3 BP4-BP5 microdeletion/duplication syndrome may include features of autism spectrum disorder, a variety of neuropsychiatric disorders, and cognitive impairment. Recognition of this broader phenotype has implications for clinical diagnostic testing and efforts to understand the underlying aetiology of this syndrome.
Wheat, rice, maize, pearl millet, and sorghum provide over half of the world's food calories. To maintain global food security, with the added challenge of climate change, there is an increasing need ...to exploit existing genetic variability and develop cultivars with superior genetic yield potential and stress adaptation. The opportunity to share knowledge between crops and identify priority traits for future research can be exploited to increase breeding impacts and assist in identifying the genetic loci that control adaptation. A more internationally coordinated approach to crop phenotyping and modeling, combined with effective sharing of knowledge, facilities, and data, will boost the cost effectiveness and facilitate genetic gains of all staple crops, with likely spill over to more neglected crops.
•Wheat, rice, maize, pearl millet, and sorghum share several stress adaptive traits.•Comparative biology can help identify robust traits for crop improvement.•Collaborative phenotyping platforms increase efficiency and capacity for research.•Crop simulation modeling enables data sharing and predicting stress adaptation.•Effective data sharing can amplify research outputs.
Background: Early detection of breast and cervical cancer by organized screening has been found to reduce mortality rates in trials, but documentation of programme results and challenges is rarely ...done from non-trial settings. This study reports results of a population-based cancer control programme in a rural block in Vellore, Tamil Nadu, population size (116,085), targeting a population of 18,490 women aged 25-60 years, between November 2014 and March 2018.
Methods: Village-based health education sessions were conducted by social workers, using trained volunteers and health workers to motivate eligible women. Screening was done at a secondary level hospital, by trained general physicians using visual inspection with acetic acid and clinical breast examination, followed by colposcopy, radiological imaging (breast) and biopsy as required.
Results: A total of 8 volunteers and 17 health workers motivated women for 93 health education and screening sessions, in 46 out of 82 villages. While 1,890/18,490 (10.2 per cent) were screened for breast cancer, 1,783 (9.6 per cent) were screened for cervical cancer, with a yield of 3.4/1,000 for cervical pre-cancer/cancer. The main challenges were creating time for screening activities in a busy secondary hospital and difficulty in ensuring treatment completion of screen-detected cases.
Conclusions: Population-based cancer screening programs can be offered by secondary hospitals that also run primary care services, to increase screening rates. Clear referral systems need to be established, bearing in mind that social factors, especially poor family support, may pose a threat to treatment, in spite of easy availability of cure.
A series of compounds with systematically varied molecular structures which exhibit very large effective two-photon cross sections has been synthesized and characterized in solution using a nonlinear ...transmission technique. The general structure of these compounds can be categorized into two basic structural families: acceptor/donor/donor/acceptor and donor/bridge/acceptor. This study attempts to determine certain molecular structure/effective two-photon absorption relationships by careful characterization and as a function of systematically varied changes in the organic structure of the dye molecules. Such information can be useful in the design of more efficient two-photon dyes for imaging and power-limiting applications. The results of the study indicate that with the incorporation of certain combinations of structural elements, dyes can be synthesized which have greatly increased effective cross sections as high as 152.5 × 10-48 cm4 s/photon molecule in benzene solution at 800 nm using 8 ns pulses. This value is orders of magnitude higher than commercially available organic dyes measured at the same wavelength. Although the process is thought to involve a combination of two-photon absorption and excited state absorption phenomena, the information gathered from these new families of dyes has provided an important first step in producing improved materials for use in many different two-photon technology application.
Neurotrophin receptor tyrosine kinases (Trks) have well-defined trophic roles in nervous system development through kinase activation by neurotrophins. Yet Trks have typical cell-adhesion domains and ...express noncatalytic isoforms, suggesting additional functions. Here we discovered noncatalytic TrkC in an unbiased hippocampal neuron-fibroblast coculture screen for proteins that trigger differentiation of neurotransmitter release sites in axons. All TrkC isoforms, but not TrkA or TrkB, function directly in excitatory glutamatergic synaptic adhesion by neurotrophin-independent high-affinity trans binding to axonal protein tyrosine phosphatase receptor PTPσ. PTPσ triggers and TrkC mediates clustering of postsynaptic molecules in dendrites, indicating bidirectional synaptic organizing functions. Effects of a TrkC-neutralizing antibody that blocks TrkC-PTPσ interaction and TrkC knockdown in culture and in vivo reveal essential roles of TrkC-PTPσ in glutamatergic synapse formation. Thus, postsynaptic TrkC trans interaction with presynaptic PTPσ generates bidirectional adhesion and recruitment essential for excitatory synapse development and positions these signaling molecules at the center of synaptic pathways.
► Postsynaptic TrkC and presynaptic PTPσ
trans interact at glutamatergic synapses ► TrkC-PTPσ acts bidirectionally to induce pre- and postsynaptic differentiation ► Catalytic activity and NT-3 binding are not required for TrkC synaptogenic functions ► Disruption of the TrkC-PTPσ interaction suppresses excitatory synapse formation
Abstract
Background
Multivalent influenza vaccine products provide protection against influenza A(H1N1)pdm09, A(H3N2), and B lineage viruses. The 2018–2019 influenza season in the United States ...included prolonged circulation of A(H1N1)pdm09 viruses well-matched to the vaccine strain and A(H3N2) viruses, the majority of which were mismatched to the vaccine. We estimated the number of vaccine-prevented influenza-associated illnesses, medical visits, hospitalizations, and deaths for the season.
Methods
We used a mathematical model and Monte Carlo algorithm to estimate numbers and 95% uncertainty intervals (UIs) of influenza-associated outcomes prevented by vaccination in the United States. The model incorporated age-specific estimates of national 2018–2019 influenza vaccine coverage, influenza virus–specific vaccine effectiveness from the US Influenza Vaccine Effectiveness Network, and disease burden estimated from population-based rates of influenza-associated hospitalizations through the Influenza Hospitalization Surveillance Network.
Results
Influenza vaccination prevented an estimated 4.4 million (95%UI, 3.4 million–7.1 million) illnesses, 2.3 million (95%UI, 1.8 million–3.8 million) medical visits, 58 000 (95%UI, 30 000–156 000) hospitalizations, and 3500 (95%UI, 1000–13 000) deaths due to influenza viruses during the US 2018–2019 influenza season. Vaccination prevented 14% of projected hospitalizations associated with A(H1N1)pdm09 overall and 43% among children aged 6 months–4 years.
Conclusions
Influenza vaccination averted substantial influenza-associated disease including hospitalizations and deaths in the United States, primarily due to effectiveness against A(H1N1)pdm09. Our findings underscore the value of influenza vaccination, highlighting that vaccines measurably decrease illness and associated healthcare utilization even in a season in which a vaccine component does not match to a circulating virus.
We estimated that influenza vaccination prevented an estimated 4.4 million illnesses, 2.3 million medical visits, 58 000 hospitalizations, and 3500 deaths in the 2018–2019 influenza season.
BACKGROUND:The Third National Health and Nutrition Examination Survey suggested some Mexican American children are at risk of zinc deficiency. OBJECTIVE:We measured the effects of zinc and ...micronutrients or of micronutrients alone on indexes of cell-mediated immunity and antiinflammatory plasma proteins. DESIGN:Subjects (n = 54) aged 6-7 y were randomly assigned and treated in double-blind fashion in equal numbers with 20 mg Zn (as sulfate) and micronutrients or with micronutrients alone 5 d/wk for 10 wk. RESULTS:Before treatment the mean ± SD plasma zinc was 14.9 ± 1.7 μmol/dL and the range was within the reference; hair zinc was 1.78 ± 0.52 μmol/g and 41.6% were less-than or equal to1.68 μmol/g; serum ferritin was 25.7 ± 18.6 μg/L and 50.0% were less-than or equal to20 μg/L. The zinc and micronutrients treatment increased the lymphocyte ratios of CD4⁺ to CD8⁺ and of CD4⁺CD45RA⁺ to CD4⁺CD45RO⁺, increased the ex vivo generation of interleukin-2 (IL-2) and interferon-γ (IFN-γ), decreased the generation of interleukin-10 (IL-10), and increased plasma interleukin-1 receptor antagonist (sIL-1ra) and soluble tumor necrosis factor receptor 1 (sTNF-R1). Micronutrients alone increased the ratio of CD4⁺ to CD8⁺ but not of CD4⁺CD45RA⁺ to CD4⁺CD45RO⁺, increased IFN-γ but had no effect on IL-2 or IL-10, and increased sIL-1ra but not sTNF-R1. Efficacy of zinc and micronutrients was greater than micronutrients alone for all indexes except the ratio of CD4⁺ to CD8⁺, which was affected similarly. CONCLUSIONS:Before treatment, concentrations of hair zinc in 41.6% of subjects and serum ferritin in 50% were consistent with the presence of zinc deficiency. The greater efficacy of the zinc and micronutrients treatment compared with micronutrients alone supports this interpretation.
Existing comorbidity indices were not developed for adolescent and young adults (AYA) 15 to 39 years of age. The aim of this study was to assess impact of comorbidities on health care service needs ...and health status among AYA cancer survivors using the newly developed AYA HOPE comorbidity index in comparison with the existing indices.
Data on comorbid conditions were obtained from medical records and service needs and health status were from a survey of AYA cancer survivors. Prevalence of comorbidities was based on the AYA HOPE index. Charlson and NCI indices were compared. Multivariable logistic regression was used.
Of the 485 patients, 14.6% had ≥2 comorbidities based on the AYA HOPE Index. Prevalence of mental illness and obesity/overweight, which were not included in existing indices, were 8.2% and 5.8%, respectively. Prevalence of cardiovascular, endocrine, gastrointestinal, and neurologic conditions were higher with the AYA HOPE Index than the other two indices. Forty percent of AYA patients reported service needs, particularly for mental health services (25.2%) and support groups (17.7%). Having ≥2 comorbidities on the AYA index was associated with higher mental health service needs OR, 2.05; 95% confidence interval (CI), 1.10-3.82 adjusting for demographic and clinical factors. Comorbidities were associated with fair/poor self-reported health status.
The AYA HOPE Index is a more comprehensive comorbidity index for AYA cancer patients than existing indices, and the number of comorbidities is associated with service needs and health status.
The AYA HOPE index could identify patients' additional service needs early in therapy.
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