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People who are homeless and using substances frequently encounter barriers to accessing support. This paper aims to inform policy and practice by analysing changes in the tobacco, alcohol and illicit drug use of people experiencing homelessness.Data derive from a qualitative longitudinal study (undertaken 2020/2021) and involving telephone interviews (n = 310) conducted with 34 people accommodated in two London hotels provided as part of a UK policy response to COVID-19. The hotels offered various supports, including opioid replacement therapy, prescribed alcohol, licensed nicotine replacement therapy, and e-cigarettes. Participants' substance use data were organised by Iterative Categorization and subjected to a content analysis to identify patterns and themes..At entry to the hotel, 5/34 participants (14.7%) had never used alcohol nor illicit drugs; 10/34 (29.4%) had only ever used alcohol (mostly without a problem); 11/34 (32.4%) had ever used illicit drugs but without a problem; and 8/34 (23.5%) had ever had a problem with illicit drugs. Sub-groups had different socio-demographic characteristics, particularly regarding being/not being a UK national, sex, and homelessness duration. Tobacco smoking was common across all sub-groups (18/34; 52.9%). Participants were often anxious about living with others who were using substances, and some worried about their own substance use. Substance use was changeable, with more decreases than increases. Changes related to intrapersonal (psychological), interpersonal (social) and structural (resource-based) factors. For example, decreases were precipitated by people feeling motivated to change, separation from others who used drugs, and receiving treatment or support.Findings indicate that various interventions and accommodation models may benefit people who are homeless and using substances. An initiative that combined shelter and basic amenities, pharmacological treatment, psychosocial support, and space where substances were not available and other people using substances could be avoided resulted in an overall reduction in substance use amongst those accommodated.

Background: Randomised controlled trials (RCTs) are considered the gold standard research design for assessing the efficacy of health care treatments and are essential for improving knowledge and outcomes. However, the challenges of running RCTs in the alcohol addiction field are rarely discussed. The Nominal Group Technique (NGT) is a method designed to encourage contributions and elicit agreement on what to prioritise. This paper aims to identify challenges of alcohol addiction RCTs and solutions to these challenges using the NGT.Method: Six researchers from the Addictions Department, King’s College London, experienced in running alcohol addiction trials as trial managers, principal investigators and chief investigators, took part in a two-round decision conference, which involved impartial facilitation, on-the-spot modelling and interactive group discussion according to the NGT. The data generated from the first session was viewed and refined in the second session to create a priority list of challenges and solutions for future alcohol addiction RCTs.Results: The model produced a range of challenges when conducting alcohol addiction RCTs and solutions, which were rated according to priority by experts. After refinement of the model, these were categorised into five themes including: Staff, Recruitment, Follow ups, Governance and Funding. Each of these contained challenges and solutions when conducting alcohol addiction RCTs.Conclusion: The challenges to running alcohol addiction RCTs were discussed by a group experienced in this area in order to promote discussion and solutions. The process of sharing experiences and ideas allows for furthering knowledge to improve the running of alcohol addiction RCTs. There were some challenges that were discussed where no solutions were known or thought of. Current research activity should be more open to discussing and sharing challenges and possible solutions to improve research outcomes.

Introduction Thymoma is the most common solid, primary mediastinal tumour, accounting for 20% of mediastinal neoplasms. Malignant thymus tumours (thymomas and thymic carcinomas) metastasize primarily locally. Distant metastases, especially to liver are very rare. Presentation of case We review the case of a 59 year-old female patient, who underwent resection of the thymus with a diagnosed type B2 thymoma 20 years ago. The patient was referred to our hospital with a newly discovered space-occupying lesion in the liver, which had been detected in a routine follow-up magnetic resonance imaging scan. Since a malignant tumour of the liver could not be excluded, a conventional left hemihepatectomy was performed. Histological examination revealed a liver metastasis of the type B2 thymoma, which had been removed 20 years ago. Clinical discussion The case was discussed in the interdisciplinary tumour board. Based on the very long history of the primary removal of the thymoma as well as the R0 resection of the liver metastasis, a follow-up regimen with CT scans on a regular basis was recommended. Conclusions Newly discovered lesions of the liver in patients even with a long history of a thymoma should raise the suspicion of a liver metastasis that should be surgically resected as the therapy of choice. Further, this case indicates the importance for long-term radiographic follow-up., Highlights • Thymomas are common tumours mainly found in the mediastinum. • Thymic carcinoma accounts for about 25% of thymic tumours • Thymic carcinomas metastasize mainly locally and rarely distally. • Liver metastasis of thymic carcinoma can occur many years after resection of the primary tumour. • Liver metastases of thymic carcinoma are rare.

To the Editor: Zika virus (ZIKV), a mosquitoborne flavivirus, was first isolated from a rhesus monkey in Uganda in 1947 (1). This positive-sense, single-stranded RNA virus (family Flaviviridae, genus Flavivirus) has a 10,794-nt genome and is most closely related to Spondweni virus (2,3). Phylogenetic analyses have revealed 2 major lineages: Asian and African (2–4). The first human infection with ZIKV was reported in Nigeria in 1954 (5). The virus caused only sporadic infections until 2007, when a large outbreak occurred on Yap, an island in the Federated States of Micronesia (6). In October 2013, ZIKV was detected in French Polynesia; since then, >400 laboratory-confirmed cases have been reported (7). ZIKV has spread across the South Pacific, and autochthonous cases have been reported in New Caledonia, Easter Island, and the Cook Islands. Several cases of ZIKV infections have been reported in travelers to Southeast Asia (4,8) and French Polynesia (3,7). In March 2012, a prospective longitudinal cohort study, which included active surveillance for acute febrile illness, was initiated in Cebu City, Philippines (I. Yoon, unpub. data). Participants contacted study staff to report fever and were also contacted weekly by staff to determine if they had fever during the previous 7 days. Fever episodes triggered an acute-illness visit by a study nurse, who performed a clinical assessment of the patient and collected an acute-phase blood sample. During the first year of surveillance, 270 acute febrile illnesses were detected; 267 of the patients had samples available for serologic testing for evidence of influenza, dengue, chikungunya, Japanese encephalitis, and Zika virus infections. In May 2012, a 15-year-old boy in Cebu City reported a subjective fever; an acute-illness investigation followed. Other symptoms included headache, conjunctivitis, sore throat, myalgias, stomach pain, anorexia, nausea, and vomiting, but no rash. The boy did not seek medical care or require hospitalization; his only treatment was acetaminophen. He had no recent travel history, and no other members of his household were ill. The boy recovered fully by the 3-week study follow-up visit. An acute-phase blood sample, collected 2 days after symptom onset, was negative for dengue and chikungunya viruses by reverse transcription PCR. An in-house dengue/Japanese encephalitis IgM/IgG capture ELISA and chikungunya ELISA were used to test paired acute- and convalescent-phase blood samples; all results were negative. ZIKV ELISA was not available at the testing laboratory. However, by using real-time reverse transcription PCR targeting the gene that encodes the precursor of membrane protein, we detected ZIKV RNA in the patient’s serum sample (6). Virus was then isolated by intrathoracically inoculating Toxorhynchites splendens mosquitoes and by inoculating C6/36 cells with patient serum. The MiSeq platform (Illumina, Hayward, CA, USA) was used to obtain sequence reads by next-generation genomic sequencing, which identified a 789-bp contig as a partial sequence of the ZIKV gene that encodes the nonstructural 5 protein (GenBank accession no. {"type":"entrez-nucleotide","attrs":{"text":"KM851038","term_id":"822599142","term_text":"KM851038"}}KM851038). Maximum-likelihood phylogenetic analysis of the gene encoding the nonstructural 5 protein sequence showed that the isolate belonged to the ZIKV Asian lineage (Figure). Pair-wise genetic distance calculation indicated that the isolate was most closely related to the 2007 strain from Micronesia (p-distance = 0.013), with which it shared ≈99% nt (779/789) similarity. Figure Maximum-likelihood phylogenetic tree of fragments of Zika virus was determined using the general time-reversible plus gamma distribution plus invariable site model with 13 reference Zika virus strains from GenBank. The contig sequence, obtained from de ... During the past decade, ZIKV has caused 2 large epidemics in Micronesia and French Polynesia. The virus has a high potential for ongoing geographic expansion into countries where Aedes spp. mosquitoes are present and are known to transmit ZIKV; most notable among these vectors are A. aegypti mosquitoes, which are widespread throughout the Philippines (9). ZIKV infections have been reported in travelers to areas in the South Pacific with known ZIKV transmission and to areas such as Thailand (4) and Indonesia (8), where no recent endemic cases have been described. However, a case of endemic ZIKV infection has been reported in a child in Cambodia, and serologic evidence of ZIKV infection has been reported in Thailand, Vietnam, Malaysia, Indonesia, and the Philippines (2). Phylogenetic analysis of the isolate from our study indicated that it is more closely related to the strain from Micronesia that was responsible for the 2007 Yap outbreak than to strains identified in Cambodia (2010), Thailand (2013), or French Polynesia (2013). It is possible that the ZIKV infection in our study was an isolated case (the virus was confirmed in only 1/270 episodes of acute febrile illness). However, because the symptoms of disease are similar to those for other known endemic arboviruses, it is also possible that the strain was introduced into the Philippines before 2012 and remained undetected. The spectrum of ZIKV-associated clinical disease remains uncertain. Although reports indicate most cases of infection are mild, infections may be associated with more severe disease outcomes, such as Guillain-Barre syndrome (10). Increased surveillance for ZIKV disease, using pan-flavivirus or ZIKV-specific molecular testing, may lead to more frequent identification of cases, which could give a clearer indication of the true number of ZIKV infections. Additional surveillance and research studies are needed to improve our understanding of this disease, including the potential epidemiologic and clinical effects of ZIKV co-circulation with other flaviviruses.

Background Child mortality due to pneumonia is a major global health problem and is associated with hypoxemia. Access to safe and continuous oxygen therapy can reduce mortality; however, low-income countries may lack the necessary resources for oxygen delivery. We have previously demonstrated proof-of-concept that solar-powered oxygen (SPO2) delivery can reliably provide medical oxygen remote settings with minimal access to electricity. This study aims to demonstrate the efficacy of SPO2 in children hospitalized with acute hypoxemic respiratory illness across Uganda. Methods Objectives: Demonstrate efficacy of SPO2 in children hospitalized with acute hypoxemic respiratory illness. Study design: Multi-center, stepped-wedge cluster-randomized trial. Setting: Twenty health facilities across Uganda, a low-income, high-burden country for pediatric pneumonia. Site selection: Facilities with pediatric inpatient services lacking consistent O2 supply on pediatric wards. Participants: Children aged Randomization methods: Random installation order generated a priori with allocation concealment. Study procedure: Patients receive standard of care within pediatric wards with or without SPO2 system installed. Outcome measures: Primary: 48-h mortality. Secondary: safety, efficacy, SPO2 system functionality, operating costs, nursing knowledge, skills, and retention for oxygen administration. Statistical analysis of primary outcome: Linear mixed effects logistic regression model with 48-h mortality (dependent variable) as a function of SPO2 treatment (before versus after installation), while adjusting for confounding effects of calendar time (fixed effect) and site (random effect). Sample size: 2400 patients across 20 health facilities, predicted to provide 80% power to detect a 35% reduction in mortality after introduction of SPO2, based on a computer simulation of > 5000 trials. Discussion Overall, our study aims to demonstrate mortality benefit of SPO2 relative to standard (unreliable) oxygen delivery. The innovative trial design (stepped-wedge, cluster-randomized) is supported by a computer simulation. Capacity building for nursing care and oxygen therapy is a non-scientific objective of the study. If successful, SPO2 could be scaled across a variety of resource-constrained remote or rural settings in sub-Saharan Africa and beyond. Trial registration Clinicaltrials.gov, NCT03851783. Registered on 22 February 2019.

Background. Malaria remains a major cause of global mortality. Extracellular heme, released during malaria-induced hemolysis, mediates a number of pathogenic processes associated with vascular and organ injury. Hemopexin (hpx) facilitates the degradation of extracellular heme. In this study, we explore the hypothesis that dysregulation of the heme-hpx axis is associated with disease severity, acute kidney injury (AKI), and outcome. Methods. Plasma levels of hemin and hpx (at admission, day 3, and day 14) were assessed in children with severe malaria in Jinja, Uganda. Results. The ratio of heme to hpx was higher at admission and decreased with recovery (median, 0.043 [interquartile range {IQR}, 0.007–0.239] on day 1, 0.024 [IQR, 0.005–0.126] on day 3, and 0.008 [IQR, 0.002–0.022] on day 14; P < .001). Ratios of heme to hpx at admission were higher in children with as compared to those without severe anemia (median, 0.124 [IQR, 0.024–0.431] vs 0.016 [IQR, 0.003–0.073]; P < .0001), children with as compared to those without respiratory distress (median, 0.063 [IQR, 0.017–0.413] vs 0.020 [IQR, 0.004–0.124]; P < .01), and children with as opposed to those without stage 3 AKI (median, 0.354 [IQR, 0.123–2.481] vs 0.037 [IQR, 0.005–0.172], P < .01). The heme to hpx ratio at admission was associated with 6-month mortality (median, 0.148 [IQR, 0.042–0.500] vs 0.039 [IQR, 0.007–0.172]; P = .012). Conclusions. The ratio of heme to hpx is associated with disease severity and adverse clinical outcomes in Ugandan children, and dysregulation of the heme axis may contribute to malaria pathogenesis.

Background Severe malaria is a leading cause of acquired neurodisability in Africa and is associated with reduced nitric oxide (NO) bioavailability. A neuroprotective role for inhaled NO has been reported in animal studies, and administration of inhaled NO in preterm neonates with respiratory distress syndrome is associated with a 47% reduced risk of cognitive impairment at two years of age. Methods A randomized double-blind placebo-controlled trial of inhaled NO versus placebo as an adjunctive therapy for severe malaria was conducted in Uganda between 2011 and 2013. Children received study gas for a maximum 72 hours (inhaled NO, 80 parts per million; room air placebo). Neurocognitive testing was performed on children

Dengue causes more human morbidity globally than any other vector-borne viral disease. Recent research has led to improved epidemiological methods that predict disease burden and factors involved in transmission, a better understanding of immune responses in infection, and enhanced animal models. In addition, a number of control measures, including preventative vaccines, are in clinical trials. However, significant gaps remain, including the need for better surveillance in large parts of the world, methods to predict which individuals will develop severe disease, and immunologic correlates of protection against dengue illness. During the next decade, dengue will likely expand its geographic reach and become an increasing burden on health resources in affected areas. Licensed vaccines and antiviral agents are needed in order to effectively control dengue and limit disease.

Background. Vitamin D deficiency and excess of circulating fibroblast growth factor 23 (FGF23) contribute to cardiovascular mortality in patients with chronic kidney disease (CKD). FGF23 activates FGF receptor 4 and (FGFR4) calcineurin/nuclear factor of activated T cells (NFAT) signaling in cardiac myocytes, thereby causing left ventricular hypertrophy (LVH). Here, we determined if 1,25-dihydroxyvitamin D (calcitriol) inhibits FGF23-induced cardiac signaling and LVH. Methods. 5/6 nephrectomized (5/6 Nx) rats were treated with different doses of calcitriol for 4 or 10 weeks and cardiac expression of FGF23/FGFR4 and activation of calcineurin/NFAT as well as LVH were analyzed. FGFR4 activation and hypertrophic cell growth were studied in cultured cardiac myocytes that were co-treated with FGF23 and calcitriol. Results. In 5/6Nx rats with LVH, we detected elevated FGF23 expression in bone and myocardium, increased cardiac expression of FGFR4 and elevated cardiac activation of calcineurin/NFAT signaling. Cardiac expression levels of FGF23 and FGFR4 significantly correlated with the presence of LVH in uremic rats. Treatment with calcitriol reduced LVH as well as cardiac FGFR4 expression and calcineurin/NFAT activation. Bone and cardiac FGF23 expression were further stimulated by calcitriol in a dose-dependent manner, but levels of intact cardiac FGF23 protein were suppressed by high-dose calcitriol. In cultured cardiac myocytes, co-treatment with calcitriol blocked FGF23-induced activation of FGFR4 and hypertrophic cell growth. Conclusions. Our data suggest that in CKD, cardioprotective effects of calcitriol stem from its inhibitory actions on the cardiac FGF23/FGFR4 system, and based on their counterbalancing effects on cardiac myocytes, high FGF23 and low calcitriol synergistically contribute to cardiac hypertrophy.

The prevalence of smoking in people with serious mental illness is up to 5.3 times higher than in the general population and many die prematurely from smoking-related diseases. There is a need to develop effective, accessible, acceptable smoking cessation services that are tailored to this client group. Scimitar is a flexible, bespoke intervention based on a traditional NHS smoking cessation model with a ‘cut down to quit’ option. Cultural factors in mental health services may still create barriers to service users giving up smoking, and all mental health nurses should be trained to provide smoking cessation advice as part of their routine preparation for practice.

Background Exposure of red blood cells to oxidants increases production of methemoglobin (MHb) resulting in impaired oxygen delivery to tissues. There are no reliable estimates of methemoglobinemia in low resource clinical settings. Our objectives were to: i) evaluate risk factors for methemoglobinemia in Ugandan children hospitalized with fever (study 1); and ii) investigate MHb responses in critically ill Ugandan children with severe malaria treated with inhaled nitric oxide (iNO), an oxidant that induces MHb in a dose-dependent manner (study 2). Methods Two prospective studies were conducted at Jinja Regional Referral Hospital in Uganda between 2011 and 2013. Study 1, a prospective cohort study of children admitted to hospital with fever (fever cohort, n = 2089 children 2 months to 5 years). Study 2, a randomized double-blind placebo-controlled parallel arm trial of room air placebo vs. 80 ppm iNO as an adjunctive therapy for children with severe malaria (RCT, n = 180 children 1–10 years receiving intravenous artesunate and 72 h of study gas). The primary outcomes were: i) masimo pulse co-oximetry elevated MHb levels at admission (>2 %, fever cohort); ii) four hourly MHb levels in the RCT. Results In the fever cohort, 34 % of children admitted with fever had elevated MHb at admission. Children with a history of vomiting, delayed capillary refill, elevated lactate, severe anemia, malaria, or hemoglobinopathies had increased odds of methemoglobinemia (p 10 % occurred in 5.7 % of children receiving iNO. There were no differences in rates of study gas discontinuation between trial arms. Conclusions Hospitalized children with evidence of impaired oxygen delivery, metabolic acidosis, anemia, or malaria were at risk of methemoglobinemia. However, we demonstrated high-dose iNO could be safely administered to critically ill children with severe malaria with appropriate MHb monitoring. Trial registration ClinicalTrials.gov Identifier: NCT01255215 (Date registered: December 5, 2010).

Here, we present the complete genome sequences of two Zika virus (ZIKV) strains, Zika virus/ Homo sapiens -tc/THA/2014/SV0127-14 and Zika virus/ H. sapiens -tc/PHL/2012/CPC-0740, isolated from the blood of patients collected in Thailand, 2014, and the Philippines, 2012, respectively. Sequencing and phylogenetic analysis showed that both strains belong to the Asian lineage.

Background The mean age of dengue has been increasing in some but not all countries. We sought to determine the incidence of dengue virus (DENV) infection in adults and children in a prospective cohort study in the Philippines where dengue is hyperendemic. Methodology/Principal Findings A prospective cohort of subjects ≥6 months old in Cebu City, Philippines, underwent active community-based surveillance for acute febrile illnesses by weekly contact. Fever history within the prior seven days was evaluated with an acute illness visit followed by 2, 5, and 8-day, and 3-week convalescent visits. Blood was collected at the acute and 3-week visits. Scheduled visits took place at enrolment and 12 months that included blood collections. Acute samples were tested by DENV PCR and acute/convalescent samples by DENV IgM/IgG ELISA to identify symptomatic infections. Enrolment and 12-month samples were tested by DENV hemagglutination inhibition (HAI) assay to identify subclinical infections. Of 1,008 enrolled subjects, 854 completed all study activities at 12 months per-protocol undergoing 868 person-years of surveillance. The incidence of symptomatic and subclinical infections was 1.62 and 7.03 per 100 person-years, respectively. However, in subjects >15 years old, only one symptomatic infection occurred whereas 27 subclinical infections were identified. DENV HAI seroprevalence increased sharply with age with baseline multitypic HAIs associated with fewer symptomatic infections. Using a catalytic model, the historical infection rate among dengue naïve individuals was estimated to be high at 11–22%/year. Conclusions/Significance In this hyperendemic area with high seroprevalence of multitypic DENV HAIs in adults, symptomatic dengue rarely occurred in individuals older than 15 years. Our findings demonstrate that dengue is primarily a pediatric disease in areas with high force of infection. However, the average age of dengue could increase if force of infection decreases over time, as is occurring in some hyperendemic countries such as Thailand., Author Summary The average age of dengue has been increasing in some but not all dengue endemic countries. To investigate the age pattern of dengue in people of all ages ≥6 months old, a prospective community-based cohort study was undertaken in Cebu City, Philippines where dengue virus has been circulating for many decades. Active surveillance for acute fevers was performed, and acute/convalescent blood samples were tested for evidence of symptomatic dengue. Blood was also collected at enrolment and one year later, and tested serologically to identify subclinical infections. Overall, 1.62 symptomatic and 7.03 subclinical infections per 100 person-years of surveillance were detected. Among people older than 15 years, only one symptomatic dengue case occurred while 27 subclinical infections were identified. By analyzing age-specific dengue serology data, the historical infection rate among people with no prior dengue virus infection was found to be high at around 11–22% per year. Our results show that dengue is primarily a childhood disease in endemic settings where the historical infection rate has been high. However, the average age of dengue could increase if the infection rate decreases over time as is happening in some endemic countries like Thailand.

Acute kidney injury is common in severe malaria and associated with short- and long-term mortality developing in 50% of cases after admission. Cystatin C and BUN are associated with the severity of AKI, are elevated at admission and predict mortality., Background. Acute kidney injury (AKI) is a well recognized complication of severe malaria in adults, but the incidence and clinical importance of AKI in pediatric severe malaria (SM) is not well documented. Methods. One hundred eighty children aged 1 to 10 years with SM were enrolled between 2011 and 2013 in Uganda. Kidney function was monitored daily for 4 days using serum creatinine (Cr). Acute kidney injury was defined using the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Blood urea nitrogen (BUN) and Cr were assessed using i-STAT, and cystatin C (CysC) was measured by enzyme-linked immunosorbent assay. Results. Eighty-one (45.5%) children had KDIGO-defined AKI in the study: 42 (51.9%) stage 1, 18 (22.2%) stage 2, and 21 (25.9%) stage 3. Acute kidney injury evolved or developed in 50% of children after admission of hospital. There was an increased risk of AKI in children randomized to inhaled nitric oxide (iNO), with 47 (54.0%) of children in the iNO arm developing AKI compared with 34 (37.4%) in the placebo arm (relative risk, 1.36; 95% confidence interval [CI], 1.03–1.80). Duration of hospitalization increased across stages of AKI (P = .002). Acute kidney injury was associated with neurodisability at discharge in the children receiving placebo (25% in children with AKI vs 1.9% in children with no AKI, P = .002). Mortality increased across stages of AKI (P = .006) in the placebo arm, reaching 37.5% in stage 3 AKI. Acute kidney injury was not associated with neurodisability or mortality at discharge in children receiving iNO (P > .05 for both). Levels of kidney biomarkers were predictive of mortality with areas under the curves (AUCs) of 0.80 (95% CI, .65–.95; P = .006) and 0.72 (95% CI, .57–.87; P < .001), respectively. Admission levels of CysC and BUN were elevated in children who died by 6 months (P < .0001 and P = .009, respectively). Conclusions. Acute kidney injury is an underrecognized complication in young children with SM and is associated with increased mortality.

Zika virus (ZIKV) is an emerging mosquito-borne pathogen with reported cases in Africa, Asia, and large outbreaks in the Pacific. No autochthonous ZIKV infections have been confirmed in Thailand. However, there have been several cases reported in travelers returning from Thailand. Here we report seven cases of acute ZIKV infection in Thai residents across the country confirmed by molecular or serological testing including sequence data. These endemic cases, combined with previous reports in travelers, provide evidence that ZIKV is widespread throughout Thailand.

Background Chikungunya virus (CHIKV) is a globally re-emerging arbovirus for which previous studies have indicated the majority of infections result in symptomatic febrile illness. We sought to characterize the proportion of subclinical and symptomatic CHIKV infections in a prospective cohort study in a country with known CHIKV circulation. Methods/Findings A prospective longitudinal cohort of subjects ≥6 months old underwent community-based active surveillance for acute febrile illness in Cebu City, Philippines from 2012-13. Subjects with fever history were clinically evaluated at acute, 2, 5, and 8 day visits, and at a 3-week convalescent visit. Blood was collected at the acute and 3-week convalescent visits. Symptomatic CHIKV infections were identified by positive CHIKV PCR in acute blood samples and/or CHIKV IgM/IgG ELISA seroconversion in paired acute/convalescent samples. Enrollment and 12-month blood samples underwent plaque reduction neutralization test (PRNT) using CHIKV attenuated strain 181/clone25. Subclinical CHIKV infections were identified by ≥8-fold rise from a baseline enrollment PRNT titer 50 years old. Baseline CHIKV PRNT titer ≥10 was associated with 100% (95%CI: 46.1, 100.0) protection from symptomatic CHIKV infection. Phylogenetic analysis demonstrated Asian genotype closely related to strains from Asia and the Caribbean. Conclusions Subclinical infections accounted for a majority of total CHIKV infections. A positive baseline CHIKV PRNT titer was associated with protection from symptomatic CHIKV infection. These findings have implications for assessing disease burden, understanding virus transmission, and supporting vaccine development., Author Summary Chikungunya virus (CHIKV) is a re-emerging mosquito-borne pathogen for which the majority of infections have been considered to result in febrile illness. We sought to characterize the proportion of subclinical and symptomatic CHIKV infections in a prospective cohort of subjects ≥6 months old who underwent active surveillance for acute febrile illness from 2012–13 in Cebu City, Philippines. Symptomatic CHIKV infections were detected by PCR and/or ELISA in acute/convalescent blood samples. Subclinical infections were identified by neutralizing antibody seroconversion between enrollment and 12-month visits without symptomatic infection. Among 853 subjects who completed all study activities at 12 months, 19 symptomatic and 87 subclinical infections occurred (2.19 and 10.03 per 100 person-years, respectively). A positive baseline CHIKV PRNT titer was associated with 100% (95%CI: 46.1, 100.0) protection from symptomatic infection. Phylogenetic analysis showed Asian genotype closely related to strains from the recent Caribbean epidemic. These findings can help to assess disease burden, understand virus transmission, and support vaccine development.

Background Currently, no dengue NS1 detection kit has regulatory approval for the diagnosis of acute dengue fever. Here we report the sensitivity and specificity of the InBios DEN Detect NS1 ELISA using a panel of well characterized human acute fever serum specimens. Methodology/Principal Findings The InBios DENV Detect NS1 ELISA was tested using a panel composed of 334 serum specimens collected from acute febrile patients seeking care in a Bangkok hospital in 2010 and 2011. Of these patients, 314 were found to have acute dengue by either RT-PCR and/or anti-dengue IgM/IgG ELISA. Alongside the InBios NS1 ELISA kit, we compared the performance characteristics of the BioRad Platelia NS1 antigen kit. The InBios NS1 ELISA Ag kit had a higher overall sensitivity (86% vs 72.8%) but equal specificity (100%) compared to the BioRad Platelia kit. The serological status of the patient significantly influenced the outcome. In primary infections, the InBios NS1 kit demonstrated a higher sensitivity (98.8%) than in secondary infections (83.5%). We found significant variation in the sensitivity of the InBios NS1 ELISA kit depending on the serotype of the dengue virus and also found decreasing sensitivity the longer after the onset of illness, showing 100% sensitivity early during illness, but dropping below 50% by Day 7. Conclusion/Significance The InBios NS1 ELISA kit demonstrated high accuracy when compared to the initial clinical diagnosis with greater than 85% agreement when patients were clinically diagnosed with dengue illness. Results presented here suggest the accurate detection of circulating dengue NS1 by the InBios DENV Detect NS1 ELISA can provide clinicians with a useful tool for diagnosis of early dengue infections., Author Summary Infections by the mosquito-transmitted dengue virus continue to increase, threatening the health of people in over a hundred countries worldwide. The lack of effective mosquito control, licensed dengue vaccines or specific therapeutics to treat dengue infections presents challenges to reduce the burden of this disease. Rapid and accurate diagnosis of dengue infections is critical for the reduction of patients' morbidity and mortality. We present data that support the use of the InBios DENV Detect NS1 ELISA for the detection of dengue NS1 in patient serum. The InBios NS1 ELISA kit was tested against sera collected from acute fever patients seeking medical care in a Bangkok, Thailand hospital during 2010 and 2011. The data demonstrate the InBios DENV Detect NS1 ELISA accurately detects circulating dengue NS1 in the tested specimens, demonstrating high sensitivity and specificity. Nonetheless, the sensitivity of the NS1 ELISA kits was found to vary depending on the serological status of the patient (primary versus secondary dengue infection), time of specimen collection and dengue serotype. Further, the performance characteristics of the InBios DENV Detect NS1 ELISA were found to meet and exceed those of the commonly used Platelia Dengue NS1 Ag kit.

A four-year longitudinal cohort and geographic cluster study in rural Thailand was conducted to characterize the clinical spectrum of dengue virus (DENV) infection. Symptomatic DENV infections in the cohort were detected by active school absence-based surveillance that triggered cluster investigations around ill cohort children. Data from 189 cohort children with symptomatic DENV infection and 126 contact children in the clusters with DENV infection were analyzed. Of infected contacts, only 19% were asymptomatic; 81% were symptomatic, but only 65.9% reported fever. Symptom-based case definitions were unreliable for diagnosis. Symptomatic infections in contacts were milder with lower DENV RNA levels than the cohort. Infections in contacts with fever history were more likely to have detectable DENV RNA than infections without fever history. Mild infections identified by cluster investigations account for a major proportion of all DENV infections. These findings are relevant for disease burden assessments, transmission modeling, and determination of vaccine impact.

Introduction Laos has the highest maternal mortality ratio in mainland Southeast Asia and a high incidence of infectious diseases. Globally, malaria has been the pathogen most intensively investigated in relation to impact on pregnancy, but there has been relatively little research on the aetiology and impact of other diseases. We therefore aimed to determine the causes and impact of fever in pregnant women admitted to two central hospitals in Vientiane City, Lao PDR (Laos). Materials and Methods This hospital-based prospective study was conducted in Mahosot Hospital and the Mother and Child Hospital, Vientiane, between 2006 and 2010, with the aim to recruit 250 consenting pregnant women admitted with tympanic temperature ≥37.5°C. Primary outcome was the cause of fever and secondary outcomes were pregnancy outcomes. Specific investigations (culture, antigen, molecular and serological tests) were performed to investigate causes of fever. After discharge, all pregnant women were asked to return for review and convalescence serum on day 10–14 and were monitored until delivery. Principle findings 250 pregnant women were recruited to this study between February 2006 and November 2010. Fifty percent were pregnant for the first time. Their median (range) gestational age on admission was 24 (4–43) weeks. The median (range) tympanic admission temperature was 38.5°C (37.5–40.5°C). Fifteen percent of patients stated that they had taken antibiotics before admission. Headache, myalgia, back pain and arthralgia were described by >60% of patients and 149 (60%) were given a laboratory diagnosis. Of those with confirmed diagnoses, 132 (53%) had a single disease and 17 (7%) had apparent mixed diseases. Among those who had a single disease, dengue fever was the most common diagnosis, followed by pyelonephritis, scrub typhus, murine typhus and typhoid. Patients were also diagnosed with tuberculosis, appendicitis, Staphylococcus aureus septicemia, leptospirosis, Japanese encephalitis virus infection and Plasmodium falciparum malaria. Severe consequences, including maternal death, miscarriage, stillbirth, low birth weight and preterm birth, were found among 28 (78%) mothers with dengue fever, rickettsioses and typhoid. Conclusion Fevers other than malaria, such as dengue, pyelonephritis, rickettsioses and typhoid are common causes of fever during pregnancy in the Asian tropics. Further investigations of their impact in the community on maternal death, fetal loss, vertical transmission, low birth weight and preterm birth are needed., Author Summary Laos has a high incidence of infectious diseases and high prevalence of poverty. Malaria in pregnancy if of great public health interest. However, malaria has not been reported in Vientiane City for decades, but others diseases such as dengue fever, rickettsioses, typhoid fever, leptospirosis and Japanese encephalitis, have. In this prospective hospital-based study of the causes of fever in pregnancy, dengue fever was the most common diagnosis, followed by pyelonephritis with Escherichia coli, murine typhus, scrub typhus and typhoid fever. Severe consequences, including maternal death, miscarriage, stillbirth, low birth weight and preterm birth, were found among mothers with dengue fever, rickettsioses and typhoid. As a hospital-based study it has limitations and large community cohort studies will help us to learn more about fevers and their impact in pregnancy.

Serum cortisol concentrations may be altered in severe, chronic pain due to excess stimulation of the hypothalamic-pituitary-adrenal axis. Among 40 consecutive patients with severe, chronic pain 26 (65.0%) demonstrated abnormal serum cortisol concentration. After 90 days of treatment, only 7 (17.5%; p

To the editor, Chronic pain is usually defined as any persistent or intermittent pain that lasts more than 3 months.1 When this definition is used, more than 40% of the general population reports having chronic pain, primarily due to arthritis or other musculoskeletal disorder.2 Based on our clinical observations, within the chronic pain population, a subgroup has an intractable pain syndrome or disease. All have incurable, extremely painful conditions, as evidenced by failure of various interventions to control their pain, including surgery, nerve blocks, physical rehabilitation, and weak opioids. Patients describe their pain as constant, debilitating, and potent enough to interfere with sleep and sexual function. Many report suicidal thoughts for the sole purpose of stopping the pain, incessant crying spells, fatigue, depression, social isolation, restriction of mobility, and numerous bed- or couch-bound days. California, Oregon, and Washington have passed “intractable pain” laws, primarily to allow physicians to legally prescribe opioids to needy pain patients Objective assessment of these patients invariably reveals intermittently elevated blood pressure and pulse rate and abnormal concentrations of serum cortisol and other adrenal hormones, indicating the presence of a severe and extended stress state.3 Others have also recently postulated that severe chronic pain may produce an extended, destructive stress state characterized by neuroendocrine dysregulation, fatigue, dysphoria, myalgia, and impaired mental and physical performance.4 We suggest that this constellation of abnormalities be called “intractable pain disease.” About a dozen states, including California, Oregon, and Washington, have passed “intractable pain” laws, primarily to allow physicians to legally prescribe opioids to needy pain patients. Although the legal and legislative definition of “intractable” in the various state laws may be vague, the legislative intent of all these laws is clearly to identify the subgroup of patients with chronic pain who require opioids. It, therefore, appears prudent and practical to adopt the term intractable for those patients with severe, chronic pain who demonstrate the extended, severe stress response described above. Although some other name could be adopted for this tragic group of afflicted patients, an intractable pain syndrome clearly needs to be recognized, treated, and researched independently as a separate disease that differs from simple chronic pain whose symptoms may merely be minor, mild, intermittent, or persistent for longer than 3 months.

Transmucosal fentanyl (TF) has recently become available for treatment of breakthrough pain in cancer patients who are already tolerant to opioids. In addition to cancer patients, there is a growing number of chronic pain patients who regularly use and are tolerant to opioids and require a breakthrough opioid for adequate pain control. This pilot study was done to determine if TF is effective and acceptable to non-malignant, chronic pain patients who are opioid tolerant and require a breakthrough opioid(s) for pain control. Sixty patients with chronic, non-malignant pain who were maintained on a long-acting opioid and who required breakthrough pain control were given TF in an initial dose of 400 or 600 mcg per single, transmuscosal administration. Among the study group 35 (58.3%) experienced chronic pain due to injuries to the spine and 25 (41.7%) were due to medical conditions other than cancer. After at least three months of usage, patients were asked if they desired to continue TF and the reason(s) why they believed it to be effective. Fifty-eight (96.7%) of these subjects perceived that TF was an effective breakthrough opioid and desired to continue it. The single, effective dosage ranged from 800 to 1600 mcg per administration, and the number of separate monthly dosages ranged from 2 to 360. The majority of patients used TF only for emergency, pain purposes but others preferred TF as their major breakthrough opioid and ceased use of other short-acting opioids including injectable meperidine. Reported reasons for widespread patient acceptance included TF's fast action, fewer bed-bound days, increased energy, decreased use of other opioids, less depression, and fewer emergency room visits. This pilot study indicates that TF is effective and desired as a preferential opioid for breakthrough pain by a high percentage of chronic, non-malignant pain patients.

It has been postulated that chronic pain over-stimulates the hypothalamus-pituitary-adrenal axis to produce an extended stress response. If this assumption is true, patients with severe, chronic pain should demonstrate abnormalities of the pituitary-adrenal axis. To evaluate this premise, we screened 40 adult, chronic pain patients in the first week of treatment with serum cortisol concentrations taken between 8:00 and 10:00 AM. Criteria for inclusion in this study required that pain be present for at least one year and be constant, incurable, interfere with sleep, and cause the patient to be bed or house-bound without opioid treatment. Sixteen (16) of the subjects were challenged with cosyntropin, 0.25mg, given intramuscularly immediately after blood was drawn for determination of baseline serum cortisol concentration. Normal serum cortisol concentrations was considered to range from 5.0 to 25.0 ug/dl at baseline, and normal cortisol reserve was considered to be at least a doubling of the baseline concentration determined one hour after cosyntropin administration. Ten (25%) of the patients had evaluated serum cortisol concentrations above 25ug/dl with the highest being 54.4 ug/dl. Nine (20%) demonstrated low serum cortisol concentrations under 5 ug/dl, and 5 of 16 (31.25%) given cosyntropin challenge demonstrated inadequate adrenal reserve by failing to double their baseline cortisol concentration. All patients with high or low serum cortisol concentration demonstrated a normal cortisol concentration following pain control with a long-acting opioid including methadone, extended-length morphine or oxycodone, or transdermal fentanyl. This study suggests that severe, chronic pain may produce profound abnormalities of serum cortisol and cortisol reserve, and normalization of these alterations may require pain treatment with long-acting opioids.

Severe, chronic pain is postulated to produce an extended stress state with overstimulation of the autonomic nervous system and hypothalamus-pituitary-adrenal axis (HPA). To determine if this postulate is valid, we studied 60 patients who were consecutively admitted to ambulatory treatment for severe, chronic pain. All had chronic pain for over one year and characterized their pain as being constantly present, interfering with sleep, and debilitating to the point of being bed-or house-bound without opioid treatment. All were referred after failing multiple pain treatments, and all were being treated with low dosages of various oral opioids which reported to be inadequate. To evaluate these patients, pressure and pulse rates were determined at monthly intervals for four consecutive months. A morning blood specimen was taken to determine serum concentrations of the adrenal hormones, cortisol, pregnenolone, dehydroepiandrosterone, and androstenedione. Fifty-five (91.7%) subjects demonstrated hypertension above 130/90 mmHg and/or tachycardia above 84 beats per minute. Fifty-one (85.0%) demonstrated one or more abnormalities of serum adrenal hormone concentrations. All 60 subjects (100%) demonstrated at least one cardiovascular or adrenal hormone abnormality. This study suggests that severe, chronic pain may be associated with a neuroendocrine syndrome that may, itself, have clinical complications, and adequate pain control should be such that identified neuroendocrine abnormalities are normalized.

Background Severe malaria remains a major cause of childhood mortality globally. Decreased endothelial nitric oxide is associated with severe and fatal malaria. The hypothesis was that adjunctive inhaled nitric oxide (iNO) would improve outcomes in African children with severe malaria. Methods A randomized, blinded, placebo-controlled trial of iNO at 80 ppm by non-rebreather mask versus room air placebo as adjunctive treatment to artesunate in children with severe malaria was conducted. The primary outcome was the longitudinal course of angiopoietin-2 (Ang-2), an endothelial biomarker of malaria severity and clinical outcome. Results One hundred and eighty children were enrolled; 88 were assigned to iNO and 92 to placebo (all received IV artesunate). Ang-2 levels measured over the first 72 h of hospitalization were not significantly different between groups. The mortality at 48 h was similar between groups [6/87 (6.9 %) in the iNO group vs 8/92 (8.7 %) in the placebo group; OR 0.78, 95 % CI 0.26–2.3; p = 0.65]. Clinical recovery times and parasite clearance kinetics were similar (p > 0.05). Methaemoglobinaemia >7 % occurred in 25 % of patients receiving iNO and resolved without sequelae. The incidence of neurologic deficits ( 0.05). Conclusions iNO at 80 ppm administered by non-rebreather mask was safe but did not affect circulating levels of Ang-2. Alternative methods of enhancing endothelial NO bioavailability may be necessary to achieve a biological effect and improve clinical outcome. Trial Registration: ClinicalTrials.gov NCT01255215 Electronic supplementary material The online version of this article (doi:10.1186/s12936-015-0946-2) contains supplementary material, which is available to authorized users.

In March 2020, the ‘Everyone In’ initiative was introduced by the UK government as a public health response to COVID-19. This initiative sought to temporarily accommodate people experiencing rough sleeping in hotels in all local authority areas throughout England. In London, ‘Everyone In’ involved the procurement of vacant accommodation in over 100 hotels and temporarily re-housed approximately 2000 individuals. A rapid qualitative study was undertaken within two hotels to explore experiences of the initiative from the perspective of people accommodated in the hotels. This article describes how standard qualitative methods were adapted and implemented to complete the study whilst meeting COVID-19 social distancing guidelines. The research involved a longitudinal design of a two-stage qualitative interview that sought to capture residents’ experience of ‘Everyone In’ at two points in time (while in the hotel and when residents had left the hotel). Adapted qualitative methods were employed by a team of 13 researchers. These adaptations included socially distanced leaflet dropping, telephone-based participant recruitment, a remote, multistage, longitudinal qualitative telephone interviewing and rapid framework analysis. 35 hotel residents were recruited into the study (two subsequently withdrew participation). A total of 299 (of a possible 330) short interviews were completed by 33 participants (26 male and 7 female) as part of the multi-stage, longitudinal design of the study. This study indicates that adapted qualitative research methods employed during a pandemic can be successfully applied to obtain insights and experiences (of individuals and groups) otherwise difficult to reach and/or complex to understand.