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Background: Antimicrobial resistance (AMR) is a global health problem requiring a reduction in inappropriate antibiotic prescribing. Point-of-Care C-Reactive Protein (POCCRP) tests could distinguish between bacterial and non-bacterial causes of fever in malaria-negative patients and thus reduce inappropriate antibiotic prescribing. However, the cost-effectiveness of POCCRP testing is unclear in low-income settings., Methods: A decision tree model was used to estimate cost-effectiveness of POCCRP versus current clinical practice at primary healthcare facilities in Afghanistan. Data were analysed from healthcare delivery and societal perspectives. Costs were reported in 2019 USD. Effectiveness was measured as correctly treated febrile malaria-negative patient. Cost, effectiveness and diagnostic accuracy parameters were obtained from primary data from a cost-effectiveness study on malaria rapid diagnostic tests in Afghanistan and supplemented with POCCRP-specific data sourced from the literature. Incremental cost-effectiveness ratios (ICERs) reported the additional cost per additional correctly treated febrile malaria-negative patient over a 28-day time horizon. Univariate and probabilistic sensitivity analyses examined the impact of uncertainty of parameter inputs. Scenario analysis included economic cost of AMR per antibiotic prescription., Results: The model predicts that POCCRP intervention would result in 137 fewer antibiotic prescriptions (6%) with a 12% reduction (279 prescriptions) in inappropriate prescriptions compared to current clinical practice. ICERs were $14.33 (healthcare delivery), $11.40 (societal), and $9.78 (scenario analysis) per additional correctly treated case., Conclusions: POCCRP tests could improve antibiotic prescribing among malaria-negative patients in Afghanistan. Cost-effectiveness depends in part on willingness to pay for reductions in inappropriate antibiotic prescribing that will only have modest impact on immediate clinical outcomes but may have long-term benefits in reducing overuse of antibiotics. A reduction in the overuse of antibiotics is needed and POCCRP tests may add to other interventions in achieving this aim. Assessment of willingness to pay among policy makers and donors and undertaking operational trials will help determine cost-effectiveness and assist decision making., Competing Interests: The commercial affiliation of two authors (SD and TL) does not alter our adherence to PLOS ONE policies on sharing data and materials

The natural history of COVID-19 and predictors of mortality in older adults need to be investigated to inform clinical operations and healthcare policy planning. A retrospective study took place in 80 long-term nursing homes in Catalonia, Spain collecting data from March 1st to May 31st, 2020. Demographic and clinical data from 2,092 RT-PCR confirmed cases of SARS-CoV-2 infection were registered, including structural characteristics of the facilities. Descriptive statistics to describe the demographic, clinical, and molecular characteristics of our sample were prepared, both overall and by their symptomatology was performed and an analysis of statistically significant bivariate differences and constructions of a logistic regression model were carried out to assess the relationship between variables. The incidence of the infection was 28%. 71% of the residents showed symptoms. Five major symptoms included: fever, dyspnea, dry cough, asthenia and diarrhea. Fever and dyspnea were by far the most frequent (50% and 28%, respectively). The presentation was predominantly acute and symptomatology persisted from days to weeks (mean 9.1 days, SD = 10,9). 16% of residents had confirmed pneumonia and 22% required hospitalization. The accumulated mortality rate was 21.75% (86% concentrated during the first 28 days at onset). A multivariate logistic regression analysis showed a positive predictive value for mortality for some variables such as age, pneumonia, fever, dyspnea, stupor refusal to oral intake and dementia (p<0.01 for all variables). Results suggest that density in the nursing homes did not account for differences in the incidence of the infection within the facilities. This study provides insights into the natural history of the disease in older adults with high dependency living in long-term nursing homes during the first pandemic wave of March-May 2020 in the region of Catalonia, and suggests that some comorbidities and symptoms have a strong predictive value for mortality., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Childhood morbidities are common in Ghana. The present study sought to geospatially analyze morbidities among children (0-23 months of age) using five different survey datasets (1993-2014) from the Ghana Demographic and Health Survey., Methods: Logistic regression was used to examine childhood morbidity within a place of residence. Then three spatial statistical tools were applied to analyze morbidities among children (0-23 months of age). These tools were: spatial autocorrelation (Global Moran's I)-used to examine clustering or dispersion patterns; cluster and outlier analysis (Anselin's local Moran's I)-to ascertain geographic composition of childhood morbidity clusters and outliers; and hot spot analysis (Getis-Ord G)-to identify clusters of high values (hot spots) and low values (cold spots)., Results: Children in rural areas were much burdened with the occurrence of childhood morbidity. The study revealed positive spatial autocorrelation for childhood morbidity in Ghana. Childhood morbidity (diarrhoea, ARI, anaemia, and fever) clusters were identified within districts in the country. Children in rural areas were more likely to be morbid with diarrhoea, anaemia, and fever compared to those in urban areas. Hot spot districts for diarrhoea, anaemia and fever were mainly situated in semi-arid areas and those with ARI were located both at the semi-arid areas and coastal portions of Ghana., Conclusion: Rural children are much exposed to have higher burden of a childhood morbidity compared to their urban counterparts. Most semi-arid districts in Ghana are burdened with diarrhoea, ARI, anaemia, and fever. To minimize the occurrence of childhood morbidity in Ghana, designing of more context-based interventions to target hot spots districts of these morbidities are required in order to use scarce resources judiciously., Competing Interests: The authors have declared that no competing interests exist.

Severe-febrile-illness (SFI) is a common cause of morbidity and mortality across sub-Saharan Africa (SSA). The burden of SFI in SSA is currently unknown and its estimation is fraught with challenges. This is due to a lack of diagnostic capacity for SFI in SSA, and thus a dearth of baseline data on the underlying etiology of SFI cases and scant SFI-specific causative-agent prevalence data. To highlight the public health significance of SFI in SSA, we developed a Bayesian model to quantify the incidence of SFI hospital admissions in SSA. Our estimates indicate a mean population-weighted SFI-inpatient-admission incidence rate of 18.4 (6.8-31.1, 68% CrI) per 1000 people for the year 2014, across all ages within areas of SSA with stable Plasmodium falciparum transmission. We further estimated a total of 16,200,337 (5,993,249-27,321,779, 68% CrI) SFI hospital admissions. This analysis reveals the significant burden of SFI in hospitals in SSA, but also highlights the paucity of pathogen-specific prevalence and incidence data for SFI in SSA. Future improvements in pathogen-specific diagnostics for causative agents of SFI will increase the abundance of SFI-specific prevalence and incidence data, aid future estimations of SFI burden, and enable clinicians to identify SFI-specific pathogens, administer appropriate treatment and management, and facilitate appropriate antibiotic use., Competing Interests: The authors have declared that no competing interests exist.

Introduction: The current surge of mobile phone use in many African countries creates the opportunity to provide caregivers with limited access to the health care system with vital health recommendations. At the same time such communication system can be utilised to collect tempero-spatial data on disease symptoms., Objective: We assessed the feasibility of an mHealth system among caregivers with children under-five years, designed as a health information and surveillance tool in a rural district of Ghana., Methods: A mobile phone-based electronic health information and surveillance system was piloted from February to December 2015. Toll-free numbers were provided to 1446 caregivers, which they could call to receive health advice in case their children showed disease symptoms. The system was setup to evaluate the illness of a sick child. Symptoms reported via the system were evaluated and compared to clinician's report after follow-up. Cogency of the reported symptoms was assessed using Cohen's kappa coefficient., Results: A total of 169 children with disease symptoms were identified based on phone calls from caregivers. The predominant reported symptoms were fever (64%; n = 108), cough (55%; n = 93) and diarrhoea (33%; n = 55). Temporal pattern of symptomatic cases revealed a peak saturation in the month of September, with fever registering the highest number of symptoms observed. Reported symptoms and clinician's report revealed a very good agreement for fever (95%, kappa = 0.89); good for diarrhoea (87%, kappa = 0.73) and moderate for cough (76%, kappa = 0.49)., Conclusion: This pilot concept, has demonstrated the practicality of using mobile phones for assessing childhood disease symptoms and encouraging caregivers to seek early treatment for their children if needed. The strategy to use mobile phones in disease surveillance and treatment support is a promising strategy especially for areas with limited access to the health care system., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Heat shock protein 70 (HSP70) expression could be discussed as an adaption that promotes repair and counteracts cell damage. Myoglobin is released upon muscle damage of several pathways. The purpose of the present study was to determine whether the expression of HSP70 in kidney, heart and brain and of myoglobin in the kidney were associated with the cause of death and the survival times after lethal intoxications with three of the drugs most widely used in our local area (Saxony, Germany) as well as after fatal traumatic brain injury (TBI)., Methods: We retrospectively collected kidney, heart and brain samples of 50 autopsy cases with toxicological proved lethal intoxication (main drugs methamphetamine, morphine, alcohol), 14 TBI cases and 15 fatalities with acute myocardial injury in age- and gender-matched compilations., Results: Our main findings suggest that HSP70 is associated with hyperthermal and other stress factors of most cell populations. HSP70 expressions in kidney and heart muscle are useful for a differentiation between fatal intoxications and cases without toxicological influence (p < 0.05). There were significant differences in the cerebral expression patterns between methamphetamine- and morphine-associated deaths compared to alcohol fatalities (p < 0.05). An intensive staining of HSP70 in the pericontusional zone and the hippocampus after TBI (especially neuronal and vascular) was shown even after short survival times and may be useful as an additional marker in questions of vitality or wound age. A relevant myoglobin decoration of renal tubules was only shown for methamphetamine abuse in the study presented., Conclusion: In sum, the immunohistochemical characteristics presented can be supportive for determining final death circumstances and minimal trauma survival times but are not isolated usefully for the detection of drug- or trauma-induced hyperthermia.

Background: Even though health care seeking interventions potentially reduce child mortality from easily treatable diseases, significant numbers of children die without ever reaching a health facility or due to delays in seeking care in Ethiopia. This study aimed to assess health care seeking behavior for common childhood illnesses and associated factors., Methods: A community-based cross-sectional study was conducted in Jeldu District from January to February 2011. A systematic sampling method was used for sample selection. Data were collected from 422 caregivers with under-five children who experienced diseases within six weeks before the survey. Interviewer administered structured and pre-tested questionnaire which were used to collect data. Data entry and cleaning were carried out using Epi Info version 3.5.1 and analyzed using SPSS version 16. Descriptive analysis was done to determine the magnitude of health care seeking behavior. Multivariate logistic regression analyses were performed to identify associated factors., Results: A total of 422 caregivers of under-five children were participated in the study giving an overall response rate of 97.5%. Three hundred fifteen (74.6%) children sought care from health facilities for all conditions. However, only 55.4% of them were taken to health facilities as first source treatment during their illness and prompt care was also very low (13.7%). Marital status of the caregivers (AOR = 2.84; 95%CI: 1.62-4.98), number of symptoms experienced by the child (AOR = 2.04; 95%CI: 1.24-3.36) and perceived severity of the illness (AOR = 3.20; 95%CI: 1.96-5.22) were predictors of health care seeking behavior., Conclusion: Health care seeking behavior for childhood illnesses was delayed and decision to seek care from health facilities was influenced by worsening of the illnesses. Thus, community level promotion of prompt health care seeking is essential to enhance the health care seeking behavior for child hood illnesses in the locality., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To study private costs and other determinants of access to healthcare for childhood fevers in rural Tanzania., Methods: A case-control study was conducted in Tanzania to establish factors that determine access to a health facility in acute febrile illnesses in children less than 5 years of age. Carers of eligible children were interviewed in the community; cases were represented by patients who went to a facility and controls by those who did not. A Household Wealth Index was estimated using principal components analysis. A multivariable logistic regression analysis was performed to understand the factors which influenced attendance of healthcare facility including severity of the illness and household wealth/socio-demographic indicators. To complement the data on costs from community interviews, a hospital-based study obtained details of private expenditures for hospitalised children under the age of 5., Results: Severe febrile illness is strongly associated with health facility attendance (OR: 35.76, 95%CI: 3.68-347.43, p = 0.002 compared with less severe febrile illness). Overall, the private costs of an illness for patients who went to a hospital were six times larger than private costs of controls ($5.68 vs. $0.90, p<0.0001). Household wealth was not significantly correlated with total costs incurred. The separate hospital based cost study indicated that private costs were three times greater for admissions at the mission versus public hospital: $13.68 mission vs. $4.47 public hospital (difference $ 9.21 (95% CI: 7.89 -10.52), p<0.0001). In both locations, approximately 50% of the cost was determined by the duration of admission, with each day in hospital increasing private costs by about 12% (95% CI: 5% - 21%)., Conclusion: The more severely ill a child, the higher the probability of attending hospital. We did not find association between household wealth and attending a health facility; nor was there an association between household wealth and private cost.

Background: The Lab-score, based on the combined determination of procalcitonin, C-reactive protein and urinary dipstick results, has been shown accurate in detecting serious bacterial infections (SBI) in children with fever without source (FWS) on retrospective cohorts. We aimed to prospectively assess the utility of the Lab-score in safely decreasing antibiotic prescriptions in children with FWS and to determine its diagnostic characteristics compared to common SBI biomarkers., Methods: Randomized controlled trial in children 7 days to 36 months old with FWS, allocated either to the Lab-score group (Lab-score reported, blinded WBC count) or to the control group (WBC, bands and C-reactive protein determined, blinded procalcitonin and Lab-score), followed up until recovery. Demographic data, antibiotic prescription rate, admission rate and diagnostic properties of the Lab-score were analyzed., Results: 271 children were analyzed. No statistically significant difference concerning antibiotic prescription rate was observed: 41.2% (54 of 131) in the Lab-score group and 42.1% (59 of 140) in the control group (p = 1.000). If recommendations based on the Lab-score had been strictly applied, a hypothetical 30.6% treatment rate would have been encountered, compared to the overall 41.7% observed rate (p = 0.0095). A Lab-score ≥3 showed the following characteristics: sensitivity 85.1% (95% CI: 76.5-93.6%), specificity 87.3% (95% CI: 82.7-91.8%), positive predictive value 68.7% (95% CI: 58.7-78.7%), negative predictive value 94.1% (95% CI: 91.5-97.9%), positive and negative likelihood ratios: 6.68 and 0.17 respectively. Area under the receiver operating characteristic curve was best for the Lab-score (0.911, 95% CI: 0.871-0.950)., Discussion: No difference regarding antibiotic treatment rate was observed when using the Lab-score, due to lack of adherence to the related recommendations. However, if strictly followed, a significant 26.5% reduction of antibiotic prescriptions would have been encountered. Medical education needs to be reinforced in order to observe rather than treat low-risk well-appearing children with FWS., Trial Registration: ClinicalTrials.gov NCT02179398.

Introduction: Although the burden of malaria in many parts of Tanzania has declined, the proportion of children with fever has not changed. This situation underscores the need to explore the possible causes of febrile episodes in patients presenting with symptoms at the Korogwe District Hospital (KDH)., Methods: A hospital based cross-sectional study was conducted at KDH, north-eastern Tanzania. Patients aged 2 to 59 months presenting at the outpatient department with an acute medical condition and fever (measured axillary temperature ≥37.5°C) were enrolled. Blood samples were examined for malaria parasites, human immunodeficiency virus (HIV) and bacterial infections. A urine culture was performed in selected cases to test for bacterial infection and a chest radiograph was requested if pneumonia was suspected. Diagnosis was based on both clinical and laboratory investigations., Results: A total of 867 patients with a median age of 15.1 months (Interquartile range 8.6-29.9) were enrolled from January 2013 to October 2013. Respiratory tract infections were the leading clinical diagnosis with 406/867 (46.8%) of patients diagnosed with upper respiratory tract infection and 130/867 (15.0%) with pneumonia. Gastroenteritis was diagnosed in 184/867 (21.2%) of patients. Malaria infection was confirmed in 72/867 (8.3%) of patients. Bacterial infection in blood and urine accounted for 26/808 (3.2%) infections in the former, and 66/373 (17.7%) infections in the latter. HIV infection was confirmed in 10/824 (1.2%) of patients. Respiratory tract infections and gastroenteritis were frequent in patients under 36 months of age (87.3% and 91.3% respectively). Co-infections were seen in 221/867 (25.5%) of patients. The cause of fever was not identified in 65/867 (7.5%) of these patients., Conclusions: The different proportions of infections found among febrile children reflect the causes of fever in the study area. These findings indicate the need to optimise patient management by developing malaria and non-malaria febrile illnesses management protocols.

Background: Most patients with infective endocarditis (IE) manifest fever. Comparison of endocarditis patients with and without fever, and whether the lack of fever in IE is a marker for poorer outcomes, such as demonstrated in other severe infectious diseases, have not been defined., Methods and Results: Cases from the Mayo Clinic, Rochester, Minnesota, Division of Infectious Diseases IE registry, a single-center database that contains all cases of IE treated at our center. Diagnosis date between 1970 and 2006, which met the modified Duke criteria for definite endocarditis, without fever was included. There were 240 euthermic endocarditis cases included in this analysis, with 282 febrile controls selected by frequency matching on gender and decade of diagnosis. Euthermic patients had a median age of 63.6 years (± 16.1) as compared to 59.0 years (± 16.4) in the febrile control group (p=0.001). Median (IQR) symptom duration prior to diagnosis was 4.0 (1.0, 12.0) weeks in the euthermic group compared to 3.0 (1.0, 8.0) weeks in the febrile controls (p= 0.006). From unadjusted analyses, survival rates were 87% in euthermic cases versus 83% in febrile controls across 28-day follow-up (p=0.164), and 72% in euthermic group cases versus 69% in febrile controls across 1-year follow-up (p=0.345). Also unadjusted, the 1-year cumulative incidence rate of valve surgery was higher in euthermic cases versus febrile controls (50% vs. 39%, p= 0.004)., Conclusions: Patients with euthermic endocarditis are older, and lack of fever was associated with longer symptom duration and delayed diagnosis prior to IE diagnosis. Despite a higher unadjusted rate of valve surgery in euthermic patients, the result was not significant when adjusting for baseline confounders. Differences in survival rates at both 28-days and 365-days were not statistically significant between the two groups.

Objective: Although absolute values for C-reactive protein (CRP) and procalcitonin (PCT) are well known to predict sepsis in the critically ill, it remains unclear how changes in CRP and PCT compare in predicting evolution of: infectious disease, invasiveness and severity (e.g. development of septic shock, organ failure and non-survival) in response to treatment. The current study attempts to clarify these aspects., Methods: In 72 critically ill patients with new onset fever, CRP and PCT were measured on Day 0, 1, 2 and 7 after inclusion, and clinical courses were documented over a week with follow up to Day 28. Infection was microbiologically defined, while septic shock was defined as infection plus shock. The sequential organ failure assessment (SOFA) score was assessed., Results: From peak at Day 0-2 to Day 7, CRP decreased when (bloodstream) infection and septic shock (Day 0-2) resolved and increased when complications such as a new (bloodstream) infection or septic shock (Day 3-7) supervened. PCT decreased when septic shock resolved and increased when a new bloodstream infection or septic shock supervened. Increased or unchanged SOFA scores were best predicted by PCT increases and Day 7 PCT, in turn, was predictive for 28-day outcome., Conclusion: The data, obtained during ICU-acquired fever and infections, suggest that CRP may be favoured over PCT courses in judging response to antibiotic treatment. PCT, however, may better indicate the risk of complications, such as bloodstream infection, septic shock, organ failure and mortality, and therefore might help deciding on safe discontinuation of antibiotics. The analysis may thus help interpreting current literature and design future studies on guiding antibiotic therapy in the ICU.

Macrophages are often considered the sentries in innate immunity, sounding early immunological alarms, a function which speeds the response to infection. Compared to the large volume of studies on regulation of macrophage function by pathogens or cytokines, relatively little attention has been devoted to the role of physical parameters such as temperature. Given that temperature is elevated during fever, a long-recognized cardinal feature of inflammation, it is possible that macrophage function is responsive to thermal signals. To explore this idea, we used LPS to model an aseptic endotoxin-induced inflammatory response in BALB/c mice and found that raising mouse body temperature by mild external heat treatment significantly enhances subsequent LPS-induced release of TNF-α into the peritoneal fluid. It also reprograms macrophages, resulting in sustained subsequent responsiveness to LPS, i.e., this treatment reduces "endotoxin tolerance" in vitro and in vivo. At the molecular level, elevating body temperature of mice results in a increase in LPS-induced downstream signaling including enhanced phosphorylation of IKK and IκB, NF-κB nuclear translocation and binding to the TNF-α promoter in macrophages upon secondary stimulation. Mild heat treatment also induces expression of HSP70 and use of HSP70 inhibitors (KNK437 or Pifithrin-µ) largely abrogates the ability of the thermal treatment to enhance TNF-α, suggesting that the induction of HSP70 is important for mediation of thermal effects on macrophage function. Collectively, these results support the idea that there has been integration between the evolution of body temperature regulation and macrophage function that could help to explain the known survival benefits of fever in organisms following infection.

Single large doses of methamphetamine (METH) cause endoplasmic reticulum (ER) stress and mitochondrial dysfunctions in rodent striata. The dopamine D(1) receptor appears to be involved in these METH-mediated stresses. The purpose of this study was to investigate if dopamine D(1) and D(2) receptors are involved in ER and mitochondrial stresses caused by single-day METH binges in the rat striatum. Male Sprague-Dawley rats received 4 injections of 10 mg/kg of METH alone or in combination with a putative D(1) or D(2) receptor antagonist, SCH23390 or raclopride, respectively, given 30 min prior to each METH injection. Rats were euthanized at various timepoints afterwards. Striatal tissues were used in quantitative RT-PCR and western blot analyses. We found that binge METH injections caused increased expression of the pro-survival genes, BiP/GRP-78 and P58(IPK), in a SCH23390-sensitive manner. METH also caused up-regulation of ER-stress genes, Atf2, Atf3, Atf4, CHOP/Gadd153 and Gadd34. The expression of heat shock proteins (HSPs) was increased after METH injections. SCH23390 completely blocked induction in all analyzed ER stress-related proteins that included ATF3, ATF4, CHOP/Gadd153, HSPs and caspase-12. The dopamine D(2)-like antagonist, raclopride, exerted small to moderate inhibitory influence on some METH-induced changes in ER stress proteins. Importantly, METH caused decreases in the mitochondrial anti-apoptotic protein, Bcl-2, but increases in the pro-apoptotic proteins, Bax, Bad and cytochrome c, in a SCH23390-sensitive fashion. In contrast, raclopride provided only small inhibition of METH-induced changes in mitochondrial proteins. These findings indicate that METH-induced activation of striatal ER and mitochondrial stress pathways might be more related to activation of SCH23390-sensitive receptors.

Hemophagocytic lymphohistiocytosis (HLH) is a hyper-inflammatory clinical syndrome associated with neoplastic disorders especially lymphoma, autoimmune conditions, and infectious agents including bacteria, viruses, protozoa and fungi. In both human and veterinary medicine, hemophagocytic histiocytic disorders are clinically important and frequently fatal. HLH in humans can be a primary (familial, autosomal recessive) or secondary (acquired) condition, with both types generally precipitated by an infectious agent. Previously, no mouse model for secondary HLH has been reported. Using Salmonella enterica serotype Typhimurium by oral gavage to mimic naturally-occurring infection in Sv129S6 mice, we characterized the clinical, hematologic and morphologic host responses to disease thereby describing an animal model with the clinico-pathologic features of secondary HLH as set forth by the Histiocyte Society: fever, splenomegaly, cytopenias (anemia, thrombocytopenia), hemophagocytosis in bone marrow and spleen, hyperferritinemia, and hypofibrinogenemia. Disease severity correlates with high splenic and hepatic bacterial load, and we show disease course can be monitored and tracked in live animals. Whereby secondary HLH is known to occur in human patients with typhoid fever and other infectious diseases, our characterization of a viable natural disease model of secondary HLH offers an important means to elucidate pathogenesis of poorly understood mechanisms of secondary HLH and investigation of novel therapies. We characterize previously unreported secondary HLH in a chronic mouse model of typhoid fever, and novel changes in hematology including decreased tissue ferric iron storage that differs from classically described anemia of chronic disease. Our studies demonstrate S. Typhimurium infection of mice is a natural infectious disease model of secondary HLH that may have utility for elucidating disease pathogenesis and developing novel therapies.