BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency.

The transcriptional programs that guide lymphocyte differentiation depend on the precise expression and timing of transcription factors (TFs). The TF BACH2 is essential for T and B lymphocytes and is associated with an archetypal super-enhancer (SE). Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified. Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency. Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. We observed analogous lymphocyte defects in Bach2-heterozygous mice. More generally, we observed that genes that cause monogenic haploinsufficient diseases were substantially enriched for TFs and SE architecture. These findings reveal a previously unrecognized feature of SE architecture in Mendelian diseases of immunity: heterozygous mutations in SE-regulated genes identified by whole-exome/genome sequencing may have greater significance than previously recognized.

Raising AWaRe-ness of Antimicrobial Stewardship Challenges in Pediatric Emergency Care: Results from the PERFORM Study Assessing Consistency and Appropriateness of Antibiotic Prescribing Across Europe.

BACKGROUND: Optimization of antimicrobial stewardship is key to tackling antimicrobial resistance, which is exacerbated by overprescription of antibiotics in pediatric emergency departments (EDs). We described patterns of empiric antibiotic use in European EDs and characterized appropriateness and consistency of prescribing. METHODS: Between August 2016 and December 2019, febrile children attending EDs in 9 European countries with suspected infection were recruited into the PERFORM (Personalised Risk Assessment in Febrile Illness to Optimise Real-Life Management) study. Empiric systemic antibiotic use was determined in view of assigned final "bacterial" or "viral" phenotype. Antibiotics were classified according to the World Health Organization (WHO) AWaRe classification. RESULTS: Of 2130 febrile episodes (excluding children with nonbacterial/nonviral phenotypes), 1549 (72.7%) were assigned a bacterial and 581 (27.3%) a viral phenotype. A total of 1318 of 1549 episodes (85.1%) with a bacterial and 269 of 581 (46.3%) with a viral phenotype received empiric systemic antibiotics (in the first 2 days of admission). Of those, the majority (87.8% in the bacterial and 87.0% in the viral group) received parenteral antibiotics. The top 3 antibiotics prescribed were third-generation cephalosporins, penicillins, and penicillin/ß-lactamase inhibitor combinations. Of those treated with empiric systemic antibiotics in the viral group, 216 of 269 (80.3%) received ≥1 antibiotic in the "Watch" category. CONCLUSIONS: Differentiating bacterial from viral etiology in febrile illness on initial ED presentation remains challenging, resulting in a substantial overprescription of antibiotics. A significant proportion of patients with a viral phenotype received systemic antibiotics, predominantly classified as WHO Watch. Rapid and accurate point-of-care tests in the ED differentiating between bacterial and viral etiology could significantly improve antimicrobial stewardship.

Efficacy of Doxycycline and Ciprofloxacin for Treatment of Pneumonic Tularemia in Cynomolgus Macaques.

BACKGROUND: The incidence of pneumonic tularemia is very low; therefore, it is not feasible to conduct clinical efficacy testing of tularemia medical countermeasures (MCMs) in humans. The US Food and Drug Administration's Animal Model Qualification Program under the Drug Development Tools Program is a regulatory pathway for animal models used in MCM efficacy testing and approval under the Animal Rule. The National Institute of Allergy and Infectious Diseases and Biomedical Advanced Research and Development Authority worked together to qualify the cynomolgus macaque model of pneumonic tularemia. METHODS: Using the model parameters and end points defined in the qualified model, efficacy of the antibiotics doxycycline and ciprofloxacin was evaluated in separate studies. Antibiotic administration, aimed to model approved human dosing, was initiated at time points of 24 hours or 48 hours after onset of fever as an indicator of disease. RESULTS: Upon aerosol exposure (target dose of 1000 colony-forming units) to Francisella tularensis SchuS4, 80% of vehicle-treated macaques succumbed or were euthanized. Ciprofloxacin treatment led to 10 of 10 animals surviving irrespective of treatment time. Doxycycline administered at 48 hours post-fever led to 10 of 10 animals surviving, while 9/10 animals survived in the group treated with doxycycline 24 hours after fever. Selected surviving animals in both the placebo and doxycycline 48-hour group showed residual live bacteria in peripheral tissues, while there were no bacteria in tissues from ciprofloxacin-treated macaques. CONCLUSIONS: Both doxycycline and ciprofloxacin were efficacious in treatment of pneumonic tularemia, although clearance of bacteria may be different between the 2 drugs.

Old paradigms and new concepts in familial Mediterranean fever (FMF): an update 2023.

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent attacks of fever and polyserositis. Its first description as a new entity was published by Siegal in 1945. Colchicine has been the treatment of choice for this disease since 1972. Significant progress has been made over the years in understanding FMF's clinical features, diagnosis, mode of inheritance, pathogenesis and therapeutic approach. However, many old paradigms related to FMF have proven inaccurate, leading to the emergence of new concepts that provide more precise insights. The term 'FMF' is no longer appropriate as the disease is found beyond the Mediterranean basin. The concept of diagnosis based only upon clinical ground proved to be wrong. The paradigm that MEFV mutations in FMF lead to loss of function of the encoded peptide pyrin turned out to be a gain of function mutation. Finally, the concept that as a genetic disease FMF should be treated for life was found to be inaccurate for the subpopulation of the heterozygote patients. Thus, the breakthroughs of identifying the gene associated with the disease (MEFV) and the deciphering of its pathogenesis revolutionized our old paradigms and replaced them with new and more precise insights.

Understanding pre-hospital disease management of fever and diarrhoea in children-Care pathways in rural Tanzania.

OBJECTIVE: Many children in sub-Saharan Africa die from infectious diseases like malaria, pneumonia, and diarrhoea that can be prevented by early diagnosis, effective and targeted treatment. This study aimed to gain insights into case management practices by parents before they present their children to hospital. METHODS: We conducted a cross-sectional study among 332 parents attending a district hospital with their under-fives symptomatic with fever and/or diarrhoea between November 2019 and July 2020 in rural Tanzania. Timely and targeted treatment was defined as seeking health care within 24 h of fever onset, and continued fluid intake in case of diarrhoea. RESULTS: The main admission diagnoses were acute respiratory infections (61.8%), malaria (25.3%), diarrhoea (18.4%) and suspected sepsis (8.1%). The majority of children (91%) received treatment prior to admission, mostly antipyretics (75.6%), local herbal medicines (26.8%), and antibiotics (17.8%)-half of them without prescription from a clinician. For diarrhoea, the use of oral rehydration solution was rare (9.0%), although perceived as easily accessible and affordable. 49.4% of the parents presented their children directly to the hospital, 23.2% went to a pharmacy/drug shop and 19.3% to a primary health facility first. Malaria symptoms began mostly 3 days before the hospital visit; only 25.4% of febrile children visited any health facility within 24 h of disease onset. Prior use of local herbal medicine (AOR = 3.2; 95% CI 1.4-7.3), visiting the pharmacy (adjusted Odds Ratio [AOR] = 3.1; 95% confidence interval [CI]: 1.0-9.8), the dispensary being the nearest health facility (AOR = 3.0; 95% CI: 1.5-6.2), and financial difficulties (AOR = 2.2; 95% CI 1.1-4.5) were associated with delayed treatment. CONCLUSION: This study suggests that antipyretics and antibiotics dispensed at pharmacies/drug shops, as well as use of local herbal medicines, delay early diagnosis and treatment, which can be life-threatening. Pharmacies/drug shops could be integrated as key focal points for sensitising community members on how to respond to paediatric illnesses and encourage the use of oral rehydration solutions.

Fever in focus: Symptoms, diagnoses and treatment of febrile children in Ghana-A longitudinal hospital study.

BACKGROUND: Healthcare resources are often limited in areas of sub-Saharan Africa. This makes accurate and timely diagnoses challenging and delays treatment of childhood febrile illness. We explored longitudinal characteristics related to symptoms, diagnosis and treatment of hospitalised febrile children in a rural area of Ghana highly endemic for malaria. METHODS: Febrile children under 15 years, admitted to the study hospital paediatric ward, were recruited to the study and clinical data were collected throughout hospitalisation. Descriptive statistics were reported for all cases; for longitudinal analyses, a subset of visits with limited missing data was used. RESULTS: There were 801 hospitalised children included in longitudinal analyses. Malaria (n = 581, 73%) and sepsis (n = 373, 47%) were the most prevalent suspected diagnoses on admission. One-third of malaria suspected diagnoses (n = 192, 33%) were changed on the discharge diagnosis, compared to 84% (n = 315) of sepsis suspected diagnoses. Among malaria-only discharge diagnoses, 98% (n/N = 202/207) received an antimalarial and 33% (n/N = 69/207) an antibiotic; among discharge diagnoses without malaria, 28% (n/N = 108/389) received an antimalarial and 83% (n/N = 324/389) an antibiotic. CONCLUSIONS: Suspected diagnoses were largely based on clinical presentation and were frequently changed; changed diagnoses were associated with lingering symptoms, underscoring the need for faster and more accurate diagnostics. Medications were over-prescribed regardless of diagnosis stability, possibly because of a lack of confidence in suspected diagnoses. Thus, better diagnostic tools are needed for childhood febrile illnesses to enhance the accuracy of and confidence in diagnoses, and to cut down unjustified medication use, reducing the risk of antimicrobial and malaria resistance.

Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in mainland Tanzania, 2018.

BACKGROUND: The use of artemisinin-based combination therapy (ACT) is recommended by the World Health Organization for the treatment of uncomplicated falciparum malaria. Artemether-lumefantrine (AL) is the most widely adopted first-line ACT for uncomplicated malaria in sub-Saharan Africa (SSA), including mainland Tanzania, where it was introduced in December 2006. The WHO recommends regular assessment to monitor the efficacy of the first-line treatment specifically considering that artemisinin partial resistance was reported in Greater Mekong sub-region and has been confirmed in East Africa (Rwanda and Uganda). The main aim of this study was to assess the efficacy and safety of AL for the treatment of uncomplicated falciparum malaria in mainland Tanzania. METHODS: A single-arm prospective anti-malarial drug efficacy trial was conducted in Kibaha, Mlimba, Mkuzi, and Ujiji (in Pwani, Morogoro, Tanga, and Kigoma regions, respectively) in 2018. The sample size of 88 patients per site was determined based on WHO 2009 standard protocol. Participants were febrile patients (documented axillary temperature ≥ 37.5 °C and/or history of fever during the past 24 h) aged 6 months to 10 years. Patients received a 6-dose AL regimen by weight twice a day for 3 days. Clinical and parasitological parameters were monitored during 28 days of follow-up to evaluate the drug efficacy and safety. RESULTS: A total of 653 children were screened for uncomplicated malaria and 349 (53.7%) were enrolled between April and August 2018. Of the enrolled children, 345 (98.9%) completed the 28 days of follow-up or attained the treatment outcomes. There were no early treatment failures, but recurrent infections were higher in Mkuzi (35.2%) and Ujiji (23%). By Kaplan-Meier analysis of polymerase chain reaction (PCR) uncorrected adequate clinical and parasitological response (ACPR) ranged from 63.4% in Mkuzi to 85.9% in Mlimba, while PCR-corrected ACPR on day 28 varied from 97.6% in Ujiji to 100% in Mlimba. The drug was well tolerated; the commonly reported adverse events were cough, runny nose, and abdominal pain. No serious adverse event was reported. CONCLUSION: This study showed that AL had adequate efficacy and safety for the treatment of uncomplicated falciparum malaria. The high number of recurrent infections were mainly due to new infections, indicating the necessity of utilizing alternative artemisinin-based combinations, such as artesunate amodiaquine, which provide a significantly longer post-treatment prophylactic effect.

The protective effects of Zingiber zerumbet rhizome against fevers in rats.

The Zingiber zerumbet rhizomes are traditionally used to treat fever, and the in vitro inhibitory effect of ethyl acetate extract from Zingiber zerumbet rhizomes (EAEZZR) against DENV2 NS2B/NS3 (two non-structural proteins, NS2 and NS3 of dengue virus type 2) has been reported earlier. This study was carried out to establish an acute toxicity profile and evaluate the anti-fever (anti-pyretic) activities of EAEZZR in yeast-induced fever in rats. The major compound of EAEZZR, zerumbone, was isolated using chromatographic methods including column chromatography (CC) and preparative thin-layer chromatography (PTLC). Additionally, the structure of zerumbone was elucidated using nuclear magnetic resonance (NMR), liquid chromatography mass spectrometer-ion trap-time of flight (LCMS-IT-TOF), infrared (IR), and ultraviolet (UV) spectroscopy. The toxicity of EAEZZR was evaluated using Organization for Economic Cooperation and Development Test Guideline 425 (OECD tg-425) with minor modifications at concentrations EAEZZR of 2000 mg/kg, 3000 mg/kg, and 5000 mg/kg. Anti-fever effect was determined by yeast-induced fever (pyrexia) in rats. The acute toxicity study showed that EAEZZR is safe at the highest 5000 mg/kg body weight dose in Sprague Dawley rats. Rats treated with EAEZZR at doses of 125, 250, and 500 mg/kg exhibited a significant reduction in rectal temperature (TR) in the first 1 h. EAEZZR at the lower dose of 125 mg/kg showed substantial potency against yeast-induced fever for up to 2 h compared to 0 h in controls. A significant reduction of TR was observed in rats treated with standard drug aspirin in the third through fourth hours. Based on the present findings, ethyl acetate extract of Zingiber zerumbet rhizomes could be considered safe up to the dose of 5000 mg/kg, and the identification of active ingredients of Zingiber zerumbet rhizomes may allow their use in the treatment of fever with dengue virus infection.

Malaria: A focused review for the emergency medicine clinician.

INTRODUCTION: Malaria is a potentially fatal parasitic disease transmitted by the Anopheles mosquito. A resurgence in locally acquired infections has been reported in the U.S. OBJECTIVE: This narrative review provides a focused overview of malaria for the emergency clinician, including the epidemiology, presentation, diagnosis, and management of the disease. DISCUSSION: Malaria is caused by Plasmodium and is transmitted by the Anopheles mosquito. Disease severity can range from mild to severe. Malaria should be considered in any returning traveler from an endemic region, as well as those with unexplained cyclical, paroxysms of symptoms or unexplained fever. Patients most commonly present with fever and rigors but may also experience cough, myalgias, abdominal pain, fatigue, vomiting, and diarrhea. Hepatomegaly, splenomegaly, pallor, and jaundice are findings associated with malaria. Although less common, severe malaria is precipitated by microvascular obstruction with complications of anemia, acidosis, hypoglycemia, multiorgan failure, and cerebral malaria. Peripheral blood smears remain the gold standard for diagnosis, but rapid diagnostic tests are available. Treatment includes specialist consultation and antimalarial drugs tailored depending on chloroquine resistance, geographic region of travel, and patient comorbidities. Supportive care may be required, and patients with severe malaria will require resuscitation. Most patients will require admission for treatment and further monitoring. CONCLUSION: Emergency medicine clinicians should be aware of the presentation, diagnosis, evaluation, and management of malaria to ensure optimal outcomes.

Afebrile status at the time of emergency department visit is associated with delayed antibiotic therapy in patients with sepsis (revised).

OBJECTIVES: To determine whether there is a difference in antibiotic administration time and prognosis in afebrile sepsis patients compared to febrile sepsis patients. METHODS: This was retrospective multicenter observational study. Data collected from three referral hospitals. Data were collected from May 2014 through February 2016 under the SEPSIS-2 criteria and from March 2016 to April 2020 under the newly released SEPSIS-3 criteria. Patients were divided into two groups based on body temperature: afebrile (<37.3 °C) and febrile (≥37.3 °C). The relationship between initial body temperature and 28-day mortality were analyzed using multivariable logistic regression. The subgroup analysis was conducted on patients with complete Hour-1 bundle performance records. RESULTS: We included 4293 patients in this study. Initial body temperatures in 28-day survivors were significantly higher than in 28-day non-survivors (37.5 °C ± 1.2 °C versus 37.1 °C ± 1.2 °C, p < 0.01). Multivariable logistic regression analysis was performed in afebrile and febrile sepsis patients. Adjusted odds ratio of afebrile sepsis patients for 28-day mortality was 1.76 (95% Confidence interval 1.46-2.12). As a result of performing the Hour-1 bundle, the number of patients who received antibiotics within 1 h was smaller in the afebrile sepsis patients (323/2076, 15.6%) than in the febrile sepsis patients (395/2156, 18.3%) (p = 0.02). In the subgroup analysis of patients with complete Hour-1 bundle performance records adjusted odds ratio of afebrile sepsis patients for 28-day mortality was 1.68 (95% Confidence interval 1.34-2.11). The febrile sepsis patients received antibiotics faster than the afebrile sepsis patients (175.5 ± 207.9 versus 209.3 ± 277.9, p < 0.01). CONCLUSIONS: Afebrile sepsis patients were associated with higher 28-day mortality compared to their febrile counterparts and were delayed in receiving antibiotics. This underscores the need for improved early detection and treatment strategies for the afebrile sepsis patients.

Factors associated with the use of antibiotics for children presenting with illnesses with fever and cough obtained from prescription and non-prescription sources: a cross-sectional study of data for 37 sub-Saharan African countries.

INTRODUCTION: Fever and cough in under-five children are common and predominately self-limiting illnesses. Inappropriate prescribing of antibiotics in sub-Saharan Africa is a significant public health concern. However, prescription sources and use among children with fever or cough have not been explored. Therefore, we explored the factors associated with the use of antibiotics obtained from prescription and non-prescription sources for children with illnesses associated with fever and cough. METHODS: A secondary data analysis was conducted based on the Demographic and Health Survey (DHS) data from 37 sub-Saharan African countries. A total weighted sample of 18,866 under-five children who had a fever/cough and took antibiotics were considered for this study. Given the hierarchical nature of DHS data and the use of antibiotics prescribed from the formal healthcare setting (> 10%), a multilevel modified poisson regression model was fitted. Deviance was used for model comparison and the model with the lowest deviance value was chosen as the best-fitted model. Variables with p ≤ 0.2 in the bivariable analysis were considered for the multivariable modified poisson regression model. In the multivariable multilevel modified poisson regression model, the Adjusted Prevalence Odds Ratio (APOR) with a 95% Confidence Interval (CI) and p-value < 0.05 were reported to declare a significant association with taking antibiotics for fever/cough prescribed from formal healthcare setting. RESULTS: In sub-Saharan Africa, the proportion of use of antibiotics from informal healthcare setting for fever and cough among under-five children was 67.19% (95% CI: 66.51%, 67.85%). In the multilevel modified poisson regression analysis; residing in a rural area (APOR = 1.08, 95% CI: 1.04, 1.12), a child aged 36-47 months (APOR = 0.94, 95% CI: 0.90, 0.98), a child aged 48-59 months (APOR = 0.89, 95% CI: 0.84, 0.94), maternal primary education (APOR = 0.96, 95% CI: 0.93, 0.99), maternal secondary education (APOR = 0.95, 95% CI: 0.92, 0.99), belonged the middle household wealth status (APOR = 1.07, 95% CI: 1.02, 1.11), maternal exposure to news/electronic media (APR = 1.06, 95% CI: 1.02, 1.10), being from a household with 2 under-five children (APR = 0.94, 95% CI: 0.91, 0.97), being from a household with 3 under-five children (APR = 0.89, 95% CI: 0.85, 0.93), being from a household with 4 under-five children (APR = 0.90, 95% CI: 0.83, 0.98), and children of caregivers who were not involved in decision-making for their child health issues were significantly associated with taking antibiotics prescribed from formal healthcare setting for fever/cough among under-five children. CONCLUSION: Only two-thirds of the antibiotics used for children under five who had fever and cough were prescribed from formal healthcare setting. Our findings underscore the significance of addressing healthcare disparities, improving access to qualified healthcare providers, promoting maternal education, and empowering mothers in healthcare decision-making to ensure appropriate antibiotic use in this vulnerable population. Further research and interventions targeted at these factors are warranted to optimize antibiotic prescribing practices and promote responsible antibiotic use in the management of fever and cough in under-five children.

Antibiotic prescriptions to children with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis.

AIM: To investigate the rate of dispensed antibiotic prescriptions to children and adolescents with PFAPA and compare this with the rate for children in the general population. Furthermore, to compare dispensed antibiotic prescription rates before and after a diagnosis of PFAPA was established. METHODS: Patients aged 0-17 years and diagnosed with PFAPA between 1 January 2006 to 31 October 2017 were included retrospectively. Data on dispensed drug prescriptions were obtained from the Swedish National Prescribed Drug Register. RESULTS: The PFAPA cohort received more antibiotic prescriptions than the general population in all but one of the age groups and time periods that were analysed. The largest difference was seen in 2014-2017 in the youngest age group (0-4 years) when children with PFAPA received 1218 antibiotic prescriptions per 1000 person years compared to 345 in the general population (IRR 3.5; 95% CI 2.8-4.4). The yearly number of antibiotic prescriptions to PFAPA patients was reduced from 2.1 before diagnosis to 0.8 after diagnosis, a reduction of 62%. CONCLUSION: This study shows higher rates of dispensed antibiotic prescriptions for children with PFAPA than in the general population. The reduction of prescriptions after an established PFAPA diagnosis indicates that antibiotics were previously incorrectly prescribed for PFAPA episodes.

Rapid recovery in a child with febrile ulceronecrotic Mucha-Habermann disease following intravenous immunoglobulin administration.

Febrile ulceronecrotic Mucha-Habermann disease (FUMHD), a lymphocyte-mediated inflammatory skin disorder, is considered a severe variant of pityriasis lichenoides et varioliformis acuta that can lead to a fatal outcome if not managed in a timely fashion. Children with FUMHD can have systemic complications involving various organs. The scarcity of reported cases and the absence of well-designed studies or randomized clinical trials to evaluate different therapeutic modalities pose a major challenge in treating this potentially life-threatening disorder. We report a five-year-old child with FUMHD and seizures treated unsuccessfully with a combination of systemic steroids, methotrexate, dapsone, and oral erythromycin, who improved rapidly and achieved disease control with just a single infusion of low-dose intravenous immunoglobulin.

Effectiveness of two same-manufacturer intravenous immunoglobulin for Kawasaki disease.

BACKGROUND: To investigate whether two brands of intravenous immunoglobulin (IVIG) from the same manufacturer lead to varied effects when administered to patients with Kawasaki disease. (KD) METHODS: Clinical characteristics, laboratory data, IVIG response, and coronary arteries change were analyzed between two groups. RESULTS: We included 158 KD cases. The mean age at KD diagnosis was 23 ± 1.39 (range, 2-95) months. In the first IVIG course, 18 (11.4 %) patients were unresponsive. TBSF (brand T) and Privigen (brand P) were administered to 94 and 64 patients, respectively. The brand P group had a significantly longer fever (P < 0.001) and hospitalization (P = 0.007) durations after the therapy and a higher number of IVIG unresponsiveness (P = 0.016) than the brand T group. In the multivariate logistic regression analysis, a high Formosa score (≥3, Odds ratio [OR], 4.939; 95 % confidence interval [CI], 1.199-20.337; P = 0.027), high levels of CRP (≥12 mg/L, OR: 4.257,95 % CI,1.265-14.322; P = 0.019), and treatment with brand P (OR, 3.621; 95 % CI, 1.029-12.677; P = 0.045) were independent risk factors for IVIG unresponsiveness. CONCLUSIONS: Compared with brand T, brand P prolonged the fever and hospitalization durations after IVIG treatment and increased the proportion of IVIG treatment unresponsiveness, but it did not infer the coronary arteries sequelae.

2-Hydroxybenzohydrazide as a novel potential candidate against nociception, inflammation, and pyrexia: in vitro, in vivo, and computational approaches.

The current study was designed to evaluate the 2-hydroxybenzohydrazide (HBH) as a drug having efficacy against pyrexia, inflammation, and nociception. Besides, the therapeutic effects of HBH on oxidative stress and C-reactive proteins were also evaluated. The pharmacological studies on HBH (20-60 mg/kg) were conducted using nociception, inflammation, and pyrexia standard models. Naloxone antagonism was performed to assess the possible involvement of opioidergic mechanisms. The antioxidant study was conducted on ABTS and DPPH assays using gallic acid as a standard. Moreover, the binding capability of HBH with enzymes cyclooxygenase-I/II (COX-I/II) was determined using molecular modeling analysis. The findings indicated that the HBH dose-dependently inhibited pain, inflammation, and pyrexia. The HBH has significant anti-nociceptive and anti-inflammatory activities at 60 mg/kg (***p < 0.001), similar to the lower doses of diclofenac sodium (50 mg/kg) and tramadol (30 mg/kg). The HBH at 60 mg/kg reduced pyrexia as paracetamol (150 mg/kg). The HBH at 20-60 mg/kg doses declined the plasma C-reactive protein concentration. The mechanistic studies showed that the anti-nociceptive effect of HBH was antagonized by naloxone, indicating that the opioidergic mechanisms are involved. Furthermore, computational studies showed that the HBH exhibited an affinity for COX-I/II target receptors. The HBH significantly inhibited ABTS and DPPH radicals (IC50 = 33.81 and 26.74 µg/ml). These results proposed that the HBH has significant antipyretic, anti-inflammatory, and anti-nociceptive activities involving opioidergic mechanism.

Kaempferol 3-O-Rutinoside, a Flavone Derived from Tetrastigma hemsleyanum Diels et Gilg, Reduces Body Temperature through Accelerating the Elimination of IL-6 and TNF-α in a Mouse Fever Model.

Fever is a serious condition that can lead to various consequences ranging from prolonged illness to death. Tetrastigma hemsleyanum Diels et Gilg (T. hemsleyanum) has been used for centuries to treat fever, but the specific chemicals responsible for its antipyretic effects are not well understood. This study aimed to isolate and identify the chemicals with antipyretic bioactivity in T. hemsleyanum extracts and to provide an explanation for the use of T. hemsleyanum as a Chinese herbal medicine for fever treatment. Our results demonstrate that kaempferol 3-rutinoside (K3OR) could be successfully isolated and purified from the roots of T. hemsleyanum. Furthermore, K3OR exhibited a significant reduction in rectal temperature in a mouse model of fever. Notably, a 4 µM concentration of K3OR showed more effective antipyretic effects than ibuprofen and acetaminophen. To explore the underlying mechanism, we conducted an RNA sequencing analysis, which revealed that PXN may act as a key regulator in the fever process induced by lipopolysaccharide (LPS). In the mouse model of fever, K3OR significantly promoted the secretion of IL-6 and TNF-α during the early stage in the LPS-treated group. However, during the middle to late stages, K3OR facilitated the elimination of IL-6 and TNF-α in the LPS-treated group. Overall, our study successfully identified the chemicals responsible for the antipyretic bioactivity in T. hemsleyanum extracts, and it answered the question as to why T. hemsleyanum is used as a traditional Chinese herbal medicine for treating fever. These findings contribute to a better understanding of the therapeutic potential of T. hemsleyanum in managing fever, and they provide a basis for further research and development in this field.

Understanding Health Worker and Community Antibiotic Prescription-Adherence Practices for Acute Febrile Illness: A Nested Qualitative Study in the Shai-Osudoku District of Ghana and the Development of a Training-and-Communication Intervention.

BACKGROUND: The aim was to explore behavioral factors relating to the prescription and communication of prescription-adherence messages for patients with acute febrile illness, from which to develop a training-and-communication (T&C) intervention to be delivered as part of a clinical trial. METHODS: The study undertook a content analysis of primary, qualitative data collection using in-depth interviews and focus group discussions, informed by the Capability, Opportunity, Motivation (COM-B) theory of behavior, the Theoretical Domains Framework (TDF), and Behavior Change Wheel (BCW) approach, in health facilities (39 health workers) and communities (66 community members) in the Shai-Osudoku District of Ghana. RESULTS: Health workers perceive that prescribers' and dispensers' communication with patients is influenced by the following factors: patient's educational level, existing disease conditions, health worker's workload, patient's religion, language barrier between health worker and patient, outcome of laboratory results, and medicine availability. Community members' adherence to prescription was influenced by the availability of money and affordability of medicine (outside of provision by the national health insurance scheme), the severity of the condition, work schedule, and forgetfulness. CONCLUSIONS: Our study contributes to knowledge on nesting qualitative methods in a clinical trial and reveals factors that affect the antibiotic prescription communication process. Tailored messages for patient-specific needs can shape antibiotic prescription adherence behavior and ultimately contribute to decreasing the incidence of antibiotic resistance.

Antimicrobial for 7 or 14 Days for Febrile Urinary Tract Infection in Men: A Multicenter Noninferiority Double-Blind, Placebo-Controlled, Randomized Clinical Trial.

BACKGROUND: The optimal duration of antimicrobial therapy for urinary tract infections (UTIs) in men remains controversial. METHODS: To compare 7 days to 14 days of total antibiotic treatment for febrile UTIs in men, this multicenter randomized, double-blind. placebo-controlled noninferiority trial enrolled 282 men from 27 centers in France. Men were eligible if they had a febrile UTI and urine culture showing a single uropathogen. Participants were treated with ofloxacin or a third-generation cephalosporin at day 1, then randomized at day 3-4 to either continue ofloxacin for 14 days total treatment, or for 7 days followed by placebo until day 14. The primary endpoint was treatment success, defined as a negative urine culture and the absence of fever and of subsequent antibiotic treatment between the end of treatment and 6 weeks after day 1. Secondary endpoints included recurrent UTI within weeks 6 and 12 after day 1, rectal carriage of antimicrobial-resistant Enterobacterales, and drug-related events. RESULTS: Two hundred forty participants were randomly assigned to receive antibiotic therapy for 7 days (115 participants) or 14 days (125 participants). In the intention-to-treat analysis, treatment success occurred in 64 participants (55.7%) in the 7-day group and in 97 participants (77.6%) in the 14-day group (risk difference, -21.9 [95% confidence interval, -33.3 to -10.1]), demonstrating inferiority. Adverse events during antibiotic therapy were reported in 4 participants in the 7-day arm and 7 in the 14-day arm. Rectal carriage of resistant Enterobacterales did not differ between both groups. CONCLUSIONS: A treatment with ofloxacin for 7 days was inferior to 14 days for febrile UTI in men and should therefore not be recommended. CLINICAL TRIALS REGISTRATION: NCT02424461; Eudra-CT: 2013-001647-32.

Impact of the Introduction of a Package of Diagnostic Tools, Diagnostic Algorithm, and Training and Communication on Outpatient Acute Fever Case Management at 3 Diverse Sites in Uganda: Results of a Randomized Controlled Trial.

BACKGROUND: Increasing trends of antimicrobial resistance are observed around the world, driven in part by excessive use of antimicrobials. Limited access to diagnostics, particularly in low- and middle-income countries, contributes to diagnostic uncertainty, which may promote unnecessary antibiotic use. We investigated whether introducing a package of diagnostic tools, clinical algorithm, and training-and-communication messages could safely reduce antibiotic prescribing compared with current standard-of-care for febrile patients presenting to outpatient clinics in Uganda. METHODS: This was an open-label, multicenter, 2-arm randomized controlled trial conducted at 3 public health facilities (Aduku, Nagongera, and Kihihi health center IVs) comparing the proportions of antibiotic prescriptions and clinical outcomes for febrile outpatients aged ≥1 year. The intervention arm included a package of point-of-care tests, a diagnostic and treatment algorithm, and training-and-communication messages. Standard-of-care was provided to patients in the control arm. RESULTS: A total of 2400 patients were enrolled, with 49.5% in the intervention arm. Overall, there was no significant difference in antibiotic prescriptions between the study arms (relative risk [RR]: 1.03; 95% CI: .96-1.11). In the intervention arm, patients with positive malaria test results (313/500 [62.6%] vs 170/473 [35.9%]) had a higher RR of being prescribed antibiotics (1.74; 1.52-2.00), while those with negative malaria results (348/688 [50.6%] vs 376/508 [74.0%]) had a lower RR (.68; .63-.75). There was no significant difference in clinical outcomes. CONCLUSIONS: This study found that a diagnostic intervention for management of febrile outpatients did not achieve the desired impact on antibiotic prescribing at 3 diverse and representative health facility sites in Uganda.

Impact of Point-of-Care Rapid Diagnostic Tests on Antibiotic Prescription Among Patients Aged <18 Years in Primary Healthcare Settings in 2 Peri-Urban Districts in Ghana: Randomized Controlled Trial Results.

BACKGROUND: Inappropriate antibiotic prescriptions are a known driver of antimicrobial resistance in settings with limited diagnostic capacity. This study aimed to assess the impact of diagnostic algorithms incorporating rapid diagnostic tests on clinical outcomes and antibiotic prescriptions compared with standard-of-care practices, of acute febrile illness cases at outpatient clinics in Shai-Osudoku and Prampram districts in Ghana. METHODS: This was an open-label, centrally randomized controlled trial in 4 health facilities. Participants aged 6 months to <18 years of both sexes with acute febrile illness were randomized to receive a package of interventions to guide antibiotic prescriptions or standard care. Clinical outcomes were assessed on day 7. RESULTS: In total, 1512 patients were randomized to either the intervention (n = 761) or control (n = 751) group. Majority were children aged <5 years (1154 of 1512, 76.3%) and male (809 of 1512, 53.5%). There was 11% relative risk reduction of antibiotic prescription in intervention group (RR, 0.89; 95% CI, .79 to 1.01); 14% in children aged <5 years (RR, 0.86; 95% CI, .75 to .98), 15% in nonmalaria patients (RR, 0.85; 95% CI, .75 to .96), and 16% in patients with respiratory symptoms (RR, 0.84; 95% CI, .73 to .96). Almost all participants had favorable outcomes (759 of 761, 99.7% vs 747 of 751, 99.4%). CONCLUSIONS: In low- and middle-income countries, the combination of point-of-care diagnostics, diagnostic algorithms, and communication training can be used at the primary healthcare level to reduce antibiotic prescriptions among children with acute febrile illness, patients with nonmalarial fevers, and respiratory symptoms. CLINICAL TRIALS REGISTRATION: NCT04081051.