A preoptic neuronal population controls fever and appetite during sickness.

During infection, animals exhibit adaptive changes in physiology and behaviour aimed at increasing survival. Although many causes of infection exist, they trigger similar stereotyped symptoms such as fever, warmth-seeking, loss of appetite and fatigue1,2. Yet exactly how the nervous system alters body temperature and triggers sickness behaviours to coordinate responses to infection remains unknown. Here we identify a previously uncharacterized population of neurons in the ventral medial preoptic area (VMPO) of the hypothalamus that are activated after sickness induced by lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid. These neurons are crucial for generating a fever response and other sickness symptoms such as warmth-seeking and loss of appetite. Single-nucleus RNA-sequencing and multiplexed error-robust fluorescence in situ hybridization uncovered the identity and distribution of LPS-activated VMPO (VMPOLPS) neurons and non-neuronal cells. Gene expression and electrophysiological measurements implicate a paracrine mechanism in which the release of immune signals by non-neuronal cells during infection activates nearby VMPOLPS neurons. Finally, we show that VMPOLPS neurons exert a broad influence on the activity of brain areas associated with behavioural and homeostatic functions and are synaptically and functionally connected to circuit nodes controlling body temperature and appetite. Together, these results uncover VMPOLPS neurons as a control hub that integrates immune signals to orchestrate multiple sickness symptoms in response to infection.

Phase 3 Trial of Crinecerfont in Pediatric Congenital Adrenal Hyperplasia.

BACKGROUND: Children with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency require treatment with glucocorticoids, usually at supraphysiologic doses, to address cortisol insufficiency and reduce excess adrenal androgens. However, such treatment confers a predisposition to glucocorticoid-related complications. In 2-week phase 2 trials, patients with CAH who received crinecerfont, a new oral corticotropin-releasing factor type 1 receptor antagonist, had decreases in androstenedione levels. METHODS: In this phase 3, multinational, randomized trial, we assigned pediatric participants with CAH, in a 2:1 ratio, to receive crinecerfont or placebo for 28 weeks. A stable glucocorticoid dose was maintained for 4 weeks, and the dose was then adjusted to a target of 8.0 to 10.0 mg per square meter of body-surface area per day (hydrocortisone dose equivalents), provided that the androstenedione level was controlled (≤120% of the baseline level or within the reference range). The primary efficacy end point was the change in the androstenedione level from baseline to week 4. A key secondary end point was the percent change in the glucocorticoid dose from baseline to week 28 while androstenedione control was maintained. RESULTS: A total of 103 participants underwent randomization, of whom 69 were assigned to crinecerfont and 34 to placebo; 100 (97%) remained in the trial at 28 weeks. At baseline, the mean glucocorticoid dose was 16.4 mg per square meter per day, and the mean androstenedione level was 431 ng per deciliter (15.0 nmol/liter). At week 4, androstenedione was substantially reduced in the crinecerfont group (-197 ng per deciliter [-6.9 nmol/liter]) but increased in the placebo group (71 ng per deciliter [2.5 nmol/liter]) (least-squares mean difference [LSMD], -268 ng per deciliter [-9.3 nmol/liter]; P<0.001); the observed mean androstenedione value, obtained before the morning glucocorticoid dose, was 208 ng per deciliter (7.3 nmol/liter) in the crinecerfont group, as compared with 545 ng per deciliter (19.0 nmol/liter) in the placebo group. At week 28, the mean glucocorticoid dose had decreased (while androstenedione control was maintained) by 18.0% with crinecerfont but increased by 5.6% with placebo (LSMD, -23.5 percentage points; P<0.001). Headache, pyrexia, and vomiting were the most common adverse events. CONCLUSIONS: In this phase 3 trial, crinecerfont was superior to placebo in reducing elevated androstenedione levels in pediatric participants with CAH and was also associated with a decrease in the glucocorticoid dose from supraphysiologic to physiologic levels while androstenedione control was maintained. (Funded by Neurocrine Biosciences; CAHtalyst Pediatric ClinicalTrials.gov number, NCT04806451.).

Prostaglandin production selectively in brain endothelial cells is both necessary and sufficient for eliciting fever.

Fever is known to be elicited by prostaglandin E2 acting on the brain, but its origin has remained disputed. We show in mice that selective deletion of prostaglandin synthesis in brain endothelial cells, but not in neural cells or myeloid cells, abolished fever induced by intravenous administration of lipopolysaccharide and that selective rescue of prostaglandin synthesis in brain endothelial cells reinstated fever. These data demonstrate that prostaglandin production in brain endothelial cells is both necessary and sufficient for eliciting fever.

The spectrum of side effects associated with COVID-19 vaccines in patients with inborn errors of immunity.

OBJECTIVE: COVID-19 immunization was implemented with emergency-use authorization. We had concerns/lack of information on mRNA vaccine side effects in different inborn errors of immunity (IEI) types. METHODS: We enrolled 141 patients (IEIP) and 151 healthy controls(HC) who received SARS-CoV-2 vaccine/s(Sinovac and/or Pfizer-BioNTech(mRNA vaccine), one to five doses), questioned them for side-effects, evaluated in three groups according to the vaccine/s they received; only Sinovac, only Pfizer-BioNTech, and both vaccines. RESULTS: Arm pain, generalized weakness, myalgia, and fever were common side effects in IEI-P and HC groups. Generalized weakness/fatigue, fever, and palpitation were significantly frequent in IEI-P who experienced COVID-19 compared to those who did not (p = 0.021, p = 0.047, and p = 0.024, respectively). Severe symptoms after vaccination, new-onset splenomegaly and pancytopenia, urticaria, herpes simplex virus (HSV), and varicella zoster virus (VZV) reactivation were seen in four IEI-P (2.8%). CONCLUSION: IEI-P mRNA vaccination is relatively safe compared to the conventional vaccine. Individuals who experience uncommon side effects should undergo immunological screening.

Adolescent intermittent ethanol (AIE) sensitized fever in male Sprague Dawley rats exposed to poly I:C in adulthood.

Fever plays an indispensable role in host defense processes and is used as a rapid index of infection severity. Unfortunately, there are also substantial individual differences in fever reactions with biological sex, immunological history, and other demographic variables contributing to adverse outcomes of infection. The present series of studies were designed to test the hypothesis that a history of adolescent alcohol misuse may be a latent experiential variable that determines fever severity using polyinosinic:polycytidylic acid (poly I:C), a synthetic form of double-stranded RNA that mimics a viral challenge. Adult male and female Sprague Dawley rats were injected with 0 (saline) or 4 mg/kg poly I:C to first establish sex differences in fever sensitivity in Experiment 1 using implanted radiotelemetry devices for remote tracking. In Experiments 2 and 3, adolescent males and females were exposed to either water or ethanol (0 or 4 g/kg intragastrically, 3 days on, 2 days off, ∼P30-P50, 4 cycles/12 exposures total). After a period of abstinence, adult rats (∼P80-96) were then challenged with saline or poly I:C, and fever induction and maintenance were examined across a prolonged time course of 8 h using implanted probes. In Experiments 4 and 5, adult male and female subjects with a prior history of adolescent water or adolescent intermittent ethanol (AIE) were given saline or poly I:C, with tissue collected for protein and gene expression analysis at 5 h post-injection. Initial sex differences in fever sensitivity were minimal in response to the 4 mg/kg dose of poly I:C in ethanol-naïve rats. AIE exposed males injected with poly I:C showed a sensitized fever response as well as enhanced TLR3, IκBα, and IL-1ß expression in the nucleus of the solitary tract. Other brain regions related to thermoregulation and peripheral organs such as spleen, liver, and blood showed generalized immune responses to poly I:C, with no differences evident between AIE and water-exposed males. In contrast, AIE did not affect responsiveness to poly I:C in females. Thus, the present findings suggest that adolescent binge drinking may produce sex-specific and long-lasting effects on fever reactivity to viral infection, with preliminary evidence suggesting that these effects may be due to centrally-mediated changes in fever regulation rather than peripheral immunological mechanisms.

Thermoregulatory pathway underlying the pyrogenic effects of prostaglandin E2 in the lateral parabrachial nucleus of male rats.

It has been shown that prostaglandin (PG) E2 synthesized in the lateral parabrachial nucleus (LPBN) is involved in lipopolysaccharide-induced fever. But the neural mechanisms of how intra-LPBN PGE2 induces fever remain unclear. In this study, we investigated whether the LPBN-preoptic area (POA) pathway, the thermoafferent pathway for feed-forward thermoregulatory responses, mediates fever induced by intra-LPBN PGE2 in male rats. The core temperature (Tcore) was monitored using a temperature radiotelemetry transponder implanted in rat abdomen. We showed that microinjection of PGE2 (0.28 nmol) into the LPBN significantly enhanced the density of c-Fos-positive neurons in the median preoptic area (MnPO). The chemical lesioning of MnPO with ibotenate or selective genetic lesioning or inhibition of the LPBN-MnPO pathway significantly attenuated fever induced by intra-LPBN injection of PGE2. We demonstrated that EP3 receptor was a pivotal receptor for PGE2-induced fever, since microinjection of EP3 receptor agonist sulprostone (0.2 nmol) or EP3 receptor antagonist L-798106 (2 nmol) into the LPBN mimicked or weakened the pyrogenic action of LPBN PGE2, respectively, but this was not the case for EP4 and EP1 receptors. Whole-cell recording from acute LPBN slices revealed that the majority of MnPO-projecting neurons originating from the external lateral (el) and dorsal (d) LPBN were excited and inhibited, respectively, by PGE2 perfusion, initiating heat-gain and heat-loss mechanisms. The amplitude but not the frequency of spontaneous and miniature glutamatergic excitatory postsynaptic currents (sEPSCs and mEPSCs) in MnPO-projecting LPBel neurons increased after perfusion with PGE2; whereas the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) and the A-type potassium (IA) current density did not change. In MnPO-projecting LPBd neurons, neither sEPSCs nor sIPSCs responded to PGE2; however, the IA current density was significantly increased by PGE2 perfusion. These electrophysiological responses and the thermoeffector reactions to intra-LPBN PGE2 injection, including increased brown adipose tissue thermogenesis, shivering, and decreased heat dissipation, were all abolished by L-798106, and mimicked by sulprostone. These results suggest that the pyrogenic effects of intra-LPBN PGE2 are mediated by both the inhibition of the LPBd-POA pathway through the EP3 receptor-mediated activation of IA currents and the activation of the LPBel-POA pathway through the selective enhancement of glutamatergic synaptic transmission via EP3 receptors.

TMEM16C is involved in thermoregulation and protects rodent pups from febrile seizures.

Febrile seizures (FSs) are the most common convulsion in infancy and childhood. Considering the limitations of current treatments, it is important to examine the mechanistic cause of FSs. Prompted by a genome-wide association study identifying TMEM16C (also known as ANO3) as a risk factor of FSs, we showed previously that loss of TMEM16C function causes hippocampal neuronal hyperexcitability [Feenstra et al., Nat. Genet. 46, 1274-1282 (2014)]. Our previous study further revealed a reduction in the number of warm-sensitive neurons that increase their action potential firing rate with rising temperature of the brain region harboring these hypothalamic neurons. Whereas central neuronal hyperexcitability has been implicated in FSs, it is unclear whether the maximal temperature reached during fever or the rate of body temperature rise affects FSs. Here we report that mutant rodent pups with TMEM16C eliminated from all or a subset of their central neurons serve as FS models with deficient thermoregulation. Tmem16c knockout (KO) rat pups at postnatal day 10 (P10) are more susceptible to hyperthermia-induced seizures. Moreover, they display a more rapid rise of body temperature upon heat exposure. In addition, conditional knockout (cKO) mouse pups (P11) with TMEM16C deletion from the brain display greater susceptibility of hyperthermia-induced seizures as well as deficiency in thermoregulation. We also found similar phenotypes in P11 cKO mouse pups with TMEM16C deletion from Ptgds-expressing cells, including temperature-sensitive neurons in the preoptic area (POA) of the anterior hypothalamus, the brain region that controls body temperature. These findings suggest that homeostatic thermoregulation plays an important role in FSs.

[Workplace-associated fever]. / Arbeitsplatzassoziiertes Fieber oder wenn es doch das Zebra ist .

INTRODUCTION: Febrile conditions often have an infectious etiology. However, there are also fevers associated with occupational exposures. A detailed occupational history can hold the key to the diagnosis. In the case of exposure to organic dusts, the development of hypersensitivity pneumonitis (HP) is possible. Thus, HP should be considered in the presence of interstitial lung disease of unclear etiology. Failure to recognize this can have dramatic consequences and, in extreme cases, lead to lung transplantation. Differentially, organic dust toxic syndrome (ODTS) must be considered. The syndrome of metal fume fever provoked by inhalation of inorganic substances is usually benign and self-limiting. The disease manifests with fever, cough, and flu-like sensations.

Low utilization of vancomycin in febrile neutropenia: real-world evidence from 4 Brazilian centers.

PURPOSE: The prompt initiation of a betalactam antibiotic in febrile neutropenic patients is considered standard of care, while the empiric use of vancomycin is recommended by guidelines in specific situations, with a low level of evidence. The objective of this study was to assess the utilization of vancomycin in the management of febrile neutropenia within four Brazilian medical centers that implemented more stringent criteria for its administration. METHODS: A comprehensive retrospective analysis was performed encompassing all instances of febrile neutropenia observed during the period from 2013 to 2019. The primary focus was to identify the reasons for initiating vancomycin therapy. RESULTS: A total of 536 consecutive episodes of febrile neutropenia were documented, involving 384 patients with a median age of 52 years (range 18-86). Chemotherapy preceded febrile neutropenia in 59.7% of cases, while 40.3% occurred after hematopoietic stem cell transplantation. The most prevalent underlying diseases were acute myeloid leukemia (26.5%) and non-Hodgkin's lymphoma (22%). According to international guidelines, vancomycin should have been initiated at the onset of fever in 145 episodes (27%); however, it was administered in only 27 cases (5.0%). Three episodes were associated with Staphylococcus aureus bacteremia, two of which were methicillin resistant. The 15-day and 30-day mortality rates were 5.0% and 9.9%, respectively. CONCLUSIONS: The results of this study underscore the notably low utilization rate of vancomycin in cases of febrile neutropenia, despite clear indications outlined in established guidelines. These findings emphasize the importance of carefully implementing guideline recommendations, considering local epidemiological factors, especially when the strength of recommendation is weak.

Current methods of preventing infectious disease and managing febrile neutropenia in childhood cancer patients: a nationwide survey in Japan.

BACKGROUND: Preventing infection and managing febrile neutropenia (FN) is mandatory for children with cancer undergoing chemotherapy. However, the current situation in Japan is unknown. METHODS: We conducted a nationwide web-based questionnaire survey in 153 institutions treating childhood cancer in Japan. We asked about the type prophylaxis used to prevent infectious disease and manage FN. If patients with childhood cancer were managed by both pediatricians and surgeons at the same institution, we asked both to reply. RESULTS: We received replies from 117 departments at 111 centers: of these, 108 were from pediatricians. Laminar air flow for neutropenic patients, and frequent hand sanitization with ethanol, were widespread. Twenty-eight percent and forty percent of departments performed active surveillance by taking cultures from patients and the environment, respectively, before initiation of chemotherapy. Forty-four percent of departments administered prophylactic intravenous antibiotics according to patient status. Many departments measured serum (1,3)-ß-D glucan, procalcitonin, and aspergillus galactomannan at the onset of FN. Twenty-eight percent of departments used carbapenem as empirical therapy for FN. Some departments used prophylactic granulocyte-colony stimulating factor for acute leukemia. Seventy-two percent of departments used prophylactic immunoglobulin for hypogammaglobinemia caused by chemotherapy. Palivizumab was administered widely for respiratory syncytial virus prophylaxis in immunocompromised infants. CONCLUSION: As a whole, intensive care for infectious prophylaxis or FN is applied in Japan; however, the methods vary among centers, and some are excessive or inadequate. Therefore, it is desirable to conduct clinical trials and establish adequate care protocols for infection in children with cancer in Japan.

Inhibition of nitric oxide synthase or cystathionine gamma-lyase abolishes leptin-induced fever in male rats.

Leptin is an adipokine that regulates energy balance and immune function. Peripheral leptin administration elicits prostaglandin E2-dependent fever in rats. The gasotransmitters nitric oxide (NO) and hydrogen sulfide (H2S) are also involved in lipopolysaccharide (LPS)-induced fever response. However, there is no data in the literature indicating if these gasotransmitters have a role in leptin-induced fever response. Here, we investigate the inhibition of NO and H2S enzymes neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), and cystathionine γ-lyase (CSE) in leptin-induced fever response, respectively. Selective nNOS inhibitor 7-nitroindazole (7-NI), selective iNOS inhibitor aminoguanidine (AG), and CSE inhibitor dl-propargylglycine (PAG) were administered intraperitoneally (ip). Body temperature (Tb), food intake, and body mass were recorded in fasted male rats. Leptin (0.5 mg/kg ip) induced a significant increase in Tb, whereas AG (50 mg/kg ip), 7-NI (10 mg/kg ip), or PAG (50 mg/kg ip) caused no changes in Tb. AG, 7-NI, or PAG abolished leptin increase in Tb. Our results highlight the potential involvement of iNOS, nNOS, and CSE in leptin-induced febrile response without affecting anorexic response to leptin in fasted male rats 24 h after leptin injection. Interestingly, all the inhibitors alone had the same anorexic effect induced by leptin. These findings have implications for understanding the role of NO and H2S in leptin-induced febrile response.

Network pharmacology integrated with experimental verification reveals the antipyretic characteristics and mechanism of Zi Xue powder.

CONTEXT: Zi Xue Powder (ZXP) is a traditional formula for the treatment of fever. However, the potential mechanism of action of ZXP remains unknown. OBJECTIVE: This study elucidates the antipyretic characteristics of ZXP and the mechanism by which ZXP alleviates fever. MATERIALS AND METHODS: The key targets and underlying fever-reducing mechanisms of ZXP were predicted using network pharmacology and molecular docking. The targets of ZXP anti-fever active ingredient were obtained by searching TCMSP, STITCH and HERB. Moreover, male Sprague-Dawley rats were randomly divided into four groups: control, lipopolysaccharide (LPS), ZXP (0.54, 1.08, 2.16 g/kg), and positive control (acetaminophen, 0.045 g/kg); the fever model was established by intraperitoneal LPS injection. After the fever model was established at 0.5 h, the rats were administered treatment by gavage, and the anal temperature changes of each group were observed over 10 h after treatment. After 10 h, ELISA and Western blot analysis were used to further investigate the mechanism of ZXP. RESULTS: Network pharmacology analysis showed that MAPK was a crucial pathway through which ZXP suppresses fever. The results showed that ZXP (2.16 g/kg) decreased PGE2, CRH, TNF-a, IL-6, and IL-1ß levels while increasing AVP level compared to the LPS group. Furthermore, the intervention of ZXP inhibited the activation of MAPK pathway in LPS-induced fever rats. CONCLUSIONS: This study provides new insights into the mechanism by which ZXP reduces fever and provides important information and new research ideas for the discovery of antipyretic compounds from traditional Chinese medicine.

The hyperthermic effect of central cholecystokinin is mediated by the cyclooxygenase-2 pathway.

Cholecystokinin (CCK) increases core body temperature via CCK2 receptors when administered intracerebroventricularly (icv). The mechanisms of CCK-induced hyperthermia are unknown, and it is also unknown whether CCK contributes to the fever response to systemic inflammation. We studied the interaction between central CCK signaling and the cyclooxygenase (COX) pathway. Body temperature was measured in adult male Wistar rats pretreated with intraperitoneal infusion of the nonselective COX enzyme inhibitor metamizol (120 mg/kg) or a selective COX-2 inhibitor, meloxicam, or etoricoxib (10 mg/kg for both) and, 30 min later, treated with intracerebroventricular CCK (1.7 µg/kg). In separate experiments, CCK-induced neuronal activation (with and without COX inhibition) was studied in thermoregulation- and feeding-related nuclei with c-Fos immunohistochemistry. CCK increased body temperature by ∼0.4°C from 10 min postinfusion, which was attenuated by metamizol. CCK reduced the number of c-Fos-positive cells in the median preoptic area (by ∼70%) but increased it in the dorsal hypothalamic area and in the rostral raphe pallidus (by ∼50% in both); all these changes were completely blocked with metamizol. In contrast, CCK-induced satiety and neuronal activation in the ventromedial hypothalamus were not influenced by metamizol. CCK-induced hyperthermia was also completely blocked with both selective COX-2 inhibitors studied. Finally, the CCK2 receptor antagonist YM022 (10 µg/kg icv) attenuated the late phases of fever induced by bacterial lipopolysaccharide (10 µg/kg; intravenously). We conclude that centrally administered CCK causes hyperthermia through changes in the activity of "classical" thermoeffector pathways and that the activation of COX-2 is required for the development of this response.NEW & NOTEWORTHY An association between central cholecystokinin signaling and the cyclooxygenase-prostaglandin E pathway has been proposed but remained poorly understood. We show that the hyperthermic response to the central administration of cholecystokinin alters the neuronal activity within efferent thermoeffector pathways and that these effects are fully blocked by the inhibition of cyclooxygenase. We also show that the activation of cyclooxygenase-2 is required for the hyperthermic effect of cholecystokinin and that cholecystokinin is a modulator of endotoxin-induced fever.

Fever following Covid-19 vaccination in subjects with Brugada syndrome: Incidence and management.

BACKGROUND: Fever is a potential side effect of the Covid-19 vaccination. Patients with Brugada syndrome (BrS) have an increased risk of life-threatening arrhythmias when experiencing fever. Prompt treatment with antipyretic drugs is suggested in these patients. AIM OF THE STUDY: To evaluate the incidence and management of fever within 48 h from Covid-19 vaccination among BrS patients. METHODS: One hundred sixty-three consecutive patients were enrolled in a prospective registry involving five European hospitals with a dedicated inherited disease ambulatory. RESULTS: The mean age was 50 ± 14 years and 121 (75%) patients were male. Prevalence of Brugada electrocardiogram (ECG) pattern type-1, -2, and -3 was 32%, 44%, and 24%, respectively. Twenty-eight (17%) patients had an implantable cardioverter-defibrillator (ICD). Fever occurred in 32 (19%) BrS patients after 16 ± 10 h from vaccination, with a peak of body temperature of 37.9° ± 0.5°. Patients with fever were younger (39 ± 13 vs. 48 ± 13 years, p = .04). No additional differences in terms of sex and cardiovascular risk factors were found between patients with fever and not. Twenty-seven (84%) out of 32 patients experienced mild fever and five (16%) moderate fever. Pharmacological treatment with antipyretic drugs was required in 18 (56%) out of 32 patients and was associated with the resolution of symptoms. No patient required hospital admission and no arrhythmic episode was recorded in patients with ICD within 48 h after vaccination. No induced type 1 BrS ECG pattern and new ECG features were found among patients with moderate fever. CONCLUSION: Fever is a common side effect in BrS patients after the Covid-19 vaccination. Careful evaluation of body temperature and prompt treatment with antipyretic drugs may be needed.

Neural circuits mediating circulating interleukin-1ß-evoked fever in the absence of prostaglandin E2 production.

Infectious diseases and inflammatory conditions recruit the immune system to mount an appropriate acute response that includes the production of cytokines. Cytokines evoke neurally-mediated responses to fight pathogens, such as the recruitment of thermoeffectors, thereby increasing body temperature and leading to fever. Studies suggest that the cytokine interleukin-1ß (IL-1ß) depends upon cyclooxygenase (COX)-mediated prostaglandin E2 production for the induction of neural mechanisms to elicit fever. However, COX inhibitors do not eliminate IL-1ß-induced fever, thus suggesting that COX-dependent and COX-independent mechanisms are recruited for increasing body temperature after peripheral administration of IL-1ß. In the present study, we aimed to build a foundation for the neural circuit(s) controlling COX-independent, inflammatory fever by determining the involvement of brain areas that are critical for controlling the sympathetic outflow to brown adipose tissue (BAT) and the cutaneous vasculature. In anesthetized rats, pretreatment with indomethacin, a non-selective COX inhibitor, did not prevent BAT thermogenesis or cutaneous vasoconstriction (CVC) induced by intravenous IL-1ß (2 µg/kg). BAT and cutaneous vasculature sympathetic premotor neurons in the rostral raphe pallidus area (rRPa) are required for IL-1ß-evoked BAT thermogenesis and CVC, with or without pretreatment with indomethacin. Additionally, activation of glutamate receptors in the dorsomedial hypothalamus (DMH) is required for COX-independent, IL-1ß-induced BAT thermogenesis. Therefore, our data suggests that COX-independent mechanisms elicit activation of neurons within the DMH and rRPa, which is sufficient to trigger and mount inflammatory fever. These data provide a foundation for elucidating the brain circuits responsible for COX-independent, IL-1ß-elicited fevers.

Efficacy, safety, and economic impact of diazepam suppositories with as-needed acetaminophen for prevention of seizure recurrence during the same fever episode in children with suspected simple febrile seizures.

OBJECTIVE: This study was undertaken to evaluate the efficacy, safety, and economic impact of diazepam suppositories with as-needed acetaminophen in comparison with as-needed acetaminophen alone for prevention of seizure recurrence during the same fever episode in suspected pediatric simple febrile seizures (SFS). METHODS: This single-center, prospective, observational study was conducted from July 29, 2019 to February 15, 2021 at a children's hospital. Children aged 6 months to 60 months presenting to the emergency department with suspected SFS were included. Participants receiving both diazepam suppositories and as-needed acetaminophen were compared with those receiving as-needed acetaminophen alone. The primary outcome was seizure recurrence during the same fever episode. The secondary outcomes included the incidence of central nervous system (CNS) pathologies, adverse events, and medical costs. RESULTS: Of the 316 participants, 228 (72.2%) had their first febrile seizure. Diazepam (.3-.5 mg/kg for up to two doses) was administered to 88 of 316 patients (27.8%). The outcomes were available for 306 patients. The recurrence rate was 3.5% (3/85) in the patients receiving diazepam with as-needed acetaminophen and 12.2% (27/221) in the patients receiving as-needed acetaminophen alone (relative risk = .29, 95% confidence interval [CI] = .09-.93, p = .03). The adjusted odds ratio of diazepam administration against recurrence was .23 (95% CI = .07-.78, p = .02). None of the patients had a CNS pathology. No severe adverse events occurred, although mild ataxia was observed significantly more often in the patients receiving diazepam and as-needed acetaminophen (29.4% vs. 18.7%, p = .04). The median medical cost was US $199 (interquartile range [IQR] = 86-244) for the group receiving both medications and US $202 (IQR = 114-242) for the group receiving as-needed acetaminophen alone. SIGNIFICANCE: Compared with as-needed acetaminophen alone, diazepam with as-needed acetaminophen may reduce seizure recurrence more during the same fever episode without severe adverse events or additional costs in children with suspected SFS.

Complete Pathologic Response to Neoadjuvant Chemoimmunotherapy and Oxaliplatin-Induced Fever Associated With IL-6 Release in a Patient With Locally Advanced Colon Cancer

Neoadjuvant systemic therapy is a preferred treatment approach for a number of tumor types due to many potential advantages over upfront surgery, including tumor downstaging, early treatment of micrometastatic disease, and providing an in vivo test of tumor biology. For colon cancer, current standard of care is upfront surgery followed by adjuvant systemic therapy in high-risk patients. Concerns about inaccurate radiological staging and tumor progression during preoperative treatment, as well the lack of randomized data demonstrating benefit, are among the reasons for the limited use of neoadjuvant therapy in this disease. Locally advanced colon cancer, defined as primary colon cancer with direct invasion into the adjacent structures or extensive regional lymph node involvement, is not always amenable to pathological complete resection, and when attempted it comes with high incidence of postoperative morbidity and mortality because of the required multivisceral resection. Clinical trials of neoadjuvant chemotherapy for colon cancer to date have been promising with downstaging of disease and higher rates of R0 resection. Here, we report a case of a patient with locally advanced, unresectable, mismatch repair deficient sigmoid colon cancer who was treated with neoadjuvant chemoimmunotherapy followed by surgical resection leading to a complete pathologic response after preoperative systemic chemoimmunotherapy.

Maternal Fever Associated With Continuous Spinal Versus Epidural Labor Analgesia: A Single-Center Retrospective Study.

BACKGROUND: Neuraxial labor analgesia is associated with elevations in maternal temperature; the mechanism responsible is unknown. Proposed mechanisms have included infection, altered thermoregulation, and inflammation, potentially triggered by local anesthetics. Studies of the association between neuraxial labor analgesia and maternal fever have focused on epidural analgesia, and there have been no comparisons of the rate of maternal fever between continuous spinal and epidural labor analgesia. METHODS: We performed a retrospective study to compare the rate of maternal fever between patients who received continuous spinal versus epidural labor analgesia between June 2012 and March 2020. Each patient who received continuous spinal analgesia was matched to 2 patients who received epidural analgesia and had the same nulliparous status. The primary outcome of our study was the incidence of intrapartum maternal fever, which we defined as any temperature ≥38 °C before delivery and compared between the continuous spinal and epidural groups using Fisher exact test. RESULTS: We identified 81 patients who received continuous spinal analgesia and 162 matched controls who received epidural analgesia. Demographic and obstetric characteristics of the patients were similar between groups. While the duration of analgesia did not significantly differ, there was markedly increased bupivacaine consumption in women with epidural analgesia. Eight of 81 (9.9%; 95% confidence interval [CI], 5.1-18.3) women with continuous spinal analgesia developed an intrapartum fever compared to 18 of 162 (11.1%; 95% CI, 7.1-16.9) of women with epidural analgesia ( P = .83; Fisher exact test). CONCLUSIONS: There was no significant difference in the rate of maternal fever between women with continuous spinal compared to epidural labor analgesia. While the route of administration and dose of bupivacaine differs between epidural and spinal labor analgesia, they are titrated to produce similar levels of neuraxial blockade. Our results are consistent with a model in which epidural related maternal fever is due to altered thermoregulation from a central neuraxial block and argue against a direct effect of bupivacaine or fentanyl, although we cannot rule out a concentration-independent effect of bupivacaine or fentanyl or an inflammatory effect of the catheter itself. These retrospective results highlight the importance of prospective and mechanistic study of neuraxial analgesia-related maternal fever.

Analysis of older adults visiting the emergency department with fever as a suspected Covid-19 vaccine-related adverse reaction: A retrospective multicenter study.

INTRODUCTION: After COVID-19 vaccination was initiated, the number of patients visiting the emergency department (ED) with vaccine-related adverse reactions increased. We investigated the clinical features of older adults (aged 65 years and older) visiting the ED with self-reported COVID-19 postvaccination fever. METHODS: We conducted a retrospective observational study at three EDs between March 2021 and September 2021. Patients who reported adverse reactions, fever (≥37.5 °C) and/or febrile sensation or rigors following COVID-19 vaccination were included. The demographic and clinical data of these patients were collected by reviewing their medical records. RESULTS: A total of 562 patients were selected, and 396 (70.5%) were female. The older adult group included 155 (27.6%) patients, and the median age was 75 (69-79 years). The older adults less frequently had a fever (≥37.5 °C) upon ED presentation (75.5% vs. 85.7%, respectively), used more emergency medical services (43.9% vs. 18.7%, respectively), and visited an ED more frequently during early hours (00:00-06:00) (31% vs. 20.1%, respectively) compared to the younger adults (p = 0.004, p < 0.001 and p = 0.036). Fewer older adults visited an ED within 2 days of fever onset (73.5% vs. 84%) (p = 0.012), and more older adults were admitted for medical conditions other than vaccine-related adverse reactions (32.9% vs. 4.2%) (p < 0.001). Older adults received more thorough testing (laboratory and imaging tests). Among the older adults, the admission rate was associated with age (p = 0.003). CONCLUSION: Older adults presenting with fever as an adverse reaction following COVID-19 vaccination less frequently had a fever upon visiting the ED, required more ED testing, and had higher admission rates for non-vaccination-related medical conditions.

Smaller but more frequent dosing of cefepime in the treatment of febrile neutropenia.

BACKGROUND: Generally national guidelines for febrile neutropenia recommend treatment with cefepime 2 g every 8 h. Due to beta-lactam's time dependent killing effects, it is hypothesized smaller doses given more frequently might be non-inferior. The objective of this study is to retrospectively evaluate the efficacy of cefepime 1 g every 6 h versus 2 g every 8 h in cancer patients with febrile neutropenia. METHODS: This retrospective, single-center, cohort study included patients with a diagnosis of febrile neutropenia treated with cefepime during an inpatient encounter. Patients were grouped based on receipt of cefepime 2 g every 8 h (high dose cohort) versus cefepime 1 g every 6 h (low dose cohort). The primary outcome compared the time to defervescence after cefepime initiation between the two dosing strategies. A subgroup analysis of the primary endpoint was conducted in patients who received both cefepime and vancomycin. RESULTS: Ninety-seven patients were included in the high dose cohort, and seventy-six patients were included in the low dose cohort. Baseline characteristics were similar between cohorts with the exception of race. The time to defervescence between the high dose cohort and low dose cohort were comparable between groups (49.2 vs. 46.7 h). The time to defervescence in subgroup analysis of patients who received empiric vancomycin and cefepime was 65.7 versus 59.7. CONCLUSION: Patients who received cefepime 1 g every 6 h were found to have similar trends in achieving time to defervescence compared to 2 g every 8 h.