Dietary intake and quality among adults with cystic fibrosis: A systematic review.

AIMS: This systematic review aims to describe the dietary quality, dietary intake and related behaviours of adults diagnosed with cystic fibrosis. METHODS: A comprehensive literature search was conducted in four databases (Medline, CINAHL, EMBASE, CENTRAL); studies were included if they addressed dietary intake, diet quality or eating behaviours among adults (≥15 years) living with cystic fibrosis and were published from January 2000 to November 2022. The Mixed Methods Appraisal Tool was used to assess the risk of bias and quality of included studies. Findings were synthesised narratively. RESULTS: Nineteen observational studies (n = 2236) were included and considered high to moderate quality. Most (13/19) studies reported that individuals with cystic fibrosis were consuming high-energy diets; where studies reported energy intake as a proportion of requirements met, energy intake was high, even when using individualised or cystic fibrosis-specific referents. In addition, fat intakes as a proportion of energy appeared high (29%-39% of total energy), particularly as current guidelines recommend macronutrient profile similar to the general population (<30% of total energy). There was considerable variation in the reporting of fatty acid profiles and other nutrients. Five studies reported on concerns regarding diet and eating in this population. CONCLUSION: Findings from the current review suggest dietary intakes of adults with cystic fibrosis appear to be less than optimal and concerns about diet, weight and food may be emerging in this population. Future research utilising consistent measures of dietary assessment and reporting, reporting of medical therapies, and exploring potential concerns about diet and eating is warranted.

Odontogenic Cutaneous Fistula: A Zombie Diagnosis.

BACKGROUND: Odontogenic cutaneous fistula (OCF) is a pathologic communication between the cutaneous surface of the face and oral cavity. Majority of oral cutaneous fistulas are reported to arise from chronic dental infection. Delay in treatment may result in chronic tissue injury as well as cosmetic deformities. Lesions are often misdiagnosed, leading to delayed management. Misdiagnosis may be the result of the variability of clinical morphological presentation and location of lesions compounded by the lack of knowledge that these lesions can have dental etiology. It is estimated that half of patients with OCF undergo multiple dermatologic surgical operations, antibiotic regimens, and other excisions and biopsies before a correct diagnosis is made. Herein, we present a systematic review to detail cases of odontogenic cutaneous lesions that had been previously misdiagnosed or managed inappropriately. In addition, we include a case report from our own institution. The aims are to demonstrate various presentations of OCF, increase awareness of plastic surgeons and oral maxillofacial surgeons to this pathological condition, and reinforce the importance of prompt diagnosis and treatment. METHODS: The study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A literature search was conducted in PubMed, Web of Science, and Cochrane databases from January 1, 2013 to July 24, 2023. The following search terms were utilized: "odontogenic cutaneous fistula" OR "odontogenic cutaneous sinus." RESULTS: Twenty-three articles published between 2013 and 2023 were included in this review. In addition, we report a case from our own institution. A total of 28 cases were included in the review. CONCLUSIONS: Diagnosis of OCF is challenging for numerous reasons. Misdiagnosis can lead to multiple trials of antibiotics and surgical procedures as well as reoccurrence of the lesion. Cases summarized highlight the importance of communication between oral maxillofacial surgery, plastic surgery, other medical subspecialists, and dentists in the evaluation of patients with head and neck lesions. Physicians should consider dental etiology in the differential diagnosis of orofacial skin lesions, even if teeth appear normal on oral examination.

Management of Maxillofacial Trauma in Pregnant Women.

INTRODUCTION: Trauma during pregnancy deserves special attention as management must be directed towards both the mother and the fetus. Management of maxillofacial fractures in pregnancy can adversely affect the well-being of the fetus by impinging on normal functions such as respiration, mastication, and nutrition. Pregnancy complicates the management of facial injury due to the maintenance of the patent airway, anesthesia considerations, and imaging restraints. The purpose of this study is to use three illustrative from our own institution to further elucidate education on the management of mandible fracture in pregnancy with a focus on multidisciplinary treatment and outcomes. METHODS: A retrospective chart review was performed for all cases of facial fractures admitted to Ryder Trauma Center from 2012 to 2022. During this time, 4,910 patients presented with facial fractures 1319 patients were female. Three of the patients were pregnant at the time of admission. Demographics, mechanism of injury, associated injuries, and management information were collected. RESULTS: Patient 1 was a 20-year-old female presented to Ryder Trauma Center following a motor vehicle collision. She was 17 weeks pregnant at the time of admission and was found to have a left mandibular angle fracture. Patient 2 was a 14-year-old female who presented to Ryder Trauma Center status post gunshot wound to the mandible after she and her brother were unknowingly playing with a loaded gun. She was 18 weeks pregnant at the time of admission, with a past medical history of domestic violence, suicidal ideation, and major depressive disorder. Patient 3 was a 20-year-old female 36 weeks pregnant at the time of admission. She presented with a right paraymphyseal fracture and left mandibular angle fracture as a result of falling on the stairs. Patients all underwent surgical repair of fractures.

Meralgia Paresthetica as a Result of Surgery With an Emphasis on Harvesting Iliac Bone Grafts: A Review.

Meralgia paresthetica is a neurological disorder characterized by a symptom complex of numbness, burning, tingling, aching, or stabbing in the anterolateral portion of the upper thigh. Typically, this disorder is seen in patients with diabetes mellitus, obesity, and pregnancy. Also, it may result from a wide array of surgical interventions involving the region of the anterior superior iliac spine. Underlying pathophysiology concentrates on entrapment neuropathy of the lateral femoral cutaneous nerve (LFCN). Due to its location and wide anatomic variation, the LFCN is susceptible to compression, scarring, and injury during surgery. It is important to understand the regional anatomy. In addition, the plastic surgeon must have a working knowledge of the most common variations that can precipitate entrapment and increase susceptibility to injury during surgery. Surgeons lacking a substantial background on the numerous risk factors, origins, and anatomic variations of the LFCN may place patients at an even higher risk of damage to the nerve. An extensive knowledge of the anatomy and careful technique may be utilized by surgeons to prevent iatrogenic neuropathy of the LFCN.

Timing of Pediatric Incarcerated Inguinal Hernia Repair: A Review of Nationwide Readmissions Data.

INTRODUCTION: In pediatric patients, incarcerated inguinal hernias are often repaired on presentation. We hypothesize that in appropriate patients, repair may be safely deferred. METHODS: The Nationwide Readmissions Database was used to identify pediatric patients (aged < 18 y) with incarcerated inguinal hernia from 2010 to 2014. Patients were stratified by management approach (Early Repair versus Deferral). Overall frequencies of these operative strategies were calculated. Propensity score matching was then performed to control for patient age, comorbidities, perinatal conditions, and congenital anomalies. Outcomes including complications, surgical procedures, and readmissions were compared. Outpatient surgeries were not assessed. RESULTS: Among 6148 total patients with incarcerated inguinal hernia, the most common strategy was to perform Early Repair (88% versus 12% Deferral). Following propensity score matching, the cohort included 1288 patients (86% male, average age 1.7 ± 4.1 years). Deferral was associated with equivalent rates of readmission within one year (13% versus 15%, P = 0.143), but higher readmissions within the first 30 days (7% versus 3%, P = 0.002) than Early Repair. Deferral patients had lower rates of orchiectomy (2% versus 5%, P = 0.001), wound infections (< 2% versus 2%, P = 0.020), and other infections (7% versus 15%, P < 0.001). The frequency of other complications including bowel resection, oophorectomy, testicular atrophy, sepsis, and pneumonia were equivalent between groups. Three percent of Deferrals had a diagnosis of incarceration on readmission. CONCLUSIONS: Deferral of incarcerated inguinal hernia repair at index admission is associated with higher rates of hospital readmissions within the first 30 days but equivalent readmission within the entire calendar year. These patients are at risk of repeat incarceration but have significantly lower rates of orchiectomy than their counterparts who undergo inguinal hernia repair at the index admission. We propose that prospective studies be performed to identify good candidates for Elective Deferral following manual reduction and overnight observation. Such studies must capture outpatient surgical outcomes.

Knowledge, Attitude and Experiences of Students Regarding Menstrual Cup Usage in a Medical College in North Kerala, India.

BACKGROUND: Sanitary napkins form a major source of solid waste, the disposal of which often results in environmental pollution. Menstrual cups are an eco-friendly and cost-effective alternative to sanitary pads that have yet to gain much popularity among Indian women. The current study aims to assess the knowledge, attitude, and experiences of using the menstrual cup among medical students in a college in north Kerala, India.  Methods: This cross-sectional study was conducted among 109 female medical students. Data was collected through an online platform and analyzed using Epi Info version 7.2 (Centers for Disease Control and Prevention, Atlanta, GA). RESULTS: Though all the participants had heard about the menstrual cup before, only 14 (12.8%) were using it either alone or in conjunction with sanitary pads. The majority of the participants had a positive attitude towards the usage of menstrual cups with 91.74% considering it a better alternative to other sanitary products, Among the several concerns expressed by the participants, 58.7% were concerned about the insertion of a foreign material into their bodies. CONCLUSIONS: Though most of the participants displayed a positive attitude towards the menstrual cup, the number of participants who had ever tried it was very low. There are several apprehensions regarding the cup that need to be addressed before it can be expected to gain popularity.

Vi polysaccharide and conjugated vaccines afford similar early, IgM or IgG-independent control of infection but boosting with conjugated Vi vaccines sustains the efficacy of immune responses.

Introduction: Vaccination with Vi capsular polysaccharide (Vi-PS) or protein-Vi typhoid conjugate vaccine (TCV) can protect adults against Salmonella Typhi infections. TCVs offer better protection than Vi-PS in infants and may offer better protection in adults. Potential reasons for why TCV may be superior in adults are not fully understood. Methods and results: Here, we immunized wild-type (WT) mice and mice deficient in IgG or IgM with Vi-PS or TCVs (Vi conjugated to tetanus toxoid or CRM197) for up to seven months, with and without subsequent challenge with Vi-expressing Salmonella Typhimurium. Unexpectedly, IgM or IgG alone were similarly able to reduce bacterial burdens in tissues, and this was observed in response to conjugated or unconjugated Vi vaccines and was independent of antibody being of high affinity. Only in the longer-term after immunization (>5 months) were differences observed in tissue bacterial burdens of mice immunized with Vi-PS or TCV. These differences related to the maintenance of antibody responses at higher levels in mice boosted with TCV, with the rate of fall in IgG titres induced to Vi-PS being greater than for TCV. Discussion: Therefore, Vi-specific IgM or IgG are independently capable of protecting from infection and any superior protection from vaccination with TCV in adults may relate to responses being able to persist better rather than from differences in the antibody isotypes induced. These findings suggest that enhancing our understanding of how responses to vaccines are maintained may inform on how to maximize protection afforded by conjugate vaccines against encapsulated pathogens such as S. Typhi.

Neurologic Outcomes for Octogenarians Undergoing Emergent Surgery for Traumatic Acute Subdural Hematoma.

BACKGROUND: Determining the appropriate surgical indications for obtunded octogenarians with traumatic acute subdural hematoma (aSDH) has been challenging. We sought to determine which easily available data would be useful adjuncts to assist in early and quick decision-making. METHODS: We performed a single-center, retrospective review of patients aged ≥80 years with confirmed traumatic aSDH who had undergone emergent surgery. The clinical measurements included the Karnofsky performance scale score, Charlson comorbidity index, Glasgow coma scale (GCS), and abbreviated injury score. The radiographic measurements included the Rotterdam computed tomography score, aSDH thickness, midline shift, and optic nerve sheath diameter (ONSD). The neurologic outcomes were defined using the extended Glasgow outcome scale-extended (GOS-E) at hospital discharge and 3-month follow-up. The Pearson correlation coefficient was used to compare the ONSD with all clinical, radiographic, and outcome variables. Multivariate logistic regression was used to assess the relationship between the discharge and 3-month GOS-E scores between all clinical and radiographic variables. RESULTS: A total of 17 patients met the inclusion criteria. The mean age was 82.5 ± 1.6 years (range, 80-85 years), and the mean GCS score was 11.2 ± 4.1 (range, 4-15). The mean discharge and 3-month GOS-E scores were 3.4 ± 2.6 (range, 1-8) and 2.3 ± 2.1 (range, 1-7), respectively. We found significant negative correlations between the ONSD and the GCS score (r = -0.62; P < 0.01) and the ONSD and discharge GOS-E score (r = -0.49; P = 0.05). Multivariate analysis revealed a significant association between the abbreviated injury score and the discharge GOS-E score (P = 0.05). CONCLUSIONS: Octogenarians sustaining aSDH and requiring emergent surgery have poor outcomes. More data are needed to determine whether the ONSD can be a useful adjunct tool to predict the efficacy of emergent surgery.

Simple wound closure compared with surgery for civilian cranial gunshot wounds.

OBJECTIVE: A carefully selected subset of civilian cranial gunshot wound (CGSW) patients may be treated with simple wound closure (SWC) as a proactive therapy, but the appropriate clinical scenario for using this strategy is unknown. The aim of this study was to compare SWC and surgery patients in terms of their neurological outcomes and complications, including infections, seizures, and reoperations. METHODS: This was a single-center, retrospective review of the prospectively maintained institutional traumatic brain injury and trauma registries. Included were adults who sustained an acute CGSW defined as suspected or confirmed dural penetration. Excluded were nonfirearm penetrating injuries, patients with an initial Glasgow Coma Scale (GCS) score of 3, patients with an initial GCS score of 4 and nonreactive pupils, and patients who died within 48 hours of presentation. RESULTS: A total of 67 patients were included; 17 (25.4%) were treated with SWC and 50 (74.6%) were treated with surgery. The SWC group had a lower incidence of radiographic mass effect (3/17 [17.6%] SWC vs 31/50 [62%] surgery; absolute difference 44.4, 95% CI -71.9 to 16.8; p = 0.002) and lower incidence of involvement of the frontal sinus (0/17 [0%] SWC vs 14/50 [28%] surgery; absolute difference 28, 95% CI -50.4 to 5.6; p = 0.01). There were no differences in the frequency of Glasgow Outcome Scale-Extended scores ≥ 5 between the SWC and surgery groups at 30 days (4/11 [36.4%] SWC vs 12/35 [34.3%] surgery; OR 1.1, 95% CI 0.3-4.5; p > 0.99), 60 days (2/7 [28.6%] SWC vs 8/26 [30.8%] surgery; OR 0.9, 95% CI 0.3-3.4; p > 0.99), and 90 days (3/8 [37.5%] SWC vs 12/26 [46.2%] surgery; OR 0.7, 95% CI 0.1-3.6; p > 0.99). There were no differences in the incidence of infections (1/17 [5.9%] SWC vs 6/50 [12%] surgery; OR 0.5, 95% CI 0.1-4.1; p = 0.67), CSF fistulas (2/11 [11.6%] SWC vs 3/50 [6%] surgery; OR 2.1, 95% CI 0.3-13.7; p = 0.60), seizures (3/17 [17.6%] SWC vs 9/50 [18%] surgery; OR 1, 95% CI 0.2-4.1; p > 0.99), and reoperations (3/17 [17.6%] SWC vs 4/50 [8%] surgery; OR 2.5, 95% CI 0.5-12.4; p = 0.36) between the SWC and surgery groups. CONCLUSIONS: There were important clinically relevant differences between the SWC and surgery groups. SWC can be considered a safe and efficacious proactive therapy in a carefully selected subset of civilian CGSW patients.

Clinical ethics consultations: a scoping review of reported outcomes.

BACKGROUND: Clinical ethics consultations (CEC) can be complex interventions, involving multiple methods, stakeholders, and competing ethical values. Despite longstanding calls for rigorous evaluation in the field, progress has been limited. The Medical Research Council (MRC) proposed guidelines for evaluating the effectiveness of complex interventions. The evaluation of CEC may benefit from application of the MRC framework to advance the transparency and methodological rigor of this field. A first step is to understand the outcomes measured in evaluations of CEC in healthcare settings. OBJECTIVE: The primary objective of this review was to identify and map the outcomes reported in primary studies of CEC. The secondary objective was to provide a comprehensive overview of CEC structures, processes, and roles to enhance understanding and to inform standardization. METHODS: We searched electronic databases to identify primary studies of CEC involving patients, substitute decision-makers and/or family members, clinicians, healthcare staff and leaders. Outcomes were mapped across five conceptual domains as identified a priori based on our clinical ethics experience and preliminary literature searches and revised based on our emerging interpretation of the data. These domains included personal factors, process factors, clinical factors, quality, and resource factors. RESULTS: Forty-eight studies were included in the review. Studies were highly heterogeneous and varied considerably regarding format and process of ethical intervention, credentials of interventionist, population of study, outcomes reported, and measures employed. In addition, few studies used validated measurement tools. The top three outcome domains that studies reported on were quality (n = 31), process factors (n = 23), and clinical factors (n = 19). The majority of studies examined multiple outcome domains. All five outcome domains were multidimensional and included a variety of subthemes. CONCLUSIONS: This scoping review represents the initial phase of mapping the outcomes reported in primary studies of CEC and identifying gaps in the evidence. The confirmed lack of standardization represents a hindrance to the provision of high quality intervention and CEC scientific progress. Insights gained can inform the development of a core outcome set to standardize outcome measures in CEC evaluation research and enable scientifically rigorous efficacy trials of CEC.

Mimicking Native Display of CD0873 on Liposomes Augments Its Potency as an Oral Vaccine against Clostridioides difficile.

Mucosal vaccination aims to prevent infection mainly by inducing secretory IgA (sIgA) antibody, which neutralises pathogens and enterotoxins by blocking their attachment to epithelial cells. We previously demonstrated that encapsulated protein antigen CD0873 given orally to hamsters induces neutralising antibodies locally as well as systemically, affording partial protection against Clostridioides difficile infection. The aim of this study was to determine whether displaying CD0873 on liposomes, mimicking native presentation, would drive a stronger antibody response. The recombinant form we previously tested resembles the naturally cleaved lipoprotein commencing with a cysteine but lacking lipid modification. A synthetic lipid (DHPPA-Mal) was designed for conjugation of this protein via its N-terminal cysteine to the maleimide headgroup. DHPPA-Mal was first formulated with liposomes to produce MalLipo; then, CD0873 was conjugated to headgroups protruding from the outer envelope to generate CD0873-MalLipo. The immunogenicity of CD0873-MalLipo was compared to CD0873 in hamsters. Intestinal sIgA and CD0873-specific serum IgG were induced in all vaccinated animals; however, neutralising activity was greatest for the CD0873-MalLipo group. Our data hold great promise for development of a novel oral vaccine platform driving intestinal and systemic immune responses.

Targeting Macrophage Dysregulation for Viral Infections: Novel Targets for Immunomodulators.

A major barrier to human immunodeficiency virus (HIV-1) cure is the latent viral reservoir, which persists despite antiretroviral therapy (ART), including across the non-dividing myeloid reservoir which is found systemically in sanctuary sites across tissues and the central nervous system (CNS). Unlike activated CD4+ T cells that undergo rapid cell death during initial infection (due to rapid viral replication kinetics), viral replication kinetics are delayed in non-dividing myeloid cells, resulting in long-lived survival of infected macrophages and macrophage-like cells. Simultaneously, persistent inflammation in macrophages confers immune dysregulation that is a key driver of co-morbidities including cardiovascular disease (CVD) and neurological deficits in people living with HIV-1 (PLWH). Macrophage activation and dysregulation is also a key driver of disease progression across other viral infections including SARS-CoV-2, influenza, and chikungunya viruses, underscoring the interplay between macrophages and disease progression, pathogenesis, and comorbidity in the viral infection setting. This review discusses the role of macrophages in persistence and pathogenesis of HIV-1 and related comorbidities, SARS-CoV-2 and other viruses. A special focus is given to novel immunomodulatory targets for key events driving myeloid cell dysregulation and reservoir maintenance across a diverse array of viral infections.

Clinical, pathologic, and epidemiologic features of nocardioform placentitis in the mare.

Placentitis is the leading cause of infectious abortion in the horse and contributes to roughly 19% of all abortions in the United States. A type of placental infection, nocardioform placentitis (NP) is associated with gram-positive branching actinomycetes localized within the ventral body of the feto-maternal interface to create a lymphoplasmacytic mucoid lesion. While the etiology of this disease is poorly described, this placental infection continues to cause episodic abortions in addition to weak and/or growth retarded neonates. The goal of the present study was to perform a comprehensive analysis of pregnancies associated with a nocardioform-affected placenta and make inferences into the epidemiology of this elusive disease. To do so, 264 mares were enrolled in the study, with 145 as having suspected disease (n = 145; NP) either based on pregnancy-related complications or postpartum placental evaluation, while an additional 119 were enrolled as healthy pregnancies (n = 119; CON). Following diagnosis as either NP or CON based on gross and histopathology at the University of Kentucky Veterinary Diagnostic Laboratory, information was gathered on the mares and neonates for comparisons between diseased and healthy pregnancies. Clinically, a significant portion of diseased mares had clinical indications of NP, including premature mammary gland development, thickening of the placenta noted on transrectal ultrasonography, and separation between the chorioallantois and endometrium noted on abdominal ultrasonography, while vulvar discharge was not commonly noted. Additionally, NP was correlated with increased mare age, decreased gestational length, and decreased neonatal weight, although neonatal IgG and WBC were comparable to CON. Incidence of NP was not correlated with last breeding date, pre- and post-breeding therapeutics, parity, prophylactic medications, or housing. Additionally, NP did not affect postpartum fertility. While NP was associated with a poor neonatal outcome (abortion and/or growth retarded neonate), this did not appear to be influenced by the bacteria isolated (Amycolatopsis spp. vs. Crossiella equi), and mares diagnosed with NP do not appear to be infectious to other pregnant mares nor have repetitive years of the disease. Interestingly, lesion size was positively correlated with last breeding date, as mares bred later in the breeding season correlating with a larger placental lesion. In conclusion, while the etiology of NP continues to elude researchers, the epidemiology of this disease has gained clarity, providing inferences into the management of suspect mares.

Current evidence of survival benefit between chest-compression only versus standard cardiopulmonary resuscitation in out-of-hospital cardiac arrest : Updated systematic review and meta-analysis of randomized controlled trials with trial sequential analysis.

BACKGROUND: Evidence to support a better cardiopulmonary resuscitation method between standard vs. continuous chest compression (STD-CPR vs. CCC-CPR) is lacking. MATERIALS AND METHODS: Our systematic review followed PRISMA guidelines. We searched PubMed, ScienceDirect, EBSCOhost, and ProQuest database from 1985 to 26 September 2019 restricted to randomized controlled trial, human study, and English articles. Quality assessment of between-study heterogeneity and a trial sequential analysis (TSA) were conducted. We estimated overall significance with 80% power and adjusted Z values thresholds using O'Brien-Fleming α­spending function. Required information size with 21% relative risk using the estimation between-group incidences provided from the median rate across trials was determined. Inconclusive TSA result will lead to size estimation of future RCT. Quality of evidence was analyzed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) Handbook and TSA. RESULTS: Based on three trials in OHCA with dispatcher-guided and bystander-initiated CPR, our meta-analysis favors CCC-CPR for survival to hospital discharge, compared to STD-CPR (RR [Risk Ratio] = 1.21[1.01-1.46], 95% CI, p = 0.68, I2 = 0). However, current meta-analyses with 3031 patients appeared to be inconclusive. There is a significant risk of type 1 error and therefore, results are potentially false positive. It is estimated that a minimal of 4331 patients needed to deem a conclusive result and a total of 5894 patients with similar risk profile required to stabilize statistic results in future trials. Quality of evidence is downgraded to moderate due to serious imprecision based on TSA. CONCLUSION: Based on these analyses, evidence is inadequate to conclude the superiority of one CPR method over the other. Further trials with larger numbers of patients are needed to deem a conclusive and stable meta-analysis.

Mice Deficient in T-bet Form Inducible NO Synthase-Positive Granulomas That Fail to Constrain Salmonella.

Clearance of intracellular infections caused by Salmonella Typhimurium (STm) requires IFN-γ and the Th1-associated transcription factor T-bet. Nevertheless, whereas IFN-γ-/- mice succumb rapidly to STm infections, T-bet-/- mice do not. In this study, we assess the anatomy of immune responses and the relationship with bacterial localization in the spleens and livers of STm-infected IFN-γ-/- and T-bet-/- mice. In IFN-γ-/- mice, there is deficient granuloma formation and inducible NO synthase (iNOS) induction, increased dissemination of bacteria throughout the organs, and rapid death. The provision of a source of IFN-γ reverses this, coincident with subsequent granuloma formation and substantially extends survival when compared with mice deficient in all sources of IFN-γ. T-bet-/- mice induce significant levels of IFN-γ- after challenge. Moreover, T-bet-/- mice have augmented IL-17 and neutrophil numbers, and neutralizing IL-17 reduces the neutrophilia but does not affect numbers of bacteria detected. Surprisingly, T-bet-/- mice exhibit surprisingly wild-type-like immune cell organization postinfection, including extensive iNOS+ granuloma formation. In wild-type mice, most bacteria are within iNOS+ granulomas, but in T-bet-/- mice, most bacteria are outside these sites. Therefore, Th1 cells act to restrict bacteria within IFN-γ-dependent iNOS+ granulomas and prevent dissemination.

Screening of Sacrificial Excipients for Arresting Devitrification of Itraconazole from Solid Dispersion.

OBJECTIVES: The aim of the present investigation was to develop a solid dispersion of itraconazole (ITR) using sacrificial excipients like pregelatinized starch and spray-dried lactose alongside hydroxypropyl methylcellulose and Poloxamer 188, thereby arresting the conversion of the amorphous form of ITR to crystalline form, and to assess the dissolution stability of an amorphous form of the drug during short-term storage. MATERIALS AND METHODS: ITR-loaded solid dispersions were prepared by kneading. Formulation optimization was achieved by using a 24 full factorial design on the basis of cumulative percent drug released at t30, t60, and t120 min. An artificial neural network (ANN) was also applied as a statistical tool for obtaining better predictive ability and the outcomes of the ANN were compared with that of Design-Expert software. RESULTS: The spectral data revealed no drug-carrier interactions. The P-X-ray diffraction study of the optimized batch showed a decrease in the crystallinity of drug as compared to the untreated drug. The in vitro dissolution studies of the optimized batch showed higher dissolution (92% at 120 min) in comparison to the other formulations. The dissolution stability study was performed at 40°C and 75% relative humidity for 90 days for the optimized formulation. The results of the optimized batch showed insignificant changes in cumulative percentage drug release during storage. CONCLUSION: Dissolution stability could be attributed to the presence of sacrificial excipients as they tend to absorb moisture during storage and possibly get converted into crystalline form, thereby minimizing the recrystallization of ITR.

The TLR4 Agonist Monophosphoryl Lipid A Drives Broad Resistance to Infection via Dynamic Reprogramming of Macrophage Metabolism.

Monophosphoryl lipid A (MPLA) is a clinically used TLR4 agonist that has been found to drive nonspecific resistance to infection for up to 2 wk. However, the molecular mechanisms conferring protection are not well understood. In this study, we found that MPLA prompts resistance to infection, in part, by inducing a sustained and dynamic metabolic program in macrophages that supports improved pathogen clearance. Mice treated with MPLA had enhanced resistance to infection with Staphylococcus aureus and Candida albicans that was associated with augmented microbial clearance and organ protection. Tissue macrophages, which exhibited augmented phagocytosis and respiratory burst after MPLA treatment, were required for the beneficial effects of MPLA. Further analysis of the macrophage phenotype revealed that early TLR4-driven aerobic glycolysis was later coupled with mitochondrial biogenesis, enhanced malate shuttling, and increased mitochondrial ATP production. This metabolic program was initiated by overlapping and redundant contributions of MyD88- and TRIF-dependent signaling pathways as well as downstream mTOR activation. Blockade of mTOR signaling inhibited the development of the metabolic and functional macrophage phenotype and ablated MPLA-induced resistance to infection in vivo. Our findings reveal that MPLA drives macrophage metabolic reprogramming that evolves over a period of days to support a macrophage phenotype highly effective at mediating microbe clearance and that this results in nonspecific resistance to infection.

Evaluation of updated sepsis scoring systems and systemic inflammatory response syndrome criteria and their association with sepsis in equine neonates.

BACKGROUND: The original equine sepsis score provided a method of identifying foals with sepsis. New variables associated with sepsis have been evaluated, but the sepsis score has not been updated. OBJECTIVES: To evaluate the sensitivity and specificity of 2 updated sepsis scores and the systemic inflammatory response syndrome (SIRS) criteria in regard to detecting sepsis in foals. ANIMALS: Two-hundred and seventy-three ill foals and 25 healthy control foals. METHODS: Historical, physical examination, and clinicopathologic findings were used to calculate the original sepsis score and 2 updated sepsis scores. SIRS criteria were also evaluated. Sepsis scores and positive SIRS scores were statistically compared to foals with sepsis. RESULTS: One-hundred and twenty-six foals were septic and 147 sick-nonseptic. The original and updated sepsis scores were significantly higher in septic foals as compared to sick-nonseptic and healthy foals. The sensitivity and specificity of the updated sepsis scores to predict sepsis were not significantly better than those of the original sepsis score. One-hundred and twenty-seven of 273 (46.5%) foals met the original SIRS criteria and 88/273 (32%) foals met the equine neonatal SIRS criteria. The original SIRS criteria had similar sensitivity and specificity for predicting sepsis as did the 3 sepsis scores in our study. CONCLUSIONS AND CLINICAL IMPORTANCE: The updated sepsis scores did not provide improved ability in predicting sepsis. Fulfilling the original SIRS criteria provided similar sensitivity and specificity in predicting sepsis as the modified sepsis score and might serve as a diagnostic aid in identifying foals at risk for sepsis.

Use of Renal Replacement Therapy in a Neonatal Foal with Postresuscitation Acute Renal Failure.

A newborn foal was presented because it was unresponsive and in cardiopulmonary arrest. Aggressive cardiopulmonary cerebral resuscitation was administered to the foal, which revived the foal; however, acute renal failure developed. Fluid retention and azotemia occurred although the foal was alert and able to suckle. A 6-hour renal replacement therapy session using hemodiafiltration and a continuous renal replacement therapy machine was administered to the foal at 3 days of age which lowered the foal's azotemia and facilitated removal of some of the excess body fluid. Despite therapy, the foal developed pulmonary edema and was euthanized. Although the foal in this case did not survive, this report highlights the possibility of developing postresuscitation complications such as acute renal failure and describes the use of renal replacement therapy using hemodiafiltration as a viable option in neonatal foals with acute kidney injury.

Avr4 promotes Cf-4 receptor-like protein association with the BAK1/SERK3 receptor-like kinase to initiate receptor endocytosis and plant immunity.

The first layer of plant immunity is activated by cell surface receptor-like kinases (RLKs) and proteins (RLPs) that detect infectious pathogens. Constitutive interaction with the SUPPRESSOR OF BIR1 (SOBIR1) RLK contributes to RLP stability and kinase activity. As RLK activation requires transphosphorylation with a second associated RLK, it remains elusive how RLPs initiate downstream signaling. We employed live-cell imaging, gene silencing and coimmunoprecipitation to investigate the requirement of associated kinases for functioning and ligand-induced subcellular trafficking of Cf RLPs that mediate immunity of tomato against Cladosporium fulvum. Our research shows that after elicitation with matching effector ligands Avr4 and Avr9, BRI1-ASSOCIATED KINASE 1/SOMATIC EMBRYOGENESIS RECEPTOR KINASE 3 (BAK1/SERK3) associates with Cf-4 and Cf-9. BAK1/SERK3 is required for the effector-triggered hypersensitive response and resistance of tomato against C. fulvum. Furthermore, Cf-4 interacts with SOBIR1 at the plasma membrane and is recruited to late endosomes upon Avr4 trigger, also depending on BAK1/SERK3. These observations indicate that RLP-mediated resistance and endocytosis require ligand-induced recruitment of BAK1/SERK3, reminiscent of BAK1/SERK3 interaction and subcellular fate of the FLAGELLIN SENSING 2 (FLS2) RLK. This reveals that diverse classes of cell surface immune receptors share common requirements for initiation of resistance and endocytosis.