The Microbiota-Gut-Brain Axis.

The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson's disease, and Alzheimer's disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.

Prevalence and management of sleep disturbance in adults with primary brain tumours and their caregivers: a systematic review.

PURPOSE: The aims of this systematic review were to (1) examine the prevalence, severity, manifestations, and clinical associations/risk factors of sleep disturbance in primary brain tumour (PBT) survivors and their caregivers; and (2) determine whether there are any sleep-focused interventons reported in the literature pertaining to people affected by PBT. METHODS: This systematic review was registered with the international register for systematic reviews (PROSPERO: CRD42022299332). PubMed, EMBASE, Scopus, PsychINFO, and CINAHL were electronically searched for relevant articles reporting sleep disturbance and/or interventions for managing sleep disturbance published between September 2015 and May 2022. The search strategy included terms focusing on sleep disturbance, primary brain tumours, caregivers of PBT survivors, and interventions. Two reviewers conducted the quality appraisal (JBI Critical Appraisal Tools) independently, with results compared upon completion. RESULTS: 34 manuscripts were eligible for inclusion. Sleep disturbance was highly prevalent in PBT survivors with associations between sleep disturbance and some treatments (e.g., surgical resection, radiotherapy, corticosteroid use), as well as other prevalent symptoms (e.g., fatigue, drowsiness, stress, pain). While the current review was unable to find any sleep-targeted interventions, preliminary evidence suggests physical activity may elicit beneficial change on subjectively reported sleep disturbance in PBT survivors. Only one manuscript that discussed caregivers sleep disturbance was identified. CONCLUSIONS: Sleep disturbance is a prevalent symptom experienced by PBT survivors, yet there is a distinct lack of sleep-focused interventions in this population. This includes a need for future research to include caregivers, with only one study identified. Future research exploring interventions directly focused on the management of sleep disturbance in the context of PBT is warranted.

Affective Modulation after High-Intensity Exercise Is Associated with Prolonged Amygdalar-Insular Functional Connectivity Increase.

Acute moderate exercise has been shown to induce prolonged changes in functional connectivity (FC) within affect and reward networks. The influence of different exercise intensities on FC has not yet been explored. Twenty-five male athletes underwent 30 min of "low"- (35% < lactate threshold (LT)) and "high"- (20% > LT) intensity exercise bouts on a treadmill. Resting-state fMRI was acquired at 3 Tesla before and after exercise, together with the Positive and Negative Affect Scale (PANAS). Data of 22 subjects (3 dropouts) were analyzed using the FSL feat pipeline and a seed-to-network-based analysis with the bilateral amygdala as the seed region for determining associated FC changes in the "emotional brain." Data were analyzed using a repeated measures ANOVA. Comparisons between pre- and post-exercise were analyzed using a one-sample t-test, and a paired t-test was used for the comparison between "low" and "high" exercise conditions (nonparametric randomization approach, results reported at p < 0.05). Both exercise interventions induced significant increases in the PANAS positive affect scale. There was a significant interaction effect of amygdalar FC to the right anterior insula, and this amygdalar-insular FC correlated significantly with the PANAS positive affect scale (r = 0.47, p = 0.048) in the "high"-intensity exercise condition. Our findings suggest that mood changes after exercise are associated with prolonged alterations in amygdalar-insular FC and occur in an exercise intensity-dependent manner.

Immunogenicity, Lot Consistency, and Extended Safety of rVSVΔG-ZEBOV-GP Vaccine: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study in Healthy Adults.

BACKGROUND: This double-blind study assessed immunogenicity, lot consistency, and safety of recombinant vesicular stomatitis virus-Zaire Ebola virus envelope glycoprotein vaccine (rVSVΔG-ZEBOV-GP). METHODS: Healthy adults (N = 1197) were randomized 2:2:2:2:1 to receive 1 of 3 consistency lots of rVSVΔG-ZEBOV-GP (2 × 107 plaque-forming units [pfu]), high-dose 1 × 108 pfu, or placebo. Antibody responses pre-/postvaccination (28 days, 6 months; in a subset [n = 566], months 12, 18, and 24) were measured. post hoc analysis of risk factors associated with arthritis following vaccination was performed. RESULTS: ZEBOV-GP enzyme-linked immunosorbent assay (ELISA) geometric mean titers (GMTs) increased postvaccination in all rVSVΔG-ZEBOV-GP groups by 28 days (>58-fold) and persisted through 24 months. The 3 manufacturing lots demonstrated equivalent immunogenicity at 28 days. Neutralizing antibody GMTs increased by 28 days in all rVSVΔG-ZEBOV-GP groups, peaking at 18 months with no decrease through 24 months. At 28 days, ≥94% of vaccine recipients seroresponded (ZEBOV-GP ELISA, ≥2-fold increase, titer ≥200 EU/mL), with responses persisting at 24 months in ≥91%. Female sex and a history of arthritis were identified as potential risk factors for the development of arthritis postvaccination. CONCLUSIONS: Immune responses to rVSVΔG-ZEBOV-GP persisted to 24 months. Immunogenicity and safety results support continued rVSVΔG-ZEBOV-GP development. CLINICAL TRIALS REGISTRATION: NCT02503202.

Persistence of Varicella-Zoster Virus Cell-Mediated Immunity After the Administration of a Second Dose of Live Herpes Zoster Vaccine.

Protection against zoster conferred by zoster vaccine live (ZVL; Zostavax) wanes over time. We compared varicella-zoster virus cell-mediated immunity (VZV-CMI) of adults ≥70 years who received a second dose of ZVL ≥10 years after the initial dose with de novo-immunized age-matched controls. Before and during the first year after vaccination, VZV-CMI was significantly higher in reimmunized compared with de novo vaccinees. At 3 years, VZV-CMI differences between groups decreased and only memory responses remained marginally higher in reimmunized participants. In conclusion, the increase in VZV-CMI generated by reimmunization with ZVL is at least equally persistent compared with de novo immunization.

Case 263: Malaysian Charm Needles (Susuk).

History A 58-year-old woman was seen in the rheumatology clinic for bilateral wrist and knee pain that was unresponsive to physiotherapy and intra-articular steroid injections. Remote fracture of the left tibia from a motor vehicle collision was reported and was previously treated with conservative management. Serologic work-up for inflammatory disease was negative. The patient reported no prior surgical or medical history. Social history revealed remote immigration from Malaysia. Radiographs of the hands and knees were obtained.

Patient-reported outcomes following abiraterone acetate plus prednisone added to androgen deprivation therapy in patients with newly diagnosed metastatic castration-naive prostate cancer (LATITUDE): an international, randomised phase 3 trial.

BACKGROUND: In the LATITUDE trial, addition of abiraterone acetate plus prednisone to androgen deprivation therapy (ADT) improved overall survival compared with placebos plus ADT in patients with newly diagnosed, high-risk, metastatic castration-naive prostate cancer. Understanding the effects of treatments on patient-reported outcomes (PROs) and health-related quality of life (HRQOL) is important for treatment decisions; therefore we aimed to analyse the effects of ADT plus abiraterone acetate and prednisone versus ADT plus placebos on PROs and HRQOL in patients in the LATITUDE study. METHODS: In the multicentre, international, randomised, phase 3 LATITUDE trial, eligible patients were aged 18 years or older, had newly diagnosed, high-risk, metastatic castration-naive prostate cancer confirmed by bone scan (bone metastases) or by CT or MRI (visceral, soft tissue, or nodal metastases), and an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or less. Patients from 235 clinical sites in 34 countries were randomly assigned (1:1) following a country-by-country scheme done by permuted block randomisation (with two blocks) and stratified by the presence of visceral metastasis and ECOG performance status to receive ADT plus 1000 mg oral abiraterone acetate and 5 mg oral prednisone once daily or ADT plus placebos. Selection of ADT, chemical or surgical, was at the investigator's discretion. The co-primary endpoints of the trial, overall survival and radiographic progression-free survival, have been published. PRO data were collected directly on electronic tablet devices at the clinical sites during screening and before any other visit procedure on day 1 of cycles 1-3, monthly during cycles 4-13, and then every 2 months until the end of treatment, by use of the Brief Pain Inventory-Short Form (BPI-SF), Brief Fatigue Inventory (BFI), Functional Assessment of Cancer Therapy Prostate scale (FACT-P), and the EuroQol (EQ-5D-5L) questionnaires. PRO analyses were an exploratory endpoint. Analyses were by intention-to-treat. Results from the first pre-planned interim analysis (Oct 31, 2016), are presented here. This ongoing study is registered with Clinicaltrials.gov, number NCT01715285. FINDINGS: Between Feb 12, 2013, and Dec 11, 2014, 1199 patients were randomly assigned: 597 to ADT plus abiraterone acetate and prednisone and 602 to ADT plus placebos. Median follow-up was 30·9 months (IQR 21·2-33·2) in the ADT plus abiraterone acetate and prednisone group versus 29·7 months (1·4-43·5; 16·1-31·3) in the ADT plus placebos group. Median time to worst pain intensity progression assessed by the BPI-SF score was not reached in either group (ADT plus abiraterone acetate and prednisone, not reached [95% CI not reached to not reached]; 25th percentile 11·07 months [95% CI 9·23-18·43]; ADT plus placebos group, not reached [95% CI not reached to not reached]; 25th percentile 5·62 [95% CI 4·63-7·39]; hazard ratio [HR] 0·63 [95% CI 0·52-0·77]; p<0·0001). Median time to worst fatigue intensity was not reached in either the ADT plus abiraterone acetate and prednisone group (not reached [95% CI not reached to not reached]; 25th percentile 18·4 months [95% CI 12·9-27·7]) or the ADT plus placebos group (not reached [95% CI not reached to not reached]; 25th percentile 6·5 months [95% CI 5·6-9·2]; HR 0·65 [95% CI 0·53-0·81], p=0·0001). Median time to deterioration of functional status assessed by the FACT-P total score scale was 12·9 months (95% CI 9·0-16·6) in the ADT plus abiraterone acetate and prednisone group versus 8·3 months (7·4-11·1) in the ADT plus placebos group (HR 0·85 [95% CI 0·74-0·99]; p=0·032). INTERPRETATION: The addition of abiraterone acetate plus prednisone to ADT in patients with newly diagnosed, high-risk metastatic castration-naive prostate cancer improved overall PROs by consistently showing a clinical benefit in the progression of pain, prostate cancer symptoms, fatigue, functional decline, and overall HRQOL. FUNDING: Janssen Research & Development.

Safety and Immunogenicity of Zoster Vaccine Live in Human Immunodeficiency Virus-Infected Adults With CD4+ Cell Counts >200 Cells/mL Virologically Suppressed on Antiretroviral Therapy.

Background: Herpes zoster (HZ) risk is increased in human immunodeficiency virus (HIV)-infected persons. Live attenuated zoster vaccine (ZV) reduces HZ incidence and severity in adults; safety and immunogenicity data in HIV-infected adults are limited. Methods: We conducted a randomized, double-blind, placebo-controlled trial in HIV-infected adults virally suppressed on antiretroviral therapy (ART). Participants, stratified by CD4+ count (200-349 or ≥350 cells/µL), were randomized 3:1 to receive ZV or placebo on day 0 and week 6. The primary endpoint was serious adverse event or grade 3/4 signs/symptoms within 6 weeks after each dose. Immunogenicity (varicella zoster virus [VZV]-specific glycoprotein enzyme-linked immunosorbent assay and interferon-γ enzyme-linked immunospot assay responses) was assessed at 6 and 12 weeks postvaccination. Results: Of 395 participants (296 ZV vs 99 placebo), 84% were male, 47% white, 29% black, and 22% Hispanic; median age was 49 years. Safety endpoints occurred in 15 ZV and 2 placebo recipients (5.1% [95% confidence interval {CI}, 2.9%-8.2%] vs 2.1% [95% CI, .3%-7.3%]; P = .26). Injection site reactions occurred in 42% of ZV (95% CI, 36.3%-47.9%) vs 12.4% of placebo recipients (95% CI, 6.6%-20.6%) (P < .001). Week 12 median natural log VZV antibody titer was higher for ZV (6.30 [Q1, Q3, 5.64, 6.96]) vs placebo (5.48 [Q1, Q3, 4.63, 6.44]; P < .001) overall and in the high CD4+ stratum (P = .003). VZV antibody titers were similar after 1 or 2 ZV doses. Polymerase chain reaction-confirmed HZ occurred in 2 participants (1 ZV; 1 placebo); none was vaccine strain related. Conclusions: Two doses of ZV in HIV-infected adults suppressed on ART with CD4+ counts ≥200 cells/µL were safe and immunogenic. Clinical Trials Registration: NCT00851786.

Case 263.

History A 58-year-old woman was seen in the rheumatology clinic for bilateral wrist and knee pain that was unresponsive to physiotherapy and intra-articular steroid injections. Remote fracture of the left tibia from a motor vehicle collision was reported and was previously treated with conservative management. Serologic work-up for inflammatory disease was negative. The patient reported no prior surgical or medical history. Social history revealed remote immigration from Malaysia. Radiographs of the hands and knees were obtained ( Figs 1 - 4 ). [Figure: see text][Figure: see text][Figure: see text][Figure: see text].

Six-Month Safety Data of Recombinant Vesicular Stomatitis Virus-Zaire Ebola Virus Envelope Glycoprotein Vaccine in a Phase 3 Double-Blind, Placebo-Controlled Randomized Study in Healthy Adults.

Background: This study (NCT02503202) evaluated the safety of recombinant vesicular stomatitis virus-Zaire Ebola virus envelope glycoprotein vaccine (rVSVΔG-ZEBOV-GP). Methods: Overall, 1197 subjects were randomized 2:2:2:2:1; 1194 were vaccinated with 1 dose of 1 of 3 lots of rVSVΔG- ZEBOV-GP (2 × 107 plaque-forming units [pfu], n = 797; combined-lots group), a single high-dose lot of rVSVΔG-ZEBOV-GP (1 × 108 pfu, n = 264; high-dose group), or placebo (n = 133). Daily temperatures and adverse events (AEs) were recorded days 1 to 42 postvaccination. Solicited AEs included injection-site AEs from days 1 to 5, and joint pain, joint swelling, vesicular lesions (blisters), and rashes from days 1 to 42. Serious AEs (SAEs) were recorded through 6 months postvaccination. Results: Fever (≥38.0°C) was observed in 20.2% of combined lots (3.2% with ≥39.0°C), 32.2% of high-dose (4.3% with ≥39.0°C), and 0.8% of placebo (0.8% with ≥39.0°C). Incidences of AEs of interest (days 1-42) were arthralgia (17.1% combined lots, 20.4% high-dose, 3.0% placebo), arthritis (5.1% combined lots, 4.2% high-dose, 0.0% placebo), and rash (3.8% combined lots, 3.8% high-dose, 1.5% placebo). Twenty-one SAEs and 2 deaths were reported, all assessed by investigators as unrelated to vaccine. Conclusions: rVSVΔG-ZEBOV-GP was generally well-tolerated, with increased rates of injection-site and systemic AEs compared to placebo, and no vaccine-related SAEs or deaths. These findings support the use of rVSVΔG-ZEBOV-GP vaccine in persons at risk for Ebola virus disease. Clinical Trials Registration: NCT02503202.

An Electronic Tool for the Evaluation and Treatment of Sepsis in the ICU: A Randomized Controlled Trial.

OBJECTIVES: To determine whether addition of an electronic sepsis evaluation and management tool to electronic sepsis alerting improves compliance with treatment guidelines and clinical outcomes in septic ICU patients. DESIGN: A pragmatic randomized trial. SETTING: Medical and surgical ICUs of an academic, tertiary care medical center. PATIENTS: Four hundred and seven patients admitted during a 4-month period to the medical or surgical ICU with a diagnosis of sepsis established at the time of admission or in response to an electronic sepsis alert. INTERVENTIONS: Patients were randomized to usual care or the availability of an electronic tool capable of importing, synthesizing, and displaying sepsis-related data from the medical record, using logic rules to offer individualized evaluations of sepsis severity and response to therapy, informing users about evidence-based guidelines, and facilitating rapid order entry. MEASUREMENTS AND MAIN RESULTS: There was no difference between the electronic tool (218 patients) and usual care (189 patients) with regard to the primary outcome of time to completion of all indicated Surviving Sepsis Campaign 6-hour Sepsis Resuscitation Bundle elements (hazard ratio, 1.98; 95% CI, 0.75-5.20; p = 0.159) or time to completion of each element individually. ICU mortality, ICU-free days, and ventilator-free days did not differ between intervention and control. Providers used the tool to enter orders in only 28% of available cases. CONCLUSIONS: A comprehensive electronic sepsis evaluation and management tool is feasible and safe but did not influence guideline compliance or clinical outcomes, perhaps due to low utilization.

Accuracy of ultrasound and noninvasive markers of fibrosis to identify patients with cirrhosis.

BACKGROUND: Accurate identification of patients with cirrhosis using noninvasive markers of fibrosis is useful for esophageal varices and hepatocellular carcinoma surveillance programs. The aims of our study were to characterize the accuracy of ultrasonography, AST-to-platelet ratio index (APRI), and FIB-4 as noninvasive markers to identify the presence of cirrhosis. METHODS: We conducted a retrospective cohort study of patients who underwent liver biopsy at a large urban safety-net institution between November 2008 and July 2011. The sensitivity, specificity, positive predictive value (PPV), negative predictive value, and overall accuracy using receiver operator characteristic curve analysis for the detection of cirrhosis were calculated for each noninvasive marker. RESULTS: Liver biopsy was performed in 388 patients, of whom 93 (24.0 %) had cirrhosis. C-statistics for APRI and FIB-4 predicting the presence of cirrhosis were 0.68 (95 % CI 0.63-0.74) and 0.73 (95 % CI 0.68-0.78), respectively. The c-statistic for a nodular appearance on ultrasound was 0.78 (95 % CI 0.72-0.83). The PPV of a shrunken nodular-appearing liver was 64.8 %; however, PPV was significantly higher in the subset with a cirrhotic-appearing liver and signs of portal hypertension (PPV 83.6 %, p = 0.01) as well as in the subset with a noninvasive fibrosis marker also suggesting cirrhosis (PPV 77.8 %, p < 0.001). CONCLUSION: Serum and imaging noninvasive markers of fibrosis may have insufficient accuracy when used in isolation; however, a combination of markers may allow sufficient accuracy to systematically identify patients with cirrhosis.

Hippocampal subfield plasticity is associated with improved spatial memory.

Physical exercise studies are generally underrepresented in young adulthood. Seventeen subjects were randomized into an intervention group (24.2 ± 3.9 years; 3 trainings/week) and 10 subjects into a passive control group (23.7 ± 4.2 years), over a duration of 6 months. Every two months, performance diagnostics, computerized spatial memory tests, and 3 Tesla magnetic resonance imaging were conducted. Here we find that the intervention group, compared to controls, showed increased cardiorespiratory fitness, spatial memory performance and subregional hippocampal volumes over time. Time-by-condition interactions occurred in right cornu ammonis 4 body and (trend only) dentate gyrus, left hippocampal tail and left subiculum. Increases in spatial memory performance correlated with hippocampal body volume changes and, subregionally, with left subicular volume changes. In conclusion, findings support earlier reports of exercise-induced subregional hippocampal volume changes. Such exercise-related plasticity may not only be of interest for young adults with clinical disorders of hippocampal function, but also for sedentary normal cohorts.

Sonic Hedgehog contributes to gastric mucosal restitution after injury.

Eradication of Helicobacter pylori correlates with regeneration of the gastric epithelium, ulcer healing and re-expression of the gastric morphogen Sonic Hedgehog (Shh). We sought to identify the role of Shh as a regulator of gastric epithelial regeneration during wound healing. A mouse model expressing a parietal cell-specific, tamoxifen-inducible deletion of Shh (HKCre(ERT2);Shh(flox/flox) or PC-iShhKO) was developed. Stomachs were collected and compared 7-150 days after the final vehicle or tamoxifen injection. Ulcers were induced in both controls and PC-iShhKO mice using acetic acid and ulcer size compared 1 and 7 days post induction. (1) Re-expression of Shh correlates with decreased hyperproliferation: Compared to controls, PC-iShhKO mice developed foveolar hyperplasia. Restoration of normal gastric epithelial architecture and differentiation correlated with the re-expression of Shh in PC-iShhKO mice 150 days after the final tamoxifen injection. At the tamoxifen dose used to induce Cre recombination there was no genotoxicity reported in either HKCre(ERT2) or Shh(flox/flox) control mouse stomachs. (2) Delayed wound healing in PC-iShhKO mouse stomachs: To identify the role of Shh in gastric regeneration, an acetic acid ulcer was induced in control and PC-iShhKO mice. Ulcers began to heal in control mice by 7 days after induction. Ulcer healing was documented by decreased ulcer size, angiogenesis, macrophage infiltration and formation of granulation tissue that correlated with the re-expression of Shh within the ulcerated tissue. PC-iShhKO mice did not show evidence of ulcer healing. Re-expression of Shh contributes to gastric regeneration. Our current study may have clinical implications given that eradication of H. pylori correlates with re-expression of Shh, regeneration of the gastric epithelium and ulcer healing.

How Virtual Animal Anatomy facilitated a successful transition to online instruction and supported student learning during the coronavirus pandemic.

Anatomy faculty with cadaver-based laboratory courses were presented with a significant challenge in March 2020 to create equivalent learning experiences without cadaveric access. The undergraduate domestic animal anatomy course at the Colorado State University was halfway into a 16-week semester when COVID-19 lockdown orders and the transition to remote instruction began. The new course curriculum was critically evaluated using student surveys and course outcome data. Most students (92.5%) agreed that the transition to online learning was a success; however, students who valued face-to-face lectures prior to March were less likely to perceive the transition as a success. Qualitative and quantitative analyses of survey results suggest that the resources perceived as most helpful for the transition to online learning were not the same as those that helped facilitate animal anatomy learning. Most students (92.5%) agreed that the Virtual Animal Anatomy (VAA) helped them learn anatomy, and 82.2% indicated that the VAA was a valuable resource following the transition to online learning. Additional resources associated with transition success included course instructors, weekly quizzes, written descriptions of anatomical structures and open laboratory sessions. In contrast, those resources associated with facilitating learning included guided quizzes and asynchronous lecture recordings. These findings suggest that the VAA can support online anatomy learning when used in conjunction with other best practices for online teaching.

Osteoradionecrosis of the lamina papyracea leading to recurrent orbital infections-A case study.

Osteoradionecrosis (ORN) is a well-known complication of radiotherapy (RT) to the sino-nasal cavity and nasopharynx. Here, we report a case of recurrent orbital infections secondary to ORN of the lamina papyracea (LP). A 66-year-old female presented to our unit with right periorbital swelling and pain after having undergone chemotherapy and proton beam irradiation to her ethmoid sinuses for sino-nasal undifferentiated carcinoma (SNUC) 5 years prior. She had also undergone endoscopic sinus surgery for chronic rhinosinusitis about a year prior to the current presentation. Her post-operative course was notable for recurrent episodes of pre-septal cellulitis occurring about 3 months apart that were increasingly severe. Examination revealed right proptosis, and endoscopy showed an exposed and denuded LP with scant crusting of the ethmoid sinuses. Microbial studies did not yield any significant growth, and imaging showed enhancement of the right orbit. The working diagnosis was acute right orbital cellulitis secondary to ORN of the right LP. She was treated with broad spectrum intravenous antibiotics and systemic steroids, but experienced minimal symptomatic improvement. She then underwent endoscopic resection of the right LP, and histopathological examination showed osteonecrosis on an inflammatory background. Post-operatively, all orbital symptoms resolved and she was well at 6 months' follow up. In the discussion, we highlight additional factors in our patient that may have contributed to this clinical presentation, and hope that this report raises awareness of a rare complication of RT to the sino-nasal cavity.

Physical Activity Alters Functional Connectivity of Orbitofrontal Cortex Subdivisions in Healthy Young Adults: A Longitudinal fMRI Study.

Physical activity (PA) plays an important role in affect processing. Studies describe the orbitofrontal cortex (OFC) as a major hub for emotion processing and the pathophysiology of affective disorders. Subregions of the OFC show diverse functional connectivity (FC) topographies, but the effect of chronic PA on subregional OFC FC still lacks scientific understanding. Therefore, we aimed at investigating the effects of regular PA on the FC topographies of OFC subregions in healthy individuals within a longitudinal randomized controlled exercise study. Participants (age: 18-35 years) were randomly assigned to either an intervention group (IG; N = 18) or a control group (CG; N = 10). Fitness assessments, mood questionnaires, and resting state functional magnetic resonance imaging (rsfMRI) were performed four times over the duration of 6 months. Using a detailed parcellation of the OFC, we created subregional FC topography maps at each time point and applied a linear mixed model to assess the effects of regular PA. The posterior-lateral right OFC showed a group and time interaction, revealing decreased FC with the left dorsolateral prefrontal cortex in the IG, while FC in the CG increased. Group and time interaction in the anterior-lateral right OFC with the right middle frontal gyrus was driven by increased FC in the IG. The posterior-lateral left OFC showed a group and time interaction based on differential change in FC to the left postcentral gyrus and the right occipital gyrus. This study emphasized regionally distinctive FC changes induced by PA within the lateral OFC territory, while providing aspects for further research.

Randomized trial of automated, electronic monitoring to facilitate early detection of sepsis in the intensive care unit*.

OBJECTIVE: To determine whether automated identification with physician notification of the systemic inflammatory response syndrome in medical intensive care unit patients expedites early administration of new antibiotics or improvement of other patient outcomes in patients with sepsis. DESIGN: : A prospective randomized, controlled, single center study. SETTING: Medical intensive care unit of an academic, tertiary care medical center. PATIENTS: Four hundred forty-two consecutive patients admitted over a 4-month period who met modified systemic inflammatory response syndrome criteria in a medical intensive care unit. INTERVENTION: Patients were randomized to monitoring by an electronic "Listening Application" to detect modified (systemic inflammatory response syndrome) criteria vs. usual care. The listening application notified physicians in real time when modified systemic inflammatory response syndrome criteria were detected, but did not provide management recommendations. MEASUREMENTS AND MAIN RESULTS: The median time to new antibiotics was similar between the intervention and usual care groups when comparing among all patients (6.0 hr vs. 6.1 hr, p = .95), patients with sepsis (5.3 hr vs. 5.1 hr; p = .90), patients on antibiotics at enrollment (5.2 hr vs. 7.0 hr, p = .27), or patients not on antibiotics at enrollment (5.2 hr vs. 5.1 hr, p = .85). The amount of fluid administered following detection of modified systemic inflammatory response syndrome criteria was similar between groups whether comparing all patients or only patients who were hypotensive at enrollment. Other clinical outcomes including intensive care unit length of stay, hospital length of stay, and mortality were not shown to be different between patients in the intervention and control groups. CONCLUSIONS: Realtime alerts of modified systemic inflammatory response syndrome criteria to physicians in one tertiary care medical intensive care unit were feasible and safe but did not influence measured therapeutic interventions for sepsis or significantly alter clinical outcomes.