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Approximately 20% of individuals who experience a traumatic injury will subsequently develop posttraumatic stress disorder (PTSD). Physical pain following traumatic injury has received increasing attention as both a distinct, functionally debilitating disorder and a comorbid symptom related to PTSD. Studies have demonstrated that both clinician-assessed injury severity and patient pain ratings can be important predictors of nonremitting PTSD; however, few have examined pain and PTSD alongside socioenvironmental factors. We postulated that both area- and individual-level socioeconomic circumstances and lifetime trauma history would be uniquely associated with PTSD symptoms and interact with the pain–PTSD association. To test these effects, pain and PTSD symptoms were assessed at four visits across a 1-year period in a sample of 219 traumatically injured participants recruited from a Level 1 trauma center. We used a hierarchal linear modeling approach to evaluate whether (a) patient-reported pain ratings were a better predictor of PTSD than clinician-assessed injury severity scores and (b) socioenvironmental factors, specifically neighborhood socioeconomic disadvantage, individual income, and lifetime trauma history, influenced the pain–PTSD association. Results demonstrated associations between patient-reported pain ratings, but not clinician-assessed injury severity scores, and PTSD symptoms, R(2(fvm)) = .65. There was a significant interaction between neighborhood socioeconomic disadvantage and pain such that higher disadvantage decreased the strength of the pain–PTSD association but only among White participants, R(2(fvm)) = .69. Future directions include testing this question in a larger, more diverse sample of trauma survivors (e.g., geographically diverse) and examining factors that may alleviate both pain and PTSD symptoms.

90 million Americans suffer metabolic syndrome (MetSyn), increasing risk of diabetes and poor brain outcomes including neuropathology linked to lower cerebral blood flow (CBF)-predominantly in anterior regions. We tested the hypothesis total and regional CBF is lower in MetSyn more so in the anterior brain and explored three potential mechanisms. 34 Controls (25±5 yrs) and 19 MetSyn (30±9 yrs), with no history of cardiovascular disease/medications, underwent 4D flow magnetic resonance imaging (MRI) to quantify macrovascular CBF, while arterial spin labeling (ASL) quantified brain perfusion in a subset (n=38/53). Contributions of cyclooxygenase (COX; n=14), nitric oxide synthase (NOS, n=17), or endothelin receptor A signaling (ETA; n=13) were tested with indomethacin, L-NMMA, and Ambrisentan, respectively. Total CBF was 20±16% lower in MetSyn (725±116 vs. 582±119 mL/min, P

The calcium-sensing receptor (CaS, provisional nomenclature as recommended by NC-IUPHAR [47] and subsequently updated [77]) responds to multiple endogenous ligands, including extracellular calcium and other divalent/trivalent cations, polyamines and polycationic peptides, L-amino acids (particularly L-Trp and L-Phe), glutathione and various peptide analogues, ionic strength and extracellular pH (reviewed in [78]). While divalent/trivalent cations, polyamines and polycations are CaS receptor agonists [14, 110], L-amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [36, 47, 61, 108, 109]. Indeed, L-amino acids have been identified as "co-agonists", with both concomitant calcium and L-amino acid binding required for full receptor activation [149, 54]. The sensitivity of the CaS receptor to primary agonists is increased by elevated extracellular pH [18] or decreased extracellular ionic strength [109] while sensitivity is decreased by pathophysiological phosphate concentrations [20]. This receptor bears no sequence or structural relation to the plant calcium receptor, also called CaS.

As both a sensor of extracellular calcium (Ca2+o) concentration and a key controller of Ca2+o homeostasis, one of the most interesting properties of the calcium-sensing receptor (CaR) is its sensitivity to, and modulation by, ions and small ligands other than Ca2+. There is emerging evidence that extracellular phosphate can act as a partial, non-competitive CaR antagonist to modulate parathyroid hormone (PTH) secretion, thus permitting the CaR to integrate mineral homeostasis more broadly. Interestingly, phosphorylation of certain intracellular CaR residues can also inhibit CaR responsiveness. Thus, negatively charged phosphate can decrease CaR activity both extracellularly (via association with arginine) and intracellularly (via covalent phosphorylation).

Latent infection of Epstein-Barr virus (EBV) is associated with lymphoid and epithelial cell cancers, including 10% of gastric carcinomas. We previously reported that hypoxia inducible factor-1α (HIF-1α) induces EBV’s latent-to-lytic switch and identified several HIF-1α-stabilizing drugs that induce this viral reactivation. Here, we tested three classes of these drugs for preferential killing of the EBV-positive gastric cancer AGS-Akata cell line compared to its matched EBV-negative AGS control. We observed preferential killing with iron chelators [Deferoxamine (DFO); Deferasirox (DFX)] and a prolyl hydroxylase inhibitor (BAY 85-3934 (Molidustat)), but not with a neddylation inhibitor [MLN4924 (Pevonedistat)]. DFO and DFX also induced preferential killing of the EBV-positive gastric cancer AGS-BDneo and SNU-719 cell lines. Preferential killing was enhanced when low-dose DFX (10 μM) was combined with the antiviral prodrug ganciclovir. DFO and DFX induced lytic EBV reactivation in approximately 10% of SNU-719 and 20-30% of AGS-Akata and AGS-BDneo cells. However, neither DFO nor DFX significantly induced synthesis of lytic EBV proteins in xenografts grown in NSG mice from AGS-Akata cells above the level observed in control-treated mice. Therefore, these FDA-approved iron chelators are less effective than gemcitabine at promoting EBV reactivation in vivo despite their high specificity and efficiency in vitro.

Introduction The clinical presentation of lower gastrointestinal bleeding (LGIB) is variable in severity, cause and potential investigations. The British Society of Gastroenterology recently published LGIB guidelines, recommending CT angiography (CT-A) for haemodynamically unstable patients, defined by shock index (SI) greater than 1. The aim of this study was to assess the use and role of CT-A in diagnosing LGIB, by assessing the pickup rate of active LGIB defined by contrast extravasation or ‘blush’ and to determine any association between positive CT-A with various patient and clinical characteristics. Methods A retrospective analysis was carried out of 4 years of LGIB admissions. Demographics, inpatient observations and use of blood products were acquired. Vital signs nearest the time of CT-A plus abnormal vital signs preceding imaging were used to calculate SI, Age SI, National Early Warning Score 2 (NEWS2) and Standardised Early Warning Score (SEWS). A consultant gastrointestinal radiologist further reviewed all consultant-reported scans. Results In total, 930 patients were admitted with LGIB. Median age was 71 years and 51% were male; 179 (19.2%) patients received red blood cell transfusion and 93 patients (10%) underwent CT-A, who were older and were likely to be hypotensive and receive red cell transfusions. Following exclusions, 92 CT-As were included in the analysis. Nine (9.8%) were positive. Univariate analysis showed no association between positive CT-A and any scoring system. A multivariate analysis, including age and gender, showed association between both NEWS2 and SEWS scores with positive CT-A. Conclusion In our analysis of the typical LGIB population, CT-A has shown relatively low pick up rate of active bleeding. CT-A clearly has a role in the investigation of LGIB, but selection remains challenging.

Introduction Management of malignant small bowel obstruction (mSBO) is challenging. The decision to perform an operation evaluates the perceived chance of success against a patient’s fitness for operation. The aim of this study was to characterise the mSBO patient population in a tertiary UK centre and assess the patient’s treatment pathway including use and effects of palliative surgery, total parenteral nutrition (TPN), Gastrografin and dexamethasone as well as preoperative stratification. Methods Patients were included if they had mSBO confirmed on computed tomography imaging due to a primary or metastatic neoplasm. Data were collected on pathway and management, and Cox proportional hazard methods were utilised to observe effects on survival. Results Ninety-four patients were included, with 104 inpatient episodes. Mean age was 67.4 (SD 13.7), with 57 (60.6%) females. Most (89.4%) had only one admission for mSBO. Eighty-four (89.4%) patients died over the ten-year period, 18 (17.3%) within 30 days of admission. Fifty patients (53.1%) underwent operative management: 70% bypass, 24% stoma formation and 6% open-close laparotomies. Log rank testing of survival probability analysis was significant (p = 0.00018), with 50% survival probability at 107.32 days for operative management and 47.87 days for non-operative. Discussion and Conclusion Operative management forms part of the treatment pathway for a significant proportion of patients with mSBO, offering a survival benefit, though quality of survival is not known. Case selection is good, with few open-close laparotomies. Trials of non-operative interventions such as Gastrografin and dexamethasone are not utilised fully.

The serotonergic system extends throughout the central nervous system (CNS) and the gastrointestinal (GI) tract. In the CNS, serotonin (5-HT, 5-hydroxytryptamine) modulates a broad spectrum of functions, including mood, cognition, anxiety, learning, memory, reward processing, and sleep. These processes are mediated through 5-HT binding to 5-HT receptors (5-HTRs), are classified into seven distinct groups. Deficits in the serotonergic system can result in various pathological conditions, particularly depression, schizophrenia, mood disorders, and autism. In this review, we outlined the complexity of serotonergic modulation of physiologic and pathologic processes. Moreover, we provided experimental and clinical evidence of 5-HT's involvement in neuropsychiatric disorders and discussed the molecular mechanisms that underlie these illnesses and contribute to the new therapies.

As robotic assisted surgery (RAS) expands to smaller centres, platforms are shared between specialities. Healthcare providers must consider case volume and mix required to maintain quality and cost-effectiveness. This can be informed, in-part, by the volume-outcome relationship. We perform a systematic review to describe the volume-outcome relationship in intra-abdominal robotic assisted surgery to report on suggested minimum volumes standards. A literature search of Medline, NICE Evidence Search, Health Technology Assessment Database and Cochrane Library using the terms: “robot*”, “surgery”, “volume” and “outcome” was performed. The included procedures were gynaecological: hysterectomy, urological: partial and radical nephrectomy, cystectomy, prostatectomy, and general surgical: colectomy, oesophagectomy. Hospital and surgeon volume measures and all reported outcomes were analysed. 41 studies, including 983149 procedures, met the inclusion criteria. Study quality was assessed using the Newcastle-Ottawa Quality Assessment Scale and the retrieved data was synthesised in a narrative review. Significant volume-outcome relationships were described in relation to key outcome measures, including operative time, complications, positive margins, lymph node yield and cost. Annual surgeon and hospital volume thresholds were described. We concluded that in centres with an annual volume of fewer than 10 cases of a given procedure, having multiple surgeons performing these procedures led to worse outcomes and, therefore, opportunities should be sought to perform other complimentary robotic procedures or undertake joint cases.

Objective The Enhanced Recovery after Surgery Cardiac Society recommends using multimodal analgesia (MMA) for postoperative pain however, evidence-based guidelines have yet to be established. This study examines the impact of a standardized postoperative MMA pathway in reducing opioid consumption and related complications after cardiothoracic surgery (CTS). Methods Within a multicenter healthcare system, a postoperative MMA pathway was developed and implemented at two CTS intensive care units (ICU) while the other CTS ICU opted to maintain the existing opioid-based pathway. A retrospective chart review was conducted on patients admitted to a CTS ICU within this healthcare system after conventional coronary artery bypass grafting and/or valve surgery from September 1, 2018, to June 30, 2019. Comparative analysis was conducted on patients prescribed MMA versus those managed with an opioid-based pathway. The primary outcome was total opioid consumption, converted to morphine milligram equivalents, 72-h post-surgery. Secondary outcomes included mobility within one-day post-surgery, ICU length of stay (LOS), time to first bowel movement (BM), and time to first zero Richmond Agitation-Sedation Scale (RASS). Results Seven hundred sixty-two adults were included for final analysis. The MMA group had a higher body mass index, higher percentage of females, were more likely classified as African American and had higher scores for risk-adjusted complications. General Linear Model analysis revealed higher opioid consumption in the MMA group (Est. 0.22, p p p = 0.0011), and longer time to first zero RASS (OR 1.62, p = 0.0071). The analgesia groups were not a predictor for ICU LOS. Conclusions Opioid consumption was not reduced secondary to this postoperative MMA pathway. The MMA group was more likely to have mobility within one-day post-surgery. Patients in the MMA group were also more likely to have prolonged time to first BM and first zero RASS. Development and evaluation of a perioperative MMA pathway should be considered.

BACKGROUND: Impaired mineral ion metabolism is a hallmark of CKD-metabolic bone disorder. It can lead to pathologic vascular calcification and is associated with an increased risk of cardiovascular mortality. Loss of calcium-sensing receptor (CaSR) expression in vascular smooth muscle cells exacerbates vascular calcification in vitro. Conversely, vascular calcification can be reduced by calcimimetics, which function as allosteric activators of CaSR. METHODS: To determine the role of the CaSR in vascular calcification, we characterized mice with targeted Casr gene knockout in vascular smooth muscle cells ( SM22α CaSR Δflox/Δflox ). RESULTS: Vascular smooth muscle cells cultured from the knockout (KO) mice calcified more readily than those from control (wild-type) mice in vitro. However, mice did not show ectopic calcifications in vivo but they did display a profound mineral ion imbalance. Specifically, KO mice exhibited hypercalcemia, hypercalciuria, hyperphosphaturia, and osteopenia, with elevated circulating fibroblast growth factor 23 (FGF23), calcitriol (1,25-D 3), and parathyroid hormone levels. Renal tubular α-Klotho protein expression was increased in KO mice but vascular α-Klotho protein expression was not. Altered CaSR expression in the kidney or the parathyroid glands could not account for the observed phenotype of the KO mice. CONCLUSIONS: These results suggest that, in addition to CaSR's established role in the parathyroid-kidney-bone axis, expression of CaSR in vascular smooth muscle cells directly contributes to total body mineral ion homeostasis.

The artemisinin family of compounds is cytopathic in certain cancer cell lines that are positive for human papillomaviruses (HPV) and can potentially drive the regression of dysplastic lesions. We evaluated the efficacy of topical dihydroartemisinin (DHA) on cervical dysplasia and anal dysplasia in two papillomavirus mouse models: K14E6/E7 transgenic mice, which express HPV16 oncogenes; and immunodeficient NOD/SCID gamma (NSG) mice infected with Mus musculus papillomavirus (MmuPV1). Mice started treatment with DHA at 25 weeks of age (K14E6/E7) or 20 weeks post infection (MmuPV1-infected), when the majority of mice are known to have papillomavirus-induced low- to high-grade dysplasia. Mice were treated with or without topical DHA at the cervix or anus and with or without topical treatment with the chemical carcinogen 7,12 dimethylbenz(a)anthracene (DMBA) at the anus of in transgenic mice to induce neoplastic progression. Mice were monitored for overt tumor growth, and tissue was harvested after 20 weeks of treatment and scored for severity of histological disease. For MmuPV1-infected mice, anogenital lavages were taken to monitor for viral clearance. Tissues were also evaluated for viral gene expression at the RNA and/or protein levels. Treatment with topical DHA did not reduce dysplasia in the anogenital tract in either papillomavirus-induced mouse model and did not prevent progression to anal cancer in the DMBA-treated K14E6/E7 mice.

Recurrent respiratory papillomatosis (RRP), caused by laryngeal infection with low-risk human papillomaviruses, has devastating effects on vocal communication and quality of life. Factors in RRP onset, other than viral presence in the airway, are poorly understood. RRP research has been stalled by limited preclinical models. The only known papillomavirus able to infect laboratory mice

Laryngeal infection with low-risk human papillomaviruses can cause recurrent respiratory papillomatosis (RRP), a disease with severe effects on vocal fold epithelium resulting in impaired voice function and communication. RRP research has been stymied by limited preclinical models. We recently reported a murine model of laryngeal MmuPV1 infection and disease in immunodeficient mice. In the current study, we compare quantitative and qualitative measures of epithelial proliferation, apoptosis, differentiation, and barrier between mice with MmuPV1-induced disease of the larynx and surrounding tissues and equal numbers of uninfected controls. Findings supported our hypothesis that laryngeal MmuPV1 infection recapitulates many features of RRP. Like RRP, MmuPV1 increased proliferation in infected vocal fold epithelium, expanded the basal compartment of cells, decreased differentiated cells, and altered cell–cell junctions and basement membrane. Effects of MmuPV1 on apoptosis were equivocal, as with RRP. Barrier markers resembled human neoplastic disease in severe MmuPV1-induced disease. We conclude that MmuPV1 infection of the mouse larynx provides a useful, if imperfect, preclinical model for RRP that will facilitate further study and treatment development for this intractable and devastating disease.

Patients with limited English proficiency (LEP) face difficulties in access to postoperative follow-up care, including post-discharge medication refills. However, prior studies have not examined how utilization of prescription pain medications after discharge from joint replacement surgeries differs between English proficient (EP) and LEP patients.This study explored the relationship between English language proficiency and opioid prescription refill requests after hospital discharge for total knee arthroplasty (TKA).This was an observational cohort study of patients ≥18 years of age who underwent TKA between January 2015 and December 2019 at a single academic center. LEP status was defined as not having English as the primary language and requesting an interpreter. Primary outcome variables included opioid pain medication refill requests between 0 and 90 days from discharge. Multivariable logistic regression modeling calculated the odds ratios of requesting an opioid refill.A total of 2148 patients underwent TKA, and 9.8% had LEP. Postoperative pain levels and rates of prior opioid use did not differ between LEP and EP patients. LEP patients were less likely to request an opioid prescription refill within 30 days (35.3% vs 52.4%, p0.001), 60 days (48.7% vs 61.0%, p = 0.004), and 90 days (54.0% vs 62.9%, p = 0.041) after discharge. In multivariable analysis, LEP patients had an odds ratio of 0.61 of requesting an opioid refill (95% CI, 0.41-0.92, p = 0.019) within 30 days of discharge. Having Medicare insurance and longer lengths of hospitalization were correlated with lower odds of 0-30 days opioid refills, while prior opioid use and being discharged home were associated with higher odds of opioid refill requests 0-30 days after discharge for TKA.Language barriers may contribute to poorer access to postoperative care, including prescription medication refills. Barriers to postoperative care may exist at multiple levels for LEP patients undergoing surgical procedures.

Misophonia is characterized by excessive aversive reactions to specific “trigger” sounds. Although this disorder is increasingly recognized in the literature, its etiological mechanisms and maintaining factors are currently unclear. Several etiological models propose a role of Pavlovian conditioning, an associative learning process heavily researched in similar fear and anxiety-related disorders. In addition, generalization of learned associations has been noted as a potential causal or contributory factor. Building upon this framework, we hypothesized that Misophonia symptoms arise as a consequence of overgeneralized associative learning, in which aversive responses to a noxious event also occur in response to similar events. Alternatively, heightened discrimination between conditioned threat and safety cues may be present in participants high in Misophonia symptoms, as predicted by associative learning models of Misophonia. This preliminary report (n = 34) examines auditory generalization learning using self-reported behavioral (i.e., valence and arousal ratings) and EEG alpha power reduction. Participants listened to three sine tones differing in pitch, with one pitch (i.e., CS+) paired with an aversive loud white noise blast, prompting aversive Pavlovian generalization learning. We assessed the extent to which overgeneralization versus heightened discrimination learning is associated with self-reported Misophonia symptoms, by comparing aversive responses to the CS+ and other tones similar in pitch. Behaviorally, all participants learned the contingencies between CS+ and noxious noise, with individuals endorsing elevated Misophonia showing heightened aversive sensitivity to all stimuli, regardless of conditioning and independent of hyperacusis status. Across participants, parieto-occipital EEG alpha-band power reduction was most pronounced in response to the CS+ tone, and this difference was greater in those with self-reported Misophonia symptoms. The current preliminary findings do not support the notion that overgeneralization is a feature of self-reported emotional experience in Misophonia, but that heightened sensitivity and discrimination learning may be present at the neural level.

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with dementia and is a serious concern for the health of individuals and government health care systems worldwide. Gray matter atrophy and white matter damage are major contributors to cognitive deficits in AD patients, as demonstrated by magnetic resonance imaging (MRI). Many of these brain changes associated with AD begin to occur about 15 years before the onset of initial clinical symptoms. Therefore, it is critical to find biomarkers reflective of these brain changes associated with AD to identify this disease and monitor its prognosis and development. The increased plasma level of hyperphosphorylated tau 181 (p-tau181) has been recently considered a novel biomarker for the diagnosis of AD, preclinical AD, and mild cognitive impairment (MCI). In the current study, we examined the association of cerebrospinal fluid (CSF) and plasma levels of p-tau181 with structural brain changes in cortical thickness, cortical volume, surface area, and subcortical volume in MCI patients. In this cross-sectional study, we included the information of 461 MCI patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. The results of voxel-wise partial correlation analyses showed a significant negative correlation between the increased levels of plasma p-tau181, CSF total tau, and CSF p-tau181 with structural changes in widespread brain regions. These results provide evidence for the use of plasma p-tau181 as a diagnostic marker for structural changes in the brain associated with the early stages of AD and neurodegeneration.

BACKGROUND: Phosphorus levels in the range seen clinically among patients undergoing dialysis have been reported to attenuate calcium receptor activation and modify parathyroid hormone (PTH) release from isolated parathyroid glands in vitro. Some clinicians and providers of dialysis thus have suggested that calcimimetic agents are ineffective and should not be used to manage secondary hyperparathyroidism among those undergoing dialysis when serum phosphorus concentrations exceed certain threshold levels.METHODS: To determine whether hyperphosphatemia diminishes the therapeutic response to calcimimetic agents, we used data from large clinical trials to analyze the effects of etelcalcetide and cinacalcet to lower plasma PTH levels in individuals on hemodialysis who had secondary hyperparathyroidism and varying degrees of hyperphosphatemia.RESULTS: Plasma PTH levels declined progressively during 26 weeks of treatment with either etelcalcetide or cinacalcet without regard to the degree of hyperphosphatemia at baseline. However, with each calcimimetic agent, the decreases in PTH from baseline were less at each interval of follow-up during the trials among participants with serum phosphorus levels above one of three prespecified threshold values compared with those with serum phosphorus levels below these thresholds.CONCLUSIONS: These in vivo findings are the first in humans to support the idea that hyperphosphatemia attenuates calcium receptor activation by calcium ions and by calcimimetic agents. The effect of hyperphosphatemia on the responsiveness to calcimimetic agents appears relatively modest, however, and unlikely to be significant therapeutically. The efficacy of treatment with calcimimetic agents for lowering plasma PTH levels among those with secondary hyperparathyroidism remains robust despite substantial elevations in serum phosphorus.

Contains fulltext : 248755.pdf (Publisher’s version ) (Closed access) Since its beginnings in the early 20th century, the psychophysiological study of human brain function has included research into the spectral properties of electrical and magnetic brain signals. Now, dramatic advances in digital signal processing, biophysics, and computer science have enabled increasingly sophisticated methodology for neural time series analysis. Innovations in hardware and recording techniques have further expanded the range of tools available to researchers interested in measuring, quantifying, modeling, and altering the spectral properties of neural time series. These tools are increasingly used in the field, by a growing number of researchers who vary in their training, background, and research interests. Implementation and reporting standards also vary greatly in the published literature, causing challenges for authors, readers, reviewers, and editors alike. The present report addresses this issue by providing recommendations for the use of these methods, with a focus on foundational aspects of frequency domain and time-frequency analyses. It also provides publication guidelines, which aim to (1) foster replication and scientific rigor, (2) assist new researchers who wish to enter the field of brain oscillations, and (3) facilitate communication among authors, reviewers, and editors. 37 p.

Introduction Morbidity and mortality benefits have been associated with prompt surgical treatment of geriatric hip fractures. The purpose of this study was to evaluate the impact of early (≤24 hr) vs delayed (>24 hr) time to operating room (TTOR) on 1) hospital length of stay and 2) total and post-operative opiate use in geriatric hip fractures. Materials and Methods This study was a retrospective review of patients ≥65 years-old at the time of admission for surgery for hip fracture at a Level II academic trauma center. Outcome measures were length of stay (LOS), oral morphine equivalents (OME) throughout hospitalization. Patients were stratified into early and delayed TTOR groups and comparisons were made between groups. Results Between the early (n = 75, 80.6%) and late (n = 18, 19.4%) groups, there were no differences in age, fracture pattern, type of treatment, preoperative opiate use, and perioperative non-oral pain management. The early group trended toward shorter total LOS (108.0 ± 67.2 hours vs 144.8 ± 103.7 hours, P = .066), but not post-operative LOS. Total OME usage was less in the early intervention group (92.5 ± 188.0 vs 230.2 ± 296.7, P = .015), in addition to reduced post-operative OME (81.3 ± 174.9 vs 213.3 ± 271.3, P = .012). There were no differences in evaluated potential delay sources such as primary language, use of surrogate decision makers, or need for advanced imaging. Discussion Surgical treatment of geriatric hip/femur fractures in ≤24 hours from presentation is achievable and may be associated with reduced total inpatient opiate use, although daily use did not differ. Conclusion Establishing institutional TTOR goals as part of an interdisciplinary hip fracture co-management clinical pathway can facilitate prompt care and contribute to recovery and less opiate use in these patients with highly morbid injuries.

Development of severe hyponatremia after carotid endarterectomy procedure is rare. Several pathophysiological mechanisms related to the carotid endarterectomy procedure may infer an increased risk of developing this complication in specific populations., Clinicians must maintain vigilance for hyponatremia as the cause of the postoperative neurological decline after carotid endarterectomy procedures as neurological symptoms of severe hyponatremia mimic other potential complications of the procedure.

Previous work suggests that threat-related stimuli are stored to a greater degree in working memory compared to neutral stimuli. However, most of this research has focused on stimuli with physically salient threat attributes (e.g., angry faces), failing to account for how a “neutral” stimulus that has acquired threat-related associations through differential aversive conditioning influences working memory. The current study examined how differentially conditioned safe (i.e., CS–) and threat (i.e., CS+) stimuli are stored in working memory relative to a novel, non-associated (i.e., N) stimuli. Participants (n= 69) completed a differential fear conditioning task followed by a change detection task consisting of three conditions (CS+, CS–, N) across two loads (small, large). Results revealed individuals successfully learned to distinguishing CS+ from CS– conditions during the differential aversive conditioning task. Our working memory outcomes indicated successful load manipulation effects, but no statistically significant differences in accuracy, response time (RT), or Pashler’s K measures of working memory capacity between CS+, CS–, or N conditions. However, we observed significantly reduced RT difference scores for the CS+ compared to CS– condition, indicating greater RT differences between the CS+ and N condition vs. the CS– and N condition. These findings suggest that differentially conditioned stimuli have little impact on behavioral outcomes of working memory compared to novel stimuli that had not been associated with previous safe of aversive outcomes, at least in healthy populations.

Background: Dementia care programs have become more common due to a growing number of persons living with dementia and lack of substantial benefit from pharmacologic therapies. Cultural and language differences may present barriers to access and efficacy of these programs. In this article, we aimed to systematically review the current literature regarding outcomes of dementia care programs that included multicultural and non-English speaking populations. Methods: A systematic review was conducted using four scientific search engines. All studies included in the review are English language, randomized control trials evaluating various care coordination models. The initial search strategy focusing on studies specifically targeting multicultural and non-English speaking populations resulted in too few articles. We expanded our search to articles that included these populations although these populations may not have been the focus of the study. Results: Seven articles met inclusion criteria for final review. Measured outcomes included emergency room use, hospitalizations, provider visits, quality of life indicators, depression scores, and caregiver burden. Conclusions: Dementia care programs demonstrate significant ability to provide support and improve outcomes for those living with dementia and their caregivers. There is limited research in this field and thus opportunity for further study in underserved and safety net populations including more high-quality randomized controlled trials with larger sample sizes.

Bees are critical for food crop pollination, yet their populations are declining as agricultural practices intensify. Pollinator-attractive field border plantings (e.g. hedgerows and forb strips) can increase bee diversity and abundance in agricultural areas; however, recent studies suggest these plants may contain pesticides. Pesticide exposure for wild bees remains largely unknown; however, this information is needed to inform agricultural practices and pesticide regulations meant to protect bees. It is important to determine whether border plantings that attract and support pollinators may also deliver pesticides to them. In this study, we collected various samples for pesticide residue analysis, including: multiple species of wild bees, honey bees, flowers from four types of bee-attractive field border plants, and soil. Silicone bands were also utilized as passive aerial samplers of pesticide residues. The five pesticides detected most frequently across all samples were the insecticide bifenthrin, the herbicides thiobencarb, metolaclor, and propanil, and the fungicide fluopyram. We detected the greatest number of parent pesticides in bands (24), followed by soil (21). Pesticides were also detected in field border plant flowers (16), which do not receive direct pesticide applications, and included many products which were not applied to adjacent field crops. Pesticide concentrations were lower in bees than in flowers but higher in bees than in soils. Pesticide residue per bee (ng/bee) increased with increasing wild bee size, though pesticide concentration (ng/g) did not increase. While honey bees and wild bees contained a similar number and concentration of pesticides overall, pesticide mixtures varied by bee type, and included some mixtures known to cause sublethal effects. The results from this study highlight the benefits of measuring more sample types to capture the total exposome of bees, including a greater range of bee species, as well as the need to consider exposure to pesticides at the landscape level.

Background The Royal College of Surgeons of England guidelines recommends laparoscopic repair for bilateral inguinal hernias, recurrent hernia after an initial open approach and Groin hernias in women. Aim This study assessed the surgical management of inguinal hernia over 6 years to see how well we adhered to national guidelines and investigated reasons for non-adherence. Methods A retrospective study from January 2013 to December 2018 of all patients undergoing inguinal hernia repair. Data collected were patient identifiers, gender, date of birth, date of admission and discharge, type of inguinal hernia, type of repair and the operating consultant. If the type of repair performed was outside of national guidance, patients’ case-notes were reviewed. Results 2593 patients were included, 93.4% male and median age of 63 (interquartile range 49-74 years). 403 patients underwent laparoscopic repair (15.5%). For unilateral primary inguinal herniae, 221 out of 2222 patients underwent laparoscopic repair (9.9%). 29 of 170 (17%) of female patients underwent laparoscopic repair. 118 out of 160 patients with bilateral hernia underwent laparoscopic repair (73.8%) - no explanation was identified for selecting open repair in 25 out of 42. Regarding recurrent hernia, 64 out of 211 patients underwent laparoscopic repair (30.3%). No explanation for selection of open approach was identified for 61 of the 147. Conclusion National guidelines recommending laparoscopic inguinal hernia repair for females, bilateral and recurrent herniae are not well followed. A likely contributing factor is the overall low rate of laparoscopic repair. Changes to practice are underway and repeat audit is planned.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

The calcium-sensing receptor (CaS, provisional nomenclature as recommended by NC-IUPHAR [47] and subsequently updated [77]) responds to multiple endogenous ligands, including extracellular calcium and other divalent/trivalent cations, polyamines and polycationic peptides, L-amino acids (particularly L-Trp and L-Phe), glutathione and various peptide analogues, ionic strength and extracellular pH (reviewed in [78]). While divalent/trivalent cations, polyamines and polycations are CaS receptor agonists [14, 110], L-amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [36, 47, 61, 108, 109]. Indeed, L-amino acids have been identified as "co-agonists", with both concomitant calcium and L-amino acid binding required for full receptor activation [148, 54]. The sensitivity of the CaS receptor to primary agonists is increased by elevated extracellular pH [18] or decreased extracellular ionic strength [109]. This receptor bears no sequence or structural relation to the plant calcium receptor, also called CaS.

Background: National data demonstrate a trend toward outpatient same-day mastectomy. The possible drivers of this change include the costs related to hospital admission and effective management of postoperative pain. We retrospectively analyzed our single-institution experience with outpatient same-day mastectomy that incorporates a multimodal pain management regimen. Methods: We retrospectively reviewed the medical records of patients who underwent same-day mastectomy at a single academic hospital. All patients received a multimodal, perioperative pain management regimen consisting of the intraoperative administration of 1,000 mg of intravenous (IV) acetaminophen and 30 mg of IV ketorolac, combined with the operating surgeon performing a 4- to 5-level, midaxillary, intercostal nerve block using liposomal bupivacaine. All patients were discharged with a prescription for acetaminophen with codeine, along with options for nonnarcotic alternatives as needed for pain. Results: We reviewed the data on 72 patients who underwent mastectomies: 11 (15.3%) bilateral and 61 (84.7%) unilateral. The average age was 57 years, and average body mass index was 30 kg/m2. The average length of stay of 4 to 6 hours was a marked reduction compared to a 23-hour observational period or an inpatient hospital stay. The average follow-up was 20.1 weeks. Five patients presented to the emergency department (ED) within the 30-day postoperative period, with 2 patients (2.8%) requiring readmission to the hospital for non–pain-related issues. The other 3 patients (4.2%) were evaluated for specific pain-related issues but did not require admission and were discharged home from the ED. Conclusion: Our data support outpatient same-day mastectomy incorporating a multimodal, perioperative pain management regimen as a safe and feasible treatment option. Potential additional benefits may include decreased oral opioid use and cost savings for the hospital.

Purpose To describe presenting clinical features and surgical techniques that are associated with successful surgical repair of pediatric rhegmatogenous retinal detachment (RRD). Design Retrospective interventional case series. Participants Two hundred twelve eyes of 191 patients 0 to 18 years of age undergoing surgical repair for RRD between 2001 and 2015 with a minimum follow-up of 3 months. Methods Patients were divided into 3 age groups (0–6 years, 7–12 years, and 13–18 years) and comparisons were made using bivariate and multivariate generalized estimating equation models. A mixed means model was used to examine visual acuity in each age group over time. Main Outcome Measures Complete reattachment of the retina at final follow-up. Results Of 212 eyes, 166 (78%) achieved total reattachment at final follow-up. Mean follow-up was 36.3 months. Rhegmatogenous retinal detachment associated with Stickler syndrome was more likely to occur in the younger cohorts (odds ratio [OR], 0.45; 95% confidence interval [CI], 0.22–0.91), whereas RRD associated with blunt trauma was more likely to occur in the oldest cohort (OR, 2.3; 95% CI, 1.2–4.4). Subtotal RRD was more likely to be repaired successfully than total RRD (OR, 3.6; 95% CI, 1.5–8.4; P = 0.0100), and eyes with previous vitreoretinal surgery were less likely to undergo successful repair (OR, 0.30; 95% CI, 0.12–0.78; P = 0.0258). There was no significant difference between age groups in the rate of surgical success (P = 0.55). There was a significantly higher success rate with primary scleral buckle (SB; 63%; OR, 2.2; 95% CI, 1.1–4.5) and combined SB plus pars plana vitrectomy (PPV; 68%; OR, 2.3; 95% CI, 1.1–5.1) compared with PPV alone (51%). Conclusions Most pediatric patients with RRD achieved complete reattachment with surgery. Success was more common in patients with a subtotal RRD at presentation. Previous vitreoretinal surgery was a risk factor for failure. Younger patients were more likely to demonstrate RRD involving the macula, but there was no difference between age groups in successful reattachment at final follow-up. Primary PPV showed a lower rate of success than SB or combined SB plus PPV.

Gliomas are the most dreaded primary brain tumour because of their dismal cure rates. Ketogenic-type diets (kds) are high-fat, low-protein, and low-carbohydrate diets, the modified Atkins diet (mad) is a less-stringent version of a kd that still generates serum ketones in patients. The purpose of the present study was to retrospectively examine the feasibility of attaining ketosis and the safety of the mad in patients undergoing radiation and chemotherapy treatment for glioma. The rate of pseudoprogression (psp) after treatment was also assessed as a marker of radiation sensitization. To our knowledge, this dataset is the largest published relating to patients with glioma undergoing kd during radiation and chemotherapy. We retrospectively studied 29 patients with grades ii&ndash, iv astrocytoma following the mad during standard radiation and chemotherapy. Feasibility of attaining ketosis was assessed though levels of beta hydroxybutyrate in blood. Pre- and post-radiation magnetic resonance images were evaluated for psp by a neuroradiologist blinded to patient data. In the 29 patients who started the mad during radiation, ketosis was achieved in all 29 (100%). No serious adverse events occurred secondary to the mad. Of those 29 patients, 19 had glioblastoma multiforme. Of the latter 19 patients, 11 (58%) showed psp after mad and radiation and temozolomide therapy. A modified Atkins diet is feasible and safe for glioma patients during radiation and chemotherapy treatment. The mad and resulting ketosis could play a role as a radiation sensitizer.

The calcium-sensing receptor (CaS) is the principal controller of extracellular calcium (Ca2+o) homeostasis and is inhibited in vitro and in vivo by protein kinase C (PKC)-mediated phosphorylation at CaRT888. However, PKC inhibition enhances signalling even in CaSs lacking Thr-888, suggesting that an additional inhibitory site exists. An apparently equivalent PKC regulatory site in metabotropic glutamate receptor-5 (Ser-839) aligns not with CaST888 but instead with CaSS875, not previously considered a PKC site. CaSS875A (non-phosphorylatable) exhibited significantly enhanced Ca2+o sensitivity of both intracellular Ca2+ mobilisation and extracellular signal-regulated kinase 1/2 (ERK1/2) activation, whereas the phosphomimetic CaSS875D mutant exhibited a loss of function. The CaSS875A/T888A double mutant exhibited even greater Ca2+o sensitivity than CaST888 alone, a response no longer enhanced by PKC inhibition. Finally, when expressed in CaS lacking its extracellular domain, the CaSS875A/T888A double mutation elicited maximal activation even under control conditions, but remained sensitive to negative allosteric modulation (NPS-2143) or Ca2+o removal. Therefore, we have now identified CaSS875 as the missing PKC phosphorylation site that, together with CaST888, shapes the CaS signalling that underpins Ca2+o homeostasis. Together with the inactive form of the CaS9s extracellular domain, these sites attenuate Ca2+o sensitivity to attain appropriate physiological Ca2+o sensing. SIGNIFICANCE STATEMENT The calcium-sensing receptor (CaS) controls whole body calcium homeostasis by regulating parathyroid hormone secretion and renal calcium reabsorption. CaS function can be inhibited upon phosphorylation by protein kinase C (PKC), principally but not exclusively at Thr-888. Here we provide evidence that Ser-875, a previously unrecognised PKC site in CaS, is an additional inhibitory phosphorylation site for the receptor.

During the second wave of the COVID-19 pandemic in South Africa, a recurrent pattern of prolonged recovery after acute COVID-19 pneumonia, characterised by low oxygen saturation levels forgt;2 weeks, was observed in an intermediate-care facility in Cape Town. A case study together with a series of 12 patients is presented to illustrate this phenomenon, and two types of 'sats gap' are described, which were used by physiotherapists and doctors to monitor daily progress. We attempt to explain this prolonged recovery in terms of the possible pathophysiology, and suggest a number of learning points to guide further research.

Objective The neuroendocrine response to critical illness is dichotomous as it is adaptive during the acute phase then transitions to maladaptive as critical illness becomes prolonged in 25-30% of patients. Presently, monitoring all critically ill patients for endocrinopathies is not the standard of care. However, given the negative impact on patient prognosis, a need to identify those at risk for endocrinopathies, may exist. Thus, a screening tool to identify endocrinopathies along the somatotroph and gonadal axes in a cardiothoracic surgery population was developed. Methods A prospective observational pilot study was conducted in two cardiothoracic surgery intensive care units (ICU) within a multi-site healthcare system. Total testosterone and somatomedin C levels were obtained from 20 adult patients who remained in the ICU for greater than seven days after cardiothoracic surgery and were tolerating nutrition, had a risk of malnutrition and a mobility score of moderate to dependent assistance. Results Twenty patients were included for descriptive analysis (seven females). Thirteen patients tested low for total testosterone, with males more likely to have a testosterone-related endocrinopathy as compared to females (100% vs. 0 to 43%, p = 0.0072). A higher proportion of low somatomedin C levels was found in females than males (57% vs. 31%); however, the difference was not statistically significant (p = 0.251). Conclusions The screening tool used in this pilot study accurately predicted low total testosterone in all men and reasonably predicted low somatomedin C in a majority of women. However, the ability of the tool to predict low total testosterone in women and low somatomedin C in men is less certain. A gender-specific screening tool might be necessary to predict hormonal deficiencies.

There is a pressing need for novel immunotherapeutic targets in colorectal cancer (CRC). Cytotoxic T cell infiltration is well established as a key prognostic indicator in CRC, and it is known that these tumor infiltrating lymphocytes (TILs) target and kill tumor cells. However, the specific antigens that drive these CD8+ T cell responses have not been well characterized. Recently, phosphopeptides have emerged as strong candidates for tumor-specific antigens, as dysregulated signaling in cancer leads to increased and aberrant protein phosphorylation. Here, we identify 120 HLA-I phosphopeptides from primary CRC tumors, CRC liver metastases and CRC cell lines using mass spectrometry and assess the tumor-resident immunity against these posttranslationally modified tumor antigens. Several CRC tumor-specific phosphopeptides were presented by multiple patients’ tumors in our cohort (21% to 40%), and many have previously been identified on other malignancies (58% of HLA-A*02 CRC phosphopeptides). These shared antigens derived from mitogenic signaling pathways, including p53, Wnt and MAPK, and are therefore markers of malignancy. The identification of public tumor antigens will allow for the development of broadly applicable targeted therapeutics. Through analysis of TIL cytokine responses to these phosphopeptides, we have established that they are already playing a key role in tumor-resident immunity. Multifunctional CD8+ TILs from primary and metastatic tumors recognized the HLA-I phosphopeptides presented by their originating tumor. Furthermore, TILs taken from other CRC patients’ tumors targeted two of these phosphopeptides. In another cohort of CRC patients, the same HLA-I phosphopeptides induced higher peripheral T cell responses than they did in healthy donors, suggesting that these immune responses are specifically activated in CRC patients. Collectively, these results establish HLA-I phosphopeptides as targets of the tumor-resident immunity in CRC, and highlight their potential as candidates for future immunotherapeutic strategies.

The importance of nitric oxide (NO) in regulating cerebral blood flow (CBF) remains unresolved, due in part to methodological approaches, which lack a comprehensive assessment of both global and regional effects. Importantly, NO synthase (NOS) expression and activity appear greater in some anterior brain regions, suggesting region-specific NOS influence on CBF. We hypothesized that NO contributes to basal CBF in healthy adults, in a regionally distinct pattern that predominates in the anterior circulation. Fourteen healthy adults (7 females; 24 ± 5 years) underwent two magnetic resonance imaging (MRI) study visits with saline (placebo) or the NOS inhibitor, L-NMMA, administered in a randomized, single-blind approach. 4D flow MRI quantified total and regional macrovascular CBF, whereas arterial spin labelling (ASL) MRI quantified total and regional microvascular perfusion. L-NMMA (or volume-matched saline) was infused intravenously for 5 min prior to imaging. L-NMMA reduced CBF (L-NMMA: 722 ± 100 vs. placebo: 771 ± 121 ml/min, P = 0.01) with similar relative reductions (5-7%) in anterior and posterior cerebral circulations, due in part to the reduced cross-sectional area of 9 of 11 large cerebral arteries. Global microvascular perfusion (ASL) was reduced by L-NMMA (L-NMMA: 42 ± 7 vs. placebo: 47 ± 8 ml/100g/min, P = 0.02), with 7-11% reductions in both hemispheres of the frontal, parietal and temporal lobes, and in the left occipital lobe. We conclude that NO contributes to macrovascular and microvascular regulation including larger artery resting diameter. Contrary to our hypothesis, the influence of NO on cerebral perfusion appears regionally uniform in healthy young adults. KEY POINTS: Cerebral blood flow (CBF) is vital for brain health, but the signals that are key to regulating CBF remain unclear. Nitric oxide (NO) is produced in the brain, but its importance in regulating CBF remains controversial since prior studies have not studied all regions of the brain simultaneously. Using modern MRI approaches, a drug that inhibits the enzymes that make NO (L-NMMA) reduced CBF by up to 11% in different brain regions. NO helps maintain proper CBF in healthy adults. These data will help us understand whether the reductions in CBF that occur during ageing or cardiovascular disease are related to shifts in NO signalling.