Microembolic signal monitoring in patients with HeartMate 3 and HeartWare left ventricular assist devices: Association with antithrombotic treatment and cerebrovascular events.

BACKGROUND: In patients with left ventricular assist devices (LVADs), ischemic and hemorrhagic stroke are dreaded complications. Predictive markers for these events are lacking. This study aimed to investigate the prevalence and predictive value of microembolic signals (MES) for stroke, detected by Transcranial Doppler sonography (TCD) in patients with HeartMate 3 (HM 3) or HeartWare (HW). METHODS: A thirty-minute bilateral TCD monitoring of the middle cerebral artery (MCA) was performed in 62 outpatients with LVAD (HM 3 N = 31, HW N = 31) and 31 healthy controls. Prevalence and quantity of MES were investigated regarding clinical and laboratory parameters. Cerebrovascular events (CVE) were recorded on follow-up at 90 and 180 days. RESULTS: MES were detected in six patients with HM 3, three patients with HW, and three controls. Within the LVAD groups, patients on monotherapy with vitamin-K-antagonist (VKA) without antiplatelet therapy were at risk for a higher count of MES (negative binomial regression: VKA: 1; VKA + ASA: Exp(B) = 0.005, 95%CI 0.001-0.044; VKA + clopidogrel: Exp(B) = 0.012, 95%CI 0.002-0.056). There was no association between the presence of MES and CVE or death on follow-up (p > 0.05). CONCLUSION: For the first time, the prevalence of MES was prospectively investigated in a notable outpatient cohort of patients with HM 3 and HW. Despite optimized properties of the latest LVAD, MES remain detectable depending on antithrombotic therapy. No association between MES and CVE could be detected.

Four Routes to 3-(3-Methoxy-1,3-dioxopropyl)pyrrole, a Core Motif of Rings C and E in Photosynthetic Tetrapyrroles.

The photosynthetic tetrapyrroles share a common structural feature comprised of a ß-ketoester motif embedded in an exocyclic ring (ring E). As part of a total synthesis program aimed at preparing native structures and analogues, 3-(3-methoxy-1,3-dioxopropyl)pyrrole was sought. The pyrrole is a precursor to analogues of ring C and the external framework of ring E. Four routes were developed. Routes 1-3 entail a Pd-mediated coupling process of a 3-iodopyrrole with potassium methyl malonate, whereas route 4 relies on electrophilic substitution of TIPS-pyrrole with methyl malonyl chloride. Together, the four routes afford considerable latitude. A long-term objective is to gain the capacity to create chlorophylls and bacteriochlorophylls and analogues thereof by facile de novo means for diverse studies across the photosynthetic sciences.

Real-World Data on Liposomal Bupivacaine and Inpatient Hospital Costs After Colorectal Surgery.

INTRODUCTION: This study compared costs of care among colorectal surgery patients who received liposomal bupivacaine versus those who did not (control) from a health institution perspective. MATERIAL AND METHODS: This pharmacoeconomic evaluation was conducted among adults undergoing open or minimally invasive colorectal resection at an academic medical center from May 2016 to February 2018. Healthcare resource utilization was derived from the electronic health record. Total cost of care (2018 USD) was analyzed using a generalized linear model adjusted for American Society of Anesthesiologists score, enhanced recovery after surgery management, open surgery, opioid use before surgery, height, cancer, and age. The primary analysis used public costs. A sensitivity analysis used internal costs from the hospital to maximize internal validity. RESULTS: Of 486 included patients, 286 (59%) received liposomal bupivacaine. Total cost of care using public costs included perioperative local anesthetics (mean ± standard deviation [SD]: $392 ± 74 liposomal bupivacaine versus $8 ± 13 control), analgesics within 48 h after surgery (mean ± SD: $132 ± 99 liposomal bupivacaine versus $117 ± 127 control), postoperative ileus management (mean ± SD: $5 ± 51 liposomal bupivacaine versus $65 ± 284 control), and hospital length of stay (mean ± SD: $4459 ± 3576 liposomal bupivacaine versus $7769 ± 7082 control). Liposomal bupivacaine was associated with an adjusted absolute difference in total cost of care of -$1435 (95% confidence interval -$2401 to -$470; P = 0.004) using public costs and -$1345 (95% confidence interval -$2215 to -$476; P = 0.002) using internal costs. CONCLUSIONS: Use of liposomal bupivacaine in colorectal surgery was associated with a significant reduction in total cost of care that was predominately driven by reduced costs for hospital stay and postoperative ileus management despite higher medication costs.

Avoidable emergency department visits for rabies vaccination.

BACKGROUND: Administering subsequent doses of rabies vaccine is not a medical emergency and does not require access to emergency department (ED) services. This study reviewed ED visits for rabies postexposure prophylaxis (PEP) to identify avoidable ED visits for subsequent rabies vaccination. METHODS: This retrospective study included patients who received human rabies immune globulin (HRIG) or rabies vaccine at 15 EDs of a multi-hospital health system from 2016 to 2018. All ED visits were classified as initial or non-initial healthcare visits after animal exposure. Emergency department visits for non-initial healthcare were classified as necessary (HRIG administration, worsening symptoms, other emergent conditions, or vaccination during a natural disaster) or avoidable (rabies vaccination only). RESULTS: This study included 145 patients with 203 ED visits (113 initial and 90 non-initial healthcare visits). Avoidable ED visits were identified for 19% (28 of 145) of patients and 66% (59 of 90) of ED visits for non-initial healthcare. Contributing factors for avoidable ED visits were suboptimal ED discharge instructions to return to the ED for vaccination (n = 20 visits) and patients' inability to coordinate outpatient follow-up (n = 17 visits). Patients with previous avoidable ED visits had a 73% probability for unnecessarily returning to the ED for vaccination. The average number of avoidable ED visits observed per patient was 0.41 (95% CI = 0.25 to 0.56). Since the Centers for Disease Control and Prevention reports that 30,000 to 60,000 Americans initiates rabies PEP each year, we estimate that 7500 to 33,600 avoidable ED visits occur for rabies vaccination in the US each year. CONCLUSIONS: One of 5 patients who received rabies PEP in the ED had avoidable ED visits for subsequent rabies vaccination. This study highlights systemic lack of coordination following ED discharge and barriers to accessing rabies vaccine.

Wound characteristics and infiltration with immune globulin for rabies postexposure prophylaxis in the emergency department.

OBJECTIVE: This study described characteristics of wounds caused by animal exposures and evaluated patient factors and wound factors associated with wound infiltration of human rabies immune globulin (HRIG). MATERIALS AND METHODS: This retrospective cohort study evaluated wound characteristics among patients who had visible wounds and received HRIG or rabies vaccine for rabies postexposure prophylaxis (PEP) at 15 emergency departments from May 2016 to June 2018. RESULTS: Of 110 included patients (9 children, 82 adults, and 19 older adults), 21% (n = 23) had ≥2 wounds, and 10% (n = 11) had infected wounds. Twenty-eight (25%) patients had severe wounds, defined as receiving sutures (n = 20) or reaching subcutaneous tissue or bone (n = 20). Wounds were present on upper extremities for 42% (n = 46) of patients, lower extremities for 35% (n = 38), head/face for 3% (n = 3), and in multiple locations for 21% (n = 23). Wounds were < 3 cm in length for 64% (n = 70) of patients. Puncture wounds were present in 60% (n = 66) of patients, abrasions in 45% (n = 49), and lacerations in 38% (n = 42). Among 108 wounds from 82 patients with documented HRIG administration sites, 57% (n = 62) of wounds received HRIG infiltration. Infiltration occurred less frequently for wounds on the face/head/torso (adjusted odds ratio [aOR] = 0.07, 95% confidence interval [CI] = 0.01 to 0.49), wounds on hands/fingers (aOR = 0.20, 95% CI = 0.06 to 0.65), and abrasion-only wounds (aOR = 0.26, 95% CI = 0.08 to 0.80) after adjusting for age. CONCLUSIONS: Upon presentation for rabies PEP, most patients did not have severe wounds and did not require emergency services or complex wound management. Wounds on the face, head, torso, hands, or fingers and abrasions were less likely to receive HRIG infiltration.

Alteplase for the treatment of midline catheter occlusions: a retrospective, single-cohort descriptive study.

BACKGROUND: Despite the increasing popularity of midline catheters, data on the use of alteplase for restoring midline catheter patency is scarce. AIMS: This study aimed to evaluate off-label use of alteplase for midline catheter occlusions. METHOD: Adults who received alteplase into a midline catheter between January 2015 and May 2018 within a multi-hospital health system were included in this study. The primary outcome was restoration of infusion or withdrawal function from at least one lumen of a treated midline catheter. FINDINGS: Following alteplase administration, withdrawal function was restored in 47% (25/53) of occlusion events, infusion function was restored in 65% (11/17) of complete occlusion events, and infusion or withdrawal function was restored in 58% (31/53) of occlusion events. Only 34% (17/50) of catheters were replaced because of malfunction. Local bleeding was documented in 9% (n=5) of occlusion events after alteplase administration. CONCLUSION: Most midline catheter occlusions treated with alteplase demonstrated restoration of infusion or withdrawal function.

Humoral and Cellular Immune Responses Against Severe Acute Respiratory Syndrome Coronavirus 2 Variants and Human Coronaviruses After Single BNT162b2 Vaccination.

BACKGROUND: Vaccine-induced neutralizing antibodies are key in combating the coronavirus disease 2019 (COVID-19) pandemic. However, delays of boost immunization due to limited availability of vaccines may leave individuals vulnerable to infection and prolonged or severe disease courses. The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC)-B.1.1.7 (United Kingdom), B.1.351 (South Africa), and P.1 (Brazil)-may exacerbate this issue, as the latter two are able to evade control by antibodies. METHODS: We assessed humoral and T-cell responses against SARS-CoV-2 wild-type (WT), VOC, and endemic human coronaviruses (hCoVs) that were induced after single and double vaccination with BNT162b2. RESULTS: Despite readily detectable immunoglobulin G (IgG) against the receptor-binding domain of the SARS-CoV-2 S protein at day 14 after a single vaccination, inhibition of SARS-CoV-2 S-driven host cell entry was weak and particularly low for the B.1.351 variant. Frequencies of SARS-CoV-2 WT and VOC-specific T cells were low in many vaccinees after application of a single dose and influenced by immunity against endemic hCoV. The second vaccination significantly boosted T-cell frequencies reactive for WT and B.1.1.7 and B.1.351 variants. CONCLUSIONS: These results call into question whether neutralizing antibodies significantly contribute to protection against COVID-19 upon single vaccination and suggest that cellular immunity is central for the early defenses against COVID-19.

Quantitative Sensory Testing in Patients with Multisomatoform Disorder with Chronic Pain as the Leading Bodily Symptom-a Matched Case-Control Study.

OBJECTIVE: Chronic pain is a debilitating condition of multifactorial origin, often without physical findings to explain the presenting symptoms. Of the possible etiologies of persisting painful symptoms, somatoform disorders and functional somatic syndromes (FSS) are among the most challenging, with a prevalence of 8-20%. Many different somatoform disorders and FSS have overlapping symptoms, with pain being the most prevalent one. The concept of multisomatoform disorder (MSD) has been developed to acknowledge that fact. We hypothesized that the concept of MSD will be reflected in a distinct sensory profile of patients compared with healthy controls and possibly provide insight into the type and pathophysiology of the pain commonly experienced by patients. DESIGN: We performed comprehensive quantitative sensory testing (QST) in 151 patients and 149 matched controls. RESULTS: There were significant differences in the sensory profiles of patients compared with controls. Patients with MSD showed a combination of tactile and thermal hypesthesia combined with mechanical and cold hyperalgesia. This was true for measurements at test and control sites, with the exception of vibration detection threshold and mechanical pain threshold. Among the observed changes, a marked sensory loss of function, as evidenced by an increase in cold detection threshold, and a marked gain of function, as evidenced by a decrease of pressure pain threshold, were most notable. There was no evidence of concurrent medication influencing QST results. CONCLUSIONS: The observed somatosensory profile of patients with MSD resembles that of patients suffering from neuropathic pain with evidence of central sensitization.

Autophagy inhibitor 3-methyladenine potentiates apoptosis induced by dietary tocotrienols in breast cancer cells.

INTRODUCTION: Tocomin® represents commercially available mixture of naturally occurring tocotrienols (T3s) and tocopherols extracted from palm oil/palm fruits that possess powerful antioxidant, anticancer, neuro/cardioprotective and cholesterol-lowering properties. Cellular autophagy represents a defense mechanism against oxidative stress and several anticancer compounds. Recently, we reported that T3s induce apoptosis and endoplasmic reticulum stress in breast cancer cells. METHODOLOGY: We studied the effects of Tocomin® on MCF-7 and MDA-MB 231 breast cancer cells and non-tumor MCF-10A cells. RESULTS: Tocomin® inhibited cell proliferation and induced apoptosis in both MCF-7 and MDA-MB 231 breast cancer cell lines without affecting the viability of MCF-10A cells. We also showed that Tocomin® negatively modulates phosphoinositide 3-kinase and mTOR pathways and induces cytoprotective autophagic response in triple negative MDA-MB 231 cells. Lastly, we demonstrate that autophagy inhibitor 3-methyladenine (3-MA) potentiated the apoptosis induced by Tocomin® in MDA-MB 231 cells. CONCLUSION: Together, our data indicate anticancer effects of Tocomin® in breast cancer cells, which is potentiated by the autophagy inhibitor 3-MA.

Two new earthworm species of the genus Amynthas Kinberg, 1867 (Annelida, Oligochaeta, Megascolecidae) from the Southeast region, Vietnam.

Two new earthworm species, namely Amynthas rarus sp. nov. and Amynthas tayninhensis sp. nov., are described from Tay Ninh Province, southeastern Vietnam. Amynthas rarus sp. nov. is recognized by having male pores in xix, two pairs of spermathecal pores in 6/7/8, and genital markings paired in vii, viii, 18/19, and 19/20. Amynthas tayninhensis sp. nov. is distinguished by having a pair of spermathecal pores in 5/6, numerous genital markings in transverse lines in 17/18 including three surrounding male pores, and spermatheca with fully developed diverticula. The COI fragments are also provided for those two new species.

Association of TNF-α polymorphism rs1800629 with multisomatoform disorder in a group of German patients and healthy controls: an explorative study.

INTRODUCTION: The etiology of multisomatoform disorder (MSD) is still largely unknown, but genetic factors seem to have an influence on pathogenesis. Pain is a major symptom of MSD and polymorphisms of different proinflammatory cytokines have been found associated with pain in former studies. Therefore, we presumed that cytokine polymorphisms could also be associated with MSD. PATIENTS AND METHODS: Groups of 148 MSD patients with pain as the leading clinical symptom and 149 age and gender matched healthy controls participated in this study. Nine cytokine polymorphisms were genotyped and statistically analyzed for associations with MSD. RESULTS: Allelic and genotypic associations were found for rs16944 (interleukin 1ß), rs1800629 (tumor necrosis factor) and rs909253 (lymphotoxin α). After correcting for multiple testing, the association of rs1800629 with MSD remained significant. The rare A-allele was correlated with MSD (p=0.007). DISCUSSION: Since the common G-allele of rs1800629 (TNFα) occurs much more often in the control group than in the MSD group it is assumed to be protective. Being carrier of the A-allele seems to be a risk factor for MSD.

Inhibition studies on Mycobacterium tuberculosis N-acetylglucosamine-1-phosphate uridyltransferase (GlmU).

Peptidoglycan is an essential component of the cell wall of bacteria, including Mycobacterium tuberculosis, that provides structural strength and rigidity to enable internal osmotic pressure to be withstood. The first committed step in the biosynthesis of peptidoglycan involves the formation of uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) from uridine triphosphate (UTP) and GlcNAc-1-phosphate. This reaction is catalysed by N-acetylglucosamine-1-phosphate uridyltransferase (GlmU), a bifunctional enzyme with two independent active sites that possess acetyltransferase and uridyltransferase activities. Herein, we report the first inhibition study targeted against the uridyltransferase activity of M. tuberculosis GlmU. A number of potential inhibitors were initially prepared leading to the discovery of active aminoquinazoline-based compounds. The most potent inhibitor in this series exhibited an IC50 of 74 µM against GlmU uridyltransferase activity and serves as a promising starting point for the discovery of more potent inhibitors.

Prevalence, risk factors, and disease knowledge of chronic hepatitis B infection in Vietnamese Americans in California.

Our goal is to examine the prevalence, risk factors, and disease knowledge of chronic hepatitis B (CHB) among Vietnamese Americans in California. We also examined treatment eligibility and linkage to care among patients who tested positive for CHB. We enrolled 717 subjects from ten different hepatitis B virus (HBV) screening events in five locations from January 2009 to June 2010 in California. HBV status was determined by hepatitis B surface antigen (HBsAg) and antibody. Data were collected by a 36-question survey. A total of 99 patients (13.8 %) had positive HBsAg, especially those aged 31-40 years (23.6 %), and 177 (24.7 %) were still susceptible to HBV infection. A significant proportion of those who were HBsAg positive or still susceptible reported a history of HBV vaccination (10 and 20 %, respectively). Following adjustments for age and sex, significant predictors for HBsAg positivity were lack of healthcare coverage (OR=2.4, p=0.004), having a family history of CHB (OR=2.1, p=0.009), and prior occupational exposure (OR=3.0, p=0.007). Of those who tested positive, 13.3 % met criteria for antiviral therapy, but none had been initiated on treatment. HBV prevalence in Vietnamese Americans in California was high (13.8 %), especially in those between 31 and 40 years of age. Patient disease and treatment knowledge was poor, as were follow-up and management of those found to have CHB and/or have indication for antiviral therapy.

Incidence of Midline Catheter Complications Among Hospitalized Patients.

The use of midline catheters has increased to reduce excessive use of central venous access devices, and additional data on midline catheter complications are needed. This study aimed to describe midline catheter complications among hospitalized patients. This retrospective study included a random sample of 300 hospitalized patients with a midline catheter insertion in 2019. The primary outcome was a composite end point of 8 complications: occlusion, bleeding at insertion site, infiltration/extravasation, catheter-related thrombosis, accidental removal, phlebitis, hematoma, and catheter-related infection. Midline catheter failure was defined as removal prior to the end of therapy due to complications. Among 300 midline catheters, the incidence of the composite end point of 1 or more midline complications was 38% (95% confidence interval, 33%-44%). Complications included occlusion (17.0%), bleeding at insertion site (12.0%), infiltration/extravasation (10.0%), catheter-related thrombosis (4.0%), accidental removal (3.0%), phlebitis (0.3%), hematoma (0.3%), and catheter-related infection (0.3%). Midline catheter failure occurred in 16% of midline catheters (n = 48) due to infiltration/extravasation (n = 27), accidental removal (n = 10), catheter-related thrombosis (n = 9), occlusion (n = 4), and catheter-related infection (n = 1). Three catheters had 2 types of failure. The most common complications of occlusion and bleeding rarely resulted in midline catheter failure. The most common causes of midline catheter failure were infiltration/extravasation, accidental removal, and catheter-related thrombosis.

Treatment Patterns of Long-Acting Somatostatin Analogs for Neuroendocrine Tumors.

Background: Long-acting somatostatin analog therapy (LA-SSA) is recommended as first-line therapy for treatment of unresectable or metastatic neuroendocrine tumors (NETs). Understanding treatment sequencing and dosing patterns of LA-SSA is essential for clinical decision-making to provide value-based management of NETs. Objective: To describe treatment patterns of LA-SSA among patients with NETs and subgroups with carcinoid syndrome (CS) in the United States. Methods: This retrospective study utilized claims data from MarketScan® databases to identify patients with NETs and newly treated with LA-SSA between January 1, 2015, and October 31, 2020. Patients were stratified by index LA-SSA (lanreotide and octreotide long-acting release [LAR]). Reported 28-day doses were based on claim fields for days' supply/drug quantity or units of service. Dose escalation was defined as increases in quantity or frequency. Continuous variables, categorical variables, and Kaplan-Meier estimated treatment durations were compared using t-tests, chi-square/Fisher's tests, and log-rank tests, respectively. Results: The study included 241 lanreotide and 521 octreotide LAR patients. Compared with octreotide LAR patients, treatment duration was longer for lanreotide patients (median, 41.3 vs 26.8 months; log-rank p=.004). Fewer lanreotide patients received rescue treatment with short-acting octreotide (7.9% vs 14.4%; p=.011), and a first (6.2% vs 27.3%) and second dose escalation (0.8% vs 5.2%; both p<.05). Among patients with doses reported, fewer lanreotide patients received above-label doses (2.5% [5/202] vs 14.4% [60/416]; p<.001). Among patients who ended treatment during follow-up, fewer lanreotide patients transitioned to another LA-SSA (18.9% [17/90] vs 33.6% [92/274]; p=.008). Similar treatment patterns were observed in CS subgroups. Results for switched treatment patterns were limited due to insufficient sample sizes. Discussion: Real-world treatment patterns of LA-SSA were assessed using more recent administrative claims data. Compared with octreotide LAR patients, lanreotide patients were more likely to remain longer on initial treatment and starting dose without dose escalations and less likely to use rescue treatment and transition to another LA-SSA after discontinuation of the index treatment. Conclusions: Findings from this claims study suggest a potential clinical benefit of lanreotide in NET management.

Optimization of Opioid Discharge Prescriptions Following Thyroid and Parathyroid Surgery.

OBJECTIVE: To evaluate the impact of a quality improvement bundle on opioid discharge prescribing following thyroidectomy and parathyroidectomy. METHODS: This before-and-after study included patients undergoing thyroidectomy or parathyroidectomy at an academic medical center. The quality improvement bundle included a patient education flyer, electronic health record order sets with multimodal analgesia regimens, and provider education. The preimplementation cohort included patients treated from January 2018 to December 2019. The postimplementation cohort included patients treated from June 2021 to August 2021. The primary outcome was the proportion of patients who received new opioid discharge prescriptions. RESULTS: A total of 160 patients were included in the preimplementation cohort, and the first 80 patients treated after bundle implementation were included in the postimplementation cohort. Patients receiving new opioid discharge prescriptions decreased from 80% (128/160) in the preimplementation cohort to 35% (28/80) in the postimplementation cohort with an unadjusted absolute reduction of 45% (95% CI, 33%-57%; P < .001; number needed to treat = 3) and an adjusted odds ratio (OR) of 0.08 (95% CI, 0.04-0.19; P < .001). The bundle was associated with reductions in opioid discharge prescriptions that exceeded 112.5 oral morphine milligram equivalents (33% pre- vs 10% postimplementation; adjusted OR, 0.20; P = .001) or 5 days of therapy (17% pre- vs 6% postimplementation; adjusted OR, 0.34; P = .049). DISCUSSION: Implementation of a pain management quality improvement bundle reduced opioid discharge prescribing following thyroidectomy and parathyroidectomy. IMPLICATIONS FOR PRACTICE: Unnecessary opioid prescriptions generate unused opioids in patients' homes that can lead to opioid misuse. We believe that this bundle reduced the risk for opioid misuse in our community. REGISTRATION: The study was registered at ClinicalTrials.gov (NCT04955444) before implementation.

Evidence of residual micellar structures in a lipid nanocapsule dispersion. A multi-technique approach.

Nanoemulsions are metastable emulsions in the nanometric range which can be obtained using low-energy processes. A decade ago, it was demonstrated that a non-negligible amount of residual surfactant micelles may coexist with the oil nanodroplets in a model oil/surfactant system. Those micelles were called "wasted" micelles as they did not participate in the formation of the nanodroplets. Little attention has been focused on the potential presence or effect of such secondary structures in nanoemulsions used as drug delivery systems. Here, we present an extensive characterization of lipid nanocapsules, a nanoemulsion obtained from a medium-chain triglyceride mixed with a pegylated surfactant by a process comprising a temperature-dependent phase inversion followed by a cold-water quench. Lipid nanocapsules demonstrate a very good shelf stability. First, for clarity and academic purposes, we briefly present the pros and the cons of the various diffusion-based characterization techniques used i.e., multi-angle and single-angle dynamic light scattering, nanoparticle tracking analysis, fluorescence recovery after photobleaching, and diffusometry nuclear magnetic resonance. Then, combining all these techniques, we show that up to 40 wt% of the surfactant is not involved in the lipid nanocapsule construction but forms residual micellar structures. Those micelles also contain a small quantity of medium-chain triglyceride (2 wt% of the initial amount) and encapsulate around 40 wt% of a fluorescent dye originally dispersed in the oily phase.

Neurohumoral Profiles and Childhood Adversity of Patients with Multisomatoform Disorder and Pain as the Leading Bodily Symptom.

OBJECTIVE: Patients suffering from chronic pain often present with multifactorial underlying conditions, sometimes without concrete pathological physical findings. Functional somatic syndromes (FSS) and somatoform disorders show a high prevalence of 8-20% and are often associated with adverse childhood experiences (ACE) and chronic stress. As many different FSS have overlapping symptoms, the concept of multisomatoform disorder (MSD) has been introduced as an encompassing concept. We hypothesize that a common neurohumoral profile is present in patients with MSD that is distinct from gender- and age-matched controls and thus provides insight into possible common underlying mechanisms. DESIGN: In 151 patients with MSD (138 females) and 149 matched controls (131 females), we determined ACE by the Childhood Trauma Questionnaire (CTQ) and chronic stress by the Trier Inventory for Chronic Stress (TICS). Furthermore, the serum levels of leptin, FSH, LH, cortisol, DHEA-S, and IGF-1 have been assessed. RESULTS: There were significant differences in the levels of leptin, FSH, IGF-1, and cortisol between patients and controls, mainly driven by female participants. Levels of leptin were significantly correlated with BMI in patients, in controls, and in the female subgroup. This correlation was exaggerated in female patients when compared to female controls. Both CTQ and TICS predicted MSD directly and indirectly through the levels of leptin. CONCLUSION: There is evidence of a distinct neurohumoral profile in female patients with MSD when compared to matched healthy controls, similar to what has been demonstrated in other chronic pain states. The observed profile can be taken as possible evidence for a dysregulated response to chronic stress and metabolic balance as well as a state of hypocortisolism and HPA-axis dysfunction. ACE and chronic stress play a major role in the development of MSD and altered neurohumoral profile.

Implementation of Clinical Decision Support on Emergency Department Delivery of Human Rabies Immune Globulin.

Importance: Fatal human rabies infections can be prevented through appropriate rabies postexposure prophylaxis (PEP). Errors in patient selection and administration of human rabies immune globulin in the emergency department (ED) setting were identified in a previous study of rabies PEP administration. Objective: To test the a priori hypothesis that implementation of a rabies PEP bundle in the ED would improve full adherence to 6 human rabies immune globulin quality indicators compared with preimplementation controls. Design, Setting, and Participants: This quality improvement study was conducted in 15 EDs in a US multihospital health system. Patients who received human rabies immune globulin or rabies vaccine in the ED from January 2015 to June 2018 were included in the preimplementation control group and from December 2019 to November 2020 were included in the postimplementation intervention group. Data were analyzed in January 2021. Exposure: The PEP bundle was implemented in December 2019 and consisted of electronic health record enhancements, including clinical decision support, ED staff education, and patient education. Main Outcomes and Measures: Full adherence to 6 human rabies immune globulin quality indicators: patient selection, dose, timing, infiltration into wounds, administration distant from rabies vaccine site, and administration that avoids the buttock. Results: The study included 324 patients; 254 patients were in preimplementation group (mean [SD] age, 39 [21] years; 135 [53%] women) and 70 in the postimplementation group (mean [SD] age, 38 [19] years; 33 [47%] women). Most patients presented to EDs embedded in a community hospital (231 patients [71%]). Full adherence increased from 37% in the preimplementation group to 61% postimplementation (absolute increase, 24%; 95% CI, 11% to 37%; P < .001). Adherence improved for quality indicators for infiltration into wounds (137 of 254 patients [54%] to 50 of 70 patients [71%]; P = .009), administration distant from rabies vaccine site (180 of 254 [71%] to 58 of 70 [83%]; P = .04), and administration that avoids the buttock (168 of 254 [66%] to 58 of 70 [83%]; P = .007). No instances of sciatic nerve injury or compartment syndrome were observed. Conclusions and Relevance: In this quality improvement study, implementation of a rabies PEP bundle was associated with improved patient selection and delivery of human rabies immune globulin in EDs across a multihospital health system. Although the bundle included ED staff education and patient discharge education, the observed improvement was likely driven by clinical decision support from the rabies PEP ED order set. Future research should evaluate implementation of this clinical decision support at other health systems.