Search

Objective: This article describes the implementation of preemptive clinical pharmacogenomics (PGx) testing linked to an automated clinical decision support (CDS) system delivering actionable PGx information to clinicians at the point of care at UCSF Health, a large Academic Medical Center., Methods: A multidisciplinary team developed the strategic vision for the PGx program. Drug-gene interactions of interest were compiled, and actionable alleles identified. A genotyping platform was selected and validated in-house. Following HIPAA protocols, genotype results were electronically transferred and stored in electronic health records (EHRs). CDS was developed and integrated with electronic prescribing., Results: We developed a customized PGx program for 56 medications and 15 genes. Two hundred thirty-three pharmacogenomic prescribing alerts and 15 pharmacogenomic testing prompts, approved by clinicians, were built into EHR to deliver actionable clinical PGx information to clinicians., Conclusions: Our multidisciplinary team successfully implemented preemptive PGx testing linked to point-of-care CDS to guide clinicians with precise medication decision-making., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Improper opioid prescription after surgery is a well-documented iatrogenic contributor to the current opioid epidemic in North America. In fact, opioids are known to be overprescribed to liver transplant patients, and liver transplant patients with high doses or prolonged postsurgical opioid use have higher risks of graft failure and death., Methods: This is a retrospective cohort study of 552 opioid-naive patients undergoing liver transplant at an academic center between 2012 and 2019. The primary outcome was the discrepancy between the prescribed discharge opioid daily dose and each patient's own inpatient opioid consumption 24 h before discharge. Variables were analyzed with Wilcoxon and chi-square tests and logistic regression., Results: Opioids were overprescribed in 65.9% of patients, and 54.3% of patients who required no opioids the day before discharge were discharged with opioid prescriptions. In contrast, opioids were underprescribed in 13.4% of patients, among whom 27.0% consumed inpatient opioids but received no discharge opioid prescription. The median prescribed opioid daily dose was 333.3% and 56.3% of the median inpatient opioid daily dose in opioid overprescribed and underprescribed patients, respectively. Importantly, opioid underprescribed patients had higher rates of opioid refill 1 to 30 and 31 to 90 d after discharge, and the rate of opioid underprescription more than doubled from 2016 to 2019., Conclusions: Opioids are both over- and underprescribed to liver transplant patients, and opioid underprescribed patients had higher rates of opioid refill. Therefore, we proposed to prescribe discharge opioid prescriptions based on liver transplant patients' inpatient opioid consumption to provide patient-centered opioid prescriptions., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Although postsurgical overprescription has been well-studied, postsurgical opioid underprescription remains largely overlooked. This retrospective cohort study was to investigate the extent of discharge opioid overprescription and underprescription in patients after neurological surgeries. Six thousand nine hundred forty-nine adult opioid-naive patients who underwent inpatient neurosurgical procedures at the University of California San Francisco were included. The primary outcome was the discrepancy between individual patient's prescribed daily oral morphine milligram equivalent (MME) at discharge and patient's own inpatient daily MME consumed within 24 hours of discharge. Analyses include Wilcoxon, Mann-Whitney, Kruskal-Wallis, and χ 2 tests, and linear or multivariable logistic regression. 64.3% and 19.5% of patients were opioid overprescribed and underprescribed, respectively, with median prescribed daily MME 360% and 55.2% of median inpatient daily MME in opioid overprescribed and underprescribed patients, respectively. 54.6% of patients with no inpatient opioid the day before discharge were opioid overprescribed. Opioid underprescription dose-dependently increased the rate of opioid refill 1 to 30 days after discharge. From 2016 to 2019, the percentage of patients with opioid overprescription decreased by 24.8%, but the percentage of patients with opioid underprescription increased by 51.2%. Thus, the mismatched discharge opioid prescription in patients after neurological surgeries presented as both opioid overprescription and underprescription, with a dose-dependent increased rate of opioid refill 1 to 30 days after discharge in opioid underprescription. Although we are fighting against opioid overprescription to postsurgical patients, we should not ignore postsurgical opioid underprescription., (Copyright © 2023 International Association for the Study of Pain.)

Platelet-rich fibrin (PRF) is an autologous fibrin-rich matrix where activated platelets and leucocytes accumulate. PRF has a wide spectrum of clinical indications with the overall aim of supporting tissue regeneration which in dentistry includes the healing of healthy oral mucosa with epithelial cells. In oral squamous cell carcinoma lesions, however, epithelial cells undergo malignant transformation, indicated by their unrestricted proliferation and migration potential, which should not be further enhanced by a wound-healing formula. Yet, little is known about how oral squamous cell carcinomas respond to PRF lysates. The aim of the present study was, therefore, to test the capacity of PRF lysates to change the transcriptome of HSC2 oral squamous carcinoma cells and perform bioassays to support the findings. Based on the RNAseq analysis, PRF lysates caused an increase in the genes functionally linked to cell replication and migration. In support of this screening approach, PRF lysates enhanced the proliferation of HSC2 oral squamous carcinoma cells, as indicated by 3 [H]-thymidine incorporation, cell counting, and the expression of proliferation-related genes. Moreover, PRF lysates sped up cell migration in a scratch assay requiring actin polymerization. Taken together, our data showing that PRF lysates are mitogenic and stimulate motility of oral squamous carcinoma cell lines could be an indication that treatment with PRF in cases of oral carcinoma should be carefully considered.

Objectives: There is little evidence on the impact of the COVID-19 pandemic on Public Health Residents' (PHR) mental health (MH). This study aims at assessing prevalence and risk factors for depression, anxiety and stress in European PHR during the COVID-19 pandemic., Methods: Between March and April 2021, an online survey was administered to PHR from France, Italy, Portugal and Spain. The survey assessed COVID-19 related changes in working conditions, training opportunities and evaluated MH outcomes using the Depression Anxiety Stress Scales-21. Multivariable logistic regressions were applied to identify risk factors., Results: Among the 443 respondents, many showed symptoms of depression (60.5%), anxiety (43.1%) and stress (61.2%). The main outcome predictors were: female gender for depression (adjOR = 1.59, 95%CI [1.05-2.42]), anxiety (adjOR = 2.03, 95%CI [1.33-3.08]), and stress (adjOR = 2.35, 95%CI [1.53-3.61]); loss of research opportunities for anxiety (adjOR = 1.94, 95%CI [1.28-2.93]) and stress (adjOR = 1.98, 95%CI [1.26-3.11]); and COVID-19 impact on training (adjOR = 1.78, 95%CI [1.12-2.80]) for depression., Conclusions: The pandemic had a significant impact on PHR in terms of depression, anxiety and stress, especially for women and who lost work-related opportunities. Training programs should offer PHR appropriate MH support and training opportunities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Failla, Caminiti, Chen-Xu, Lo Moro, Berselli, Cabral Ferreira, Malcata, Peyre-Costa, Croci, Soldà, Capodici, Morcavallo, Traglia, Cedrone, Storti, Jaquete, Antinozzi and Vasiliu.)

Background: As the opioid epidemic accelerates in the United States, numerous sociodemographic factors have been implicated its development and are, furthermore, a driving factor of the disparities in postoperative pain management. Recent studies have suggested potential associations between the influence of race and ethnicity on pain perception but also the presence of unconscious biases in the treatment of pain in minority patients., Objective: To characterize the perioperative opioid requirements across racial groups after spine surgery., Methods: A retrospective, observational study of 1944 opioid-naive adult patients undergoing a neurosurgical spine procedure, from June 2012 to December 2019, was performed at a large, quaternary care institute. Postoperative inpatient and outpatient opioid usage was measured by oral morphine equivalents, across various racial groups., Results: Case characteristics were similar between racial groups. In the postoperative period, White patients had shorter lengths of stay compared with Black and Asian patients ( P < .05). Asian patients used lower postoperative inpatient opioid doses in comparison with White patients ( P < .001). White patients were discharged with significantly higher doses of opioids compared with Black patients ( P < .01); however, they were less likely to be readmitted within 30 days of discharge ( P < .01)., Conclusion: In a large cohort of opioid-naive postoperative neurosurgical patients, this study demonstrates higher inpatient and outpatient postoperative opioid usage among White patients. Increasing physician awareness to the effect of race on inpatient and outpatient pain management would allow for a modified opioid prescribing practice that ensures limited yet effective opioid dosages void of implicit biases., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Introduction: In the 2022 multicountry mpox (formerly named monkeypox) outbreak, several countries offered primary preventive vaccination (PPV) to people at higher risk for infection. We study vaccine acceptance and its determinants, to target and tailor public health (communication-) strategies in the context of limited vaccine supply in the Netherlands., Methods: Online survey in a convenience sample of gay, bisexual and other men who have sex with men, including transgender persons (22/07-05/09/2022, the Netherlands). We assessed determinants for being (un)willing to accept vaccination. We used multivariable multinominal regression and logistic regression analyses, calculating adjusted odds ratios (aOR) and 95 percent confidence-intervals. An open question asked for campaigning and procedural recommendations., Results: Of respondents, 81.5% ( n = 1,512/1,856) were willing to accept vaccination; this was 85.2% (799/938) in vaccination-eligible people and 77.7% (713/918) in those non-eligible. Determinants for non-acceptance included: urbanization (rural: aOR:2.2;1.2-3.7; low-urban: aOR:2.4;1.4-3.9; vs. high-urban), not knowing mpox-vaccinated persons (aOR:2.4;1.6-3.4), and lack of connection to gay/queer-community (aOR:2.0;1.5-2.7). Beliefs associated with acceptance were: perception of higher risk/severity of mpox, higher protection motivation, positive outcome expectations post vaccination, and perceived positive social norms regarding vaccination. Respondents recommended better accessible communication, delivered regularly and stigma-free, with facts on mpox, vaccination and procedures, and other preventive options. Also, they recommended, "vaccine provision also at non-clinic settings, discrete/anonymous options, self-registration" to be vaccinated and other inclusive vaccine-offers (e.g., also accessible to people not in existing patient-registries)., Conclusion: In the public health response to the mpox outbreak, key is a broad and equitable access to information, and to low-threshold vaccination options for those at highest risk. Communication should be uniform and transparent and tailored to beliefs, and include other preventive options. Mpox vaccine willingness was high. Public health efforts may be strengthened in less urbanized areas and reach out to those who lack relevant (community) social network influences., Competing Interests: PZ was employed by Soa Aids Nederland. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dukers-Muijrers, Evers, Widdershoven, Davidovich, Adam, Op de Coul, Zantkuijl, Matser, Prins, de Vries, Heijer, Hoebe, Niekamp, Schneider, Reyes-Urueña, Croci, D'Ambrosio, Valk, Posthouwer, Ackens, Waarbeek, Noori and Hoornenborg.)

We assess monkeypox vaccination acceptance among male adults in the European Region. We conducted an online survey through two dating apps targeting men who have sex with men, from 30 July to 12 August 2022. We developed Bayesian hierarchical logistic regression models to investigate monkeypox vaccination acceptance. Overall crude vaccination acceptance was 82% and higher in north-western compared to south-eastern European regions. Acceptance strongly rose with perception of increased disease severity and transmission risk, and in individuals linked to healthcare.

Up to 27 May 2022, Portugal has detected 96 confirmed cases of monkeypox. We describe 27 confirmed cases (median age: 33 years (range: 22-51); all males), with an earliest symptom onset date of 29 April. Almost all cases (n = 25) live in the Lisbon and Tagus Valley health region. Most cases were neither part of identified transmission chains, nor linked to travel or had contact with symptomatic persons or with animals, suggesting the possible previously undetected spread of monkeypox.

Background: The Centers for Disease Control and Prevention's (CDC) March 2016 opioid prescribing guideline did not include prescribing recommendations for surgical pain. Although opioid over-prescription for surgical patients has been well-documented, the potential effects of the CDC guideline on providers' opioid prescribing practices for surgical patients in the United States remains unclear., Methods: We conducted an interrupted time series analysis (ITSA) of 37,009 opioid-naïve adult patients undergoing inpatient surgery from 2013-2019 at an academic medical center. We assessed quarterly changes in the discharge opioid prescription days' supply, daily and total doses in oral morphine milligram equivalents (OME), and the proportion of patients requiring opioid refills within 30 days of discharge., Results: The discharge opioid prescription declined by -0.021 (95% CI, -0.045 to 0.003) days per quarter pre-guideline versus -0.201 (95% CI, -0.223 to -0.179) days per quarter post-guideline (p < 0.0001). Likewise, the mean daily and total doses of the discharge opioid prescription declined by -0.387 (95% CI, -0.661 to -0.112) and -7.124 (95% CI, -9.287 to -4.962) OME per quarter pre-guideline versus -2.307 (95% CI, -2.560 to -2.055) and -20.68 (95% CI, -22.66 to -18.69) OME per quarter post-guideline, respectively (p < 0.0001). Opioid refill prescription rates remained unchanged from baseline., Conclusions: The release of the CDC opioid guideline was associated with a significant reduction in discharge opioid prescriptions without a concomitant increase in the proportion of surgical patients requiring refills within 30 days. The mean prescription for opioid-naïve surgical patients decreased to less than 3 days' supply and less than 50 OME per day by 2019., (© 2022. The Author(s).)

Background: Opioids and multimodal analgesia are widely administered to manage postoperative pain. However, little is known on how improvements in inpatient pain control are correlated with high-risk (> 90 daily OME) discharge opioid prescriptions for opioid naïve surgical patients., Methods: We conducted a retrospective observational study of adult opioid-naïve patients undergoing surgery from June 2012 through December 2018 at a large academic medical center. We used multivariate logistic regression to assess whether multimodal analgesic drugs consumed in the 24 h prior to discharge was associated with a reduction in high-risk opioid discharge prescriptions. We identified other risk factors for receiving a high-risk discharge opioid prescription., Results: Among the 32,511 patients, 83% of patients were discharged with an opioid prescription. In 2013, 34.1% of patients with a discharge opioid prescription received a high-risk prescription and this declined to 17.7% by 2018. Use of multimodal analgesic agents during the final 24 h of hospitalization increased each year, with over 80% receiving at least one multimodal analgesic agent by 2018. The median OME consumed in the 24 h prior to discharge peaked in 2013 at 31 and steadily decreased to 19.8 by 2018. There was a significant association between the use of acetaminophen in the 24 h prior to discharge and a high-risk prescription at discharge (p < 0.01). OMEs consumed in the 24 h prior to discharge was a significant predictor of receiving a high-risk discharge prescription, even at low doses. Other factors associated with receipt of a high-risk discharge opioid prescription included male gender, race, history of anxiety disorder, and discharge service., Discussion: Use of multimodal analgesia regimens in hospitalized surgical patients in the 24 h prior to hospital discharge increased between 2012 and 2018. Simultaneously, opioid use prior to hospital discharge decreased. Despite these gains, approximately one in five discharge prescriptions was high-risk (> 90 daily OME). In addition, we found that prescribing of discharge opioids above inpatient opioid requirements remains common in opioid naive surgical patients., Conclusion: Providers should account for pre-discharge opioid consumption and use of multimodal analgesia when considering the total and daily OME's that may be appropriate for an individual surgical patient on the discharge opioid prescription., (© 2021. The Author(s).)

Ensuring timely access to affordable vaccines has been acknowledged as a global public health priority, as also recently testified by the debate sparked during the COVID-19 pandemic. Effective vaccine procurement strategies are essential to reach this goal. Nevertheless, this is still a neglected research topic. A narrative literature review on vaccine procurement was conducted, by retrieving articles from four academic databases (PubMed/MEDLINE, Scopus, Embase, WebOfScience), 'grey' literature reports, and institutional websites. The aim was to clarify key concepts and definitions relating to vaccine procurement, describe main vaccine procurement methods, and identify knowledge gaps and future perspectives. A theoretical conceptual framework was developed of the key factors involved in vaccine procurement, which include quality and safety of the product, forecasting and budgeting, procurement legislation, financial sustainability, and plurality of manufacture, contracting, investment in training, storage and service delivery, monitoring and evaluation. This information can be useful to support policymakers during planning, implementation, and evaluation of regional and national vaccine procurement strategies and policies.

Background and Aim: After the first cases of COVID-19 detected in Wuhan (China), the virus rapidly spread in the world, so much so that on February 20 the first autochthonous case was officially identified in Italy. However, this person had no apparent history of travel abroad or contact with people tested positive for the virus. For this reason, the aim of this literature review was to reconstruct the epidemiological dynamics of the first wave of SARS-CoV-2 infection in the Lombardy Region., Methods: To this end, a systematic review was carried out on PubMed/MEDLINE and EMBASE, and on grey literature. All article assessing incidence, mortality and hospitalizations by Lombardy province and municipality, and the impact of the main containment and organizational measures were considered eligible. In addition, data on general mortality and mortality due to COVID-19, hospital admission, and serological and environmental were also retrieved., Results: From the included studies, it emerged that Lombardy was the first European region in which the virus began to circulate as early as January 2020 (and probably even earlier). Despite the high number of cases and deaths recorded, the reproduction number observed in Lombardy Region was, at the beginning of March 2020, the same (or lower) than in other regions., Conclusions: In conclusion, data of the first epidemic wave in Lombardy, compared to other Italian and foreign regions, highlight the extreme criticality of having had the first autochthonous case (and the first substantial outbreaks) when knowledge was still scarce and individual prevention measures were not widespread.

Background: Delirium is associated with poor clinical outcomes that could be improved with targeted interventions., Objective: To determine whether a multicomponent delirium care pathway implemented across seven specialty nonintensive care units is associated with reduced hospital length of stay (LOS). Secondary objectives were reductions in total direct cost, odds of 30-day hospital readmission, and rates of safety attendant and restraint use., Methods: This retrospective cohort study included 22,708 hospitalized patients (11,018 preintervention) aged ≥50 years encompassing seven nonintensive care units: neurosciences, medicine, cardiology, general and specialty surgery, hematology-oncology, and transplant. The multicomponent delirium care pathway included a nurse-administered delirium risk assessment at admission, nurse-administered delirium screening scale every shift, and a multicomponent delirium intervention. The primary study outcome was LOS for all units combined and the medicine unit separately. Secondary outcomes included total direct cost, odds of 30-day hospital readmission, and rates of safety attendant and restraint use., Results: Adjusted mean LOS for all units combined decreased by 2% post intervention (proportional change, 0.98; 95% CI, 0.96-0.99; P = .0087). Medicine unit adjusted LOS decreased by 9% (proportional change, 0.91; 95% CI, 0.83-0.99; P = .028). For all units combined, adjusted odds of 30-day readmission decreased by 14% (odds ratio [OR], 0.86; 95% CI, 0.80-0.93; P = .0002). Medicine unit adjusted cost decreased by 7% (proportional change, 0.93; 95% CI, 0.89-0.96; P = .0002)., Conclusion: This multicomponent hospital-wide delirium care pathway intervention is associated with reduced hospital LOS, especially for patients on the medicine unit. Odds of 30-day readmission decreased throughout the entire cohort.

Background: Opioids are generally discouraged and used sparingly in liver transplant (LT) candidates prior to LT. This study examined the relationship between opioid use at the time of LT and graft and patient survival following transplantation., Methods: A retrospective single center cohort study of LT recipients from June 2012 to December 2019 was performed. Primary outcomes were graft and patient survival, analyzed with the Kaplan-Meier method and Cox proportional hazards models; primary predictor was active opioid prescription at LT., Results: 751 LT recipients were included; 16% had an opioid prescription at LT. Post-transplant death was significantly greater in opioid users (pvalue<0.001). In a multivariable Cox model examining predictors of death, opioid use remained associated with a significant increase in the risk of death (HR 2.4 CI 1.5-4.0, p < 0.001) even after controlling for other factors., Conclusion: Opioid use at LT is associated with a markedly increased risk of death following transplant., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2020. Published by Elsevier Inc.)

The current review aimed to explore the association between urban greenspaces and health indicators. In particular, our aims were to analyze the association between publicly accessible urban greenspaces exposure and two selected health outcomes (objectively measured physical activity (PA) and mental health outcomes (MH)). Two electronic databases-PubMed/Medline and Excerpta Medica dataBASE (EMBASE)-were searched from 1 January 2000 to 30 September 2020. Only articles in English were considered. Out of 356 retrieved articles, a total of 34 papers were included in our review. Of those, 15 assessed the association between urban greenspace and PA and 19 dealt with MH. Almost all the included studies found a positive association between urban greenspace and both PA and MH, while a few demonstrated a non-effect or a negative effect on MH outcomes. However, only guaranteeing access is not enough. Indeed, important elements are maintenance, renovation, closeness to residential areas, planning of interactive activities, and perceived security aspects. Overall, despite some methodological limitations of the included studies, the results have shown almost univocally that urban greenspaces harbour potentially beneficial effects on physical and mental health and well-being.

Objectives: Prolonged use of dexmedetomidine has become increasingly common due to its favorable sedative and anxiolytic properties. Hypersympathetic withdrawal symptoms have been reported with abrupt discontinuation of prolonged dexmedetomidine infusions. Clonidine has been used to transition patients off dexmedetomidine infusions for ICU sedation. The objective of this study was to compare the occurrence of dexmedetomidine withdrawal symptoms in ICU patients transitioning to a clonidine taper versus those weaned off dexmedetomidine alone after prolonged dexmedetomidine infusion., Design: This was a single-center, prospective, double cohort observational study conducted from November 2017 to December 2018., Setting: Medical-surgical, cardiothoracic, and neurosurgical ICUs in a tertiary care hospital., Patients: We included adult ICU patients being weaned off dexmedetomidine after receiving continuous infusions for at least 3 days., Interventions: Patients were either weaned off dexmedetomidine alone or with a clonidine taper at the discretion of the providers., Measurements and Main Results: The primary outcome was the incidence of at least two dexmedetomidine withdrawal symptoms during a single assessment within 24 hours of dexmedetomidine discontinuation. Time on dexmedetomidine after wean initiation and difference in medication cost were also evaluated. Forty-two patients were included in this study: 15 received clonidine (Group C) and 27 weaned off dexmedetomidine alone (Group D). There was no significant difference in the incidence of two or more withdrawal symptoms between groups (73% in Group C vs 59% in Group D; p = 0.51). Patients in Group C spent less time on dexmedetomidine after wean initiation compared with patients in Group D (19 vs 42 hr; p = 0.02). An average cost savings of $1,553.47 per patient who received clonidine was observed. No adverse effects were noted., Conclusions: Our study demonstrated that patients receiving clonidine were able to wean off dexmedetomidine more rapidly, with a considerable cost savings and no difference in dexmedetomidine withdrawal symptoms, compared with patients weaned off dexmedetomidine alone. Clonidine may be a safe, effective, and practical option to transition patients off prolonged dexmedetomidine infusions., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Extended-release (ER) opioids are indicated for the management of persistent moderate to severe pain in patients requiring around-the-clock opioid analgesics for an extended period of time. Concerns have been raised regarding safety of ER opioids due to its potential for abuse and dependence. However, little is known about perioperative prescribing practices of ER opioids. This study assessed perioperative prescribing practices of ER opioids in noncancer surgical patients stratified by type of opioid exposure prior to admission and examined predictors of postoperative opioid administration in oral morphine equivalents (OME)., Methods: This was a retrospective cohort study using the University of California San Francisco Medical Center electronic health record data. This study included 25,396 adult noncancer patients undergoing elective surgery under general anesthesia in the period 2015-2018. The primary study outcome was predictors of postoperative administration of opioids in hospitalized surgical patients. Secondary outcomes included patients discontinued and initiated on ER opioids during their hospital stay., Results: substance use disorder diagnosis and use of opioids, surgery type, and postoperative administration of nonopioid analgesics were associated with postoperative administration of opioids (P < .0001). The estimated adjusted mean (95% confidence interval [CI]) of postoperative administration of OME prior to admission in ER opioid users (170.08 mg; 147.08-196.67) was twice the amount for opioid-naïve patients (81.36 mg; 70.7-93.63; P < .0001). One in 5 prior to admission ER opioid users were weaned off ER opioids while hospitalized without adversely affecting their postoperative pain or hospital length of stay (LOS). Four of 5 patients who used ER opioids prior to admission also received ER opioids after surgery, whereas, 1 in 100 opioid-naïve patients received ER opioids during their hospital stay., Conclusions: We found significant variability in the perioperative prescribing practices of ER opioids in hospitalized noncancer surgical patients by use of opioids prior to admission and surgery type. Pain medicine practitioners and surgeons may play a significant role tackling the surgery-related risk of exposure to ER opioids and decreasing opioid-related complications.

Despite the great effort to raise awareness among health promotion, nowadays Public Health policies are not often recognized as important tools. For this reason, the Health in All Policies (HiAP) approach is instrumental in tackling this information gap. In 2018, the US Association of Schools and Programs of Public Health (ASPPH) launched an international campaign called "This is Public Health" (TIPH), whose aim was "to brand public health and raise awareness of how it affects individuals, communities and populations". The Association of Schools of Public Health in the European Region (ASPHER), in coordination with ASPPH, decided to create a European campaign to support and to reproduce the American one, by opening a challenge among the European Public Health Schools. The Schools and Programs of PH of Vita-Salute "San Raffaele" University, Milan, University of Parma, University of Pavia and Politecnico of Milan won this bid. In this "briefing on" we present a report on the Italian project for raising awareness of Public Health among general population and health care personell.

Recent events and phenomena, such as A(H1N1) pandemic in 2009, "Fluad case" (2014-2015) and the spread of vaccine hesitancy, affected influenza vaccination coverage rates in Italy. In this study, the annual coverage rates in Lombardy Region and in Italy (from 1999-2000 season) have been critically described and compared. Regarding both the general population and the elderly over-65s, Lombardy's coverages always remained consistently below the national average. However, declines and peaks occurred simultaneously. The current slight recovery, both at national and regional level, is not sufficient. Coverages are still widely below the recommended thresholds.

In Italy, over the last decade, the spread of vaccine hesitancy has caused a steep decrease in vaccination coverage rates, both at the national and regional level. In this study, we pool and critically analyze childhood immunization coverage rates (2011-2018) in Lombardy, Italy's most populated region, and compare them to national trends. Overall, childhood vaccination coverage in Lombardy is slightly higher the Italian national average. In 2017, the law on mandatory vaccinations came into force, acting as a powerful tool for coverage increase.

Objective: There is a national imperative to curb the flow of opioids into our communities. In academic medical centers, the majority of discharge opioid prescriptions are written by residents who receive predominantly ad hoc, peer-to-peer education on perioperative analgesia. We aimed to reduce opioid overprescribing after common general surgical operations through a resident led quality improvement project that involved formal educational interventions and feedback on prescribing habits., Design: A transdisciplinary team was formed to identify how current prescribing habits differed from best practices, and to identify the educational needs to bridge this gap. We then focused on multiple educational interventions, including department-wide grand rounds, case-based conferences with residents, and dedicated didactic sessions on opioid prescribing. Feedback reports of opioid prescribing habits of the residents were developed. Residents' attitudes toward opioid prescribing were assessed using an anonymous survey before and after our interventions. Actual opioid prescribing data were abstracted from the electronic health record., Setting: A single academic medical center., Participants: A surgical resident led a transdisciplinary team consisting of faculty, anesthesiologists, pharmacists, advanced practice providers, and health informaticians within the Department of Surgery., Results: After our educational intervention, residents' impression of the appropriate number of opioid pills necessary after common general surgical operations decreased significantly, as measured by surveys pre- and postintervention. Electronic health record data regarding actual opioid prescribing behavior show significant discrepancy from the survey responses, but does show a significant decrease in the quantity of opioids prescribed for most evaluated operations following the educational intervention., Conclusions: Opioid prescribing is an ideal target for resident led education and quality improvement. Residents' attitudes toward appropriate opioid prescribing tend to differ from actual prescribing habits. Our results demonstrate that a well-scoped, resident-driven quality improvement program can lead to change in both attitudes and practice surrounding opioid prescribing., (Copyright © 2019 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

To determine the incidence of dexmedetomidine withdrawal in adult critically ill patients., Design: This was a prospective, observational study of patients from November 2017 to December 2018., Setting: Medical-surgical, cardiothoracic, and neurosurgical ICUs in a tertiary care hospital., Patients: Adult critically ill patients on dexmedetomidine infusions for at least 3 days., Interventions: Indicators of withdrawal were assessed at baseline and at least daily during the dexmedetomidine wean period. Delirium was assessed using the Confusion Assessment Method for the ICU. Sedation was assessed using the Richmond Agitation-Sedation Scale. The Withdrawal Assessment Tool-1 was performed and vital signs were recorded during each assessment. Patients were considered positive for dexmedetomidine withdrawal if they had two or more of the following symptoms: positive Confusion Assessment Method for the ICU, Richmond Agitation-Sedation Scale greater than +1, positive Withdrawal Assessment Tool-1 assessment, tachycardia (heart rate > 90 beats/min), and hypertension (systolic blood pressure > 140 mm Hg or mean arterial pressure > 90)., Measurements and Main Results: Forty-two patients were included in the study, with 64% of patients experiencing signs of dexmedetomidine withdrawal. The median time on dexmedetomidine for all patients was 9.6 days (5.8-12.7 d), and the median dose of dexmedetomidine received was 0.8 µg/kg/hr (0.5-1 µg/kg/hr). Of the patients who were positive for withdrawal, the most prevalent withdrawal symptoms observed included delirium, hypertension, and agitation (93%, 48%, and 33%, respectively). We found no correlation between chronic opioid tolerance and incidence of withdrawal symptoms. Peak dexmedetomidine doses greater than 0.8 µg/kg/hr and cumulative daily doses of dexmedetomidine greater than 12.9 µg/kg/d were associated with a higher incidence of withdrawal., Conclusions: The majority of patients in our study demonstrated signs that may be indicative of dexmedetomidine withdrawal. Peak and cumulative daily dexmedetomidine dose, rather than duration of therapy, may be associated with a higher incidence of withdrawal signs. Regular screening of patients on prolonged dexmedetomidine infusions is recommended to ensure safe and effective use in critically ill patients., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Competing Interests: Competing interests: None declared.

Introduction: Genetic-guided selection of non-oncologic medications is not commonly practiced in general, and at University of California, San Francisco (UCSF) Health, specifically. Understanding the unique position of clinicians with respect to clinical pharmacogenetics (PG) at a specific institution or practice is fundamental for implementing a successful PG consult service., Objectives: To assess clinicians' current practices, needs, and interests with respect to clinical PG at UCSF Health, a large tertiary academic medical center., Methods: A list of 42 target medications with clinical PG recommendations was complied. Clinical specialties that routinely used the target medications were identified. A 12-question survey focused on practice of PG for target medications was developed. Pharmacists and physicians were surveyed anonymously in several clinical specialties. Survey results were analyzed using descriptive statistics., Results: Of the 396 clinicians surveyed, 76 physicians and 59 pharmacists participated, resulting in 27% and 50% average response rates, respectively. The current use of PG in clinical practice for physicians and pharmacists was 29% and 32%, respectively, however this number varied across clinical specialties from 0% to 80%. Of clinicians whom reported they do not currently apply PG, 63% of physicians and 54% of pharmacists expressed interest in integrating PG. However, the level of interest varied from 20% to 100% across specialties. Of the respondents, 64% of physicians and 56% of pharmacists elected to provide contact information to investigators to further discuss their interest related to clinical PG., Conclusions: While PG is not uniformly practiced at UCSF Health, there is considerable interest in utilizing PG by the respondents. Our approach was successful at identifying clinicians and services interested in PG for specific drug-gene pairs. This work has set a foundation for next steps to advance PG integration at UCSF Health. Clinicians can adopt our approach as preliminary work to build a clinical PG program at their institutions., Competing Interests: Conflict of interest: The authors have no conflict of interest to disclose.

Background: Active opioid users experience more pain and require more opioids after primary shoulder arthroplasty than non-opioid users. However, it is unknown whether discharge prescription regimens are tailored to these different postoperative opioid requirements., Methods: We performed a retrospective analysis of a prospectively collected cohort of patients who underwent primary shoulder replacement over a 15-month period. Demographic and operative variables were collected and compared between prior opioid users and non-opioid users. Inpatient opioid requirements, daily discharge prescription regimens, total prescription quantities, and rates of persistent opioid use 6 weeks after surgery were also compared between these cohorts., Results: A total of 119 patients were analyzed (mean age, 68 years; 53% men; 39.5% prior opioid users). Prior opioid users required considerably more opioids on the first (60 oral morphine equivalents [OMEs] vs 45 OMEs, P = .01) and last (42 OMEs vs 15 OMEs, P < .001) hospitalization days but were discharged with similar daily opioid regimens (90 OMEs vs 90 OMEs, P = .3), total opioid quantities (600 OMEs vs 600 OMEs, P = .24), and total pills (80 vs 60, P = .27) compared with non-opioid users. Persistent opioid use 6 weeks after surgery was 7-fold higher for prior opioid users than nonusers (71.0% vs 9.1%, P < .001)., Conclusions: Daily and total opioid regimens prescribed after primary shoulder arthroplasty were similar between prior opioid users and nonusers despite large differences in their inpatient opioid requirements. Tailoring discharge opioid prescription regimens to inpatient use appears feasible and warrants further study., (Copyright © 2018 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Background: Preoperative opioid use causes increased pain and opioid requirements after total joint arthroplasty (TJA), but the effect of depression on this relationship is not well defined., Methods: We conducted a retrospective review of primary TJA patients using an institutional database. Demographic variables, inpatient opioid requirements, and discharge prescription quantities were collected and compared between patients with and without a prior diagnosis of depression in both the prior opioid-using and nonusing cohorts., Results: Four hundred and three patients were analyzed between August 1, 2016, and July 31, 2017. Among prior opioid users, patients with depression experienced higher inpatient pain levels (4 vs 3; P  = .001), required more inpatient opioids (117 oral morphine equivalents [OMEs] vs 70 OMEs; P  = .022), were prescribed more opioids at discharge (1163 OMEs vs 750 OMEs; P  = .02), and required more long-term opioid refills (57.7% vs 15.4%; P < .001) than patients without depression. However, depression was not associated with increased pain, opioid requirements, prescription quantities, or refill rates among opioid-naive patients., Conclusions: Depression is not associated with increased pain or opioid requirements among opioid-naive patients after TJA but is associated with significantly higher pain and opioid requirements among patients who use opioids preoperatively. The interaction of these variables may highlight a target for preoperative counseling and risk modification in the arthroplasty population.

Endoglin (ENG)/CD105 is an essential endothelial cell co-receptor of the transforming growth factor β (TGF-β) superfamily, mutated in hereditary hemorrhagic telangiectasia type 1 (HHT1) and involved in tumor angiogenesis and preeclampsia. Here, we present crystal structures of the ectodomain of human ENG and its complex with the ligand bone morphogenetic protein 9 (BMP9). BMP9 interacts with a hydrophobic surface of the N-terminal orphan domain of ENG, which adopts a new duplicated fold generated by circular permutation. The interface involves residues mutated in HHT1 and overlaps with the epitope of tumor-suppressing anti-ENG monoclonal TRC105. The structure of the C-terminal zona pellucida module suggests how two copies of ENG embrace homodimeric BMP9, whose binding is compatible with ligand recognition by type I but not type II receptors. These findings shed light on the molecular basis of the BMP signaling cascade, with implications for future therapeutic interventions in this fundamental pathway., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

RNA dependent RNA polymerases (RdRp) are essential enzymes for flavivirus replication. Starting from an in silico docking analysis we identified a pyridobenzothiazole compound, HeE1-2Tyr, able to inhibit West Nile and Dengue RdRps activity in vitro, which proved effective against different flaviviruses in cell culture. Crystallographic data show that HeE1-2Tyr binds between the fingers domain and the priming loop of Dengue virus RdRp (Site 1). Conversely, enzyme kinetics, binding studies and mutational analyses suggest that, during the catalytic cycle and assembly of the RdRp-RNA complex, HeE1-2Tyr might be hosted in a distinct binding site (Site 2). RdRp mutational studies, driven by in silico docking analysis, allowed us to locate the inhibition Site 2 in the thumb domain. Taken together, our results provide innovative concepts for optimization of a new class of anti-flavivirus compounds., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

RNA virus infections can lead to the onset of severe diseases such as fever with haemorrhage, multiorgan failure, and mortality. The emergence and reemergence of RNA viruses continue to pose a significant public health threat worldwide with particular attention to the increasing incidence of flaviviruses, among others Dengue, West Nile Virus, and Yellow Fever viruses. Development of new and potent antivirals is thus urgently needed. Ivermectin, an already known antihelminthic drug, has shown potent effects in vitro on Flavivirus helicase, with EC50 values in the subnanomolar range for Yellow Fever and submicromolar EC50 for Dengue Fever, Japanese encephalitis, and tick-borne encephalitis viruses. However ivermectin is hampered in its application by pharmacokinetic problems (little solubility and high cytotoxicity). To overcome such problems we engineered different compositions of liposomes as ivermectin carriers characterizing and testing them on several cell lines for cytotoxicity. The engineered liposomes were less cytotoxic than ivermectin alone and they showed a significant increase of the antiviral activity in all the Dengue stains tested (1, 2, and S221). In the current study ivermectin is confirmed to be an effective potential antiviral and liposomes, as drug carriers, are shown to modulate the drug activity. All together the results represent a promising starting point for future improvement of ivermectin as antiviral and its delivery.

Norovirus (NV) is a major cause of gastroenteritis worldwide. Antivirals against such important pathogens are on demand. Among the viral proteins that orchestrate viral replication, RNA-dependent-RNA-polymerase (RdRp) is a promising drug development target. From an in silico-docking search focused on the RdRp active site, we selected the compound PPNDS, which showed low micromolar IC50vs. murine NV-RdRp in vitro. We report the crystal structure of the murine NV-RdRp/PPNDS complex showing that two molecules of the inhibitor bind in antiparallel stacking interaction, properly oriented to block exit of the newly synthesized RNA. Such inhibitor-binding mode mimics two stacked nucleotide-bases of the RdRp/ssRNA complex., (Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Noroviruses (NV) are +ssRNA viruses responsible for severe gastroenteritis; no effective vaccines/antivirals are currently available. We previously identified Suramin (9) as a potent inhibitor of NV-RNA dependent RNA polymerase (NV-RdRp). Despite significant in vitro activities versus several pharmacological targets, Suramin clinical use is hampered by pharmacokinetics/toxicity problems. To improve Suramin access to NV-RdRp in vivo, a Suramin-derivative, 8, devoid of two sulphonate groups, was synthesized, achieving significant anti-human-NV-RdRp activity (IC50 = 28 nM); the compound inhibits also murine NV (mNV) RdRp. The synthesis process led to the isolation/characterization of lower molecular weight intermediates (3-7) hosting only one sulphonate head. The crystal structures of both hNV/mNV-RdRps in complex with 6, were analyzed, providing new knowledge on the interactions that a small fragment can establish with NV-RdRps, and establishing a platform for structure-guided optimization of potency, selectivity and drugability.

Noroviruses are members of the Caliciviridae family of positive sense RNA viruses. In humans Noroviruses cause rapid onset diarrhea and vomiting. Currently Norovirus infection is responsible for 21 million gastroenteritis yearly cases in the USA. Nevertheless, despite the obvious public health and socio-economic relevance, no effective vaccines/antivirals are yet available to treat Norovirus infection. Since the activity of RNA-dependent RNA polymerase (RdRp) plays a key role in genome replication and in the synthesis/amplification of subgenomic RNA, the enzyme is considered a promising target for antiviral drug development. In this context, following the identification of suramin and NF023 as Norovirus RdRp inhibitors, we analyzed the potential inhibitory role of naphthalene di-sulfonate (NAF2), a fragment derived from these two molecules. Although NAF2, tested in enzymatic polymerase inhibition assays, displayed low activity against RdRp (IC50=14μM), the crystal structure of human Norovirus RdRp revealed a thumb domain NAF2 binding site that differs from that characterized for NF023/suramin. To further map the new potential inhibitory site, we focused on the structurally related molecule pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonate) tetrasodium salt (PPNDS). PPNDS displayed below-micromolar inhibitory activity versus human Norovirus RdRp (IC50=0.45μM), similarly to suramin and NF023. Inspection of the crystal structure of the RdRp/PPNDS complex showed that the inhibitor bound to the NAF2 thumb domain site, highlighting the relevance of such new binding site for exploiting Norovirus RdRp inhibitors., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Mars' polar regions are covered with ice-rich layered deposits that potentially contain a record of climate variations. The sounding radar SHARAD on the Mars Reconnaissance Orbiter mapped detailed subsurface stratigraphy in the Promethei Lingula region of the south polar plateau, Planum Australe. Radar reflections interpreted as layers are correlated across adjacent orbits and are continuous for up to 150 kilometers along spacecraft orbital tracks. The reflectors are often separated into discrete reflector sequences, and strong echoes are seen as deep as 1 kilometer. In some cases, the sequences are dipping with respect to each other, suggesting an interdepositional period of erosion. In Australe Sulci, layers are exhumed, indicating recent erosion.

The principal concern of this paper lies in the exploration of the possible role of the subjective experience of language impairment in shaping schizophrenic symptomatology. A previous model embracing the basic symptom theory and the vulnerability paradigm hypothesized that (self-perceived) impairment of receptive and expressive language and alexithymia may play a relevant role in facilitating the development of a nonparanoid prototype of schizophrenia. The experimental protocol which led to this model [emphasizing the comprehensive notion of 'language capacity' as pathoplastic modulator of overt schizophrenic syndromes (i.e. pathoplastic model)] was replicated on a wider schizophrenic sample, assessing contextually with diagnostic symptoms, depressive symptoms, alexithymia, subjective experience of negative symptoms and hedonic capacity. Since schizophrenics with self-experienced language capacity impairment did not differ from other schizophrenics, as regards positive, negative and disorganized symptoms, but just in negative symptom-related distress, an alternative interpretation of the possible role of the subjective experience of language impairment in schizophrenic psychopathology is proposed (i.e. idioplastic hypothesis)., (Copyright 2003 S. Karger AG, Basel)