After adjusting for age, axial length, spherical equivalent, RD extent, preoperative intraretinal cysts, duration of symptoms and postoperative IOP, the parafoveal GCL-IPL thickness in the PPV group was significantly reduced with respect to the SB group, both at three and 12 months . (4) Conclusions: In conclusion, the GCL-IPL is reduced in thickness in eyes with macula-off RRD treated with vitrectomy and is significantly thinner compared to eyes undergoing scleral buckling surgery.(1) Background: We evaluated macular ganglion cell layer–inner plexiform layer (GCL-IPL) thickness in patients with primary macula-off rhegmatogenous retinal detachment (RRD) treated with scleral buckling (SB) or pars plana vitrectomy (PPV) using spectral domain optical coherence tomography (SD-OCT). (2) Methods: In this retrospective, observational study, we reviewed the medical records of patients undergoing SB or PPV surgery for macula-off RRD. SD-OCT was performed at three and 12 months after surgery. The central and parafoveal GCL-IPL thicknesses in treated eyes were compared with those of healthy fellow eyes. OCT measurements between the SB and PPV group were also compared using the analysis of covariance. (3) Results: Seventy-one eyes of 71 patients with a mean age of 61.2 ± 11.7 years were included. The parafoveal GCL-IPL thickness of the PPV group was significantly reduced, with respect to fellow eyes, at three and 12 months ( A rec6 months . NeverthThe recent advent of spectral-domain optical coherence tomography (SD-OCT) has allowed the detection of microstructural changes in the retinal layers of reattached retina. Previous studies, using SD-OCT in this setting, mainly focused on the outer retinal changes ,6, whereIn the present paper, using SD-OCT automated segmentation, we evaluated macular ganglion cell layer–inner plexiform layer (GCL-IPL) thickness in patients with primary macula-off RRD treated with scleral buckling or pars plana vitrectomy compared to non-treated fellow eyes.The present investigation was an institutional retrospective study with fellow-eye comparison. The study was approved by the ethical board of the Sapienza University of Rome and was conducted in accordance with the tenets of the Declaration of Helsinki. All patients gave written informed consent to the study. We reviewed the medical records of patients who underwent anatomically successful repair for primary RRD treated with SB or PPV performed by a single experienced retinal surgeon (MG) at the Ophthalmology Unit of the Policlinico Umberto I University Hospital of Rome, from January 2013 to January 2018. The inclusion criteria were: (1) primary macula-off RRD successfully repaired by a single uncomplicated SB or PPV surgical procedure, and (2) a follow-up at least 12 months after surgery. Only patients with clear ocular media were included in this study  according to the Lens Opacities Classification System III [Exclusion criteria in the treated and fellow eye were as follows: (1) macular pathologies such as age-related macular degeneration or any disease affecting the vitreo-macular interface, e.g., epiretinal membrane and macular hole, (2) presence of glaucoma or intraocular pressure above 18 mmHg during follow-up, (3) diabetes or history of retinal vascular occlusion, (4) previous intraocular surgery other than uncomplicated cataract surgery, (5) any further surgery during the follow-up period including cataract surgery, (6) history of uveitis or any ocular pathology, other than non-complicated RRD, (7) spherical equivalent beyond three diopters and axial length above 26.5 mm or below 22 mm, (8) any proliferative vitreo-retinopathy, and (9) low-quality (<25 units) or unreliable OCT images. All patients in the SB group underwent encirclage with a 240-silicone band, external subretinal fluid drainage and cryotherapy application to the retinal break(s). A circumferential silicone scleral explant was finally positioned to close the break(s).A 23-gauge vitrectomy was performed in all cases of the PPV group, using the EVA Phaco-Vitrectomy System . After core vitrectomy, following creation or confirmation of posterior vitreous detachment, peripheral vitrectomy and vitreous base shaving was performed with scleral indentation using a non-contact wide-viewing system. Endophotocoagulation was applied to all the retinal breaks after perfluorocarbon liquid (PFCL)/air exchange. Air/gas exchange with 12% C3F8  was performed at completion of the procedure. In phakic eyes standard phacoemulsification and intraocular lens implantation was performed before vitrectomy. In the clinical setting of our tertiary center the decision to perform SB or PPV depends mainly on the presence of media opacity as well as on the number and location of retinal break(s).As part of a standardized protocol, all patients underwent a complete ophthalmological evaluation including ocular biometry  and SD-OCT, both before and after surgery at three and 12 months.Preoperative data collection included a complete medical and ophthalmic history, best-corrected visual acuity (BCVA), axial length, spherical equivalent, lens status, intraocular pressure (IOP) and time from onset of symptoms to surgery. The characteristics of the RDs and the presence of macular involvement were evaluated by binocular indirect ophthalmoscopy and OCT. BCVA was measured using the standardized, 70-letter Early Treatment Diabetic Retinopathy Study (ETDRS) chart  at a 4-m distance. For statistical analysis, both preoperative and postoperative BCVA was analyzed on a logarithm of the minimal angle of resolution scale (logMAR). LogMAR values of 1.85 and 2.30 were assigned for counting fingers and hand motions vision at 2 feet, respectively.SD-OCT  records included near infrared images and macular scans with the raster 20° × 20°, 19-line scan protocol with an interval between scans of 240 μm and 100 frames averaged for each scan. Active eye-tracking  and automated follow-up scan  were used to enable point-to-point correspondence between consecutive follow-up scans. The automated segmentation protocol of the Spectralis OCT  was used to measure retinal thicknesses of the GCL and IPL layers according to the OCT Consensus guidelines for landmarks in OCT . Two expt-test with Levene’s correction. Nonparametric distributed values were analyzed by the Mann–Whitney rank-sum test. Categorical variables were compared using Fisher’s exact test. Bivariate relationships were evaluated by the Spearman coefficient or the Pearson analysis, as appropriate. OCT measurements between treated and fellow eyes were compared using the paired t-test or the Wilcoxon’s signed ranks test, as appropriate. OCT measurements between the SB and PPV group were compared using the analysis of covariance (ANCOVA) including age, axial length, spherical equivalent, RD extent, preoperative intraretinal cysts, duration of symptoms and postoperative IOP, as covariates.Statistical analysis was performed with the SPSS for windows . Normal distribution of data was analyzed by the Kolmogorov–Smirnov test. Parametric variables were compared using the unpaired p-values of <0.05 were considered as statistically significant. Data are reported as mean values ± standard deviation.p > 0.05).We reviewed the medical records of 367 patients with simple primary RRD that were treated between January 2013 and January 2018, of whom 195 patients underwent SB surgery and 172 PPV. Retinal re-detachment was observed in 35 eyes in the SB group and 25 eyes in the PPV group. The retinal re-detachment rate at 12 months was 17.9% and 14.5% in the SB and PPV group, respectively (p > 0.05). Compared to eyes undergoing SB surgery, in the PPV group there was a higher proportion of patients with a retinal detachment involving more than two quadrants (p = 0.03). No further significant differences were observed among the recoded preoperative characteristics. The baseline clinical characteristics of treated and fellow eyes in the SB and the PPV group are shown in A total of 71 eyes of 71 patients  with a mean age of 61.2 ± 11.7 years  were finally included to address the purposes of the present study. Forty eyes underwent SB surgery and 31 eyes underwent PPV. The mean duration of visual symptoms was 7.1 ± 5.5 days . At baseline, there were no significant differences in mean age and sex distribution between groups , whereas no significant difference in the macular GCL-IPL thickness was found between treated and fellow eyes in the SB group. There were no longitudinal changes in macular GCL-IPL thickness in both groups (p > 0.05).The macular 3-mm GCL-IPL thickness of the PPV group was significantly reduced with respect to fellow eyes, at three and 12 months (p > 0.05). During the 12-month follow-up period, there were no differences in postoperative IOP between the SB and PPV group .Further, after adjusting for age, axial length, spherical equivalent, RD extent, preoperative intraretinal cysts, duration of symptoms and postoperative IOP, the macular 3-mm GCL-IPL thickness in the PPV group was significantly reduced with respect to the SB group, both at three and 12 months . Compared to baseline, BCVA improved in both groups up to 12 months after surgery (p < 0.0001). In addition, there were no difference between groups in postoperative BCVA outcome both at three and 12 months (p > 0.05).There were no significant differences in baseline BCVA between the SB and the PPV group , .Finally, in the overall sample of operated eyes, we found a significant correlation between logMAR BCVA outcome and the macular 3-mm GCL-IPL thickness (tively), . PostopeThe present study shows that, compared to fellow eyes, the macular 3-mm GCL-IPL thickness is reduced in PPV but not in SB and that, with respect to eyes treated with SB, there is a significant thinning of the macular 3-mm GCL-IPL layer in eyes treated with PPV. Correlation analysis shows a significant correlation between BCVA outcome and the macular 3-mm GCL-IPL thickness.Experimental models have shown that retinal detachment primarily affects the outer retinal layers with minimal and only late change in the inner retinal layers ,17,18,19In a previous study that analyzed retinal layers thickness after RRD repair, Kim et al. failed to demonstrate significant changes in the inner retinal layers . HoweverOverall, the results of the present study suggest that GCL-IPL thinning is a direct result of PPV surgery. In a previous prospective study, Koutsandra et al. evaluated visual field defects in RD cases treated with SB versus PPV and gas injection, they found that after surgery the retinal functionality of the preoperative attached areas was worse in the PPV group compared to the SB group . In agreIn contrast to our results, Hong et al., in a recent study on 31 RD patients undergoing PPV, found that the thickness of the parafoveal GCL-IPL layer in the treated eyes did not differ significantly from those of the fellow eyes . HoweverThere was no significant difference in visual outcome between SB- and PPV-treated eyes; however, we found a tendency of worse postoperative VA in the PPV group. This finding may be partly explained by the mechanisms mentioned above related to vitrectomy itself and/or to vitreous removal with loss of its protective and antioxidant function. However, we can certainly not exclude that our results could have been confounded by selection bias related to differences in the preoperative characteristics of RDs. In the clinical setting of our center, the decision to perform SB or PPV depends mainly on the presence of media opacity and the number and location of retinal breaks. Therefore, compared to SB eyes, PPV-treated eyes probably had a higher rate of multiple breaks and more posterior breaks. Further, in the PPV group there was a higher proportion of RD involving more than two quadrants. Interestingly, we found an overall significant correlation between VA outcome and the macular 3-mm GCL-IPL thickness up to 12 months after RRD repair. While many studies have analyzed the relation of visual outcome after RRD repair with the outer retina, few have assessed the inner retinal layers. Similar to our findings, a previous study  evaluatiOverall, our results seem to show that, with respect to SB surgery, vitrectomy may affect the GCL-IPL layer. Albeit, the macular GCL-IPL thinning in PPV eyes does not seem to significantly influence the final visual acuity, it may underpin a functional involvement at the level of retinal sensitivity as observed previously by static automated perimetry . Thus, iThe strengths of this work are the application of strict inclusion and exclusion criteria and the use of the automated segmentation software of the Spectralis SD-OCT that showed excellent repeatability and reproducibility . The shoIn conclusion, we demonstrated GCL-IPL thinning in eyes with macula-off RRD treated with vitrectomy while no changes were observed in those undergoing scleral buckling surgery. We postulated that these findings could be attributed to additional traumatizing factors related to vitrectomy. These results need to be confirmed in future investigations with a larger study population.


Plasmodium falciparum in pregnancy can result in adverse maternal and fetal sequelae. This review evaluated the adherence of the national guidelines drawn from World Health Organization (WHO) regions, Africa, Eastern Mediterranean, Southeast Asia, and Western Pacific, to the WHO recommendations on drug treatment and prevention of chloroquine-resistant falciparum malaria in pregnant women.Malaria caused by Thirty-five updated national guidelines and the President’s Malaria Initiative (PMI), available in English language, were reviewed. The primary outcome measures were the first-line anti-malarial treatment protocols adopted by national guidelines for uncomplicated and complicated falciparum malaria infections in early (first) and late (second and third) trimesters of pregnancy. The strategy of intermittent preventive treatment of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) was also addressed.This review evaluated the treatment and prevention of falciparum malaria in pregnancy in 35 national guidelines/PMI-Malaria Operational Plans (MOP) reports out of 95 malaria-endemic countries. Of the 35 national guidelines, 10 (28.6%) recommend oral quinine plus clindamycin as first-line treatment for uncomplicated malaria in the first trimester. As the first-line option, artemether–lumefantrine, an artemisinin-based combination therapy, is adopted by 26 (74.3%) of the guidelines for treating uncomplicated or complicated malaria in the second and third trimesters. Intravenous artesunate is approved by 18 (51.4%) and 31 (88.6%) guidelines for treating complicated malaria during early and late pregnancy, respectively. Of the 23 national guidelines that recommend IPTp-SP strategy, 8 (34.8%) are not explicit about directly observed therapy requirements, and three-quarters, 17 (73.9%), do not specify contra-indication of SP in human immunodeficiency virus (HIV)-infected pregnant women receiving cotrimoxazole prophylaxis. Most of the guidelines  state the recommended folic acid dose.Several national guidelines and PMI reports require update revisions to harmonize with international guidelines and emergent trends in managing falciparum malaria in pregnancy. National guidelines and those of donor agencies should comply with those of WHO guideline recommendations although local conditions and delayed guideline updates may call for deviations from WHO evidence-based guidelines. Plasmodium falciparum in pregnancy can result in adverse maternal and fetal sequelae [P. falciparum sequestration into intervillous spaces, and enhances the opsonic clearance of parasitized erythrocytes [Malaria caused by sequelae . Pregnansequelae –3. Howevsequelae –3. Placesequelae , 5. Immuhrocytes –7.The symptoms and sequelae of malaria in pregnancy vary according to the severity of transmission of malaria and levels of immunity acquired by individuals . For areprimigravidae and multigravidae are equally susceptible [In areas with low (unstable) malaria transmission , pregnant women appear to have low antibody-mediated immunity to malaria infection: they are more likely to develop severe malaria syndrome with cerebral malaria, hypoglycaemia and respiratory distress . In suchceptible . IPTp-SPP. falciparum, maternal and fetal adverse events, safety concerns, and treatment cost-effectiveness [The rational use of anti-malarial drugs for treating of falciparum malaria in pregnancy in each country is determined by several variables that include therapeutic efficacy of drugs against tiveness . Only antiveness . Physioltiveness . WHO-rectiveness  are presby Plasmodium vivax in Asia–Pacific regions is, although considered benign, associated with adverse pregnancy outcomes and requires prompt and effective management with parenteral artesunate as for severe falciparum malaria [P. vivax) or chloroquine (in countries where chloroquine is the treatment of choice) [Plasmodium knowlesi appears to be more severe than infections by other non-falciparum species and is treated as for falciparum infection [Malaria caused  malaria , 12. Folnfection .P. falciparum in pregnancy, specifically to include:uncomplicated malaria in the first trimester;uncomplicated and complicated malaria in the second and third trimesters;complicated malaria during all trimesters;chemoprophylaxis of malaria in pregnancy in moderate-to-high transmission areas.This review aims to evaluate critically the degree to which national guidelines comply with WHO recommendations  to treatIn this review, the focus is on falciparum malaria and not on other species common in some of the countries reviewed in view of the magnitude of the problem due to implications on perinatal morbidity and mortality, emergent anti-malarial resistance and updates on drug therapy recommendations.National and international malaria treatment guidelines were retrieved using PubMed Medical Subject Heading terms: “guidelines” and “malaria”. The Worldwide Web via Google was used with the following phrases: malaria treatment guidelines followed by the country name  or organizations such as WHO, US Centers for Disease Control and Prevention (US CDC) and President’s Malaria Initiatives (PMI)-Malaria Operational Plans (MOP). The data analysis was limited to publications, literature and reports from December 2012 onwards about 2 years after the release of the second edition of WHO Guidelines for Treatment of Malaria . It was Updated national guidelines emerged 2012 onwards and PMI-MOP reports for 2018–2019 published in English were included. Based on WHO regional classification , countriExcept for malaria chemoprevention in pregnancy, there was no significant difference between the 3rd  and 2nd According to WHO recommendations on treatment of chloroquine-resistant falciparum malaria in pregnant women, the primary outcome measures evaluated were: (1) first-line drugs for treating either uncomplicated or complicated (severe) malaria infection during any trimesters of pregnancy; (2) IPTp-strategy with SP combination, guidance on folic acid supplementation and concomitant IPTp-SP with cotrimoxazole in HIV-positive pregnant women.The authors independently carried out an assessment of outcome measures in a non-blinded standardized manner. Any discrepancy was resolved in consultation with another clinical pharmacologist.PMI is a US Government initiative, one of the largest international sources of funding to control and eradicate malaria in PMI-supported countries. PMI works in partnership with host-country governments in SSA and GMS to: (a) provide effective therapeutic and prophylactic intervention to those at risk of malaria; (b) develop annual MOPs; and, (c) complement and expand malaria monitoring and evaluation strategies .A total of 38 international and national guidelines and updated PMI-MOP reports fulfilled the inclusion criteria. WHO region-wide breakdown of the 35 national guidelines/reports was as follows: SSA: 25, Eastern Mediterranean: 3, Southeast Asia: 5, Western Pacific region: 2.Contrary to WHO recommendations , oral quAs first-line treatment, artemether-lumefantrine (AL), an SPC, was the most common artemisinin-based combination recommended by 26/35 (74.3%) guidelines for treating uncomplicated malaria in second and third trimesters, and as the preferred option for completing treatment following parenteral artesunate/quinine for complicated malaria in second and third trimesters. The proportion of national guidelines/PMI reports that adopted oral quinine or quinine plus clindamycin for completing of initial parenteral quinine for complicated malaria in first trimester was 12/35 (34.3%) and 3/35 (8.6%), respectively (Table Intravenous artesunate has been approved by 18/35 (51.4%) and 31/35 (88.6%) of guidelines/reports for treating severe malaria in early (first trimester) and late (second and third trimesters) of pregnancy, respectively Table .Of the 23 guidelines/PMI reports to implement IPTp-SP strategy, emphasis on DOT was overlooked by 8 (34.8%). The standard dose of folic acid (400 µg daily) recommended by WHO Guidelines was adopted by 18/23 (78.3%) of SSA countries that implemented IPTp-SP strategy  that may compromise therapeutic efficacy, is a concern with a 3-day course of AL in treating malaria during late pregnancy , 50. TheP. falciparum and to be at least twice the minimum parasiticidal concentration on day 7 after the start of treatment in order to optimize the cure rates and to reduce the emergence of resistance and early stages of gametocyte development [The oral bioavailability of lumefantrine, a lipophilic drug, is enhanced if it is administered along with milk or fat-rich meal . Fat-ricelopment . Ingestielopment , Saudi Aelopment , South Aelopment , and Srielopment , the vasSevere malaria in pregnancy needs a fast-acting and very effective treatment to save the mother’s life so that the risk/benefit equation overcomes any concerns about the safety of parenteral AS. Artesunate is first-line anti-malarial drug recommended for treatment of complicated (severe) malaria in all trimesters of pregnancy by international guidelines , 56, basWhereas 18 of 35 (51.4%) of the reviewed guidelines/PMI reports have adhered to international guidelines regarding intravenous artesunate as a first-line option for treating complicated malaria in first trimester of pregnancy , almost Based on robust evidence, WHO , 9 has pThe requirement to administer daily dose of folic acid in the IPTp-SP strategy merits further attention. The recommended dose of folic acid in early pregnancy (400 µg daily) along with iron is for prevention of maternal anaemia. However, women with high risk or family history of neural tube defects should receive 5000 µg (5 mg) daily instead, to prevent neural tube defects, ideally administered before pregnancy, but if in first trimester when it would not conflict with IPTp since it is not recommended in the first trimester. The therapeutic dilemma over folic acid is among those women who have severe anaemia, especially associated with risk of severe malaria, who may require iron and higher dose of folic acid in excess of the usual recommended dose; WHO Guidelines are not clear on how this should be managed. According to WHO recommendations , folic aPneumocystis jirovecii opportunistic infection [P. falciparum [Falciparum malaria in pregnancy causes several harmful severe effects on maternal and fetal outcomes. WHO IPTp-SP strategy is recommended to prevent or mitigate malaria-related outcomes . In pregnfection . Of notenfection . WHO IPTlciparum . Howeverlciparum . Therefolciparum , and morlciparum . Howeverlciparum . Despitelciparum , the natFirst, non-inclusion of several national guidelines of Eastern Mediterranean and Asian countries known to be endemic with malaria such as Yemen, Syria, Iran, Iraq, Pakistan, and Afghanistan; second, non-inclusion of Francophone countries in North Africa, and Hispanophone and Lusophone countries of PAHO in Central and South America eliminated the national guidelines of many countries with high malaria prevalence.This review revealed that most of the revised national guidelines/PMI-MOP reports are non-compliant to WHO Guidelines recommendations. Two-third of the revised guidelines have adopted oral quinine monotherapy to treat uncomplicated malaria during first trimester, instead of quinine plus clindamycin combination recommended by WHO Guidelines. Among ACT, three-quarters of guidelines for uncomplicated and complicated malaria recommend AL during second and third trimesters. A few of the guidelines continue to recommend intravenous quinine instead of artesunate for treating complicated malaria infections in late pregnancy in spite of potential high risk of refractory and fatal hypoglycaemia. Some countries have been slow to adopt parenteral artesunate at all, unrelated to specific concerns around safety in pregnancy.Contrary to WHO recommendations, half of the guidelines recommend intravenous quinine instead of artesunate for treating complicated malaria in first trimester, most likely due to drug cost considerations. As a component of IPTp-SP strategy, DOT has been overlooked by one-third of the guidelines that recommend IPTp-SP policy. Three-quarters of the revised guidelines have overlooked the contra-indication of IPTp-SP implementation in HIV-co-infected pregnant women receiving cotrimoxazole prophylaxis. These lacunae in the guidelines of several countries must be addressed by policymakers to comply with current evidence-based international guidelines.


Background: Suboptimal care transitions increases the risk of adverse events resulting from poor care coordination among providers and healthcare facilities. The National Transition of Care Coalition recommends shifting the discharge paradigm from discharge from the hospital, to transfer with continuous management. The patient centered medical home is a promising model, which improves care coordination and may reduce hospital readmissions. Methods: This is a quality improvement report, the geriatric patient-aligned care team (GeriPACT) at Tennessee Valley Healthcare System (TVHS) participated in ongoing quality improvement ) cycles during teamlet meetings. Post home discharge follow-up for GeriPACT patients was provided by proactive telehealth communication by the Registered Nurse (RN) care manager and nurse practitioner. Periodic operations data obtained from the Data and Statistical Services (DSS) coordinator informed the PDSA cycles and teamlet meetings. Results: at baseline (July 2018–June 2019) the 30-day all-cause readmission for GeriPACT was 21%. From July to December 2019, 30-day all-cause readmissions were 13%. From January to June 2020, 30-day all-cause readmissions were 15%. Conclusion: PDSA cycles with sharing of operations data during GeriPACT teamlet meetings and fostering a shared responsibility for managing high-risk patients contributes to improved outcomes in 30-day all-cause readmissions. The cost of unplanned all-cause 30-day hospital readmissions to the Medicare program is estimated at over $12 billion yearly [Suggestions for improvement have been advanced by the National Transitions of Care Coalition, a work group convened by the Patient-Centered Outcomes Research Institute (PCORI) identified eight transitional care components and operational strategies to enhance transitional care, based on real-world patient and caregiver experiences. The categories included (1) patient engagement, (2) caregiver engagement, 3) complexity/medication management, (4) patient/caregiver education and respecting caregiver role, (5) patient and caregiver well-being, (6) care continuity, (7) accountability of clinician, team, and caregiver, and (8) clinician and team organization [ complexiThe patient centered medical home is a promising model, which includes many of these components and may reduce hospital readmissions.We describe our experience implementing this model with a goal of improving post-hospital transitions of care.My healthevet, with telemedicine capabilities. Data were collected by chart review with operations data extracted. The Department of Veterans Affairs (VA) operates Tennessee Valley Healthcare System (TVHS), an integrated healthcare system of over 100,000 patients in Middle Tennessee comprised of 2 medical centers located 40 miles apart, and 12 community-based outpatient clinics. In 2011, TVHS developed a geriatric patient-centered medical home model for geriatric primary care—the geriatric patient-aligned care team (GeriPACT) . The GerRisk Stratification: the clinical assessment of need (CAN) is a clinical predictor of future hospitalization and death developed for VA populations . This meIn July 2019, GeriPACT at TVHS participated in rapid-cycle (RCQI)  ongoing Plan—plan the test for observation, including a plan for collecting data, state the objective of the test;Do—try out the test on a small scale, document problems, and observations;Study-check—analyze the data, compare the data to previous experience and reflect on what was learned;Act—refine the change based on what was learned from the test, determining what modification should be made and develop a plan for the next test.Quality Improvement (QI)Process: Plan, Do, Study, Act (PDSA) cycles, originally described by Deming of Bell Laboratories, were adopted to introduce quality improvement into primary care. Deciding on a topic important to the practice, implementing, and measuring change can help the teamwork collectively to achieve common goals. PDSA Cycles include the following components:Hospital case managers notified GeriPACT daily about VA Hospital discharges to home. Post home discharge follow-up for patients was provided by proactive telehealth communication (phone and video connect) by the RN care manager and nurse practitioner, preventing potential gaps in care by addressing medication reconciliation, referrals and follow-up appointments, goals of care, advance directive completion, home and community-based resources, and caregiver concerns. Approximately 6 open access visits per week were generated after contacting patients. Periodic operations data obtained from the Data and Statistical Services Coordinator informed the PDSA cycles and teamlet (treatment team) meetings.The Merit-Based Incentive Payment System (MIPS), Medicare, Quality Measure 356 is defined as Measure Description—Numerator: total number of unique GeriPACT patients > age 65 with all-cause re-admissions to TVHS within 30 days of discharge during the measurement period. Denominator: total number of index hospitalizations that occurred during the measurement period  .This is a quality improvement report and has been informed by the Standards for QUality Improvement Reporting Excellence (SQUIRE) criteria , and thiResults include pre- and post-intervention data of numbers of unique individuals over age 65 having a repeat hospitalization at TVHS within 30 days, divided by the total number of index hospitalizations . At baseline (July 2018–June 2019) the 30-day all-cause readmission for GeriPACT was 41/191 (23%). From July to December 2019, 30-day all-cause readmissions were 13/101 (18%). From January to June 2020, 30-day all-cause readmissions were 12/79 (15%). A randomized trial including 3054 patients showed no evidence of an impact on 30-day readmissions from a hospital-managed nurse follow-up telephone call program within 3 to 7 days of discharge, designed to assess understanding and provide education and assistance to support discharge plan implementation, but not provide ongoing continuity of care . GeriPACLimitations: this study was conducted at a Veterans Health Administration facility and conclusions may not be directly applicable to other settings. However, our results may encourage development of patient centered medical homes in other healthcare systems. While all patients utilized the VA as a primary source of care, we could not account for potential patients admitted to community hospitals. Only home discharges from the VA hospital were included in the intervention. Our project overlapped the COVID  pandemic, and while this did not influence the telehealth intervention, we cannot determine its effect on patient decisions to seek hospital care.PDSA cycles with sharing of operations data during GeriPACT teamlet meetings and fostering a shared responsibility for managing high-risk patients contributes to improved outcomes in 30-day all-cause readmissions.


Is the recently developed ABC –bleeding risk score for patients with atrial fibrillation (AF) useful to identify patients with different risks of bleeding during concomitant aspirin and anticoagulation therapy?This cohort study examined a total of 24 349 patients with AF from 2 randomized clinical trials and found that the ABC-bleeding risk score identified patients with different risks of bleeding when combining aspirin and oral anticoagulation.The ABC-bleeding risk score may be a useful tool for decision support concerning intensity and duration of combination antithrombotic treatment in patients with AF and coronary artery disease. This cohort study evaluates whether the ABC –bleeding risk score might be useful to identify patients with atrial fibrillation (AF) who have different risks of bleeding during concomitant aspirin and anticoagulation therapy. Most patients with atrial fibrillation (AF) and coronary artery disease have indications for preventing stroke with oral anticoagulation therapy and preventing myocardial infarction and stent thrombosis with platelet inhibition.To evaluate whether the recently developed ABC –bleeding risk score might be useful to identify patients with AF with different risks of bleeding during concomitant aspirin and anticoagulation therapy.The biomarkers in the ABC-bleeding risk score  were measured in blood samples collected at randomization between 2006 and 2010 in the ARISTOTLE  trial and between 2005 and 2009 in the RE-LY  trial, both of which were multinational randomized clinical trials. The trials were reported 2011 and 2009, respectively. A total of 24 349 patients with AF  were analyzed in the present cohort study. The median (interquartile range) length of follow-up was 1.8 (1.3-2.3) years in the ARISTOTLE cohort and 2.0 (1.6-2.3) years in the RE-LY cohort. Data analysis was performed from February 2018 to June 2019.Concomitant aspirin treatment during study follow-up.Time to first occurrence of a major bleeding was determined according to International Society on Thrombosis and Hemostasis definition. Hazard ratios were estimated with Cox models adjusted for ABC-bleeding risk score and randomized treatment.P < .001; RE-LY, hazard ratio, 1.70; 95% CI, 1.42-2.04; P < .001). Thus, a low annual ABC-bleeding risk  would with concomitant aspirin result in an annual rate of 0.8%, and a high estimated ABC-bleeding risk  would result in a substantially higher rate of 5.0%.The median (interquartile range) age was 70 (63-76) years in the ARISTOTLE cohort and 72 (67-77) years in the RE-LY cohort (5238 patients [35.6%] in the ARISTOTLE cohort and 3086 patients [36.4%] in the RE-LY cohort were women). The total number of patients with a first major bleeding event was 651 (207 with aspirin and 444 without) in ARISTOTLE and 463 (238 with aspirin and 225 without) in RE-LY. For both cohorts, in those with a low ABC-bleeding risk score, the absolute bleeding rate was low even with concomitant aspirin treatment, whereas in those with a higher ABC-bleeding risk score, the rate of bleeding was higher with concomitant aspirin compared with oral anticoagulation alone (ARISTOTLE, hazard ratio, 1.65; 95% CI, 1.40-1.95; These findings suggest that the ABC-bleeding risk score identifies patients with different risks of bleeding when combining aspirin and oral anticoagulation. The ABC-bleeding risk score may, therefore, be a useful tool for decision support concerning intensity and duration of combination antithrombotic treatment in patients with AF and coronary artery disease. However, current bleeding risk scores provide limited guidance in the setting of AF and concomitant CAD.5 Recently, the ABC –bleeding risk score was developed and validated in patients with AF receiving oral anticoagulation therapy for estimation of major bleeding events.7 The biomarker-based ABC-bleeding risk score outperformed other risk scores based on clinical variables, such as the HAS-BLED  score. Importantly, the ABC-bleeding risk score was also shown to be well-calibrated in several cohorts of patients with AF.8 The ABC-bleeding score has, therefore, been mentioned in the recent European AF and Dual Antiplatelet Therapy guidelines2 as a possible tool to estimate risk of major bleeding in patients with AF. In this cohort study, we evaluated whether the ABC-bleeding risk score might be useful to identify patients with different risks of bleeding during concomitant antiplatelet (aspirin) and anticoagulation therapy based on 9369 patients from the RE-LY  trial9 and 14 980 patients with AF from the ARISTOTLE  trial.10 We hypothesized that the biomarker-based ABC-bleeding risk score can differentiate between the bleeding risk in patients with AF taking oral anticoagulation and concomitant aspirin.In patients with atrial fibrillation (AF) and coronary artery disease (CAD), there are indications for preventing stroke with oral anticoagulation therapy and preventing myocardial infarction (MI) and stent thrombosis with platelet inhibition.11 Biomarker samples were available at baseline for 14 697 participants, with a median (interquartile range) length of follow-up of 1.8 (1.3-2.3) years. The RE-LY trial randomized 18 113 patients with AF to dabigatran or warfarin and was reported in 2009.12 Biomarker samples were available at baseline for 8468 participants, with a median (interquartile range) length of follow-up of 2.0 (1.6-2.3) years. Overall, both the ARISTOTLE and RE-LY biomarker cohorts were representative of each respective study cohort and have been described in detail elsewhere.14 Institutional review board or ethics committee approval was obtained at all sites for both trials, and all patients provided written informed consent, including consent for the biomarker substudy program. This study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.The ARISTOTLE trial randomized 18 201 patients with AF and an increased risk of stroke to warfarin or apixaban and was reported in 2011.10 Blinded clinical event committees reviewed and centrally adjudicated the outcome events.In both the ARISTOTLE and the RE-LY trials, the primary safety outcome was major bleeding defined according to the International Society on Thrombosis and Hemostasis.17In both the ARISTOTLE and RE-LY studies, blood samples were collected at randomization into EDTA tubes and immediately centrifuged, frozen in aliquots, and stored at −70 °C until analyzed centrally at the Uppsala Clinical Research Center laboratory in Uppsala, Sweden. High-sensitive cardiac troponin T and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) were analyzed with high-sensitivity immunoassays on the Cobas Analytics e601 (Roche Diagnostics), and growth differentiation factor–15 (GDF-15) levels were detected with the Elecsys growth differentiation factor–15 precommercial assay kit P03 with the same standardization as the recently introduced routine reagent (Roche Diagnostics). All analyses were performed according to the instructions of the manufacturer and have been described elsewhere.All patients with no missing values for the variables included in the ABC-bleeding score  measured at baseline were included in the analyses. The ABC-bleeding score was defined in this study as the estimated 1-year major bleeding risk.18The consistency of the ABC-bleeding score with concomitant aspirin use was assessed using a Cox regression model. The model included aspirin use and the estimated 1-year ABC-bleeding risk as a restricted cubic spline, with 4 knots placed at the 5th, 35th, 65th, and 95th sample percentiles, and the interaction between aspirin status and the linear part of the ABC-bleeding risk. If the test of the interaction was not significant, a model excluding the interaction term was fitted to estimate the relative hazard of bleeding according to aspirin use. The fitted model was also used to estimate the absolute increase in bleeding for 2 examples of low (0.5%) and high (3.0%) ABC-bleeding risks without aspirin. These examples were chosen because there are no established cutoffs for low or high annual major bleeding risks in patients with AF; previously, risks below 1% and above 2% have been indicated, although not established.7In the ARISTOTLE trial, aspirin use was recorded continuously during follow-up and was therefore included as a time-updated covariate in the model. In the RE-LY trial, a patient was assumed to be taking aspirin if she or he was taking aspirin at any time during follow-up. The models did not include any further adjustment for confounders because the ABC-bleeding risk score already incorporates the main risk factors for major bleeding and further adjustment would not be expected to improve the model.Nevertheless, in a sensitivity analysis of the ARISTOTLE data, a Cox regression model including potential baseline and time-updated confounders was fitted. Baseline variables included age, sex, diabetes, hypertension, history of MI, history of peripheral arterial disease, and history of vascular disease. Postrandomization variables included whether the patient was currently taking the study drug, MI, angina, percutaneous coronary intervention, coronary stenting, nonmajor bleeding and interactions between prior MI and nonmajor bleeding, MI and nonmajor bleeding, study drug and angina, study drug and percutaneous coronary intervention, and nonmajor bleeding. The results were materially unaltered compared with the unadjusted model; therefore, we only present the results from the simpler model. Furthermore, the 3-way interaction between the ABC-bleeding risk score, aspirin use, and study treatment was evaluated by fitting a Cox model including the ABC-bleeding risk score, a treatment combination variable  and the interaction between the ABC-bleeding risk score and the treatment combination variable.7Results from all models are presented graphically as plots of hazard ratios (HRs) with an arbitrary reference point set to 2.0% 1-year ABC-bleeding risk in the no-aspirin group. The ABC-bleeding and HAS-BLED risk scores were calculated according to previously described methods.P < .05 denoting statistical significance. All analyses were done using R statistical software version 3.6.1 . Data analysis was performed from February 2018 to June 2019.All tests were 2-sided, with 4 In the RE-LY cohort, the proportion of patients taking concomitant aspirin at any time during follow-up was 36.4% (3413 patients). In both cohorts, a higher proportion of patients receiving concomitant aspirin had vascular disease . The presence of diabetes was also more common in patients with concomitant aspirin. Patients with prior vitamin K antagonist use were more common in the group without concomitant aspirin.A total of 24 349 patients with AF were analyzed in the present cohort study. The median (interquartile range) age was 70 (63-76) years in the ARISTOTLE cohort and 72 (67-77) years in the RE-LY cohort; 5238 patients (35.6%) in the ARISTOTLE cohort and 3086 patients (36.4%) in the RE-LY cohort were women. The characteristics according to concomitant aspirin use or no aspirin use are shown in P value for the test of the null hypothesis of no multiplicative interaction was .07. In a model without the interaction term, adjusted for ABC-bleeding risk score and randomized treatment, concomitant aspirin treatment increased bleeding significantly . Thus, a low ABC-bleeding risk score without aspirin  would with concomitant aspirin result in an annual rate of 0.8%, and a high estimated ABC-bleeding risk score without aspirin  would result in a substantially higher absolute annual rate for major bleeding of 5.0%.The total number of patients with a first major bleeding event was 651 (207 while taking aspirin and 444 while not taking aspirin) during 24 903 person-years of follow-up. The annual rate of major bleeding during follow-up was higher in patients taking aspirin than in those not taking aspirin (4.04% vs 2.24%) . The botThe observed event rate for major bleeding as a function of the ABC-bleeding score by the different combinations of antithrombotic treatment is shown in P for interaction = 0.2). In Cox models adjusted for ABC-bleeding risk score and randomized treatment, concomitant aspirin treatment increased bleeding significantly . Thus, a low ABC-bleeding risk score without aspirin  would with concomitant aspirin result in an annual rate of 0.85%, and a high estimated ABC-bleeding risk score without aspirin,  would result in a substantially higher annual rate for major bleeding of 5.1%.The total number of patients with first major bleeding events was 463 (238 with aspirin and 225 without) during 16 212 person-years of follow-up. The annual rate of major bleeding during follow-up was higher in patients with aspirin than without aspirin (4.18% vs 2.14%) . OverallAlthough limited by a smaller number of events, sensitivity analyses were performed in relation to different oral anticoagulant therapies. The results were similar between the ARISTOTLE cohort  A and theThe risk of major bleeding according to the HAS-BLED score in patients with oral anticoagulation taking aspirin compared with those not taking aspirin are shown in eFigure in the The main findings in this study are that the ABC-bleeding risk score is able to stratify patients with AF receiving the combination of aspirin and oral anticoagulation according to their risk of bleeding. A low estimated risk of major bleeding according to the ABC-bleeding risk score showed a low bleeding risk even with concomitant aspirin treatment, whereas a higher ABC-bleeding risk score was associated with higher bleeding risk. These findings suggest that the ABC-bleeding risk score may be a useful tool for decision support concerning intensity and duration of combination antithrombotic treatment in patients with AF and CAD to improve the risk-benefit balance with different antithrombotic strategies.21 The ABC-bleeding risk score, which includes the most relevant variables, including both biomarkers and clinical data, was developed and validated using robust methods and very large cohorts of patients with AF.23 The ABC-bleeding risk score outperforms traditional risk scores for stroke, death, and major bleeding, in comparison with risk scores based on clinical variables. In addition, the ABC-bleeding risk score has shown to be well calibrated, with estimated risk aligning well with observed risk during follow-up.23 Biomarkers and the ABC-bleeding risk scores in patients with AF have, therefore, been suggested as potential new tools for improved risk estimation in the latest European guidelines for management of AF.1 Similarly, the European Dual Antiplatelet Therapy guidelines refer to, among others, the ABC-bleeding risk score as a possible tool to estimate bleeding risk in patients with AF with an indication for added antiplatelet therapy to assess the bleeding risk and make informed decisions regarding the intensity and duration of concomitant antiplatelet therapy.2 Patients with AF and CAD considered to have a high ischemic risk  should, according to the guidelines, be considered for a more intense and prolonged antithrombotic strategy. If these patients are considered to have a high risk of bleeding, a less intense and shorter duration of concomitant antiplatelet therapy is suggested in the guidelines. To our knowledge, the present study is the first to evaluate the ABC-bleeding risk score in patients with AF and chronic CAD receiving concomitant single-antiplatelet therapy vs oral anticoagulation, and our findings support that the ABC-bleeding risk score is useful for estimating bleeding risk in such patients.The added value of biomarkers for improved risk estimation in patients with AF have so far been rather consistent in several cohorts, including randomized clinical trial cohorts, as well as less selected observational registry cohorts.24 have showed that patients taking NOACs have similar or lower risks of major bleeding in comparison with patients taking warfarin. Furthermore, substudies from these NOAC trials have shown that the risk of major bleeding increases with concomitant use of aspirin, although with preserved safety with NOACs compared with warfarin; for example, even if the risk of major bleeding increases with concomitant antiplatelet therapy in both the NOAC as well as the warfarin groups, the relative risk is still lower with NOACs.27 Nonetheless, in some patients, the risk of ischemic events may warrant a more aggressive antithrombotic treatment strategy. Recent randomized clinical trials have repeatedly highlighted the changing balance between benefits and risks with increasing intensity of antithrombotic treatment. For instance, the COMPASS trial,28 which compared the use of dual therapy (low-dose rivaroxaban in combination with aspirin) with single-antithrombotic therapy  in patients with stable CAD without AF, found that the combination of low-dose rivaroxaban with aspirin significantly reduced the risk of ischemic cardiovascular events. However, this comes at a cost of increased risk of major bleeding events. A similar pattern is also evident early after coronary events  when comparing triple- and dual-antithrombotic therapy strategies in patients with AF.30 These studies consistently show that the risk of clinically relevant, as well as major, bleeding events are substantially lower with less-aggressive antithrombotic treatment strategies .30 However, this might, to varying degrees, come at the price of an increased risk of ischemic events, including stent thrombosis.31 Risk score models that improve the risk stratification concerning bleeding events would thus be useful to better identify patients for whom more intensive antithrombotic therapy is suitable. By providing an individualized treatment strategy, these models would also improve patient outcomes.The landmark non–vitamin K antagonist oral anticoagulant (NOAC) trialsIn the present study, we expanded on previous findings by showing that the biomarker-based ABC-bleeding risk score successfully identifies patients with different risks of bleeding when combining single-antiplatelet therapy with aspirin and oral anticoagulation. The ABC-bleeding risk score may, therefore, be a useful tool for decision support concerning the intensity and duration of combination antithrombotic treatment in patients with AF and stable CAD. However, it is important to keep in mind that concomitant use of aspirin will offset the calibration of the ABC-bleeding score, because the observed risk of bleeding will increase by adding concomitant antiplatelet therapy.NCT03753490) is desirable to fully assess the clinical usefulness of the ABC-bleeding score for better tailoring of antithrombotic treatment strategies.This study has limitations that should be addressed. The patients in the ARISTOTLE trial were clinically stable, and the biomarkers used in the ABC-bleeding risk score, in particular troponin, will be affected in patients with acute coronary syndromes. Thus, the ABC-bleeding risk score should preferably be assessed at a later time point, such as during routine outpatient postdischarge check-up, for the most accurate ABC-bleeding risk estimation. Because antiplatelet therapy was not randomized, there may be confounding by indication, and thus evaluation of ischemic risks was not performed. For the ARISTOTLE data, it was possible to use an advanced statistical model in which aspirin was used as a time-updated covariable. In the RE-LY cohort, the status of concomitant antiplatelet therapy was defined as any time during the study and may not completely reflect the medication during study follow-up. Nevertheless, the results were very consistent between the 2 cohorts. Furthermore, as with every risk score, a prospective evaluation of the risk score such as the ongoing ABC-AF study (ClinicalTrials.gov identifier The ABC-bleeding risk score accurately identifies patients with different risks of bleeding when combining aspirin and oral anticoagulation; low ABC-bleeding risk scores were associated with low bleeding risk, and higher ABC-bleeding risk scores were associated with higher bleeding risk. These data suggest that the ABC-bleeding risk score may provide useful information concerning intensity and duration of combination antithrombotic treatment in patients with AF and stable CAD.


Pain can be difficult to objectively assess in animals, especially in prey animals that hide their symptoms from others. Donkeys are also known to mask and hide these signs. Owners often describe donkeys as “stubborn”, but veterinarians and equine ethologists describe donkeys more as “stoic”. Among veterinarians it is known that donkeys hide their pain symptoms even more than horses. Therefore, objective and valid pain measurement tools are needed to assess pain in donkeys. In this study, two pain scales  have been developed and tested in 79 donkeys with various types of acute pain  and in 185 healthy pain-free control donkeys. The authors found that the Equine Utrecht University Scale for Donkey Composite Pain Assessment (EQUUS-DONKEY-COMPASS) and the Equine Utrecht University Scale for Donkey Facial Assessment of Pain (EQUUS-DONKEY-FAP) can both be effective to objectively assess various types of acute pain in donkeys and could potentially be used to monitor pain and improve welfare in donkeys.n = 12 acute colic, n = 25 acute orthopaedic pain, n = 18 acute head-related pain, n = 24 postoperative pain, and n = 185 controls) was performed. Both pain scales showed differences between donkeys with different types of pain and their control animals (p < 0.001). The EQUUS-DONKEY-COMPASS and EQUUS-DONKEY-FAP showed high inter-observer reliability . Sensitivity of the EQUUS-DONKEY-COMPASS was good for colic and orthopaedic pain , but poor for head-related and postoperative pain . Sensitivity of the EQUUS-DONKEY-FAP was good for colic and head-related pain , but moderate for orthopaedic and postoperative pain . Specificity was good for all types of pain with both scales (91%–99%). Different types of acute pain in donkeys can be validly assessed by either a composite or a facial expression-based pain scale.Objective pain assessment in donkeys is of vital importance for improving welfare in a species that is considered stoic. This study presents the construction and testing of two pain scales, the Equine Utrecht University Scale for Donkey Composite Pain Assessment (EQUUS-DONKEY-COMPASS) and the Equine Utrecht University Scale for Donkey Facial Assessment of Pain (EQUUS-DONKEY-FAP), in donkeys with acute pain. A cohort follow-up study using 264 adult donkeys ( The importance of objective pain assessment in horses and donkeys was reported by Asley, et al. 2005)  and Robe005  and The importance of behavioural parameters to assess welfare and pain in working donkeys and mules was described by Pritchard et al. . They deAlthough it is known that donkeys have certain specific variations that make them different to horses, for example their behaviour, physiology, and susceptibility to disease , they haThe aim of the current study was to develop a composite pain scale for assessment of acute pain in donkeys, the Equine Utrecht University Scale for Donkey Composite Pain Assessment (EQUUS-DONKEY-COMPASS), and a facial expression-based pain scale, the Equine Utrecht University Scale for Donkey Facial Assessment of Pain (EQUUS-DONKEY-FAP). The equine EQUUS-COMPASS and EQUUS_FAP have proved reliable in scientific studies and during practical applications. Therefore, they were combined with the earlier mentioned donkey-specific studies, interviews, and a pilot project as a starting point for the development of the donkey pain assessment scales. As previous work in horses had identified that the sensitivity of different types of pain scales was dependent on the type of acute pain experienced , two difThe institutional Ethics Committee on the Care and Use of Experimental Animals approved the study design in compliance with Dutch and English legislation on animal experimentation. Because the procedures used in this study only consist of behavioural observations and physiologic assessments  that are routinely taken in the clinical setting and are deemed not likely to cause pain, suffering, or distress or lasting harm equivalent to, or higher than, that caused by the introduction of a needle (article 1.5f EU directive 2010/63/EU), ethical approval was granted without a formal application and hence no official approval number was given. Written owner’s consent was obtained for all animals participating in this study. n = 12) (impaction colic or other colic) were enrolled. Orthopaedic cases (n = 25) comprised mainly donkeys with acute laminitis and solar abscesses; the acute head-related injuries/pain (n = 18) cases comprised donkeys with acute uveitis and corneal injuries/ulcers and dental pain, and donkeys in the group of postoperative pain (n = 24) comprised mainly those who had undergone sarcoid removal, castration (n = 7), and dental extractions . More details of the patients can be found in Seventy-nine donkeys presenting with acute pain  that were observed between 2016 and 2018 were enrolled in this study . PatientThe EQUUS-DONKEY-COMPASS is based on the EQUUS-COMPASS that has been described for the assessment of horses with acute colic pain ,16. SincThe EQUUS-DONKEY-FAP is based on the EQUUS-FAP, that has been designed and validated for the assessment of horses with acute colic ,16 and hBefore starting the study, the observers were given training in the use of both pain scales in donkeys without signs of pain (subjects not subsequently included in the study) under the supervision of two of the authors (M.v.D. and T.v.L.). Basically, the same protocol as used in the previous equine studies ,16 was fU tests: none of the patients–control comparisons differed from each other. The possible confounding correlation between age and a pain score was analysed by means of Spearman’s rho , while for postoperative pain the score at T0b (= 4 h after surgery) was used, when it was deemed to be most painful. For the four subgroups of patients, pain scores of patients and pooled control animals were analysed using Mann–Whitney U tests. Data of castration patients (as part of the group of postoperative pain) were analysed separately and compared to control animals. Cut-off values for both pain scales between patients and control animals were determined based on pilot data and were set at ≥5 for EQUUS-DONKEY-COMPASS and ≥2 for EQUUS-DONKEY-FAP to obtain maximal differentiation between donkeys with acute pain and healthy animals. Sensitivity , specificity , and positive and negative predictive values (respectively the probability that pain was indeed present when the test was positive or the probability that pain was indeed not present when the test was negative) were determined using these cut-off values. Weighting factors for individual parameters of both scales were determined using cut-off values of equal or higher than 1 for individual parameters, with weighting factor = 0 if sensitivity or specificity were <25%, weighting factor = 1 if sensitivity and specificity were between 25% and 50%; weighting factor = 2 if sensitivity and specificity were between 50% and 75%; and weighting factor = 3 if both sensitivity and specificity were ≥75%. Effects over time for both pain scores were only displayed visually and not statistically analysed due to differences in group sizes. Statistical analysis was performed using commercially available software . Statistical significance was accepted at p < 0.05. All pain scoring data are expressed as medians and quartiles. Differences in ages between patients and control animals were statistically tested for normality by the Shapiro Wilks test. Since the age was not normally distributed in some subgroups, the distribution of age within all subgroups was tested by means of Mann–Whitney  rho See . All scop < 0.001 for EQUUS-DONKEY-COMPASS, Cronbach´s alpha = 0.94, p < 0.001 for EQUUS-DONKEY-FAP). p values ranged between 0.088 and 0.939 see . All four subgroups of patients showed higher pain scores compared to their control animals for EQUUS-DONKEY-COMPASS and for EQUUS-DONKEY-FAP)   compared to their controls at that time  . When thhat time . n = 7), orthopaedic pain (n = 16), colic pain (n = 7), and postoperative pain . n = 79). For the EQUUS-DONKEY-FAP, overall sensitivity was moderate (57.0%) while overall specificity was high as well , with cut-off values of 5 (COMPASS) and 2 (FAP). Sensitivity values for both colic and orthopaedic pain were 83% and 88%, respectively, in the EQUUS-DONKEY-COMPASS but 17% and 21%, respectively, for head-related pain and postoperative pain. For EQUUS-DONKEY-FAP the sensitivity values for colic and head-related pain were 75% and 78%, respectively, while they were 40% and 50%, respectively, for orthopaedic pain and postoperative pain. For castration patients only, sensitivity was 57.0% for EQUUS-DONKEY-COMPASS and 42.9% for EQUUS-DONKEY-FAP , while overall specificity was high  for the COMPASS scale. On the other hand, the EQUUS-DONKEY-FAP scale differentiated well between the donkeys with acute head-related pain and donkeys with colic and their controls (sensitivity for both >75%). Our findings imply that acute orthopaedic pain would be best assessed with the EQUUS-DONKEY-COMPASS scale, while donkeys with acute head-related pain would be best assessed with the EQUUS-DONKEY-FAP. This corresponds to the findings in horses, where acute head-related pain is best assessed by means of facial expression-based pain scales as well . For donn = 10, COMPASS score 0.9 ± 0.7; FAP score 1.6 ± 2.1 four hours after surgery) or castrations . Additionally, analgesic medication was always provided pre- and post-surgery. These factors could explain why the postoperative patients did not reach high sensitivity in both pain scores. However, when post-castration pain was evaluated separately and compared to their control animals, donkeys did show both increased FAP and COMPASS scores. Both scores were higher compared to control animals, and sensitivity to differentiate between castration pain and control animals increased from 21% to 57% for the COMPASS scores (with a specificity of 100%), while it did decrease somewhat for the FAP scores (sensitivity 50% to 43% with a specificity of 94%). Donkeys in the current study were anaesthetised with protocols including preoperative administration of NSAIDs, general anaesthesia, and intratesticular administration of local anaesthetics. In the study by Dalla Costa et al. [For donkeys with post-operative pain, both scales had difficulties with differentiating patients from control animals. However, different types of surgery with different levels of surgical invasiveness were taken together in this group of animals. Most of the surgeries comprised sarcoid removals  for horses (EquiFacs) has been described by Wathan et al.  and variLimitations of the current study were the fact that direct and unblinded observations were performed by the observers since this study was performed under field conditions . To date, this approach has more often been chosen when clinical studies with horses were conducted and pain behaviour was assessed as well. However, the fact that the observers were aware of the condition that the donkey was experiencing could always influence pain scoring to some extent, because of expectation bias . To dateThe EQUUS-DONKEY-COMPASS and EQUUS-DONKEY-FAP are composite and facial expression-based pain scales that provide valid, rapid, and clinically applicable tools to assess donkeys in acute pain under field conditions. Both scales showed high inter-observer reliability, which enables comparisons between different observers, and therefore also point towards a strong internal consistency of both scales. The EQUUS-DONKEY-COMPASS proved most useful to assess orthopaedic pain and pain after surgical castration, while the EQUUS-DONKEY-FAP proved most useful to assess acute colic and head-related pain in donkeys. In the future, blinded studies with for instance different analgesic treatment regimens could be conducted to further validate carefully selected EQUUS-DONKEY-FAP colic, orthopaedic, or surgical patients and their matched controls.


As the vagus nerve affects both inflammation and specific immune response, we propose that vagus nerve stimulation by invasive or non-invasive devices and acupuncture at ST36, PC6, or GV20, are also feasible approaches to activate the CAP and control COVID-19. It is worth to investigate the efficacy and safety of the strategy in patients with COVID-19.The outbreak of coronavirus disease 2019 (COVID-19) underlined the urgent need for alleviating cytokine storm. We propose here that activating the cholinergic anti-inflammatory pathway (CAP) is a potential therapeutic strategy. However, there is currently no approved drugs targeting the regulatory pathway. It is evident that nicotine, anisodamine and some herb medicine, activate the CAP and exert anti-inflammation action  A novel human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been rapidly spreading across the world. SARS-CoV-2 is a single-strand, positive-sense, RNA virus and shares ~79% similarity of the genome sequence with human severe acute respiratory syndrome coronavirus (SARS-CoV) , 2. WHO To date, no drugs have proven effective in reducing mortality, although some showed benefits in improving symptoms and shortening course. The Food and Drug Administration (FDA) has issued an emergency-use authorization (EUA) of remdesivir as the first drug approved to treat COVID-19 on Oct. 22, 2020 . HoweverAccumulating evidence showed clinical and laboratory features of a cytokine storm syndrome in patients with severe COVID-19 . CytokinThe existing, approved drugs with inflammation suppression are proposed as therapeutic options. Corticosteroids are getting special attention. However, their effects are still debatable, because they not only suppress lung inflammation but also impair the immune system’s ability to fight viruses. Clinical data did not support survival benefit from corticosteroids use in patients with coronavirus infection including SARS-CoV-2, even there are several possible harms  . Severalvia adrenergic receptors (AR), and promotes the production and release of T cell-derived acetylcholine (ACh). The ACh then interacts with α7 subunit-containing nicotinic receptor (α7nAChR) on macrophages and other immune cells, inhibits the release of pro-inflammatory cytokines and protects the body against damage. The efferent arm of this ‘inflammatory reflex’ is the CAP . It could sharply reduce the mortality rate of various sepsis in clinic, such as fulminant epidemic meningitis, toxic bacillary dysentery, lobar pneumonia, etc. , 54.Many mechanisms for the anti-shock action of anisodamine were proposed. Ruan et al. found anti-shock effect of anisodamine might be related to its anti-inflammation action . It can via the α7nAChR  COVID-19 and sticky phlegm in the lung: It was found a lot of sticky phlegm in the bronchioli and alveoli in COVID-19 death autopsy in China, which might be one of important lethal cause . Accordi α7nAChR , amelior α7nAChR . The α7nAs a muscarinic antagonist, the adverse effects of anisodamine include reducing salivation, lacrimation and sweat, diminishing gastrointestinal motility, mydriasis, and increasing heart rate, which is tolerable and will disappear within 1–3 h . The usuMany herbs have proven effective in the treatment of inflammatory diseases. With the development of modern medicine, their action mechanisms have been gradually determined. Especially, accumulating evidence showed that CAP plays a critical role in the anti-inflammation effect of some herbs, which provides the theoretical basis of modern medicine for their usage in COVID-19 infection.1) Huang-Lian-Jie-Du decoction (HLJDD) is a Chinese formulation, and composed of rhizoma coptidis, radix scutellariae, cortex phellodendri, and fructus gardenia . It has Qing-Fei-Pai-Du decoction (QFPDD) was the most widely used prescription in China’s campaign to contain COVID-19 . ClinicaVNS may act as a physical approach to treat COVID-19 infection by activating intrinsic CAP , 91, 92.VNS is already approved by FDA for the treatment of drug-resistant epilepsy and depression. The first device for VNS is invasive, which needs an electrode surgically implanted in the neck around the left vagus nerve . ClinicaSuch invasive VNS involves an additional intervention with surgical exposure of the vagus nerve. Most of the cases will encounter no problems. Perioperative complications of VNS are mostly related with cardiac dysrhythmias, which could be adjusted by elongating the off period . For sevNon-invasive VNS devices (nVNS) has become the latest hot spot in recent years and are widely used for sick individuals with relative safety and tolerability, such as GammaCore and NEMOS . GammaCovia α7nAChR-mediated CAP  is an external device that provides transcutaneous VNS (tVNS) by using a dedicated intra-auricular electrode (like an earphone) which stimulates the auricular branch of the vagus nerve . Studiesated CAP , indicatAcupuncture, an important part of traditional Chinese medicine (TCM), has been used in China for the treatment of a variety of conditions for at least 5,200 years. It is nowadays widely used throughout the world including Asia, Europe, and the USA. Acupuncture is one of the most popular complementary and alternative therapies, and has steadily claimed its usefulness . TherapeThe foundation of acupuncture is based on a complex meridians theory according to TCM. Modern physiologists have raised a “neural hypothesis” that acupuncture could primarily stimulate sensory nerves close to the inserting needle underneath the skin, transmit signals to brain, and produce clinical influence. This is the most rational basis for defining meridians . Some acvia the CAP , National Key Research and Development Program of China , Shanghai Sailing Program (19YF1459500 to ZQ) and Science and Technology Innovation Action Plan Project (19401900100 to XL and 19431901400 to ZQ).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.


Mortality from COVID-19 has been particularly high in elderly patients on mechanical ventilation. Treatment outcomes for patients with do-not-intubate (DNI) status are unknown. One hundred patients admitted to the non-ICU ward during the “first wave” were retrospectively analyzed. Mortality rate was 49% in patients with a DNI order. This subgroup was characterized by significantly higher age, more comorbidity, and care dependency. Mortality among DNI patients was three times higher than other patients, but not higher than some of the published mortality rates for elderly mechanically ventilated patients. Advanced care planning is essential in COVID-19 to assist patient autonomy and prevent non-beneficial medical interventions. In-hospital mortality rates due to COVID-19 have primarily been determined by ICU mortality. In the first months of the pandemic, there was an average 42% risk of mortality when admitted to the ICU . MortaliThe Erasmus MC is the Netherlands’ largest university hospital, and Amphia Hospital is a large teaching hospital. In this retrospective analysis, we reviewed the files of 100 patients (the first 50 patients per center) admitted to the dedicated non-ICU COVID-19 wards, with admission dates between 17 March and 23 April 2020. Cases of COVID-19 were all confirmed by real-time PCR of nasopharyngeal swabs. Of these 100 patients, patient characteristics, clinical signs and symptoms, comorbidities, treatment, and outcomes were compared between patients with and without a DNI order. Comorbidities were scored using Charlson comorbidity index (CCI) .Of 100 patients, the average age was 68 years, body mass index (BMI) was 27, and 67% of the patients were male. Of these patients, 82% had at least one pre-existing comorbidity, with an average Charlson comorbidity index (CCI) of 4.2 points (see Table For 39 patients (39%), a DNI order was noted in the patient file. In 29/39 patients (74%), the DNI status was chosen at admission after counselling by the attending physician. For 8/39 patients (21%), the DNI status had already been chosen previously. For two patients (5%), the DNI status was decided during hospital stay after confirmation of COVID-19 diagnosis because of expected poor prognosis of mechanical ventilation for COVID-19 pneumonia. The reported reasons to choose a DNI status were combined frailty, multimorbidity, and age ; the patient’s explicit wish ; severe neurologic comorbidity ; active malignancy ; cardiac comorbidity ; pulmonary comorbidity ; and severe cognitive impairment .p<0.01), had more comorbidities resulting in a significantly higher CCI , and lived significantly less often at home unassisted   were admitted to the ICU for mechanical ventilation when their condition deteriorated, of which 10/16 patients died (62.5%)  and three times higher than patients without DNI status admitted to the same wards in the same period. It is also about two times higher than overall COVID-19 mortality in our hospitals during the same time period  and “first wave” mortality rates in the literature . CompareRemarkably, only 5 patients were living at a nursing home prior to admission. In all those patients, a DNI status was ordered. Many nursing home residents with COVID-19 have been cared for in their facility and were not referred to the hospitals. Advanced care planning including patient’s views on resuscitation, intubation, and referral to hospitals are routine practice in Dutch nursing homes, allowing optimal attention to palliative care where indicated and prioritization of advanced medical care to the patients with greatest benefit. Although total capacity and logistics of ICU beds for COVID-19 patients became a topic of national interest during the weeks of peak incidence, there was no “black list” for triaging ICU access. In our cohort, ICU capacity was available for all eligible patients, and all DNI orders were chosen after counselling with patients and/or their relatives. In recently published guidance on advanced care planning in COVID-19, this practice has been recommended as standard care , 8.In conclusion, during the peak of the COVID-19 outbreak in the Netherlands, mortality in the dedicated non-ICU COVID-19 wards of our centers was high, especially in patients who had a DNI status. This group of patients was characterized by old age, high burden of comorbidities, and assisted living or nursing home residency. Advanced care planning is essential in COVID-19 to assist patient autonomy and prevent non-beneficial medical interventions.The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.Not applicable


Objective: We determined the reliability of The Kiddie-Schedule forAffective Disorders and Schizophrenia for School-Age Children–Present andLifetime (K-SADS-PL) for screening and diagnosing ADHD in children.Method: K-SADS-PL was administered to 2,074 children in thecommunity. Psychometric properties, factorial structure, and clinical validityof K-SADS-PL in screening or diagnosis of ADHD were examined.Results: Internal consistency was excellent for items in thescreening interview  and diagnostic supplement . Thestandardized coefficients for items in the screening interview were acceptable(0.59-0.85), while fit indices for single factorial structure reached acceptablelevels. Screening items were associated with high sensitivity  and specificity  for diagnosis ofADHD in the supplement. The test-retest and interinformant reliability asmeasured by intraclass correlation coefficient was good for most of the items.Conclusion: This large study shows that K-SADS-PL can bereliably used to screen and diagnose ADHD in children in Kenya. ADHD is one of the most common neuropsychiatric disorders in childhood that canpersist into adulthood. According to the Global Burden of Disease, ADHD wasresponsible for 500,000 disability adjusted life years (DALYS), which is 0.2% of allmental health disorders . In spitDiagnostic and Statistical Manual of Mental DisordersDSM-5  version is popular for epidemiological andclinical studies of neuropsychiatric disorders in children, as it is regarded as agold standard for We evaluated the psychometric properties, reliability, and validity of ADHD module ofK-SADS-PL in screening and diagnosing ADHD in epidemiological studies conducted inAfrica. In particular, we aimed to examine the item reliability (includingstandardized coefficients/loadings); compute fit indices for the one-dimensionK-SADS-PL; assess polychoric correlations, sensitivity/specificity/positivepredictive values (PPV)/negative predictive values (NPV) of the screen interviewswith diagnostic supplements; and determine test-retest and interraterreliability.This study was conducted on a rural area of Kenya in a demographic surveillancearea . FieldwoAll children aged 6 to 9 years living within demographic area, who form a totalpopulation of about 28,000 were eligible. This current study was nested in alarge epidemiological study which aimed at screening about 15,000 childrenrandomly selected from the 28,000 children aged 6 to 9 years within thedemographic. The RAND command of MySQL was used to randomly select theeligible children. The age group of 6 to 9 years was chosen because this is whenmost neurodevelopmental disorders such as ADHD become apparent. In this baselineepidemiological study, 11,223 children were successfully screened withneurodevelopmental disorders screening tool (NDST), and 2,162 invited forfurther clinical and neuropsychological assessments including administration ofthe K-SADS-PL. During piloting, NDST screened ADHD with a sensitivity of 89.2% and a specificity of 94.8% .DSM-5 criteria: (a) predominantly inattentive subtype; (b)predominantly hyperactive-impulsive sub-type; (c) combined type; and (d) otherspecified ADHD; all of which manifests either in the past (>6 months ago) orthe present (≤6 months to present).ADHD module of K-SADS-PL is a semistructured interview with two components: ascreening interview and diagnostic supplement . The scrhttp://www.who.int/substance_abuse/research_tools/translation/en/).A panel approach was used to harmonize the translation. A team made up of adevelopmental psychologist, epidemiologists, and professionals  fluent in English, Swahili, and familiar withthe local culture were members of this harmonization team. All the tools werepiloted to test their appropriateness in assessing neurodevelopment and adaptedaccordingly before use in the epidemiological survey. Translation, adaptation,and administration of K-SADS-PL was supervised by a developmental psychologist(A.A.); child and adolescent psychiatrist (J.P.O.); linguists fluent in English,Kiswahili, and Mijikenda; and neuroepidemiologists (S.K. and C.N.).The ADHD module of K-SADS-PL was translated into the local language, Kiswahili,through a standardized forward and back translation process according tointernational guidelines (K-SADS-PL was administered by assessors trained by a consultant child andadolescent psychiatrist (J.P.O.), who actively supervised the assessors on aweekly basis so that difficulties in rating items and making decisions ondiagnosis could be resolved. The child and adolescent psychiatrist hasreliability approval for administering and supervising administration ofK-SADS-PL from an approved K-SADS-PL trainer .Trained administrators of the tool first introduced the purpose of the K-SADS-PLto the parents and the child, including explaining the scoring requirements tomove from screening interview to diagnostic supplement. Questions were asked toboth the parent and the child, with the assessor integrating their responses.Although ADHD module of K-SADS-PL requires parent–child participation, we reliedmostly on the parent’s or caretaker’s accounts of the child’s behavior. In thescreening interview, a response was rated as either absent (coded as 1),subthreshold levels (coded as 2), or threshold levels (coded as 3). While in thediagnostic supplement, ratings were done on a scale of 0, 1, or 2, with 2representing presence of ADHD symptoms. Opposition defiant disorders, anxietydisorders, and other neuropsychiatric disorders (not reported in this study)were also considered for differential diagnosis when diagnosing ADHD.Two weeks after initial screening with ADHD module of K-SADS-PL, 29 children wererandomly selected for readministration of the screening interviews of the toolto examine the test-retest reliability. Another 20 children with and withoutADHD in the supplement ADHD module of K-SADS-PL were examined through directclinical interviews and/or recorded videos by a child and adolescentpsychiatrist who was blinded to the initial diagnosis made by trainedadministrators of K-SADS-PL.Written informed consent for the study was obtained from parents of children whoparticipated in this work.psych package of R, with their CIs estimated bybootstrapping for 1,000 iterations. Reliability measured by ω presents betterestimates than that of Cronbach’s alpha (α) when the tool or test hasasymmetrical items, violation of normality introduced by small samples, ormissing tau-equivalence (congeneric)  orR statistical software (version 3.4.0 (2017-04-21)). The internal consistency orinteritem correlation was computed as MacDonald’s Omega (ω), using thegeneric) , and so irr package in RR as intraclass correlationcoefficients, specifying consistency types for test-retests, agreement types forinterrater reliability, and one-way random effect to allow the estimates to varyacross the participants. We also examined the overlap of ADHD with oppositionaldefiant disorders and anxiety disorders, using proportions and tetrachoriccorrelations and hypothesized that overlap will be more substantial in theformer  than in the latter.Using structural equation models that assumed a linear trend for thethree-ordinal responses of items of K-SADS-PL, we generated the standardizedcoefficients or loadings associated with responses from the screening interviewand from the diagnostic supplement, while also investigating the fit indices associated with a one-dimensional factorialstructure of the ADHD module of K-SADS-PL . We ensuInitial screen with ADHD K-SADS-PL module was done on 2,074 children, which is~95% of those approached, following initial screening with NDST in Stage I. Ofthe 2,074 children aged 6 to 9 years, 1,084 (52.3%) were males. Those whoreached the threshold in the initial screening were 385/2,074 (18.5%); responsefor individual questions is shown in The item reliability coefficients for the screening stage were excellent. The items reliabilitycoefficients for the supplement stage were excellent as well . The item reliability coefficients for K-SADS-PL screening itemswere comparable for males  and females .The standardized coefficients associated with each item of the screening ADHDmodule of K-SADS-PL ranged from 0.59 to 0.85, with an overall mean of 0.75  see . Most ofFit indices for the one-dimensional structure ) and two negative correlations (ρ = −0.17 for hyperactive/impulsive typeand ρ = −0.17 for the unspecified ADHD type) . The scrReaching a threshold score of 3 points in the relevant subsection of thescreening component was associated with very high sensitivity  and specificity  for diagnosis of ADHD in thesupplement stage, with NPV being higher than PPV, as expected of diagnostictools . Asexpep < .001), except for impulsivity (p < .001), except forimpulsivity  and so were moststandardized coefficients and fit indices for a single factorial structure.Screening interview ratings correlated well with those of the diagnostic supplement,with very high sensitivities (~97%) and specificities (~95%). Additionally, most ofthe items had an acceptable test-retest and interrater reliability (up to 0.77). Asexpected, the ADHD symptoms showed little overlap with anxiety disorders (1%), andhigh overlap with oppositional defiant disorders (25%).The findings in this study are similar to studies in other cultures. For instance,similar interrater reliability (0.77 in our study vs. 0.75) and positive screen rate(15.8% in our study vs. 15.2%) in the Korean study . The proThe internal consistency is an important measure of the relatedness of the individualitems used to assess or diagnose ADHD . In ourItem scale reliability (as measured by standardized coefficients) was withinacceptable ranges for all items in the screening interview. This is important intest administration as it means the questions are capturing what they are intendedto measure. However, standardized coefficients were much lower in the diagnosticsupplement, which is less detrimental as its administration is dependent on reachinga threshold on the screening interview, whose standardized coefficients were allacceptable. In the screening interview, impulsivity had the lowest standardizedcoefficients, implying that this term is either (a) not fully understood in thisregion or (b) not a common manifestation of ADHD in this area. Our findings tendedto support the former possibility as polychoric correlations with unspecified ADHD(symptoms not fully described/understood by parents/children) were largest withscreening for impulsivity.We performed polychoric correlations to examine how well ratings for the screeninginterview domains related with those of the diagnostic supplement, and two screeningdomains showed consistent significant correlations with all ratings of thediagnostic supplement. These were “difficulty sustaining attention” and “easilydistracted” which may be the traits of ADHD that are best understood by parents inthis community. The directionality (positive or negative) of these correlationsdepends on the broad categories of ADHD in the supplement (either hyperactivity orattention-deficit) the screening item of interest is designed to assess. Forexample, “difficulty sustaining attention” assesses the ADHD category“attention-deficit” and not “hyperactivity,” and so is positively correlated withthe former category of ADHD and negatively with the latter. However, to improvesensitivity of obtaining reliable estimates of ADHD in epidemiological studies,other two screening items should also be included as they correlated with at leastone ADHD type from supplement.The sensitivities and specificities of positivity to any screening interviewquestions are very high, implying that these questions may be useful in identifyingchildren requiring clinical assessment and care particularly in LMIC, whereresources are so limited that full administration of the ADHD module of K-SADS-PLcan be logistically intensive. High sensitivities are also important in detectingADHD in epidemiological studies. Sensitivity may depend on the number of questionsin a tool or their ability to accurately describe the symptoms of a condition ofinterest such as ADHD. Low sensitivity can result in false negatives and therebymissed opportunities for management and targeted care, which can be avoided byensuring that a tool has adequate items that accurately describe the symptoms, andthat the questions are properly adapted during translation for use in the localpopulation. Nevertheless, all screening questions should be asked, as individualquestions had higher specificities as expected. The sensitivities may depend on thecorrect diagnosis of ADHD at the supplement; fortunately, interrater reliabilityagainst a child psychiatrist was good for most items. Test-retest reliabilityscreening interview questions, as measured by ICC, showed that most of the questionswere stable over time and may persist. Although low test-retest ICC may suggest thatADHD symptoms were transient, those for impulsivity warrants further work, as itsinterrater reliability was also low.This is the largest study in Africa to evaluate the utility of K-SADS-PL in screeningand diagnosing ADHD, having involved over 2,000 children. The participants wererandomly drawn from the general population as part of an epidemiological survey, andis thus far much more representative than hospital samples. In addition topsychometric properties and validity, the article additionally examines internalconsistency and the factorial structure of ADHD module of K-SADS-PL, which were notreported in most previous studies. However, the study has a small overlap withanxiety disorders, may lead to slight misclassification limitations, which could beaddressed by screening for both conditions. The Child and Adolescent Psychiatristwas not able to interact directly with many children receiving K-SADS-PL and had toreview recorded videos of these children. This is understandable since thepsychiatrist practices in the United Kingdom, and travelled severally to the studyarea to train the administrators of K-SADS-PL.We conclude that K-SADS-PL can be reliably used in rural settings in Africa to screenand diagnose ADHD in children. Neuropsychological assessors and primary health careworkers can be trained and supervised by child and adolescent psychiatrists toadminister K-SADS-PL in rural Kenya. Further work would still be needed to improvecommunity understanding of ADHD symptoms such as impulsivity.


Co-trimoxazole is a broad-spectrum antibiotic associated with hyperkalemia.To determine the incidence of hyperkalemia and its risk factors in patients receiving co-trimoxazole.A retrospective observational study involving all patients who received co-trimoxazole between 1 January 2012 and 1 January 2013 was conducted. Subjects were identified through a list generated from a computerized pharmacy system. The patients’ demographic and clinical characteristics were retrieved from electronic medical records. Data were analyzed using univariate and multivariate logistic regression.One hundred sixty-one patients fulfilled the eligibility criteria. Of these, 46 (28.6%) experienced hyperkalemia. Around 35 (76%) of the patients who experienced hyperkalemia received co-administered medications that might induce hyperkalemia. The co-administration of co-trimoxazole with other medications that may induce hyperkalemia was found to be associated with higher incidence of hyperkalemia when compared to co-trimoxazole administration alone . Additionally, age > 60 years was associated with an increased risk of hyperkalemia when compared to younger age group 18–39 years .Co-trimoxazole use is associated with high incidence of hyperkalemia, especially among older patients and those receiving it in combination with other medications that might contribute to hyperkalemia development such as calcineurin inhibitors and β-blockers. Co-trimoxazole, a broad-spectrum antibiotic comprising trimethoprim and sulfamethoxazole, is widely used for the treatment and prophylaxis of Gram-positive bacteria, Gram-negative bacteria, and some parasitic infections.This study aimed to investigate the incidence of hyperkalemia among patients who received co-trimoxazole and had normal serum potassium concentrations at baseline and to identify potential risk factors for the hyperkalemia.This was a retrospective observational study of patients who received co-trimoxazole for therapeutic or prophylactic indications at Hamad General Hospital (HGH) in Qatar. The therapeutic indications included treatment of acute spontaneous bacterial peritonitis (SBP), mild diabetic foot infection, toxoplasmosis, urinary tract infection, and Pneumocystis pneumonia. The prophylactic indications included bite wound infection prophylaxis, SBP long-term secondary prevention, and Pneumocystis pneumonia prevention in immunocompromised patients. Patients were identified through a computerized pharmacy system, via an automated report generated between 1 January 2012 and 1 January 2013. Baseline potassium serum level was considered as any level within one week prior to initiation of co-trimoxazole; all subsequent levels were follow-up. Hyperkalemia was defined as serum potassium level above 5.5 mEq/L.This study was reviewed and approved by the Institutional Review Board (IRB) of the Medical Research Center at Hamad Medical Corporation (HMC's MRC) in Qatar . This is a retrospective observational chart review and obtaining informed consent to participate in the study from the research subjects was not applicable. In such cases, the IRB typically grants a waiver of consent. Further, all patient data accessed complied with relevant data protection and privacy regulations in Qatar.2) who received co-trimoxazole during the study period and had documented potassium serum levels at baseline and during follow-up were included. Patients who received less than two doses of co-trimoxazole and/or had no potassium follow-up were excluded from the study.Adult patients (≥18 years) with normal renal function ; dose, frequency, and duration of co-trimoxazole; comorbid conditions, and concurrent medications potentially affecting potassium serum levels including β-blockers (selective and non-selective), calcineurin inhibitors, heparin, ACE-I, ARBs, potassium-sparing diuretics , nonsteroidal anti-inflammatory drugs (NSAIDs), and antifungals (fluconazole). In addition, relevant laboratory data like serum potassium and serum creatinine concentrations were collected. Baseline potassium and creatinine levels were considered as any level within one week prior to initiation of co-trimoxazole. Any potassium or creatinine level within the first week of the short-treatment course or within one month of the long-term prophylactic indications were considered as follow-up readings.® Statistics for Windows; IBM Corp, Armonk, New York, USA). Both descriptive and inferential statistics were applied for the data analysis. The 95% confidence intervals (CIs) for each mean were also calculated. Chi-square was used to compare the incidence of hyperkalemia between different factors. Univariate and multivariate logistic regression analyses were conducted to determine the association between risk factors and development of co-trimoxazole-induced hyperkalemia and compute adjusted and unadjusted odds ratios (ORs). The factors included in the multivariate logistic regression analysis were age, gender, total daily dose [the once and twice daily doses of the double strength (DS) tablet 800/160 mg], and the co-administered medications. The level of statistical significance was defined as p≤ 0.05.Data were analyzed using SPSS version 18 (IBM SPSS2), 168 did not have follow-up data, and 50 patients received less than two doses of co-trimoxazole. One hundred sixty-one patients who fulfilled the inclusion criteria were included  was observed in 46 (28.6%) patients, of whom, 25/46 (54.3%) were in the twice-daily dosing group. Thirty-five (76%) of the patients who developed hyperkalemia were receiving concurrent medications known to increase potassium serum levels . ReceiviAfter adjusting the confounders with the multivariate logistic regression analysis, only age and co-administered medications were found to be significant. Patients with age >60 years were more prone to develop hyperkalemia when compared to the younger age group 18–39 years . Moreover, the middle age group (40–60 years) was also found to have higher incidence of hyperkalemia than the younger age group 18–39 years . In addition, the co-administration of other medications that may induce hyperkalemia was found to be associated with higher incidence of hyperkalemia when compared to those receiving co-trimoxazole alone .Almost one-third of the patients receiving co-trimaxazole developed hyperkalemia, with age >60 years identified as high-risk. In addition, co-administration of medications that are known to raise potassium serum level increased the risk of hyperkalemia by three folds . However, dosing frequency did not significantly influence the hyperkalemia incidence.A previous study by Fralick et al affirmed that co-trimoxazole use with an ACE-I or ARB was associated with increased risk of sudden death due to severe hyperkalemia [OR 1.38: 95% CI (1.09 to 1.76)] when compared with amoxicillin.A recent cohort study showed a 0.28 mmol/l  increase in serum potassium level was associated with co-trimoxazole use compared to ceftriaxone use. It is noteworthy that the population of the study was older adults [mean age 73.8 (12.5) years]; hence, the incidence of hyperkalemia was more pronounced.In this study, the co-administration of calcineurin inhibitors, either alone or in combination with β-blockers, was significantly associated with increased incidence of hyperkalemia. Several studies and case reports found that tacrolimus and cyclosporine cause elevation in plasma potassium concentration, which can be further augmented by co-administration of an ACE-I or an ARB.16A review by Perazella et al reported that co-trimoxazole can cause hyperkalemia regardless of dose.There is some evidence that pharmacists have a crucial role in monitoring drug therapy to detect and prevent ADRs.This study has the inherent limitations of a retrospective study design in that only the specific data collected and recorded during routine clinical practice could be captured. While we excluded those with renal impairment, hyperkalemia could be a result of other factors such as excess dietary potassium intake, renal and adrenal insufficiencies, and other factors. The limited sample size may have meant that the study was underpowered for the comparison made; hence, the results should be interpreted with caution. There may also be issues with generalizability to other populations and settings. Furthermore, the study was completed several years earlier, although clinical practice is relatively unchanged hence the data and findings remain valid. There is a need for prospective studies with adequate sample sizes and more frequent monitoring of potassium and serum creatinine levels.Co-trimoxazole administration was associated with an increased risk of hyperkalemia especially among older patients and those receiving other co-administered medications that may induce hyperkalemia. Caution should be exercised when co-trimoxazole is used in older people and patients receiving other medications affecting potassium levels such as calcineurin inhibitors and the combination of calcineurin inhibitors and β-blockers.