Lived experience of work and long COVID in healthcare staff.

BACKGROUND: Healthcare workers (HCWs) had a greater occupational risk of exposure to coronavirus disease 2019 (COVID-19) and reported higher rates of long COVID (LC). This has implications for the provision of health care in already stretched health services. AIMS: This study explored the impact of LC on a range of UK National Health Service (NHS) HCWs, their health and well-being, the effect on work patterns, and occupational support received. METHODS: Mixed-methods study, online survey and qualitative interviews. Participants self-reporting LC symptoms were recruited through social media and NHS channels. Interviews used maximum variation sampling of 50 HCWs including healthcare professionals, ancillary and administration staff. Thematic analysis was conducted using NVivo software. RESULTS: A total of 471 HCWs completed the online survey. Multiple LC symptoms were reported, revealing activity limitations for 90%. Two-thirds had taken sick leave, 18% were off-work and 33% reported changes in work duties. There were few differences in work practices by occupational group. Most participants were working but managing complex and dynamic symptoms, with periods of improvement and exacerbation. They engaged in a range of strategies: rest, pacing, planning and prioritizing, with work prioritized over other aspects of life. Symptom improvements were often linked to occupational medicine, managerial, colleague support and flexible workplace adjustments. CONCLUSIONS: LC has a significant impact on the lives of HCWs suffering prolonged symptoms. Due to the variability and dynamic nature of symptoms, workplace support and flexible policies are needed to help retain staff.

Intranasal steroid use and COVID-19 mortality among patients with asthma and COPD: A retrospective cohort study.

BACKGROUND: Systemic corticosteroids have been widely used for treating patients with severe acute respiratory distress syndrome. Inhaled corticosteroids may have a protective effect for treating acute coronavirus disease 2019 (COVID-19); however, little is known about the potential effect of intranasal corticosteroids (INCS) on COVID-19 outcomes and severity. OBJECTIVE: To assess the impact of prior long-term INCS exposure on COVID-19 mortality among patients with chronic respiratory disease and in the general population. METHODS: A retrospective cohort study was conducted. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between INCS exposure and all-cause and COVID-19 mortality, adjusted by age, sex, deprivation, exacerbations in the last year, and comorbidities. RESULTS: Exposure to INCS did not have a significant association with COVID-19 mortality among the general population or cohorts with chronic obstructive pulmonary disease or asthma, with HRs of 0.8 (95% CI, 0.6-1.0, P = .06), 0.6 (95% CI, 0.3-1.1, P = .1), and 0.9 (95% CI, 0.2-3.9, P = .9), respectively. Exposure to INCS was, however, significantly associated with reduction in all-cause mortality in all groups, which was 40% lower (HR, 0.6 [95% CI, 0.5-0.6, P < .001]) among the general population, 30% lower (HR, 0.7; 95% CI, 0.6-0.8, P < .001) among patients with chronic obstructive pulmonary disease, and 50% lower (HR, 0.5; 95% CI, 0.3-0.7, P = .003) among patients with asthma. CONCLUSION: The role of INCS in COVID-19 is still unclear, but exposure to INCS does not adversely affect COVID-19 mortality. Further studies are needed to explore the association between their use and inflammatory activation, viral load, angiotensin-converting enzyme 2 gene expression, and outcomes, exploring different types and doses of INCS.

Anthropometric measures and breast cancer risk among Hispanic women in Puerto Rico.

INTRODUCTION: Increased risk of postmenopausal breast cancer associated with anthropometric measures including Body Mass Index (BMI), adult weight gain, and waist circumference has been observed in North American and European populations, but little evidence is available for Hispanic women. Breast cancer is the leading type of cancer, and leading cause of cancer-related deaths among Hispanic women in Puerto Rico (PR). However, compared with the United States, breast cancer incidence rates are lower but increasing more rapidly. PURPOSE: To examine associations between anthropometric characteristics and breast cancer risk in Hispanic women in PR. METHODS: Data from a population-based case-control study in the San Juan metropolitan region (cases = 315; controls = 348) were used to examine associations between anthropometric measures and breast cancer risk, also considering menopausal status and hormone therapy (HT). RESULTS: Among premenopausal participants, there was a significant trend for lower odds of breast cancer with higher BMI and borderline significant with higher waist to height ratio (WHtR). For postmenopausal participants, a significant trend for lower odds of breast cancer was observed with higher WHtR, and waist to hip ratio (WHR), borderline significant with higher BMI, and higher odds with height. Among postmenopausal participants using HT, a significant trend for lower odds of breast cancer was observed with higher waist circumference, WHtR, WHR, and body shape index. CONCLUSION: Our study provides evidence of anthropometric differences in relation to breast cancer risk in PR compared to previous studies. Future studies should include analyses of fat and lean mass distribution, and hormone receptor status to further understand anthropometry and breast cancer risk among Hispanic women.

Effects of Smoking Reduction and Cessation on Birth Outcomes in a Scheduled Gradual Reduction Cessation Trial.

INTRODUCTION: Smoking during pregnancy can affect infant birthweight. We tested whether an intervention that promoted scheduled gradual reduction improved birth outcomes among pregnant women who smoked. We also examined race differences in birth outcomes. METHODS: We conducted a 2-arm randomized controlled trial where pregnant women who smoked received either SMS text-delivered scheduled gradual smoking reduction (SGR) program plus support texts or support messages only throughout their pregnancy. The outcomes for this paper were birth outcomes including birth weight and gestational age obtained from chart review. Analyses were conducted using chi-square and t-tests in SAS. RESULTS: We approached 2201 pregnant women with smoking history. Of the 314 women recruited into the study, 290 completed a medical release form (92%). We did not find any significant differences in birth outcomes by arm or race. The majority of participants reduced smoking by the 80%. Women who reduced more than 50% of their baseline cigarettes per day had a birth weight increase of 335 g compared to those that did not (p = 0.05). The presence of alcohol/drug use in prenatal visit notes was associated with low infant birth weight (p = 0.05). DISCUSSION: The scheduled gradual reduction intervention did not improve birth outcomes. Additional research is needed to help improve birth outcomes for pregnant women who engage in tobacco and illicit substance use. CLINICAL TRIAL #: NCT01995097.

Trajectories of Situational Temptations in Pregnant Smokers participating in a Scheduled Gradual Reduction Cessation Trial.

OBJECTIVE: The purpose of this paper was to examine changes in situational temptations to smoke among women in early to late pregnancy enrolled in a texting trial to help them quit smoking. We compared changes between (1) intervention arms, (2) those who quit, (3) those who reduced by 50% or more, and (4) those who reduced by less than 50%. We also examined cravings overtime in the intervention arm and the relationship between real-time cravings assessed via text message and situational temptations. METHODS: This was a secondary analysis of the Baby Steps trial, a randomized controlled trial testing the efficacy of a text-based scheduled gradual reduction (SGR) intervention on cessation. We used t-tests to examine changes across intervention arms and repeated measured proc mixed to explore changes in situational temptations and cravings. RESULTS: Among all women, situational temptations decreased from early to late pregnancy for the positive, negative, and habitual subscales, (ps < 0.001). We found no difference in situational temptations across arms. We found a positive relationship between negative situational temptation and average craving during the Weeks 2 and Weeks 3 of the intervention. Negative ST increased by 0.11 for each unit increase of craving at Week 2. CONCLUSIONS: As women progress through pregnancy their temptation to smoke reduces. A different relationship might exist, however with negative affect situations in which women reported higher craving but not in response to other temptations. Future work might have a particular focus on the intersection of negative affect with cravings and temptations to promote cessation during pregnancy. CLINICAL TRIAL: NCT01995097.

Association between anticholinergic burden and oropharyngeal dysphagia among hospitalized older adults.

BACKGROUND: Oropharyngeal dysphagia is an emerging age-related disorder that affects 23% of inpatients leading to malnutrition, dehydration, or aspiration pneumonia. Anticholinergic drugs can cause reduced peristalsis and dry mouth, both related to dysphagia. AIM: To determine the association between anticholinergic burden and oropharyngeal dysphagia in older inpatients. METHODS: Retrospective descriptive observational study. There are 239 patients. Dysphagia diagnosis based on routine volume-viscosity swallow test. Characteristics: age, functional loss (instrumental and basic activities), frailty (Frail-VIG-Index), geriatric syndromes, polypharmacy, and anticholinergic-cognitive-burden scale at admission. RESULTS: 25.5% of elderly patients diagnosed with dysphagia are more dependent and frailer than non-dysphagic patients. 83.6% scored ≥ 3 points on the ACB Scale [odds ratio: 4.46 (2.13-9.33)], which is statistically associated with dysphagia (p < 0.001). CONCLUSION: Patients with an ACB of ≥ 3 points at admission are more than four times as likely to develop oropharyngeal dysphagia. Evaluating anticholinergic burden routinely should be considered and, whenever possible, reduce it.

Efficacy of a Texting Program to Promote Cessation Among Pregnant Smokers: A Randomized Control Trial.

INTRODUCTION: Smoking during pregnancy poses serious risks to baby and mother. Few disseminable programs exist to help pregnant women quit or reduce their smoking. We hypothesized that an SMS text-delivered scheduled gradual reduction (SGR) program plus support texts would outperform SMS support messages alone. METHODS: We recruited 314 pregnant women from 14 prenatal clinics. Half of the women received theory-based support messages throughout their pregnancy to promote cessation and prevent relapse. The other half received the support messages plus alert texts that gradually reduced their smoking more than 3-5 weeks. We conducted surveys at baseline, end of pregnancy, and 3 months postpartum. Our primary outcome was biochemically validated 7-day point prevalence abstinence at late pregnancy. Our secondary outcome was reduction in cigarettes per day. RESULTS: Adherence to the SGR was adequate with 70% responding to alert texts to smoke within 60 minutes. Women in both arms quit smoking at the same rate (9%-12%). Women also significantly reduced their smoking from baseline to the end of pregnancy from nine cigarettes to four; we found no arm differences in reduction. CONCLUSIONS: Support text messages alone produced significant quit rates above naturally occurring quitting. SGR did not add significantly to helping women quit or reduce. Sending support messages can reach many women and is low-cost. More obstetric providers might consider having patients who smoke sign up for free texting programs to help them quit. IMPLICATIONS: A disseminable texting program helped some pregnant women quit smoking.Clinical Trial Registration number: NCT01995097.

Pilot Test of Connecting Pregnant Women who Smoke to Short Message Service (SMS) Support Texts for Cessation.

INTRODUCTION: Most pregnant women know that smoking poses serious risks to baby and mother, yet many still smoke. We conducted a large randomized controlled trial and found that an SMS text-delivered program helped about 10% of these women quit smoking. In this paper, we describe the feasibility of disseminating a text-based intervention to pregnant women who smoke. METHODS: We tested dissemination in two ways from prenatal clinics and compared recruitment rates to those found in our large randomized controlled trial. The first method involved "direct texting" where study staff identified women who smoked and sent them a text asking them to text back if they wanted to receive texts to help them quit. The second involved "nurse screening" where clinic staff from county health departments screened women for smoking and asked them to send a text to the system if they wanted to learn more about the program. Our primary outcome was feasibility assessed by the number of women who texted back their baby's due date, which served as "enrolling" in the texting program, which we compared to the recruitment rate we found in our large trial. RESULTS: Over 4 months, we texted 91 women from the academic health system. Of those, 17 texted back and were counted as "enrolled." In the health departments, across the 4 months, 12 women texted the system initially. Of those, 10 were enrolled. This rate was similar to the rate enrolled in the randomized controlled trial. DISCUSSION: Two different methods connected pregnant women who smoke to a texting program. One of these methods can be automated further and have the potential of helping many women quit smoking with minimal effort. Clinical Trial # NCT01995097.

An Evaluation of Florida's Zika Response Using the WHO Health Systems Framework: Can We Apply These Lessons to COVID-19?

OBJECTIVES: From 2016 to 2018 Florida documented 1471 cases of Zika virus, 299 of which were pregnant women (Florida Department of Health, https://www.floridahealth.gov/diseases-and-conditions/mosquito-bornediseases/surveillance.html , 2019a). Florida's response required unprecedented rapid and continuous cross-sector communication, adaptation, and coordination. Zika tested public health systems in new ways, particularly for maternal child health populations. The systems are now being challenged again, as the Coronavirus COVID-19 pandemic spreads throughout Florida. This qualitative journey mapping evaluation of Florida's response focused on care for pregnant women and families with infants exposed to Zika virus. METHODS: Fifteen focus groups and interviews were conducted with 33 public health and healthcare workers who managed outbreak response, case investigations, and patient care in south Florida. Data were thematically analyzed, and the results were framed by the World Health Organization's (WHO) Healthcare Systems Framework of six building blocks: health service delivery, health workforce, health information systems, access to essential medicines, financing, and leadership and governance (World Health Organization, https://www.who.int/healthsystems/strategy/everybodys_business.pdf , 2007, https://www.who.int/healthinfo/systems/monitoring/en/ , 2010). RESULTS: Results highlighted coordination of resources, essential services and treatment, data collection, communication among public health and healthcare systems, and dissemination of information. Community education, testing accuracy and turnaround time, financing, and continuity of health services were areas of need, and there was room for improvement in all indicator areas. CONCLUSIONS: The WHO Framework encapsulated important infrastructure and process factors relevant to the Florida Zika response as well as future epidemics. In this context, similarities, differences, and implications for the Coronavirus COVID-19 pandemic response are discussed.

Alternative techniques in cochlear implant surgery: Subtotal petrosectomy.

OBJECTIVES: To report and analyze three cases of subtotal petrosectomy (SP) in cochlear implant surgery at our institution, and establish the indications, surgical technique and complications encountered. MATERIALS AND METHOD: A retrospective descriptive study is proposed, analyzing a series of three clinical cases of subtotal petrosectomy as surgical technique for cochlear implant surgery at San Ignacio University Hospital (Bogotá, Colombia) from year 2004 to 2019. RESULTS: A total of three cases of subtotal petrosectomy as surgical technique in cochlear implant candidates were analyzed. The indications were the presence of a wide mastoid cavity after canal wall down mastoidectomy, extrusion of the electrode into the external auditory canal with a wide mastoid cavity and erosion of the posterior wall of the ear canal, and the presence of cholesteatoma in a cophotic ear with previous surgery. The ear canal was defunctionalized in all three cases; in two of them with obliteration of the Eustachian tube and in none of the cases the mastoid was obliterated. There was a single complication associated with the procedure corresponding to a small retention cholesteatoma in the skin of the obliterated duct sac, that didn't required surgical intervention. CONCLUSION: Subtotal petrosectomy is a surgical alternative for cochlear implant surgery in patients with chronic ear pathology, wide cavities or cochlear implant extrusion, not associated to significant complications.

Central nervous system evaluation of an ethanol extract of Bidens odorata Cav (Asteraceae) leaves, and its antinociceptive interaction with paracetamol and naproxen.

INTRODUCTION: Bidens odorata Cav (Asteraceae) is a medicinal plant employed for the treatment of pain, anxiety, and depression. This study aimed to evaluate some neuropharmacological effects of an ethanol extract of B. odorata (BOE) and assess its antinociceptive interaction with naproxen and paracetamol. MATERIALS AND METHODS: The following neuropharmacological effects were evaluated with the ethanolic extract of B. odorata leaves (BOE) (10-200 mg/kg p.o.): the strychnine-induced-convulsion assay (anticonvulsant effect), rotarod test (locomotor activity), tail suspension test (anti-depressant-like activity), cylinder exploratory test (anxiolytic-like actions), and pentobarbital-induced sleep test (sedative effect). The interaction of the BOE-paracetamol and BOE-naproxen combinations were evaluated with the acetic acid-induced writhing test. The ED50 value of each drug was estimated and the combinations of paracetamol and naproxen with BOE were calculated. RESULTS: BOE (100-200 mg/kg) showed anti-convulsant activity by increasing the latency to occurrence of strychnine-induced convulsions, antidepressant-like effects by 28% and 33%, respectively, exerted anxiolytic actions (ED50 = 125 mg/kg), but did not affect motor locomotion. The pre-treatment with 2 mg/kg flumazenil or 20 mg/kg pentylenetetrazol partially reverted the anxiolytic activity shown by BOE alone. BOE (200 mg/kg) prolonged the duration of sleep with similar effect in comparison to clonazepam (1.5 mg/kg). The combinations of BOE-paracetamol (1:1) and BOE-naproxen (1:1) showed antinociceptive synergism. CONCLUSION: BOE induces sedative and anticonvulsant effects. The anxiolytic actions shown by BOE are probably induced by the participation of the GABAergic system. BOE exerts antinociceptive synergistic interaction with paracetamol and naproxen probably by the participation of nitric oxide and ATP-sensitive K+ channels, respectively.

Changes in resistance among coliform bacteraemia associated with a primary care antimicrobial stewardship intervention: A population-based interrupted time series study.

BACKGROUND: Primary care antimicrobial stewardship interventions can improve antimicrobial prescribing, but there is less evidence that they reduce rates of resistant infection. This study examined changes in broad-spectrum antimicrobial prescribing in the community and resistance in people admitted to hospital with community-associated coliform bacteraemia associated with a primary care stewardship intervention. METHODS AND FINDINGS: Segmented regression analysis of data on all patients registered with a general practitioner in the National Health Service (NHS) Tayside region in the east of Scotland, UK, from 1 January 2005 to 31 December 2015 was performed, examining associations between a primary care antimicrobial stewardship intervention in 2009 and primary care prescribing of fluoroquinolones, cephalosporins, and co-amoxiclav and resistance to the same three antimicrobials/classes among community-associated coliform bacteraemia. Prescribing outcomes were the rate per 1,000 population prescribed each antimicrobial/class per quarter. Resistance outcomes were proportion of community-associated (first 2 days of hospital admission) coliform (Escherichia coli, Proteus spp., or Klebsiella spp.) bacteraemia among adult (18+ years) patients resistant to each antimicrobial/class. 11.4% of 3,442,205 oral antimicrobial prescriptions dispensed in primary care over the study period were for targeted antimicrobials. There were large, statistically significant reductions in prescribing at 1 year postintervention that were larger by 3 years postintervention when the relative reduction was -68.8% (95% CI -76.3 to -62.1) and the absolute reduction -6.3 (-7.6 to -5.2) people exposed per 1,000 population per quarter for fluoroquinolones; relative -74.0% (-80.3 to -67.9) and absolute reduction -6.1 (-7.2 to -5.2) for cephalosporins; and relative -62.3% (-66.9 to -58.1) and absolute reduction -6.8 (-7.7 to -6.0) for co-amoxiclav, all compared to their prior trends. There were 2,143 eligible bacteraemia episodes involving 2,004 patients over the study period (mean age 73.7 [SD 14.8] years; 51.4% women). There was no increase in community-associated coliform bacteraemia admissions associated with reduced community broad-spectrum antimicrobial use. Resistance to targeted antimicrobials reduced by 3.5 years postintervention compared to prior trends, but this was not statistically significant for co-amoxiclav. Relative and absolute changes were -34.7% (95% CI -52.3 to -10.6) and -63.5 (-131.8 to -12.8) resistant bacteraemia per 1,000 bacteraemia per quarter for fluoroquinolones; -48.3% (-62.7 to -32.3) and -153.1 (-255.7 to -77.0) for cephalosporins; and -17.8% (-47.1 to 20.8) and -63.6 (-206.4 to 42.4) for co-amoxiclav, respectively. Overall, there was reversal of a previously rising rate of fluoroquinolone resistance and flattening of previously rising rates of cephalosporin and co-amoxiclav resistance. The limitations of this study include that associations are not definitive evidence of causation and that potential effects of underlying secular trends in the postintervention period and/or of other interventions occurring simultaneously cannot be definitively excluded. CONCLUSIONS: In this population-based study in Scotland, compared to prior trends, there were very large reductions in community broad-spectrum antimicrobial use associated with the stewardship intervention. In contrast, changes in resistance among coliform bacteraemia were more modest. Prevention of resistance through judicious use of new antimicrobials may be more effective than trying to reverse resistance that has become established.

Short-course versus long-course therapy of the same antibiotic for community-acquired pneumonia in adolescent and adult outpatients.

BACKGROUND: Community-acquired pneumonia (CAP) is a lung infection that can be acquired during day-to-day activities in the community (not while receiving care in a hospital). Community-acquired pneumonia poses a significant public health burden in terms of mortality, morbidity, and costs. Shorter antibiotic courses for CAP may limit treatment costs and adverse effects, but the optimal duration of antibiotic treatment is uncertain. OBJECTIVES: To evaluate the efficacy and safety of short-course versus longer-course treatment with the same antibiotic at the same daily dosage for CAP in non-hospitalised adolescents and adults (outpatients). We planned to investigate non-inferiority of short-course versus longer-term course treatment for efficacy outcomes, and superiority of short-course treatment for safety outcomes. SEARCH METHODS: We searched CENTRAL, which contains the Cochrane Acute Respiratory Infections Group Specialised Register, MEDLINE, Embase, five other databases, and three trials registers on 28 September 2017 together with conference proceedings, reference checking, and contact with experts and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing short- and long-courses of the same antibiotic for CAP in adolescent and adult outpatients. DATA COLLECTION AND ANALYSIS: We planned to use standard Cochrane methods. MAIN RESULTS: Our searches identified 5260 records. We did not identify any RCTs that compared short- and longer-courses of the same antibiotic for the treatment of adolescents and adult outpatients with CAP.We excluded two RCTs that compared short courses (five compared to seven days) of the same antibiotic at the same daily dose because they evaluated antibiotics (gemifloxacin and telithromycin) not commonly used in practice for the treatment of CAP. In particular, gemifloxacin is no longer approved for the treatment of mild-to-moderate CAP due to its questionable risk-benefit balance, and reported adverse effects. Moreover, the safety profile of telithromycin is also cause for concern.We found one ongoing study that we will assess for inclusion in future updates of the review. AUTHORS' CONCLUSIONS: We found no eligible RCTs that studied a short-course of antibiotic compared to a longer-course (with the same antibiotic at the same daily dosage) for CAP in adolescent and adult outpatients. The effects of antibiotic therapy duration for CAP in adolescent and adult outpatients remains unclear.

OSCANN: Technical Characterization of a Novel Gaze Tracking Analyzer.

Eye-movement analysis has grown exponentially in recent decades. The reason is that abnormalities in oculomotor movements are usually symptoms of injuries in the nervous system. This paper presents a novel regulated solution named OSCANN. OSCANN aims at providing an innovative tool for the control, management and visualization of oculomotor neurological examinations. This solution utilizes an eye-tracker sensor based on video electro-oculography (VOG) technology to capture eye movements and store them in video files. Such a sensor can store images at a rate of 100 frames per second. A characterization study was performed using twenty-two volunteers (13 male, 9 female, ages 22-45 years, mean 29.3 years, SD = 6.7) to assess the accuracy and precision specifications of OSCANN during oculomotor movement analysis. The accuracy was evaluated based on the offset, whereas precision was estimated with Root Means Square (RMS). Such a study reported values lower than 0.4 ∘ and 0.03 ∘ of accuracy and precision, respectively. These results suggest that OSCANN can be considered as a powerful tool to measure oculomotor movement alterations involved in some neurological disease progression.

(-)-Shikimic Acid as a Chiral Building Block for the Synthesis of New Cytotoxic 6-Aza-Analogues of Angucyclinones.

We describe the syntheses of nine new angucyclinone 6-aza-analogues, achieved through a hetero Diels-Alder reaction between the shikimic acid derivative-azadiene 13, with different naphthoquinones. The cytotoxic activity of the new synthesized compounds and five angucyclinones, previously reported, was evaluated in vitro against three cancer cell lines: PC-3 (prostate cancer), HT-29 (colon cancer), MCF-7 (breast cancer), and one non-tumoral cell line, human colon epithelial cells (CCD841 CoN). Our results showed that most 6-azadiene derivatives exhibited significant cytotoxic activities, which was demonstrated by their IC50 values (less than 10 µM), especially for the most sensitive cells, PC-3 and HT-29. From a chemical point of view, depending on the protected group of ring A and the pattern of substitution on ring D, cytotoxicity elicited these compounds, in terms of their potency and selectivity. Therefore, according to these chemical features, the most promising agents for every cancer cell line were 7a, 17, and 19c for PC-3 cells; 7a, 17, and 20 for HT-29 cells, and 19a for MCF-7 cells.

Has primary care antimicrobial use really been increasing? Comparison of changes in different prescribing measures for a complete geographic population 1995-2014.

Objectives: To elucidate how population trends in total antimicrobials dispensed in the community translate into individual exposure. Methods: Retrospective, population-based observational study of all antimicrobial prescribing in a Scottish region in financial years 1995, 2000 and 2005-14. Analysis of temporal changes in all antimicrobials and specific antimicrobials measured in: WHO DDD per 1000 population; prescriptions per 1000 population; proportion of population with ≥1 prescription; mean number of prescriptions per person receiving any; mean DDD per prescription. Results: Antimicrobial DDD increased between 1995 and 2014, from 5651 to 6987 per 1000 population [difference 1336 (95% CI 1309-1363)]. Prescriptions per 1000 fell (from 821 to 667, difference -154, -151 to -157), as did the proportion prescribed any antimicrobial [from 39.3% to 30.8% (-8.5, -8.4 to -8.6)]. Rising mean DDD per prescription, from 6.88 in 1995 to 10.47 in 2014 (3.59, 3.55-3.63), drove rising total DDD. In the under-5s, every measure fell over time (68.2% fall in DDD per 1000; 60.7% fall in prescriptions per 1000). Among 5-64 year olds, prescriptions per 1000 were lowest in 2014 but among older people, despite a reduction since 2010, the 2014 rate was still higher than in 2000. Trends in individual antimicrobials provide some explanation for overall trends. Conclusions: Rising antimicrobial volumes up to 2011 were mainly due to rising DDD per prescription. Trends in dispensed drug volumes do not readily translate into information on individual exposure, which is more relevant for adverse consequences including emergence of resistance.

The discovery of IDX21437: Design, synthesis and antiviral evaluation of 2'-α-chloro-2'-ß-C-methyl branched uridine pronucleotides as potent liver-targeted HCV polymerase inhibitors.

Herein we describe the discovery of IDX21437 35b, a novel RPd-aminoacid-based phosphoramidate prodrug of 2'-α-chloro-2'-ß-C-methyluridine monophosphate. Its corresponding triphosphate 6 is a potent inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRp). Despite showing very weak activity in the in vitro Huh-7 cell based HCV replicon assay, 35b demonstrated high levels of active triphosphate 6 in mouse liver and human hepatocytes. A biochemical study revealed that the metabolism of 35b was mainly attributed to carboxyesterase 1 (CES1), an enzyme which is underexpressed in HCV Huh-7-derived replicon cells. Furthermore, due to its metabolic activation, 35b was efficiently processed in liver cells compared to other cell types, including human cardiomyocytes. The selected RP diastereoisomeric configuration of 35b was assigned by X-ray structural determination. 35b is currently in Phase II clinical trials for the treatment of HCV infection.

Effect of nepafenac on the foveal profile of glaucomatous patients undergoing phacoemulsification.

PURPOSE: Retrospective, pilot study to determine whether nepafenac treatment pre- and postcataract surgery in glaucoma patients using topical hypotensive agents minimized cystoid macular edema by comparing pre- and postsurgical foveal characteristics, as in some cases these agents cannot be withdrawn and, hypothetically, their inflammatory effect on the fovea could be neutralized by the addition of nepafenac. METHODS: Patients were divided into two subgroups depending on whether or not topical nepafenac was added to the surgical protocol (NEP = nepafenac group and nNEP = non nepafenac group). All had undergone phacoemulsification and data on pre- and postoperative macular status were recorded. RESULTS: In the nNEP group, there was a significant increase in foveal thickness (FT) in the first month postoperative visit with respect to the preoperative status (p = 0.006), and this situation did not change at the third postoperative month (p = 0.9411). In the NEP group, the increase in FT was not significant at the first month after surgery (p = 0.056) nor at the final visit (p = 0.268), in contrast to the nNEP group. CONCLUSION: This study of the possible prophylactic effect of nepafenac on postoperative macular edema supports the results of other studies that confirm subclinical edema post phacoemulsification, and found a significantly lower gradient in the increase in FT in patients treated pre- and postoperatively with nepafenac.

The rising tide of polypharmacy and drug-drug interactions: population database analysis 1995-2010.

BACKGROUND: The escalating use of prescribed drugs has increasingly raised concerns about polypharmacy. This study aims to examine changes in rates of polypharmacy and potentially serious drug-drug interactions in a stable geographical population between 1995 and 2010. METHODS: This is a repeated cross-sectional analysis of community-dispensed prescribing data for all 310,000 adults resident in the Tayside region of Scotland in 1995 and 2010. The number of drug classes dispensed and the number of potentially serious drug-drug interactions (DDIs) in the previous 84 days were calculated, and age-sex standardised rates in 1995 and 2010 compared. Patient characteristics associated with receipt of ≥ 10 drugs and with the presence of one or more DDIs were examined using multilevel logistic regression to account for clustering of patients within primary care practices. RESULTS: Between 1995 and 2010, the proportion of adults dispensed ≥ 5 drugs doubled to 20.8%, and the proportion dispensed ≥ 10 tripled to 5.8%. Receipt of ≥ 10 drugs was strongly associated with increasing age (20-29 years, 0.3%; ≥ 80 years, 24.0%; adjusted OR, 118.3; 95% CI, 99.5-140.7) but was also independently more common in people living in more deprived areas (adjusted OR most vs. least deprived quintile, 2.36; 95% CI, 2.22-2.51), and in people resident in a care home (adjusted OR, 2.88; 95% CI, 2.65-3.13). The proportion with potentially serious drug-drug interactions more than doubled to 13% of adults in 2010, and the number of drugs dispensed was the characteristic most strongly associated with this (10.9% if dispensed 2-4 drugs vs. 80.8% if dispensed ≥ 15 drugs; adjusted OR, 26.8; 95% CI 24.5-29.3). CONCLUSIONS: Drug regimens are increasingly complex and potentially harmful, and people with polypharmacy need regular review and prescribing optimisation. Research is needed to better understand the impact of multiple interacting drugs as used in real-world practice and to evaluate the effect of medicine optimisation interventions on quality of life and mortality.