To send content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about sending content to .
To send content items to your Kindle, first ensure firstname.lastname@example.org
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about sending to your Kindle.
Note you can select to send to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
Despite knowing for many decades that depressive psychopathology is common in first-episode schizophrenia spectrum disorders (FES), there is limited knowledge regarding the extent and nature of such psychopathology (degree of comorbidity, caseness, severity) and its demographic, clinical, functional and treatment correlates. This study aimed to determine the pooled prevalence of depressive disorder and caseness, and the pooled mean severity of depressive symptoms, as well as the demographic, illness, functional and treatment correlates of depressive psychopathology in FES.
This systematic review, meta-analysis and meta-regression was prospectively registered (CRD42018084856) and conducted in accordance with PRISMA and MOOSE guidelines.
Forty studies comprising 4041 participants were included. The pooled prevalence of depressive disorder and caseness was 26.0% (seven samples, N = 855, 95% CI 22.1–30.3) and 43.9% (11 samples, N = 1312, 95% CI 30.3–58.4), respectively. The pooled mean percentage of maximum depressive symptom severity was 25.1 (38 samples, N = 3180, 95% CI 21.49–28.68). Correlates of depressive psychopathology were also found.
At least one-quarter of individuals with FES will experience, and therefore require treatment for, a full-threshold depressive disorder. Nearly half will experience levels of depressive symptoms that are severe enough to warrant diagnostic investigation and therefore clinical intervention – regardless of whether they actually fulfil diagnostic criteria for a depressive disorder. Depressive psychopathology is prominent in FES, manifesting not only as superimposed comorbidity, but also as an inextricable symptom domain.
The almost universally-occurring aggregated distributions of helminth burdens in host populations have major significance for parasite population ecology and evolutionary biology, but the mechanisms generating heterogeneity remain poorly understood. For the direct life cycle monogenean Discocotyle sagittata infecting rainbow trout, Oncorhynchus mykiss, variables potentially influencing aggregation can be analysed individually. This study was based at a fish farm where every host individual becomes infected by D. sagittata during each annual transmission period. Worm burdens were examined in one trout population maintained in isolation for 9 years, exposed to self-contained transmission. After this year-on-year recruitment, prevalence was 100% with intensities 10–2628, mean 576, worms per host. Parasite distribution, amongst hosts with the same age and environmental experience, was highly aggregated with variance to mean ratio 834 and negative binomial parameter, k, 0.64. The most heavily infected 20% of fish carried around 80% of the total adult parasite population. Aggregation develops within the first weeks post-infection; hosts typically carried intensities of successive age-specific cohorts that were consistent for that individual, such that heavily-infected individuals carried high numbers of all parasite age classes. Results suggest that host factors alone, operating post-infection, are sufficient to generate strongly overdispersed parasite distributions, rather than heterogeneity in exposure and initial invasion.
Direct numerical simulations (DNS) are performed in a triply periodic unit cell of a face-centred cubic (FCC) lattice covering the unsteady inertial, to fully turbulent, flow regimes. The DNS data are used to quantify the flow topology, integral scales, turbulent kinetic energy (TKE) transport and anisotropy distribution in the tortuous geometry. Several unique flow features are observed within this low porosity configuration, where the mean flow undergoes strong acceleration and deceleration regions with presence of three-dimensional helical motions, weak wake-like structures behind spheres, stagnation and jet-impingement-like flows together with merging and spreading jets in the main pore space. The jet-impingement and weak wake-like flow structures give rise to regions with negative total TKE production. Unlike flows in complex shaped ducts, the turbulence intensity levels in the cross-stream directions are found to be larger than those in the streamwise direction. Furthermore, due to the compact nature and confined geometry of the FCC packing, the turbulent integral length scales are estimated to be less than 10 % of the bead diameter even for the lowest Reynolds number studied, indicating the absence of macroscale turbulence structures for this configuration. This finding suggests that even for the highly anisotropic flow within the pore, the upscaled flow statistics are captured well by the representative volumes defined by the unit cell.
Introduction: There is increasing evidence supporting ultrasonography for the determination of optimal chest compression location during cardiac arrest. Radiological studies have demonstrated that in up to 1/3 of patients the aortic root or outflow tract is being compressed during standard CPR. Out-of-hospital-cardiac-arrests (OHCA) could benefit from cardiac localization, undertaken with scaled-down ultrasound equipment by which the largest fluid filled structure in the chest (the heart) is identified to guide optimal compression location. We intend to evaluate 1) where the left ventricle is in supine patients, 2) the accuracy and precision as well as 3) the feasibility and reliability of cardiac localization with a scaled down ultrasound device (bladder scanners). Methods: We are recruiting men and women over the age of 40. The scanning protocol involves using a bladder scanner on a 15-point grid over the subject's left chest and parasternal, midclavicular, and anterior axillary intercostal spaces 3-7. Detected volumes will be recorded, with the presumption that the intercostal space with the largest measured volume is centered over the heart. Echocardiography will then be used to confirm the bladder scanner accuracy and to better describe the patient's internal chest anatomy. Having assessed procedural feasibility on 3 pilot subjects, we are now recruiting 100 participants, with planned interim analysis at 50 participants for sample size reassessment. Maximal volume location frequencies from the echocardiograms will be described and assessed for variation utilizing the goodness-of-fit test. The proportion of agreement across the two modalities regarding the maximal volume location will also be examined. Results: Among the 3 volunteers (pilot study), the scanner identified fluid in 4-8 of 15 intercostal spaces. In each of the three pilot study patients, the maximal volume identified by the bladder scanner was found to be at the parasternal location of the 6th intercostal space. This was also the location of the mid left ventricular diameter on echocardiography. Conclusion: Our literature review and pilot study data support the premise that lay persons and emergency medical personnel may improve compressions (and thus outcomes) during OHCA by using a scaled-down ultrasound to identify the location of optimal compression. We are currently enrolling patients in our study.
Innovation Concept: The fairness of the Canadian Residency Matching Service (CaRMS) selection process has been called into question by rising rates of unmatched medical students and reports of bias and subjectivity. We outline how the University of Saskatchewan Royal College emergency medicine program evaluates CaRMS applications in a standardized, rigorous, equitable and defensible manner. Methods: Our CaRMS applicant evaluation methods were first utilized in the 2017 CaRMS cycle, based on published Best Practices, and have been refined yearly to ensure validity, standardization, defensibility, rigour, and to improve the speed and flow of data processing. To determine the reliability of the total application scores for each rater, single measures intraclass correlation coefficients (ICCs) were calculated using a random effects model in 2017 and 2018. Curriculum, Tool or Material: A secure, online spreadsheet was created that includes applicant names, reviewer assignments, data entry boxes, and formulas. Each file reviewer entered data in a dedicated sheet within the document. Each application was reviewed by two staff physicians and two to four residents. File reviewers used a standardized, criterion-based scoring rubric for each application component. The file score for each reviewer-applicant pair was converted into a z-score based on each reviewer's distribution of scores. Z-scores of all reviewers for a single applicant were then combined by weighted average, with the group of staff and group of residents each being weighted to represent half of the final file score. The ICC for the total raw scores improved from 0.38 (poor) in 2017 to 0.52 (moderate) in 2018. The data from each reviewer was amalgamated into a master sheet where applicants were sorted by final file score and heat-mapped to offer a visual aid regarding differences in ratings. Conclusion: Our innovation uses heat-mapped and formula-populated spreadsheets, scoring rubrics, and z-scores to normalize variation in scoring trends between reviewers. We believe this approach provides a rigorous, defensible, and reproducible process by which Canadian residency programs can appraise applicants and create a rank order list.
An (improper) graph colouring has defect d if each monochromatic subgraph has maximum degree at most d, and has clustering c if each monochromatic component has at most c vertices. This paper studies defective and clustered list-colourings for graphs with given maximum average degree. We prove that every graph with maximum average degree less than (2d+2)/(d+2)k is k-choosable with defect d. This improves upon a similar result by Havet and Sereni (J. Graph Theory, 2006). For clustered choosability of graphs with maximum average degree m, no (1-ɛ)m bound on the number of colours was previously known. The above result with d=1 solves this problem. It implies that every graph with maximum average degree m is
-choosable with clustering 2. This extends a result of Kopreski and Yu (Discrete Math., 2017) to the setting of choosability. We then prove two results about clustered choosability that explore the trade-off between the number of colours and the clustering. In particular, we prove that every graph with maximum average degree m is
-choosable with clustering 9, and is
-choosable with clustering O(m). As an example, the later result implies that every biplanar graph is 8-choosable with bounded clustering. This is the best known result for the clustered version of the earth–moon problem. The results extend to the setting where we only consider the maximum average degree of subgraphs with at least some number of vertices. Several applications are presented.
Unlike for many other respiratory infections, the seasonality of pertussis is not well understood. While evidence of seasonal fluctuations in pertussis incidence has been noted in some countries, there have been conflicting findings including in the context of Australia. We investigated this issue by analysing the seasonality of pertussis notifications in Australia using monthly data from January 1991 to December 2016. Data were made available for all states and territories in Australia except for the Australian Capital Territory and were stratified into age groups. Using a time-series decomposition approach, we formulated a generalised additive model where seasonality is expressed using cosinor terms to estimate the amplitude and peak timing of pertussis notifications in Australia. We also compared these characteristics across different jurisdictions and age groups. We found evidence that pertussis notifications exhibit seasonality, with peaks observed during the spring and summer months (November–January) in Australia and across different states and territories. During peak months, notifications are expected to increase by about 15% compared with the yearly average. Peak notifications for children <5 years occurred 1–2 months later than the general population, which provides support to the theory that older household members remain an important source of pertussis infection for younger children. In addition, our results provide a more comprehensive spatial picture of seasonality in Australia, a feature lacking in previous studies. Finally, our findings suggest that seasonal forcing may be useful to consider in future population transmission models of pertussis.
Over the past 25 years, numerous studies of polymers utilizing both X-ray diffraction (XRD) and differential scanning calorimetry (DSC) have been reported in the literature. These studies have suffered because the two techniques must be performed on separate samples and under conditions that are often dissimilar. By combining the two techniques into one instrument, typical problems encountered with variations in sample preparation and thermal and atmospheric environment are eliminated. This is quite important in the study of polymers since one must match not only temperatures between the two techniques, but also heating rates as well. Matched thermal conditions are necessary because polymer properties such as crystallinity and crystallite size depend on both the temperature and thermal history of the sample under study.
Atmospheric aerosol particles have been sampled near a Los Angeles freeway and analyzed by proton-induced X-ray emission, PIXE, as a sulfur baseline study in September 1974 before 1975-model auto mobiles, equipped with catalytic emission control devices, appeared in large numbers. The sampling plan was optimized a c cording to the requirements of X-ray analysis techniques, fluctuations in air flow across the freeway, and the time and particlesise resolution of the aerosol sampling equipment. During five selected two-hour intervals with cross wind conditions, particles were collected as a function of size by six cascade impactorsope rating simultaneously on three towers at 2 and 7 meters above road level 35 meters upwind and 35 meters downwind of the traffic lanes. Particles as a function of time were sampled continuously, for the 100-hour duration of the experiment, from the three 7-meter heights using time series streaker filter samplers with two-hour time resolution. Precise analyses of S, Cl, K, Ca, Fe, Br, and. Pb established relationships which permit estimates to be made of future increases in particulate sulfur as a consequence of increased sulfate emissions from catalytic automobiles.
Community-acquired pneumonia (CAP) results in substantial numbers of hospitalisations and deaths in older adults. There are known lifestyle and medical risk factors for pneumococcal disease but the magnitude of the additional risk is not well quantified in Australia. We used a large population-based prospective cohort study of older adults in the state of New South Wales (45 and Up Study) linked to cause-specific hospitalisations, disease notifications and death registrations from 2006 to 2015. We estimated the age-specific incidence of CAP hospitalisation (ICD-10 J12-18), invasive pneumococcal disease (IPD) notification and presumptive non-invasive pneumococcal CAP hospitalisation (J13 + J18.1, excluding IPD), comparing those with at least one risk factor to those with no risk factors. The hospitalised case-fatality rate (CFR) included deaths in a 30-day window after hospitalisation. Among 266 951 participants followed for 1 850 000 person-years there were 8747 first hospitalisations for CAP, 157 IPD notifications and 305 non-invasive pneumococcal CAP hospitalisations. In persons 65–84 years, 54.7% had at least one identified risk factor, increasing to 57.0% in those ⩾85 years. The incidence of CAP hospitalisation in those ⩾65 years with at least one risk factor was twofold higher than in those without risk factors, 1091/100 000 (95% confidence interval (CI) 1060–1122) compared with 522/100 000 (95% CI 501–545) and IPD in equivalent groups was almost threefold higher (18.40/100 000 (95% CI 14.61–22.87) vs. 6.82/100 000 (95% CI 4.56–9.79)). The CFR increased with age but there were limited difference by risk status, except in those aged 45 to 64 years. Adults ⩾65 years with at least one risk factor have much higher rates of CAP and IPD suggesting that additional risk factor-based vaccination strategies may be cost-effective.
To evaluate the impact of changes to urine testing orderables in computerized physician order entry (CPOE) system on urine culturing practices.
Retrospective before-and-after study.
A 1,250-bed academic tertiary-care referral center.
Hospitalized adults who had ≥1 urine culture performed during their stay.
The intervention (implemented in April 2017) consisted of notifications to providers, changes to order sets, and inclusion of the new urine culture reflex tests in commonly used order sets. We compared the urine culture rates before the intervention (January 2015 to April 2016) and after the intervention (May 2016 to August 2017), adjusting for temporal trends.
During the study period, 18,954 inpatients (median age, 62 years; 68.8% white and 52.3% female) had 24,569 urine cultures ordered. Overall, 6,662 urine cultures (27%) were positive. The urine culturing rate decreased significantly in the postintervention period for any specimen type (38.1 per 1,000 patient days preintervention vs 20.9 per 1,000 patient days postintervention; P < .001), clean catch (30.0 vs 18.7; P < .001) and catheterized urine (7.8 vs 1.9; P < .001). Using an interrupted time series model, urine culture rates decreased for all specimen types (P < .05).
Our intervention of changes to order sets and inclusion of the new urine culture reflex tests resulted in a 45% reduction in the urine cultures ordered. CPOE system format plays a vital role in reducing the burden of unnecessary urine cultures and should be implemented in combination with other efforts.
To evaluate the long-term safety and tolerability of deutetrabenazine in patients with tardive dyskinesia (TD) at 2years.
In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale scores compared with placebo, and there were low rates of overall adverse events (AEs) and discontinuations associated with deutetrabenazine.
Patients who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12mg/day, titrating up to a maximum total daily dose of 48mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration period and a long-term maintenance phase. Safety measures included incidence of AEs, serious AEs (SAEs), and AEs leading to withdrawal, dose reduction, or dose suspension. Exposure-adjusted incidence rates (EAIRs; incidence/patient-years) were used to compare AE frequencies for long-term treatment with those for short-term treatment (ARM-TD and AIM-TD). This analysis reports results up to 2 years (Week106).
343 patients were enrolled (111 patients received placebo in the parent study and 232 received deutetrabenazine). There were 331.4 patient-years of exposure in this analysis. Through Week 106, EAIRs of AEs were comparable to or lower than those observed with short-term deutetrabenazine and placebo, including AEs of interest (akathisia/restlessness [long-term EAIR: 0.02; short-term EAIR range: 0–0.25], anxiety [0.09; 0.13–0.21], depression [0.09; 0.04–0.13], diarrhea [0.06; 0.06–0.34], parkinsonism [0.01; 0–0.08], somnolence/sedation [0.09; 0.06–0.81], and suicidality [0.02; 0–0.13]). The frequency of SAEs (EAIR 0.15) was similar to those observed with short-term placebo (0.33) and deutetrabenazine (range 0.06–0.33) treatment. AEs leading to withdrawal (0.08), dose reduction (0.17), and dose suspension (0.06) were uncommon.
These results confirm the safety outcomes seen in the ARM-TD and AIM-TD parent studies, demonstrating that deutetrabenazine is well tolerated for long-term use in TD patients.
Presented at: American Academy of Neurology Annual Meeting; April 21–27, 2018, Los Angeles, California,USA
Funding Acknowledgements: Funding: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel
To evaluate long-term efficacy of deutetrabenazine in patients with tardive dyskinesia (TD) by examining response rates from baseline in Abnormal Involuntary Movement Scale (AIMS) scores. Preliminary results of the responder analysis are reported in this analysis.
In the 12-week ARM-TD and AIM-TD studies, the odds of response to deutetrabenazine treatment were higher than the odds of response to placebo at all response levels, and there were low rates of overall adverse events and discontinuations associated with deutetrabenazine.
Patients with TD who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12mg/day, titrating up to a maximum total daily dose of 48mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration and a long-term maintenance phase. The cumulative proportion of AIMS responders from baseline was assessed. Response was defined as a percent improvement from baseline for each patient from 10% to 90% in 10% increments. AlMS score was assessed by local site ratings for this analysis.
343 patients enrolled in the extension study (111 patients received placebo in the parent study and 232 patients received deutetrabenazine). At Week 54 (n=145; total daily dose [mean±standard error]: 38.1±0.9mg), 63% of patients receiving deutetrabenazine achieved ≥30% response, 48% of patients achieved ≥50% response, and 26% achieved ≥70% response. At Week 80 (n=66; total daily dose: 38.6±1.1mg), 76% of patients achieved ≥30% response, 59% of patients achieved ≥50% response, and 36% achieved ≥70% response. Treatment was generally well tolerated.
Patients who received long-term treatment with deutetrabenazine achieved response rates higher than those observed in positive short-term studies, indicating clinically meaningful long-term treatment benefit.
Presented at: American Academy of Neurology Annual Meeting; April 21–27, 2018, Los Angeles, California, USA.
Funding Acknowledgements: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel.
During the summer of 2016, the Hawaii Department of Health responded to the second-largest domestic foodborne hepatitis A virus (HAV) outbreak in the post-vaccine era. The epidemiological investigation included case finding and investigation, sequencing of RNA positive clinical specimens, product trace-back and virologic testing and sequencing of HAV RNA from the product. Additionally, an online survey open to all Hawaii residents was conducted to estimate baseline commercial food consumption. We identified 292 confirmed HAV cases, of whom 11 (4%) were possible secondary cases. Seventy-four (25%) were hospitalised and there were two deaths. Among all cases, 94% reported eating at Oahu or Kauai Island branches of Restaurant Chain A, with 86% of those cases reporting raw scallop consumption. In contrast, a food consumption survey conducted during the outbreak indicated 25% of Oahu residents patronised Restaurant Chain A in the 7 weeks before the survey. Product trace-back revealed a single distributor that supplied scallops imported from the Philippines to Restaurant Chain A. Recovery, amplification and sequence comparison of HAV recovered from scallops revealed viral sequences matching those from case-patients. Removal of product from implicated restaurants and vaccination of those potentially exposed led to the cessation of the outbreak. This outbreak further highlights the need for improved imported food safety.
The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)–pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D–pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (Prace difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (Prace difference=0·56). Among EA, the 25(OH)D–FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.
Objectives: Although subjective cognitive complaints (SCC) are an integral component of the diagnostic criteria for mild cognitive impairment (MCI), previous findings indicate they may not accurately reflect cognitive ability. Within the Alzheimer’s Disease Neuroimaging Initiative, we investigated longitudinal change in the discrepancy between self- and informant-reported SCC across empirically derived subtypes of MCI and normal control (NC) participants. Methods: Data were obtained for 353 MCI participants and 122 “robust” NC participants. Participants were classified into three subtypes at baseline via cluster analysis: amnestic MCI, mixed MCI, and cluster-derived normal (CDN), a presumptive false-positive group who performed within normal limits on neuropsychological testing. SCC at baseline and two annual follow-up visits were assessed via the Everyday Cognition Questionnaire (ECog), and discrepancy scores between self- and informant-report were calculated. Analysis of change was conducted using analysis of covariance. Results: The amnestic and mixed MCI subtypes demonstrated increasing ECog discrepancy scores over time. This was driven by an increase in informant-reported SCC, which corresponded to participants’ objective cognitive decline, despite stable self-reported SCC. Increasing unawareness was associated with cerebrospinal fluid Alzheimer’s disease biomarker positivity and progression to Alzheimer’s disease. In contrast, CDN and NC groups over-reported cognitive difficulty and demonstrated normal cognition at all time points. Conclusions: MCI participants’ discrepancy scores indicate progressive underappreciation of their evolving cognitive deficits. Consistent over-reporting in the CDN and NC groups despite normal objective cognition suggests that self-reported SCC do not predict impending cognitive decline. Results demonstrate that self-reported SCC become increasingly misleading as objective cognitive impairment becomes more pronounced. (JINS, 2018, 24, 842–853)
We prove that for every surface
of Euler genus
, every edge-maximal embedding of a graph in
is at most
edges short of a triangulation of
. This provides the first answer to an open problem of Kainen (1974).
We investigated risk factors for severe acute lower respiratory infections (ALRI) among hospitalised children <2 years, with a focus on the interactions between virus and age. Statistical interactions between age and respiratory syncytial virus (RSV), influenza, adenovirus (ADV) and rhinovirus on the risk of ALRI outcomes were investigated. Of 1780 hospitalisations, 228 (12.8%) were admitted to the intensive care unit (ICU). The median (range) length of stay (LOS) in hospital was 3 (1–27) days. An increase of 1 month of age was associated with a decreased risk of ICU admission (rate ratio (RR) 0.94; 95% confidence intervals (CI) 0.91–0.98) and with a decrease in LOS (RR 0.96; 95% CI 0.95–0.97). Associations between RSV, influenza, ADV positivity and ICU admission and LOS were significantly modified by age. Children <5 months old were at the highest risk from RSV-associated severe outcomes, while children >8 months were at greater risk from influenza-associated ICU admissions and long hospital stay. Children with ADV had increased LOS across all ages. In the first 2 years of life, the effects of different viruses on ALRI severity varies with age. Our findings help to identify specific ages that would most benefit from virus-specific interventions such as vaccines and antivirals.