Control Series Research Articles

Association between oral fluoroquinolone use and the development of retinal detachment: a systematic review and meta-analysis of observational studies.

Several observational studies have been published investigating the association between oral fluoroquinolone use and the development of retinal detachment; however, the findings are not concordant. This study is a meta-analysis of the existing literature and estimates the overall absolute risk of such an event. Electronic databases were searched for observational studies on the association between oral fluoroquinolone and retinal detachment up to August 2014. Studies that did not meet the criteria for meta-analysis were narratively reviewed. Cases of retinal detachment during current fluoroquinolone use were also extracted for absolute risk calculation. Seven observational studies were included. Three (case-control and self-controlled case series studies) were eligible for meta-analysis and four (cohort studies) were narratively reviewed. The rate ratio of the case-control studies was 1.82 (95% CI 0.67-4.93), I(2) =96% and the incidence rate ratio of the self-controlled case series was 1.03 (95% CI 0.84-1.27), I(2) =36%. Three of the four cohort studies found no significant association between oral fluoroquinolone use and the development of retinal detachment. The pooled absolute risk of retinal detachment whilst on current oral fluoroquinolone treatment is estimated to be 4.85 per 1000000 prescriptions (95% CI 0.78-8.91). The findings of this systematic review and meta-analysis do not support an association between oral fluoroquinolone use and the development of retinal detachment. Given the low absolute risk, such an event would be rare if there were an association. The current prescribing practice for fluoroquinolones should not be altered because of a previously suggested potential risk of retinal detachment.

Risk factors for maternal injuries in a population-based sample of pregnant women.

The prevalence of injuries during pregnancy is largely underestimated, as previous research has focused on more severe injuries resulting in emergency department visits and hospitalizations. The objective of our study was to estimate the frequency, risk factors, and causes of injuries in a population-based sample of pregnant women. This article is an analysis of postpartum interviews among the control series from a case-control study (n=1,488). Maternal, pregnancy, and environmental characteristics associated with injury during pregnancy in control subjects were examined to identify population-based risk factors for injury. We collected data on self-reported injury during pregnancy, including the month of pregnancy, whether medical attention was sought, the mechanism of injury, and the number and location of bodily injuries. Logistic regression was used to calculate unadjusted and adjusted odds ratios (aORs) of injury. Over 5% of women reported an injury during pregnancy, with falls being the most common mechanism of injury. Women at highest adjusted risk for injury had unintended pregnancies (aOR: 2.28 [1.40-3.70]) and no partner during pregnancy (aOR: 2.45 [1.16-5.17]) relative to women without injuries. Pregnant women with risk factors for many pregnancy-related complications are also at increased risk of injury during pregnancy. Further studies of pregnancy-related injuries are needed to consider environmental and maternal characteristics on risk of injury.

CT pulmonary angiography in pregnant and postpartum women: low yield, high dose

PurposeTo compare the diagnostic utility of computed tomography pulmonary angiography (CTPA) in pregnant/postpartum women with age-matched controls. MaterialsWe performed a retrospective case–control series of pregnant/postpartum women and control women who underwent CTPA from 2008 to 2011. ResultsThe study included 34 pregnant women, 16 postpartum women, and 50 controls. CTPAs were positive in 2% of pregnant/postpartum women and 16% of controls (P=.003). The main pulmonary artery mean opacification was 271 Hounsfield units (HU) for pregnant/postpartum women vs. 303 HU (P=.12). Radiation exposure was high in both groups but lower in pregnant/postpartum women, 10 vs. 14mSv (P=.003). ConclusionCTPA in pregnant and postpartum women had low yield and remained high dose.

Does use of the optokinetic chart stimulation based OKCSIB protocol improve recovery of upper and lower limb movements, function and quality of life at 3 year follow up in dense strokes? A retrospective case control series.

The aim was to compare follow up impairment, function and quality of life outcomes between dense parietal centred strokes treated by the optokinetic chart based OKCSIB protocol and those treated by conventional neuro-physiotherapy. Follow up retrospective case control series in the community. 643 persons with stroke were eligible for initial screening to see if they met inclusion criteria. Only 37 potential participants were eligible, with 18 of them still alive. From the 18 only 8 consented to participate in the follow up study. Sixteen mortalities that occurred post discharge were all from the conventional group. The OKCSIB group had statistically significant improved upper limb STREAM scores (p < 0.05). The OKCSIB group had statistically significant reduction in hand spasticity with none of the OKCSIB participants developing hand spasticity (p < 0.05). The OKCSIB group also had better lower limb STREAM scores although these were not statistically significant (p > 0.05). Barthel Index, and quality of Life improvements were non-significant (p > 0.05). The OKCSIB protocol led to better recovery of voluntary movements at 3 year follow up. However lack of randomisation and the small number of participants, necessitate further research to be carried out.

Geniotubercle advancement with a uvulopalatal flap and its effect on swallow function in obstructive sleep apnea.

Evaluate swallowing characteristics before and after geniotubercle advancement (GTA) with a uvulopalatal flap (UPF). Prospective case control series in an academic military practice. Fourteen patients with apnea-hypopnea index (AHI) >10 scheduled for GTA were enrolled consecutively, eight of whom completed all aspects of the study for evaluation. Video fluoroscopic swallow study was performed preoperatively and 4 months postoperatively. National Institute of Health freeware ImageJ64 software was used to measure hyolaryngeal elevation and displacement. Video recordings assessed vallecular pooling, aspiration, and bolus movement. Studies were reviewed by a speech pathologist and an otolaryngologist. Preoperatively, the mean AHI was 48.3 ± 48.45 events per hour, with a median of 48.5 (range, 12.4-76). Postoperatively the mean AHI was 11.6 ± 10.7 events per hour, with a median of 10.75 (range, 3.8-29) (P = .003). There was no reported pre- or postoperative dysphagia or aspiration. No radiographic evidence of silent aspiration was seen. Hyolaryngeal movements were measured as a percentage of C2-C4 reference distance. The superior elevations were pre- and postoperatively 40% and 37% (P = .85), anterior displacement changes 18.9% and 18.8% (P = .23), and total motion 49% and 42% (P = .26), respectively. GTA with UPF surgery did not significantly affect the hyolaryngeal function of patients.

Development of characterization procedure of particulate matter pollution collected in immediate vicinity of urban residents

Advantage of using individual dust meters over traditional stationary particulate matter (PM) air pollution monitoring is evaluated. Data of air pollution levels obtained from the three municipal stationary monitoring stations were compared with data of individual dust meters SidePak AM 510. Results of a few control series of this comparison have indicated important differences between the mentioned two types of synchronised measurements. Taking into account that vast majority of time people spend indoors, one may expect that individual samplers better characterise exposition of any human being on the PM urban pollution. As a result, a new sampling procedure is proposed. It allows the collection of particulate matter in the immediate vicinity of human being: As collectors of the PM, we propose mobile phones, accompanying people whatever is their everyday activity. Namely, dust deposited in the inner parts of the used mobile phones is extracted and analysed. The procedure consists of bulk analysis performed with spark source mass spectrometry (SSMS) and depth profile analysis made by secondary ion mass spectrometry (SIMS). Exemplary results are presented of the particulate material deposited on high purity indium foils. Ion erosion is done with 5 keV Ar+, 150‐µm diameter ion beam scanned over 2 × 2.5 mm area. The analyser is equipped with Physical Electronics ion gun and QMA‐410 Balzers quadrupole mass spectrometer. Copyright © 2014 John Wiley &amp; Sons, Ltd.

Factores de riesgo para la infección en prótesis de rodilla, incluyendo la fractura intraoperatoria y la trombosis venosa profunda, no descritos previamente

PurposeTo carry out a statistical analysis on the significant risk factors for deep late infection (prosthetic joint infection, PJI) in patients with a knee arthroplasty (TKA). MethodsA retrospective observational case-control study was conducted on a case series of 32 consecutive knee infections, using an analysis of all the risk factors reported in the literature. A control series of 100 randomly selected patients operated in the same Department of a University General Hospital during the same period of time, with no sign of deep infection in their knee arthroplasty during follow-up. Statistical comparisons were made using Pearson for qualitative and ANOVA for quantitative variables. ResultsThe significant (p>0.05) factors found in the series were: Preoperative previous knee surgery, glucocorticoids, immunosuppressants, inflammatory arthritis. Intraoperativeprolonged surgical time, inadequate antibiotic prophylaxis, intraoperative fractures. Postoperative secretion of the wound longer than 10 days, deep palpable haematoma, need for a new surgery, and deep venous thrombosis in lower limbs. Distant infections cutaneous, generalized sepsis, urinary tract, pneumonia, abdominal. ConclusionsThis is the first report of intraoperative fractures and deep venous thrombosis as significantly more frequent factors in infected TKAs. Other previously described risk factors for TKA PJI are also confirmed.

Removal of bisphenol A (BPA) in a nitrifying system with immobilized biomass

The potential for bisphenol A (BPA) removal by mixed consortia of immobilized microorganisms with high nitrification activity was investigated with BPA concentrations in the influent from 2.5 to 10.0mg/L. The presence of BPA limited ammonium oxidation; nitrification efficiency decreased from 91.2±1.3% in the control series to 47.4±9.4% when BPA concentration in wastewater was the highest. The efficiency of BPA removal rose from 87.1±5.5% to 92.9±2.9% with increased BPA concentration in the influent. Measurement of oxygen uptake rates by biomass exposed to BPA showed that BPA was mainly removed by heterotrophic bacteria. A strong negative correlation between the BPA removal efficiency and nitrification efficiency indicated the limited contribution of ammonia-oxidizing bacteria (AOB) to BPA biodegradation. Exposure of biomass to BPA changed the quantity and diversity of AOB in the biomass as shown by real-time PCR and denaturing gradient gel electrophoresis.

Morphological Changes in the Aortic Wall after Blood Loss (An experimental Study)

Objective: to reveal aortic structural changes in the recovery period after longterm hemorrhagic hypotension and further blood reinfusion. Material and methods. Two (control and experimental) series of eexperiments were carried out on 10 out bred albino male rats in each. The animals were anesthetized with sodium thiopental (25 mg/kg). Sixtyminute hemorrhagic hypotension (40 mm Hg) was induced by left common carotid artery catheterization, followed by blood reinfusion and wound closure. The animals were observed for 60 days, thereafter thoracic and abdominal aortic fragments were taken. The histological sections were stained with hematoxylin and eosin by the methods of Van Gieson, Verhoeff, and Veigert. Morphometric and histometric parameters, including the percentage of layers in the vascular wall and transmission capac ity coefficients, were determined. Results. The thoracic and abdominal aortic sections have been found to differ in morphometric parameters, which determined their different hemodynamic conditions in critical conditions. Hypertrophy of the media of the abdominal aorta due to thickening of the smooth muscle layers suggests that there are remodeling processes in its wall, which is accompanied by a smaller number of elastic membranes and by the expression of сollagencontaining structures after massive blood loss. For the thoracic aortic segment, such changes are manifested by a decreased medial area, a considerable advential thickening, and a drastic fall in transmission capacity coefficients. Conclusion. The found morphometric characteristics of different aortic segments should be considered as the basis for longlasting adaptation, which can supply blood to the vital organs as efficiently as possible in late recovery periods.

Lateral sol–gel cross-linking of polyurethane using the a grafted triethoxysilyl group

3-Triethoxysilylpropyl isocyanate was used to graft a triethoxysilyl group to polyurethane (PU), and the grafted triethoxysilyl groups were used to cross-link PU chains through a sol–gel process. The soft segment melting temperature and enthalpy change were not significantly altered by the sol–gel cross-linking. The sol–gel cross-linked PUs exhibited significantly increased tensile strength and better tensile strain compared to the plain linear PU: the maximum stress and strain increased to 41 MPa and 1,972 %, respectively. Control series containing tetraethyl orthosilicate, a series without cross-linking, was also prepared for comparison with the sol–gel cross-linked PU series. The control series did not exhibit the increased tensile strength shown by the sol–gel cross-linked PU series. The cyclic shape memory tests demonstrated that the shape recovery was as high as 97 %, and both shape recovery and shape retention remained high after the four repeated tests. The sol–gel cross-linked PU series exhibited enhanced low-temperature flexibility compared to the plain linear PU due to the flexible silyl cross-linking group.

Below the Belt

Originally described in 1982, scalp somatosensory evoked potential responses can be recorded after stimulation of multiple different pudendal nerve- and sacral root-supplied structures. The resulting P40 response is usually the highest amplitude at Cz. Responses are generally easy to resolve and therefore should be of equivalent ease to follow for neurophysiologic intraoperative monitoring versus lower limb peripheral nerve somatosensory evoked potentials (e.g., tibial or fibular [peroneal] nerves), but sizeable reports of pudendal somatosensory evoked potential monitoring are few. Direct orthodromic sensory nerve action potential recording from the cauda equina in response to single such sacral stimuli has been reported of utility for preserving roots that participate in urinary control during dorsal rhizotomy procedures for spasticity. Technical application of both techniques is quite straightforward. As in most areas of neurophysiologic intraoperative monitoring, there are no well-constructed historical control series informing use of these techniques and, certainly, no clinical trials. Given the socially devastating consequences of urinary and anal continence disturbances and a fairly high rate of functional postoperative disturbances when sacral roots are manipulated, this field begs more active clinical investigation.

Multiscale mechanical quantification of self-healing concrete incorporating non-ureolytic bacteria-based healing agent

This paper investigated non-ureolytic bacterially-induced precipitation of calcium carbonate as a self-healing strategy for concrete cracking. By incorporating bacteria and calcium source nutrients as a two-component healing agent in concrete matrix, the process of bacterially mediated calcium carbonate deposition was trigged upon crack formation and self-sealing of cracks can be expected. The effectiveness of healing was evaluated by mechanical tests in macroscale (flexural and ultrasonic pulse velocity) and nanoscale (nanoindentation), respectively. Both the repair method and the type of calcium source have a significant impact on the healing efficiency. The healing ratio and recovery ratios of flexural strength and modulus of the two-component self-healing with calcium glutamate were higher than that of control series by a factor of 2. A transition zone, whose average nanomechanical values were approximately 20% higher than that of outer precipitates, acted as a strong bond between the matrix and deposited layer from calcium glutamate.

Use of waste marble and recycled aggregates in self-compacting concrete for environmental sustainability

Abstract Nowadays, due to an increase in marble and concrete production, emerged wastes are disposed into empty fields. This waste causes environmental pollution. In this study, the use of marble waste (MW) and recycled aggregate (RA) from crushed concrete in the production of SCC was investigated. Control series were produced with crushed limestone aggregate (LS) in different water to binder ratios. Then, LS was replaced with MW or RA in ratio of 100%. Fresh concrete experiments such as slump-flow, the J-ring test, unit weight and air content were carried out. Furthermore, compressive strength, splitting-tensile strength, stress–strain relationship, modulus of elasticity and ultrasonic pulse velocity experiments on the hardened specimens were carried out, and mechanical properties of all the concrete types were compared. According to the results obtained, workability of SCC such as flow-ability, blocking resistance and segregation resistance is increased by use of pieces of MW instead of LS. Moreover, important differences were not observed in the mechanical properties of SCC by using MW and RA. For this reason, crushed marble stone and recycled coarse aggregates that were obtained using lower energy than that required for obtaining the LS, can be used in the SCC.

Polio-like disease in the news: much ado about nothing?

Polio-like disease in the news: much ado about nothing?

Urinary bladder cancer risk variants: recent findings and new challenges of GWAS and confirmatory studies

polymorphisms (SNPs) associated with a moderate UBC risk at sixteen chromosomal locations, besides GSTM1 (Table 1; reviews, see Golka et al. 2011; Dudek et al. 2013). While most of them could be confirmed in independent follow-up case–control series, novel UBC risk SNPs are still requiring validation. It can be assumed that the most relevant loci are discovered now as the size of the GWAS is considerable large with more than 6,900 cases and 45,000 controls (Kiemeney et al. 2010; rothman et al. 2010; rafnar et al. 2011; Figueroa et al. 2014a, b), and the density of the SNP chips combined with highly accurate imputation algorithms results in a sufficient representation of the genetic variation. Subsequent fine-mapping studies aim to identify the functional relevant genetic variants that are in linkage disequilibrium with the initial findings that are often located in non-coding regions more than 20 kb and several haploblocks apart of the next genes (review: Dudek et al. 2013; see also Selinski 2013). Tang et al. (2012), and Fu et al. (2012) used this approach to localize the genetic variants explaining the bladder cancer risk associated with SNPs in the UGTA1 and PSCA gene, respectively (Wu et al. 2009; rothman et al. 2010). however, further finemapping and functional studies are required to elucidate the functional relationship between polymorphism and disease for most of the SNPs. Currently, subgroup analyses, e.g., restricted to smokers or high-grade tumors, are becoming more and more relevant. First results of a GWAS on SNPs that interact with smoking habits suggest at least two novel loci that modify UBC risk in non-smokers or in smokers (Figueroa et al. 2014a). Besides, discovery of novel loci in subgroups stratification and interaction analyses of known risk factors indicate how and to which extend genetic risk factors modify bladder cancer risk in presence or absence of exogenous risk factors, e.g., smoking (Garcia-Closas et al. 2013) and Urinary bladder cancer (UBC) is the fourth most common cancer in men and the fourteenth most common cancer in women in western europe (Ferlay et al. 2013). Approximately 50 % of the UBC cases are caused by cigarette smoking (Schwender et al. 2012; Burger et al. 2013). Further, 7.1–20 % of the bladder cancer cases can be attributed to occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons (Golka et al. 2004, 2009, 2012; Delclos and Lerner 2008; rushton et al. 2012; Burger et al. 2013; Carreon et al. 2014). Genetic risk factors explain about 31 % of the bladder cancer cases (Lichtenstein et al. 2000). As segregation analysis in 1,193 families failed to identify a major gene (Aben et al. 2006), a polygenetic basis of bladder cancer can be assumed. This is consistent with recent findings of a number of polymorphisms each conferring a small to moderate UBC risk (Golka et al. 2011; Selinski 2012). Polymorphisms of phase II metabolizing enzymes are well known to increase bladder cancer risk and to modulate the effect of bladder carcinogen exposure via smoking and occupation (Garcia-Closas et al. 2005; Golka et al. 2009; Moore et al. 2011). Most relevant is the deletion variant of glutathione S-transferase M1 (GSTM1) (Arand et al. 1996; Golka et al. 1997, 2009; Garcia-Closas et al. 2005; Ovsiannikov et al. 2012) and polymorphisms in the N-acetyltransferase 2 (NAT2) gene resulting in a reduced acetylation capacity (Golka et al. 1996, 2002; Moore et al. 2011; Selinski et al. 2011, 2013). Meanwhile, genome-wide association studies (GWAS) have identified a number of novel single nucleotide

Standard principles of infection control: infection control series, part 2

Last year, 15.146 million people were admitted to NHS hospitals as inpatients; the number of people admitted has been rising over the past ten years ( NHS Confederation, 2014 ). Changes in healthcare practice have led to a major decline in healthcare-associated infections (Walker and Fowler, 2011:69; Health Protection Agency (HPA), 2012 ). Standard principles of infection control are the rock on which all efforts to reduce infection rates are embedded. Population changes have led to the NHS treating greater numbers of older people, who are extremely vulnerable to infection ( Nazarko, 2014 ). Increasing levels of antibiotic resistance mean that infections are more difficult to treat ( Department of Health (DH), 2013 ). These changes mean that good practice in infection control is vital. Every single person who works in healthcare has a responsibility to reduce infection risks by practising standard principles of infection control. This article aims to enable readers to be aware of what infection control is, what infection risks exist, how infection spreads and what can be done to reduce infection risks.

Effect of Autologous Plasma, Ascorbic Acid and Glucose Local Infusions on Pelvic Fracture Healing in Experiment

The efficacy of reparative osteogenesis stimulation by local infusion of autologous plasma in combination with ascorbic acid and glucose solutions was experimentally demonstrated in ani- mals (dogs) using the models of transverse acetabular ( n =20) and iliac shaft fracture ( n= 6). Either intraarticular or intraosseous solution infusions via injection system with automatic drug pump were performed from 2nd to 5th day after transverse osteotomy, reposition and stable external fixation. Fixator was dismounted on 21st postoperative day. In control series of experiment (intraarticular and intraosseous infusion of saline) fibrocartilagenous junction was formed and bone deformity due to secondary bone fragments displacement was noted after device removal. In experimental series primary pelvic bone fragments consolidation was observed in 14 days after operation and no displacement of fragments occurred after external fixation device removal.

Effect of Autologous Plasma, Ascorbic Acid and Glucose Local Infusions on Pelvic Fracture Healing in Experiment

The efficacy of reparative osteogenesis stimulation by local infusion of autologous plasma in combination with ascorbic acid and glucose solutions was experimentally demonstrated in ani- mals (dogs) using the models of transverse acetabular ( n =20) and iliac shaft fracture ( n= 6). Either intraarticular or intraosseous solution infusions via injection system with automatic drug pump were performed from 2nd to 5th day after transverse osteotomy, reposition and stable external fixation. Fixator was dismounted on 21st postoperative day. In control series of experiment (intraarticular and intraosseous infusion of saline) fibrocartilagenous junction was formed and bone deformity due to secondary bone fragments displacement was noted after device removal. In experimental series primary pelvic bone fragments consolidation was observed in 14 days after operation and no displacement of fragments occurred after external fixation device removal.

Adverse Effect of Femoral Nerve Blockade on Quadriceps Strength and Function after ACL Reconstruction

The purpose of this study was to determine if quadriceps strength and functional outcomes were similar at 6 months following anterior cruciate ligament [ACL] reconstruction in patients receiving a continuous 48-hour femoral nerve blockade for postoperative analgesia (FNB group) versus patients with no FNB (control group). A retrospective cohort was designed including athletes who underwent primary ACL reconstruction with patellar tendon autograft between 2005 and 2010 at our institution with identical rehabilitation protocols. The FNB group included 96 patients with an average age of 21 years and the control group included 100 patients with an average age of 20 years. At 6 months following ACL reconstruction, isokinetic strength (slow and fast activation) and functional tests including vertical jump, single hop, triple hop, and return to sport were analyzed with an α value < 0.05 as significant. Multivariate regression models were used to compare these outcomes between the FNB and control groups after adjusting for gender and competitive athlete status. At 6 months, fast extension isokinetic strength was inferior in the FNB group (78 vs. 85%; p < 0.01). After adjusting for gender and competitive athlete status, fast (p = 0.002) and slow extension strength (p = 0.01), vertical jump (p = 0.03) and single jump (p = 0.02) were also inferior in the FNB group. There were no significant differences in full return to sport between the two groups (86% at 7.5 months in the FNB group vs. 93% at 7.3 months in the control group). In this retrospective comparative study, the hypothesis that patients treated with continuous FNB for postoperative analgesia following ACL reconstruction with patellar tendon autograft will have inferior knee extension (quadriceps) strength and function at 6 months follow-up was affirmed. However, no differences were observed in return to sport, bringing into question whether these statistical differences translate into meaningful clinical consequences after ACL reconstruction. The level of evidence was level III, retrospective case-control series.

ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease

Recent genome-wide association studies (GWAS) of late-onset Alzheimer’s disease (LOAD) have identified single nucleotide polymorphisms (SNPs) which show significant association at the well-known APOE locus and at nineteen additional loci. Among the functional, disease-associated variants at these loci, missense variants are particularly important because they can be readily investigated in model systems to search for novel therapeutic targets. It is now possible to perform a low-cost search for these “actionable” variants by genotyping the missense variants at known LOAD loci already cataloged on the Exome Variant Server (EVS). In this proof-of-principle study designed to explore the efficacy of this approach, we analyzed three rare EVS variants in APOE, p.L28P, p.R145C and p.V236E, in our case control series of 9114 subjects. p.R145C proved to be too rare to analyze effectively. The minor allele of p.L28P, which was in complete linkage disequilibrium (D’ = 1) with the far more common APOE ϵ4 allele, showed no association with LOAD (P = 0.75) independent of the APOE ϵ4 allele. p.V236E was significantly associated with a marked reduction in risk of LOAD (P = 7.5×10−05; OR = 0.10, 0.03 to 0.45). The minor allele of p.V236E, which was in complete linkage disequilibrium (D’ = 1) with the common APOE ϵ3 allele, identifies a novel LOAD-associated haplotype (APOE ϵ3b) which is associated with decreased risk of LOAD independent of the more abundant APOE ϵ2, ϵ3 and ϵ4 haplotypes. Follow-up studies will be important to confirm the significance of this association and to better define its odds ratio. The ApoE p.V236E substitution is the first disease-associated change located in the lipid-binding, C-terminal domain of the protein. Thus our study (i) identifies a novel APOE missense variant which may profitably be studied to better understand how ApoE function may be modified to reduce risk of LOAD and (ii) indicates that analysis of protein-altering variants cataloged on the EVS can be a cost-effective way to identify actionable functional variants at recently discovered LOAD loci.