Prognostic Signals From Moderate Valve Disease in Big Data: An Artefact of Digital Imaging and Communications in Medicine Structured Reporting?

BACKGROUND: Recent studies have identified an association between moderate aortic stenosis (AS) and outcome. We assessed whether Digital Imaging and Communications in Medicine (DICOM) structured reporting (SR), which captures and inserts echocardiographic measurements and text data directly into radiological reports, may lead to misclassifying patients with severe AS as moderate. METHODS: Moderate or severe AS cases were filtered from an echocardiography data set based on aortic valve area (AVA) < 1.5 cm2, indexed AVA (AVAi) ≤ 0.85 cm2/m2, mean pressure gradient ≥ 25 mm Hg, dimensionless severity index (DSI) ≤ 0.5, or peak velocity > 3 m/sec. Data validation was conducted by verification of each parameter. All echocardiographic parameters and definitions of AS were compared pre- and postvalidation by taking differences in measurements. Misclassification rates were assessed by determining the percentage of cases that changed AS severity classification and impact on outcomes. Patients were followed over 4.3 ± 1.5 years. RESULTS: Of 2,595 validated echocardiograms with AS, up to 36% of the echocardiographic parameters for AS criteria had a >10% difference between DICOM-SR and manual validation, the highest with mean pressure gradient (36%) and the lowest with DSI (6.5%). The validation process changed the reported degree of AS in up to 20.6% of echocardiograms with resultant changes in AS severity and its association with mortality or heart failure-related hospitalizations. In contrast to multiple quantitative metrics in DICOM-SR after manual validation, clinicians' evaluation of AS severity was unable to distinguish composite outcomes over 3 years between moderate and severe AS. The risk of composite outcomes was significantly increased when severe AS was evidenced by at least 1 echocardiographic parameter of severe AS (hazard ratio = 1.24; 95% CI, 1.12-1.37; P < .001). The greatest hazard was based on DSI only (hazard ratio = 1.26; 95% CI, 1.10-1.44; P < .001), which was higher after manual validation compared to DICOM-SR. Averaging of repeated echo measures including invalid values contributed the most to erroneous data. CONCLUSIONS: Nonpeak data in DICOM-SR led to incorrect categorization of a high proportion of patients based on AS severity definitions. Standardization of data fields and curation to ensure that only peak values are imported from DICOM-SR data are essential.

Population Pharmacokinetic Models of Vancomycin in Paediatric Patients: A Systematic Review.

BACKGROUND: Vancomycin is commonly used to treat gram-positive bacterial infections in the paediatric population, but dosing can be challenging. Population pharmacokinetic (popPK) modelling can improve individualization of dosing regimens. The primary objective of this study was to describe popPK models of vancomycin and factors that influence pharmacokinetic (PK) variability in paediatric patients. METHODS: Systematic searches were conducted in the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, International Pharmaceutical Abstracts and the grey literature without language or publication status restrictions from inception to 17 August 2020. Observational studies that described the development of popPK models of vancomycin in paediatric patients (< 18 years of age) were included. Risk of bias was assessed using the National Heart, Lung and Blood Institute Study Quality Assessment Tool for Case Series Studies. RESULTS: Sixty-four observational studies (1 randomized controlled trial, 13 prospective studies and 50 retrospective studies of 9019 patients with at least 25,769 serum vancomycin concentrations) were included. The mean age was 2.5 years (range 1 day-18 years), serum creatinine was 47.1 ± 33.6 µmol/L, and estimated creatinine clearance was 97.4 ± 76 mL/min/1.73m2. Most studies found that vancomycin PK was best described by a one-compartment model (71.9%). There was a wide range of clearance and volume of distribution (Vd) values (range 0.014-0.27 L/kg/h and 0.43-1.46 L/kg, respectively) with interindividual variability as high as 49.7% for clearance and 136% for Vd, proportional residual variability up to 37.5% and additive residual variability up to 17.5 mg/L. The most significant covariates for clearance were weight, age, and serum creatinine or creatinine clearance, and weight for Vd. Variable dosing recommendations were suggested. CONCLUSION: Numerous popPK models of vancomycin were derived, however external validation of suggested dosing regimens and analyses in subgroup paediatric populations such as dialysis patients are still needed before a popPK model with best predictive performance can be applied for dosing recommendations. Significant intraindividual and interindividual PK variability was present, which demonstrated the need for ongoing therapeutic drug monitoring and derivation of PK models for vancomycin for certain subgroup populations, such as dialysis patients.

Risk stratification of cardiovascular complications using CHA2DS2-VASc and CHADS2 scores in chronic atherosclerotic cardiovascular disease.

Background The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial showed that rivaroxaban plus aspirin reduced major adverse cardiovascular events (MACE) in patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD). We explored whether CHA2DS2-VASc or CHADS2 scores, well-validated tools for assessing risk of thromboembolic events in atrial fibrillation, can identify vascular patients at highest risk of recurrent events who may derive greatest benefits of treatment. Methods Predictive accuracies of the CHA2DS2-VASc and CHADS2 scores for MACE, were assessed in this analysis of the COMPASS trial. Kaplan-Meier estimates of cumulative risk were used to compare the effects of rivaroxaban plus aspirin (n = 9152) with aspirin alone (n = 9126) according to risk scores. Results High CHA2DS2-VASc (6-9) or CHADS2 (3-6) scores were associated with over three times greater absolute risk of MACE compared with CHA2DS2-VASc score of 1-2 or CHADS2 score of 0. The effects of rivaroxaban plus aspirin compared with aspirin alone were consistent across CHA2DS2-VASc and CHADS2 score categories for MACE, bleeding and net clinical benefit, with greatest reduction in MACE observed in patients treated for 30 months with highest CHADS2 score (3-6) (hazard ratio = 0.67, 95% CI: 0.53-0.86, p = 0.0012, 25 events per 1000 patients prevented). Conclusion The CHA2DS2-VASc and CHADS2 scores can be used in patients with chronic CAD and/or PAD to identify patients who are at highest risk of MACE. Those identified at highest risk by CHADS2 scores had greatest benefit from dual pathway inhibition with rivaroxaban plus aspirin. Clinical Trial Registration: NCT01776424.

Prognosis of Severe Low-Flow, Low-Gradient Aortic Stenosis by Stroke Volume Index and Transvalvular Flow Rate.

OBJECTIVES: This study determined whether flow state classified by stroke volume index (SVi) or transvalvular flow rate (FR) improved risk stratification of all-cause mortality, hospitalization due to heart failure, and aortic valvular interventions for patients with severe aortic stenosis (AS). BACKGROUND: SVi is a widely accepted classification for flow state in severe low-flow, low-gradient (LFLG) AS. Recent studies suggest that FR more closely approximates true AS severity and provides more useful prognostication than SVi. METHODS: Patients with severe AS over a 7-year period were subclassified by echocardiographic parameters. LFLG-AS was defined as severe AS (aortic valve area index [AVAi]: <0.6 cm2/m2), with a mean transvalvular pressure gradient of <40 mm Hg in the setting of low flow state: SVi of <35 ml/m2 and/or FR of <200 ml/s and subclassified into preserved (≥50%; paradoxical) or reduced (<50%; classical) left ventricular ejection fraction (LVEF). RESULTS: Among 621 consecutive patients with severe AS, the proportions of patients classified as LFLG-AS were different between SVi and FR (p < 0.001). Classification using SVi, FR, and LVEF was a strong predictor of the composite endpoint at the 2-year follow-up. The addition of SVi to the echocardiographic and clinical model provided significant improvement in reclassification (net reclassification improvement: 0.089; 95% confidence interval [CI]: 0.045 to 0.133; p = 0.04), whereas addition of FR did not (net reclassification improvement: 0.061; 95% CI: 0.016 to 0.106; p = 0.17). C-statistics indicated improved risk discrimination when AVAi, LVEF, and SVi or FR were added as predictive variables to the clinical model (p = 0.006). CONCLUSIONS: Low SVi or FR was associated with adverse cardiovascular events and showed improvement in discrimination, but only SVi, not FR, significantly improved risk reclassification compared to other conventional clinical and echocardiographic predictors. This suggests that FR is not superior to SVi in distinguishing true severe from pseudosevere forms of AS and identification of patients with LFLG-AS who have worse outcomes.

Incidence of Premature Lead Failure in 2088 TendrilTM Pacing Leads: A Single Centre Experience.

BACKGROUND: Recent reports describe a high rate of premature lead failure in the St Jude/Abbott TendrilTM 2088 (St. Jude Medical Inc., St. Paul, MN, USA) pacing lead principally manifested by electrical noise. This finding awaits confirmation. METHODS: We performed a retrospective analysis of 2088 TendrilTM leads among 362 patients implanted from 2010 to 2018. Eligible leads were those with device interrogations beyond one month from lead implantation. Review of serial device interrogations was conducted for each lead, particularly focussing on electrical noise as a marker of premature lead dysfunction. RESULTS: Four hundred and eight (408) leads among 337 patients were included in this study, with an average patient age of 81±11 years at the time of lead implantation. Mean follow-up was 2.5±1.8 years. There were eight leads with electrical noise indicating premature lead failure. This reflects an overall 1.7% rate of lead dysfunction; the failure rate was 6.2% at 4 years. The majority of cases were detected during routine checks without adverse clinical consequences. Four (4) cases required device reprogramming to avoid interference or inhibition due to noise. CONCLUSION: The rate of Tendril TM 2088 premature lead failure appears to be similar to recent local and international studies. This study reports a significantly higher rate of lead dysfunction at 4 years (6.2%) than the published Abbott product performance reports.

Antihypertensive therapies in moderate or severe aortic stenosis: a systematic review and meta-analysis.

BACKGROUND: Hypertension confers a poor prognosis in moderate or severe aortic stenosis (AS), however, antihypertensive therapy (AHT) is often not prescribed due to the perceived deleterious effects of vasodilation and negative inotropes. OBJECTIVE: To assess the efficacy and safety outcomes of AHT in adults with moderate or severe AS. DESIGN: Systematic review and meta-analysis. DATA SOURCES: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and grey literature were searched without language restrictions up to 9 September 2019. STUDY ELIGIBILITY CRITERIA, APPRAISAL AND SYNTHESIS METHODS: Two independent reviewers performed screening, data extraction and risk of bias assessments from a systematic search of observational studies and randomised controlled trials comparing AHT with a placebo or no AHT in adults with moderate or severe AS for any parameter of efficacy and safety outcomes. Conflicts were resolved by the third reviewer. Meta-analysis with pooled effect sizes using random-effects model, were estimated in R. MAIN OUTCOME MEASURES: Mortality, Left Ventricular (LV) Mass Index, systolic blood pressure, diastolic blood pressure and LV ejection fraction RESULTS: From 3025 publications, 31 studies (26 500 patients) were included in the qualitative synthesis and 24 studies in the meta-analysis. AHT was not associated with mortality when all studies were pooled, but heterogeneity was substantial across studies. The effect size of AHT differed according to drug class. Renin-angiotensin-aldosterone system inhibitors (RAASi) were associated with reduced risk of mortality (Pooled HR 0.58, 95% CI 0.43 to 0.80, p=0.006), The differences in changes of haemodynamic or echocardiographic parameters from baseline with and without AHT did not reach statistical significance. CONCLUSION: AHT appears safe, is well tolerated. RAASi were associated with clinical benefit in patients with moderate or severe AS.

Metformin treatment in heart failure with preserved ejection fraction: a systematic review and meta-regression analysis.

BACKGROUND: Observational series suggest a mortality benefit from metformin in the heart failure (HF) population. However, the benefit of metformin in HF with preserved ejection fraction (HFpEF) has yet to be explored. We performed a systematic review and meta-analysis to identify whether variation in EF impacts mortality outcomes in HF patients treated with metformin. METHODS: MEDLINE and EMBASE were searched up to October 2019. Observational studies and randomised trials reporting mortality in HF patients and the proportion of patients with an EF > 50% at baseline were included. Other baseline variables were used to assess for heterogeneity in treatment outcomes between groups. Regression models were used to determine the interaction between metformin and subgroups on mortality. RESULTS: Four studies reported the proportion of patients with a preserved EF and were analysed. Metformin reduced mortality in both preserved or reduced EF after adjustment with HF therapies such as angiotensin converting enzyme inhibitors (ACEi) and beta-blockers (ß = - 0.2 [95% CI - 0.3 to - 0.1], p = 0.02). Significantly greater protective effects were seen with EF > 50% (p = 0.003). Metformin treatment with insulin, ACEi and beta-blocker therapy were also shown to have a reduction in mortality (insulin p = 0.002; ACEi p < 0.001; beta-blocker p = 0.017), whereas female gender was associated with worse outcomes (p < 0.001). CONCLUSIONS: Metformin treatment is associated with a reduction in mortality in patients with HFpEF.

Premature ventricular contraction-induced dilated cardiomyopathy: a case report.

BACKGROUND: Premature ventricular complexes (PVCs) are ectopic heartbeats caused by early myocardial depolarizations, previously thought to be benign. Recent studies found high PVC burden above 24% can induce or contribute to cardiomyopathy and heart failure. We present a case of PVC-induced dilated cardiomyopathy (DCM). CASE SUMMARY: A 68-year-old woman was admitted with pneumonia after an overseas trip with a preceding viral respiratory tract infection. An initial chest X-ray was suggestive of cardiomegaly. A transthoracic echocardiogram (TTE) revealed DCM with global systolic dysfunction (left ventricular ejection fraction <30%) without valvular lesions. Biochemistry and coronary angiography were normal. Clinical deterioration occurred despite medical therapy. A 24-h Holter monitoring detected 27% PVCs, which was thought to have caused DCM. As an alternative to cardiac resynchronization therapy and an implantable cardiac defibrillator for primary prevention, ablation of the PVC focus led to complete suppression of ectopy. Post-procedure TTEs and Holter monitoring showed normalized systolic function and low PVC burden. DISCUSSION: Because high PVC burden can lead to cardiomyopathy and heart failure, suppression of PVC should be considered to restore ventricular function for patients with structural heart disease and frequent symptomatic PVCs. This case highlights that PVCs may be a modifiable risk factor for heart failure that can be successfully treated with pharmacological therapies or catheter ablation.

Impact of socioeconomic status on incident heart failure and left ventricular dysfunction: systematic review and meta-analysis.

AIMS: Socioeconomic status (SES) is recognizably linked with incident heart failure (HF) risk and the association of SES with geography presents a potential target for geographical location of preventive health services. To better inform policy we sought to quantify the independent association between SES and incident HF and investigate differences by type of SES measure. METHODS AND RESULTS: MEDLINE and EMBASE were searched up to August 2018. Observational studies and randomized trials reporting adjusted HF incidence by stratified socioeconomic measures were included. Effect sizes reflected HF incidence in the lowest vs. highest SES stratum and were pooled using a random-effects model. Low SES referred to the lowest resource stratum, the definition of which varied across studies: meta-analysis was only performed where strata were comparable. Statistical heterogeneity was assessed using the I2 statistic. Eleven studies comprising 6 308 006 individuals and 104 217 HF events found that low SES was associated with an increase in risk of incident HF ranging between 43% and 87% depending on SES measure, with an overall estimate of 62% [hazard ratio (HR) 1.62, 95% confidence interval (CI) 1.50-1.76]. By individual measure, HRs of 1.66 (95% CI 1.3-2.11), 1.87 (95% CI 1.33-2.62), and 1.54 (95% CI 1.22-1.95) were observed for education, income, and occupation, respectively. For area-level indexes, HRs were 1.43 (95% CI 1.2-1.69) (Carstairs index) and 1.61 (95% CI 1.56-1.65) (index of multiple deprivation). CONCLUSION: Low SES assessed by all common measures confers independent risk for incident HF. These findings carry implications for the design and delivery of HF prevention programmes.

His-Bundle Pacing in a Patient with Transcatheter Aortic Valve Implantation-Induced Left Bundle Branch Block.

Transcatheter aortic valve implantation (TAVI) is an effective intervention for severe aortic stenosis in patients at intermediate or high surgical risk, but damage to the native conduction system such as left bundle branch block (LBBB) may offset its benefits. New onset LBBB is associated with a higher risk of cardiovascular morbidity and mortality. His-bundle pacing (HBP) may be useful to treat TAVI-induced LBBB but has yet to be reported. We present the case of a 76-year-old man with severe symptomatic aortic stenosis treated with TAVI. His preoperative electrocardiogram showed sinus rhythm with a narrow QRS complex. Insertion of a CoreValve Evolut R transcatheter aortic valve was uneventful apart from the development of LBBB with a long PR interval. A dual-lead DDD pacemaker was implanted via the left cephalic vein on the following day. HV was mildly prolonged at 60 ms. Capture of the proximal His restored AV synchrony without correction of LBBB. Repositioning of the lead with capture of the left bundle branch enabled complete ventricular resynchronisation with a single lead. Our case demonstrates that LBBB in the setting of TAVI may be corrected by HBP.

Fractal analysis of heart rate variability as a predictor of mortality: A systematic review and meta-analysis.

Previous studies have suggested benefits of applying fractal analysis to intervals between R waves in electrocardiography as an additional prognostic marker. The aim of this study was to investigate whether fractal analysis can provide an independent predictor of cardiac mortality or all-cause mortality. Prognostic cohort studies reporting fractal heart rate variability results from 24-h Holter monitor recordings were selected for comparison. Populations were subdivided into four groups-post-myocardial infarction, left ventricular dysfunction, other cardiac, and non-cardiac patients-and analysed using ANOVA, Forest plots (using pooled mean difference), and Funnel plots. The most significant mean differences were recorded in short-term fractal self-similarity (α1) (-0.17, 95% CI [-0.21, -0.13], p < 0.00001) and the traditional measure called standard deviation of NN intervals (SDNN) (-13.31, 95% CI [-18.89, -7.73], p < 0.00001) between the deceased and survivor groups. Fractal measures of long-term fractal self-similarity (α2), 1/f scaling (ß), and traditional heart rate variability measures of high frequency to low frequency ratio show promise. This review indicated that fractal measure α1 and traditional measure SDNN could be potential predictors of mortality, but require further assessment to determine appropriate thresholds for clinical significance and additional targeted prognostic studies to properly define their applicability as prognostic markers. Therefore, clinicians should interpret fractal and traditional measures with caution since such measures have yet to be fully described as biomarkers for clinical application.

Tolvaptan for Heart Failure in Chronic Kidney Disease Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Heart failure (HF) is frequently associated with renal impairment. Tolvaptan is reported to be effective in treating congestion in HF without significant electrolyte loss compared to conventional diuretics. However, the safety and efficacy of its use in patients with chronic kidney disease (CKD) is uncertain. This systematic review and meta-analysis evaluated the efficacy and safety outcomes of tolvaptan for HF management in patients with CKD, with a focus at a physiologic basis related to safety. METHODS: We searched for observational studies and randomised clinical trials (RCTs) that assessed the effects of tolvaptan against placebo or standard care in adult patients with HF and CKD. Our protocol was registered with PROSPERO (number CRD42017052775). RESULTS: Seventeen studies were included in the qualitative review and six in the meta-analysis involving 1597 patients. Tolvaptan was associated with an increase in sodium concentration. No significant differences in change of eGFR and serum creatinine were found between tolvaptan and control groups. Urine flow rate appears to increase significantly with tolvaptan compared to baseline (p<0.0001). The meta-analysis demonstrated no heterogeneity between studies but the possibility of publication bias due to incomplete reporting in excluded studies and lack of RCTs. CONCLUSIONS: The safety profile of tolvaptan appears acceptable for patients with HF and CKD. There is evidence for an improvement in serum sodium and reduction in body water without deterioration in renal function. Further research is needed to elucidate the long-term benefits of tolvaptan as an adjunct or alternative to diuretics in such patients.

Hyperreactio Luteinalis: Maternal and Fetal Effects.

Hyperreactio luteinalis is a rare condition in which there is massive cystic enlargement of the ovaries, mimicking malignancy, during pregnancy. When confronted with this condition, the fear of missing a cancer diagnosis often leads the physician to react with unnecessary surgical intervention, potentially resulting in impaired future fertility. The literature on the subject contains mainly case reports and one small case series. A recent review attempted to summarize what is currently known, but there has not yet been a pervasive change in the approach to the management of this condition. In order to define the natural history of the condition and its maternal and fetal effects, we examined all case reports available in the English literature from 1993 to 2014, in addition to another as yet unpublished case report. Our analysis suggests that, despite its impressive presentation with ovarian enlargement and hyperandrogenism, hyperreactio luteinalis tends to be self-limiting, with spontaneous postpartum resolution and without untoward maternal or fetal sequelae. In particular, fetal virilization is rare, and dependent on the timing of hyperandrogenism. Adverse pregnancy outcomes are likely a consequence of the abnormally high hCG levels observed in many of these gestations, and the subset of women with these abnormal values should be considered for enhanced surveillance. Vaginal delivery is preferred, and strategies to sustain the potential for breastfeeding must be introduced while maternal androgen levels fall, allowing lactation to be established. Considering its benign nature and postpartum resolution, management of HL must be conservative, and continued education of health care professionals who may encounter this entity is vital.

L'hyperreactio luteinalis est un trouble rare qui donne lieu à une hypertrophie kystique des ovaires de grande envergure, laquelle imite la présence d'une tumeur maligne, pendant la grossesse. La présence d'une telle situation mène souvent le médecin à procéder inutilement à une intervention chirurgicale motivée par la crainte de voir un diagnostic de cancer passer inaperçu, ce qui pourrait affecter la fertilité future de la patiente. La littérature sur le sujet consiste principalement en des exposés de cas et en une série de cas de faible envergure. Bien qu'une récente analyse ait tenté de résumer les données connues à ce sujet à l'heure actuelle, aucune modification n'a encore été universellement apportée à la prise en charge de cette pathologie. Afin de définir l'histoire naturelle de cette dernière et d'en déterminer les effets maternels et fœtaux, nous nous sommes penchés sur tous les exposés de cas ayant été publiés en anglais entre 1993 et 2014, ainsi que sur un exposé de cas n'ayant pas encore été publié. Notre analyse laisse entendre que, malgré sa présentation spectaculaire (hypertrophie ovarienne et hyperandrogénie), l'hyperreactio luteinalis a tendance à être spontanément résolutive à la suite de l'accouchement, sans séquelles indésirables pour la mère ou le fœtus. En particulier, la virilisation fœtale est rare et dépend de la chronologie de l'hyperandrogénie. Les issues de grossesse indésirables sont probablement attribuables aux taux anormalement élevés de hCG qui sont constatés dans bon nombre des grossesses affectées; la mise en œuvre d'une surveillance accrue devrait être envisagée pour ce qui est du sous-groupe des femmes qui présentent de telles valeurs anormales. L'accouchement vaginal est à privilégier et des stratégies visant à soutenir le potentiel d'allaitement doivent être mises en œuvre pendant la chute des taux maternels d'androgènes, afin de permettre la lactation. Compte tenu de la nature bénigne de l'hyperreactio luteinalis et de sa résolution postpartum, la prise en charge de ce trouble doit être conservatrice; de plus, la formation continue des professionnels de la santé qui pourraient devoir y faire face est cruciale.

Etomidate in the management of hypercortisolaemia in Cushing's syndrome: a review.

This review addresses the practical usage of intravenous etomidate as a medical therapy in Cushing's syndrome. We reviewed the relevant literature, using search terms 'etomidate', 'Cushing's syndrome', 'adrenocortical hyperfunction', 'drug therapy' and 'hypercortisolaemia' in a series of public databases. There is a paucity of large randomised controlled trials, and data on its use rely only on small series, case study reports and international consensus guideline recommendations. Based on these, etomidate is an effective parenteral medication for the management of endogenous hypercortisolaemia, particularly in cases with significant biochemical disturbance, sepsis and other serious complications such as severe psychosis, as well as in preoperative instability. We suggest treatment protocols for the safe and effective use of etomidate in Cushing's syndrome.

The ongoing pursuit of a prophylactic HSV vaccine.

HSV is among the most common human pathogens in the world. It is known to cause painful, persistent skin lesions, while also being the most common cause of fatal non-epidemic encephalitis as well as the leading cause of corneal blindness. The development of prophylactic vaccines could substantially reduce global health problems associated with HSV. So far, HSV vaccine strategies have shown noticeable efficacy in early development during preclinical phases but remained unsuccessful or unproven in human trials. New understanding of how the immune system mounts a defence against HSV offers practical strategies for vaccine development. A number of promising vaccine candidates are currently awaiting clinical development or already undergoing clinical testing. Therefore, this is a suitable time to assess the progress of HSV vaccine development and consider existing challenges and future improvements needed to achieve an effective prophylactic HSV vaccine.