Feasibility study of micronutrient status and body mass index of newly diagnosed pediatric oncology patients: Research commentary.

We conducted a feasibility study to evaluate micronutrients and body mass index (BMI). Fat soluble vitamins A, D, E and trace elements copper (Cu), selenium (Se), and zinc (Zn) levels were evaluated. Weight, height, BMI, and Z-scores were recorded. Side effects or specific adverse events were documented. No patient had a Z-score for height, weight, or BMI of less than 2 SD or greater than 2 SD. Ninety percent of patients had one or more micronutrient levels below normal. These results suggest that micronutrient abnormalities are common despite no obvious evidence of malnutrition. Side effects of chemotherapy may be exacerbated by micronutrient depletion.

Scaling of Activity Space in Marine Organisms across Latitudinal Gradients.

AbstractUnifying models have shown that the amount of space used by animals (e.g., activity space, home range) scales allometrically with body mass for terrestrial taxa; however, such relationships are far less clear for marine species. We compiled movement data from 1,596 individuals across 79 taxa collected using a continental passive acoustic telemetry network of acoustic receivers to assess allometric scaling of activity space. We found that ectothermic marine taxa do exhibit allometric scaling for activity space, with an overall scaling exponent of 0.64. However, body mass alone explained only 35% of the variation, with the remaining variation best explained by trophic position for teleosts and latitude for sharks, rays, and marine reptiles. Taxon-specific allometric relationships highlighted weaker scaling exponents among teleost fish species (0.07) than sharks (0.96), rays (0.55), and marine reptiles (0.57). The allometric scaling relationship and scaling exponents for the marine taxonomic groups examined were lower than those reported from studies that had collated both marine and terrestrial species data derived using various tracking methods. We propose that these disparities arise because previous work integrated summarized data across many studies that used differing methods for collecting and quantifying activity space, introducing considerable uncertainty into slope estimates. Our findings highlight the benefit of using large-scale, coordinated animal biotelemetry networks to address cross-taxa evolutionary and ecological questions.

Invariant natural killer T cells recognize glycolipids from pathogenic Gram-positive bacteria.

Natural killer T cells (NKT cells) recognize glycolipid antigens presented by CD1d. These cells express an evolutionarily conserved, invariant T cell antigen receptor (TCR), but the forces that drive TCR conservation have remained uncertain. Here we show that NKT cells recognized diacylglycerol-containing glycolipids from Streptococcus pneumoniae, the leading cause of community-acquired pneumonia, and group B Streptococcus, which causes neonatal sepsis and meningitis. Furthermore, CD1d-dependent responses by NKT cells were required for activation and host protection. The glycolipid response was dependent on vaccenic acid, which is present in low concentrations in mammalian cells. Our results show how microbial lipids position the sugar for recognition by the invariant TCR and, most notably, extend the range of microbes recognized by this conserved TCR to several clinically important bacteria.

Risk of ventricular arrhythmias following implantable cardioverter-defibrillator generator change in patients with recovered ejection fraction: Implications for shared decision-making.

INTRODUCTION: Guidelines indicate primary-prevention implantable cardioverter-defibrillators (ICDs) for most patients with left ventricular ejection fraction (LVEF) ≤ 35%. Some patients' LVEFs improve during the life of their first ICD. In patients with recovered LVEF who never received appropriate ICD therapy, the utility of generator replacement upon battery depletion remains unclear. Here, we evaluate ICD therapy based on LVEF at the time of generator change, to educate shared decision-making regarding whether to replace the depleted ICD. METHODS: We followed patients with a primary-prevention ICD who underwent generator change. Patients who received appropriate ICD therapy for ventricular tachycardia or ventricular fibrillation (VT/VF) before generator change were excluded. The primary endpoint was appropriate ICD therapy, adjusted for the competing risk of death. RESULTS: Among 951 generator changes, 423 met inclusion criteria. During 3.4 ± 2.2 years follow-up, 78 (18%) received appropriate therapy for VT/VF. Compared to patients with recovered LVEF > 35% (n = 161 [38%]), those with LVEF ≤ 35% (n = 262 [62%]) were more likely to require ICD therapy (p = .002; Fine-Gray adjusted 5-year event rates: 12.7% vs. 25.0%). Receiver operating characteristic analysis revealed the optimal LVEF cutoff for VT/VF prediction to be 45%, the use of which further improved risk stratification (p < .001), with Fine-Gray adjusted 5-year rates 6.2% versus 25.1%. CONCLUSION: Following ICD generator change, patients with primary-prevention ICDs and recovered LVEF have significantly lower risk of subsequent ventricular arrhythmias compared to those with persistent LVEF depression. Risk stratification at LVEF 45% offers significant additional negative predictive value over a 35% cutoff, without a significant loss in sensitivity. These data may be useful during shared decision-making at the time of ICD generator battery depletion.

Prevalence of Poverty and Hunger at Cancer Diagnosis and Its Association with Malnutrition and Overall Survival in South Africa.

Many South African children live in poverty and food insecurity; therefore, malnutrition within the context of childhood cancer should be examined. Parents/caregivers completed the Poverty-Assessment Tool (divided into poverty risk groups) and the Household Hunger Scale questionnaire in five pediatric oncology units. Height, weight, and mid-upper arm circumference assessments classified malnutrition. Regression analysis evaluated the association of poverty and food insecurity with nutritional status, abandonment of treatment, and one-year overall survival (OS). Nearly a third (27.8%) of 320 patients had a high poverty risk, associated significantly with stunting (p = 0.009), food insecurity (p < 0.001) and residential province (p < 0.001) (multinomial regression). Stunting was independently and significantly associated with one-year OS on univariate analysis. The hunger scale was significant predictor of OS, as patients living with hunger at home had an increased odds ratio for treatment abandonment (OR 4.5; 95% CI 1.0; 19.4; p = 0.045) and hazard for death (HR 3.2; 95% CI 1.02, 9.9; p = 0.046) compared to those with food security. Evaluating sociodemographic factors such as poverty and food insecurity at diagnosis is essential among South African children to identify at-risk children and implement adequate nutritional support during cancer treatment.

Psychological distress of adolescent and young adult childhood cancer survivors in a South African cohort.

BACKGROUND: We investigated psychological distress in a South African childhood cancer survivor (CCS) cohort. METHODS: Adult CCSs treated at Tygerberg Hospital, Cape Town, completed the Brief Symptom Inventory-18. Internal consistency was acceptable: Cronbach's alpha values were 0.91 (Global Severity Index (GSI)), 0.85 (depression), 0.83 (somatization), and 0.75 (anxiety). We compared results utilizing different case rules (GSI T scores of ≥50, ≥57, and ≥63) for the identification of psychological distress. RESULTS: Forty CCSs (median age 24 years; median follow-up period 16 years) participated. Most (58%; 23 out of 40) completed school or tertiary education, were unmarried (90%; 36 out of 40), and unemployed (59.5%; 22 out of 37). The diagnoses included hematological malignancies (65%; 26 out of 40) and solid tumors (35%; 14 out of 40). The GSI T scores of ≥63, ≥57, and ≥50 identified 10% (four out of 40), 32.5% (13 out of 40), and 45% (18 out of 40) of survivors with psychological distress, respectively. Radiotherapy (odds ratio (OR) 4.6; p = .035), presence of ≥six late effects (OR 7.5; p = .026), and severe late effects (OR 6.6; p = .024) were significant risk factors (GSI T score ≥57). Follow-up period of 11-20 years (OR 7.3; p = .034) was significant for a GSI T score ≥50. CONCLUSION: This South African CCS cohort had higher levels of psychological distress utilizing the GSI T score ≥50 and ≥57 case rules than reported in the literature. Most were unmarried or unemployed. Significant contributing factors were radiotherapy, number and severity of late effects, and follow-up period. CCSs must be screened for psychological distress.

Prevalence of vitamin and iron deficiencies at cancer diagnosis at two pediatric oncology units in South Africa.

This study investigates the prevalence of vitamin and iron deficiencies at cancer diagnosis. Newly diagnosed children between October 2018 and December 2020 at two South African pediatric oncology units (POUs) were assessed for nutritional and micronutrient status (Vit A, Vit B12, Vit D, folate, and iron). A structured interview with caregivers provided information regarding hunger and poverty risks. There were 261 patients enrolled with a median age of 5.5 years and a male-to-female ratio of 1:0.8. Nearly half had iron deficiency (47.6%), while a third had either Vit A (30.6%), Vit D (32.6%), or folate (29.7%) deficiencies. Significant associations existed between moderate acute malnutrition (MAM) and low levels of Vit A (48.4%; p = .005), Vit B12 (29.6%; p < .001), and folate (47.3%; p = .003), while Vit D deficiency was associated with wasting (63.6%) (p < .001). Males had significantly lower Vit D levels (respectively, 40.9%; p = .004). Folate deficiency was significantly associated with patients born at full term (33.5%; p = .017), age older than five years (39.8%; p = .002), residing in provinces Mpumalanga (40.9%) and Gauteng (31.5%) (P = .032); as well as having food insecurity (46.3%; p < .001), or hematological malignancies (41.3%; p = .004). This study documents the high prevalence of Vit A, Vit D, Vit B12, folate, and iron deficiency in South African pediatric cancer patients, demonstrating the need to include micronutrient assessment at diagnosis to ensure optimal nutritional support for macro-and micronutrients.

Sacubitril/valsartan: An antiarrhythmic drug?

INTRODUCTION: Heart failure (HF) is a major cause of morbidity and mortality, with nearly half of all HF-related deaths resulting from sudden cardiac death (SCD), most often from an arrhythmic event. The pathophysiologic changes that occur in response to the hemodynamic stress of HF may lead to increased arrhythmogenesis. Theoretically, medications that block these arrhythmogenic substrates would decrease the risk of SCD. The combined angiotensin receptor and neprilysin inhibitor (ARNi; tradename Entresto) is the newest commercially available medication for the treatment of heart failure. METHODS AND RESULTS: We reviewed and synthesized the available literature regarding sacubitril/valsartan and its effects on cardiac rhythm. ARNi has been shown to decrease cardiovascular mortality and hospitalization in patients with HF with reduced ejection fraction (HFrEF). Emerging evidence suggests that ARNi also may play a role in reducing arrhythmogenesis and thereby SCD. CONCLUSION: This review summarizes the current data regarding this ARNi and its potential antiarrhythmic effects.

Pluripotent stem cell-derived NK cells with high-affinity noncleavable CD16a mediate improved antitumor activity.

Antibody-dependent cellular cytotoxicity (ADCC) is a key effector mechanism of natural killer (NK) cells that is mediated by therapeutic monoclonal antibodies (mAbs). This process is facilitated by the Fc receptor CD16a on human NK cells. CD16a appears to be the only activating receptor on NK cells that is cleaved by the metalloprotease a disintegrin and metalloproteinase-17 upon stimulation. We previously demonstrated that a point mutation of CD16a prevents this activation-induced surface cleavage. This noncleavable CD16a variant is now further modified to include the high-affinity noncleavable variant of CD16a (hnCD16) and was engineered into human induced pluripotent stem cells (iPSCs) to create a renewable source for human induced pluripotent stem cell-derived NK (hnCD16-iNK) cells. Compared with unmodified iNK cells and peripheral blood-derived NK (PB-NK) cells, hnCD16-iNK cells proved to be highly resistant to activation-induced cleavage of CD16a. We found that hnCD16-iNK cells were functionally mature and exhibited enhanced ADCC against multiple tumor targets. In vivo xenograft studies using a human B-cell lymphoma demonstrated that treatment with hnCD16-iNK cells and anti-CD20 mAb led to significantly improved regression of B-cell lymphoma compared with treatment utilizing anti-CD20 mAb with PB-NK cells or unmodified iNK cells. hnCD16-iNK cells, combined with anti-HER2 mAb, also mediated improved survival in an ovarian cancer xenograft model. Together, these findings show that hnCD16-iNK cells combined with mAbs are highly effective against hematologic malignancies and solid tumors that are typically resistant to NK cell-mediated killing, demonstrating the feasibility of producing a standardized off-the-shelf engineered NK cell therapy with improved ADCC properties to treat malignancies that are otherwise refractory.

A randomized controlled trial of a structured exercise intervention after the completion of acute cancer treatment in adolescents and young adults.

BACKGROUND: Cancer treatments are frequently associated with impaired physical fitness, quality of life (QOL), and fatigue, often persisting into survivorship.  Studies in older adults with cancer have demonstrated benefits from exercise; however, this has not been rigorously investigated in adolescents and young adults (AYA). The aim of this study was to determine whether a structured 10-week exercise intervention was associated with improved cardiorespiratory fitness (VO2peak ), fatigue, and QOL in AYA who have recently completed cancer treatment. METHOD: Forty-three AYA (median age 21 ± 6 years) were randomly assigned to an exercise group (n = 22) or a control group (n = 21). The exercise group received a structured 10-week exercise program comprising progressive aerobic and resistance exercise; the control arm received routine care. VO2peak was measured at baseline, 10 weeks, and six months. Fatigue and QOL were assessed by the FACIT fatigue scale and the PEDS QL, respectively. RESULTS: Mean VO2peak at baseline was 26.5 ± 7.2 mL.kg-1 .min-1 , which is substantially lower than population norms. The exercise group demonstrated significant improvement in VO2peak at 10 weeks compared with controls (33.8 ± 8.1 vs 29.6 ± 7.6 mL.kg-1 .min-1 , P = 0.0002), but by six months, the difference was no longer significant (32.9 ± 7.0 vs 30.9 ± 11.0 mL.kg-1 .min-1 , P = 0.21). There were no significant differences in fatigue or total QOL scores between groups. CONCLUSION: Cancer treatment is associated with reduced VO2peak in AYA. Improvement in VO2peak was accelerated by a 10-week exercise program; however, no significant benefit was observed in QOL or fatigue. The plateau in VO2peak at six months suggests that a maintenance exercise program may be beneficial.

Class 1C antiarrhythmic drugs in atrial fibrillation and coronary artery disease.

BACKGROUND: Class 1C antiarrhythmic drugs (AADs) are effective first-line agents for atrial fibrillation (AF) treatment. However, these agents commonly are avoided in patients with known coronary artery disease (CAD), due to known increased risk in the postmyocardial infarction population. Whether 1C AADs are safe in patients with CAD but without clinical ischemia or infarct is unknown. Reduced coronary flow capacity (CFC) on positron emission tomography (PET) reliably identifies myocardial regions supplied by vessels with CAD causing flow limitation. OBJECTIVE: To assess whether treatment with 1C AADs increases mortality in patients without known CAD but with CFC indicating significantly reduced coronary blood flow. METHODS: In this pilot study, we compared patients with AF and left ventricular ejection fraction ≥50% who were treated with 1C AADs to age-matched AF patients without 1C AAD treatment. No patient had clinically evident CAD (ie, reversible perfusion defect, known ≥70% epicardial lesion, percutaneous coronary intervention, coronary artery bypass grafting, or myocardial infarction). All patients had PET-based quantification of stress myocardial blood flow and CFC. Death was assessed by clinical follow-up and social security death index search. RESULTS: A total of 78 patients with 1C AAD exposure were matched to 78 controls. Over a mean follow-up of 2.0 years, the groups had similar survival (P = .54). Among patients with CFC indicating the presence of occult CAD (ie, reduced CFC involving ≥50% of myocardium), 1C-treated patients had survival similar to (P = .44) those not treated with 1C agents. CONCLUSIONS: In a limited population of AF patients with preserved left ventricle function and PET-CFC indicating occult CAD, treatment with 1C AADs appears not to increase mortality. A larger study would be required to confidently assess the safety of these drugs in this context.

Positron emission tomography absolute stress myocardial blood flow for risk stratification in nonischemic cardiomyopathy.

INTRODUCTION: Sudden cardiac death is a substantial cause of mortality in patients with cardiomyopathy, but evidence supporting implantable cardioverter-defibrillator (ICD) implantation is less robust in nonischemic cardiomyopathy (NICM) than in ischemic cardiomyopathy. Improved risk stratification is needed. We assessed whether absolute quantification of stress myocardial blood flow (sMBF) measured by positron emission tomography (PET) predicts ventricular arrhythmias (VA) and/or death in patients with NICM. METHODS: In this pilot study, we prospectively followed patients with NICM (left ventricular ejection fraction ≤ 35%) and an ICD who underwent cardiac PET stress imaging with sMBF quantification. NICM was defined as the absence of angiographic obstructive coronary stenosis, significant relative perfusion defects on imaging, coronary revascularization, or acute coronary syndrome. Endpoints were appropriate device therapy for VA and all-cause mortality. Subgroup analysis was performed in patients who had no prior history of VA (ie, the primary prevention population). RESULTS: We followed 37 patients (60 ± 14 years, 46% male) for 41 ± 23 months. The median sMBF was 1.56 mL/g/min (interquartile range: 1.00-1.82). Lower sMBF predicted VA, both in the whole population (hazard ratio [HR] for each 0.1 mL/g/min increase: 0.84, P = .015) and in the primary prevention subset (n = 27; HR for each 0.1 mL/g/min increase: 0.81, P = .049). Patients with sMBF below the median had significantly more VA than those above the median, both in the whole population (P = .004) and in the primary prevention subset (P = .046). Estimated 3-year VA rates in the whole population were 67% among low-flow patients vs 13% among high-flow patients, and 39% vs 8%, respectively, among primary-prevention patients. sMBF did not predict all-cause mortality. CONCLUSIONS: In patients with NICM, lower sMBF predicts VA. This relationship may be useful for risk stratification for ventricular arrhythmia and decision making regarding ICD implantation.

Development of System Performance Indicators for Adolescent and Young Adult Cancer Care and Control in Canada.

OBJECTIVES: To develop an expert-group, consensus-based list of system performance indicators to be used for monitoring, evaluating, and benchmarking progress for cancer care and control in adolescents and young adults (AYAs) in Canada. METHODS: A national multidisciplinary panel of AYA oncology experts was convened; they prepared a literature review and undertook a brainstorming exercise to create a comprehensive list of indicators based on a previously defined framework for AYA cancer care and control in Canada. A modified Delphi process was then undertaken to cull the list based on 3 quick screen criteria. Three rounds of ranking were required. The fourth stage employed a face-to-face meeting, and the final stage utilized a survey to rank the indicators on the basis of importance and feasibility. RESULTS: Nineteen participants contributed to the 5-stage process. From an initial list of 114 indicators, 14 were ultimately endorsed, representing 5 themes: active care, survivorship, psychosocial issues, palliative care, and research. The 5 highest ranked indicators were assessed as very to moderately feasible, with only a single indicator (clinical trial enrollment) in the top 5 assigned a least feasible ranking. CONCLUSION: The 14 indicators provide a starting point for the development of a standard set of metrics for AYA cancer care and control in Canada and have potential for international utility.

The relevance of nutrition to pediatric oncology: A cancer control perspective.

It is indisputable that adequate and appropriate nutrition is fundamental to the health, growth, and development of infants, children, and adolescents, including those with cancer. Nutrition has a role in most of the accepted components of the cancer control spectrum, from prevention through to palliation. The science of nutrigenomics, nutrigenetics, and bioactive foods (phytochemicals), and how nutrition affects cancer biology and cancer treatment, is growing. Nutritional epigenetics is giving us an understanding that there are possible primary prevention strategies for pediatric cancers, especially during conception and pregnancy, which need to be studied. Primary prevention of cancer in adults, such as colorectal cancer, should commence early in childhood, given the long gestation of nutritionally related cancers. Obesity avoidance is definitely a target for both pediatric and adult cancer prevention, commencing in childhood. There is now compelling evidence that the nutritional status of children with cancer, both overweight and underweight, does affect cancer outcomes. This is a potentially modifiable prognostic factor. Consistent longitudinal nutritional assessment of patients from diagnosis through treatment and long-term follow-up is required so that interventions can be implemented and evaluated. While improving, there remains a dearth of basic and clinical nutritional research in pediatric oncology. The perspective of evaluating nutrition as a cancer control factor is discussed in this article.

Utility of serial measurement of biomarkers of cardiovascular stress and inflammation in systolic dysfunction.

AIMS: Evidence links markers of systemic inflammation and heart failure (HF) with ventricular arrhythmias (VA) and/or death. Biomarker levels, and the risk they indicate, may vary over time. We evaluated the utility of serial laboratory measurements of inflammatory biomarkers and HF, using time-dependent analysis. METHODS AND RESULTS: We prospectively enrolled ambulatory patients with left ventricular ejection fraction (LVEF) ≤35% and a primary-prevention implanted cardioverter-defibrillator (ICD). Levels of established inflammatory biomarkers [C-reactive protein, erythrocyte sedimentation rate (ESR), suppression of tumourigenicity 2 (ST2), tumour necrosis factor alpha (TNF-α)] and brain natriuretic peptide (BNP) were assessed at 3-month intervals for 1 year. We assessed relationships between biomarkers modelled as time-dependent variables, VA, and death. Among 196 patients (66±14 years, LVEF 23±8%), 33 experienced VA, and 18 died. Using only baseline values, BNP predicted VA, and both BNP and ST2 predicted death. Using serial measurements at 3-month intervals, time-varying BNP independently predicted VA, and time-varying ST2 independently predicted death. C-statistic analysis revealed no significant benefit to repeated testing compared with baseline-only measurement. C-reactive protein, ESR, and TNF-α, either at baseline or over time, did not predict either endpoint. CONCLUSION: In stable ambulatory patients with systolic cardiomyopathy and an ICD, BNP predicts ventricular tachyarrhythmia, and ST2 predicts death. Repeated laboratory measurements over a year's time do not improve risk stratification beyond baseline measurement alone. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT01892462 (https://clinicaltrials.gov/ct2/show/NCT01892462).

Gender role orientation, thinking style preference and facets of adult paranormality: A mediation analysis.

This study examines the extent to which masculine and feminine gender role orientations predict self-reported anomalous experiences, belief, ability and fear once relevant correlates including biological sex are controlled for. The extent to which rational versus intuitive thinking style preference mediates these relationships is also examined. Path analysis (n = 332) found heightened femininity directly predicts stronger intuitive preference plus more anomalous experiences, belief and fear with, additionally, intuitive preference mediating several gender role-paranormality relationships. By comparison, heightened masculinity directly predicts both thinking styles plus lower anomalous fear. The latter relationship is also shaped by the nature of mediators with (a) more anomalous experiences and belief associated with more anomalous fear and (b) either heightened rationality else more anomalous ability linked to, conversely, less anomalous fear. The extent to which findings support a gender (or social) role account of adult paranormality, together with methodological limitations and ideas for future research, is discussed.

Unmet Needs in Nutritional Care in African Paediatric Oncology Units.

BACKGROUND: Up to 50% of children diagnosed with cancer in low- and middle-income countries are malnourished, which likely affects survival. SUBJECTS AND METHODS: An online survey to paediatric oncology units (POUs) in Africa was done regarding nutritional assessment and care. RESULTS: Sixty-six surveys were received from POUs in 31 countries. Only 44.4% had a dedicated dietician for nutritional assessment and support; 29.6% undertook routine nutritional assessment during treatment. None reported defined criteria for nutritional intervention. Total parenteral nutrition was not available for 42.6% of POUs, while 51.8% did not have access to commercial enteral nutrition for inpatients, and 25.9% of the hospitals could not supply any home-based nutritional supplements. CONCLUSION: Nutritional assessment in POUs in Africa is neither routinely undertaken nor are there defined criteria to initiate nutritional interventions. Standardized guidelines for nutritional assessment and interventions are needed for African POUs to enable improved outcome.

An account of subjective probability judgment for joint events: Conjunctive and disjunctive.

Probability judgment is a vital part of many aspects of everyday life. In the present paper, we present a new theory of the way in which individuals produce probability estimates for joint events: conjunctive and disjunctive. We propose that a majority of individuals produce conjunctive (disjunctive) estimates by making a quasi-random adjustment, positive or negative, from the less (more) likely component probability with the other component playing no obvious role. In two studies, we produce evidence supporting propositions that follow from our theory. First, the component probabilities do appear to play the distinct roles we propose in determining the joint event probabilities. Second, contrary to probability theory and other accounts of probability judgment, we show that the conjunctive-less likely probability difference is unrelated to the more likely disjunctive probability difference (in normative theory these quantities are identical). In conclusion, while violating the norms of probability judgment, we argue that estimates produced in the manner we propose will be close enough to the normative values especially given the changing nature of the external environment and the incomplete nature of available information.

Broadly Neutralizing Antibodies Display Potential for Prevention of HIV-1 Infection of Mucosal Tissue Superior to That of Nonneutralizing Antibodies.

Definition of the key parameters mediating effective antibody blocking of HIV-1 acquisition within mucosal tissue may prove critical to effective vaccine development and the prophylactic use of monoclonal antibodies. Although direct antibody-mediated neutralization is highly effective against cell-free virus, antibodies targeting different sites of envelope vulnerability may display differential activity against mucosal infection. Nonneutralizing antibodies (nnAbs) may also impact mucosal transmission events through Fc-gamma receptor (FcγR)-mediated inhibition. In this study, a panel of broadly neutralizing antibodies (bnAbs) and nnAbs, including those associated with protection in the RV144 vaccine trial, were screened for the ability to block HIV-1 acquisition and replication across a range of cellular and mucosal tissue models. Neutralization potency, as determined by the TZM-bl infection assay, did not fully predict activity in mucosal tissue. CD4-binding site (CD4bs)-specific bnAbs, in particular VRC01, were consistent in blocking HIV-1 infection across all cellular and tissue models. Membrane-proximal external region (MPER) (2F5) and outer domain glycan (2G12) bnAbs were also efficient in preventing infection of mucosal tissues, while the protective efficacy of bnAbs targeting V1-V2 glycans (PG9 and PG16) was more variable. In contrast, nnAbs alone and in combinations, while active in a range of cellular assays, were poorly protective against HIV-1 infection of mucosal tissues. These data suggest that tissue resident effector cell numbers and low FcγR expression may limit the potential of nnAbs to prevent establishment of the initial foci of infection. The solid protection provided by specific bnAbs clearly demonstrates their superior potential over that of nonneutralizing antibodies for preventing HIV-1 infection at the mucosal portals of infection. IMPORTANCE: Key parameters mediating effective antibody blocking of HIV-1 acquisition within mucosal tissue have not been defined. While bnAbs are highly effective against cell-free virus, they are not induced by current vaccine candidates. However, nnAbs, readily induced by vaccines, can trigger antibody-dependent cellular effector functions, through engagement of their Fc-gamma receptors. Fc-mediated antiviral activity has been implicated as a secondary correlate of decreased HIV-1 risk in the RV144 vaccine efficacy trial, suggesting that protection might be mediated in the absence of classical neutralization. To aid vaccine design and selection of antibodies for use in passive protection strategies, we assessed a range of bnAbs and nnAbs for their potential to block ex vivo challenge of mucosal tissues. Our data clearly indicate the superior efficacy of neutralizing antibodies in preventing mucosal acquisition of infection. These results underscore the importance of maintaining the central focus of HIV-1 vaccine research on the induction of potently neutralizing antibodies.

Optimal method of measuring the T-peak to T-end interval for risk stratification in primary prevention.

Aims: Several published investigations demonstrated that a longer T-peak to T-end interval (Tpe) implies increased risk for ventricular tachyarrhythmia (VT/VF) and mortality. Tpe has been measured using diverse methods. We aimed to determine the optimal Tpe measurement method for screening purposes. Methods and results: We evaluated 305 patients with LVEF ≤ 35% and an implantable cardioverter-defibrillator implanted for primary prevention. Tpe was measured using seven different methods described in the literature, including six manual methods and the automated algorithm '12SL', and was corrected for heart rate. Endpoints were VT/VF and death. To account for differences in the magnitude of Tpe measurements, results are expressed in standard deviation (SD) increments. We evaluated the clinical utility of each measurement method based on predictive ability, fraction of immeasurable tracings, and intra- and interobserver correlation. >Over 31 ± 23 months, 82 (27%) patients had VT/VF, and over 49 ± 21 months, 91 (30%) died. Several rate-corrected Tpe measurement methods predicted VT/VF (HR per SD 1.20-1.34; all P < 0.05), and nearly all methods (both corrected and uncorrected) predicted death (HR per SD 1.19-1.35; all P < 0.05). Optimal predictive ability, readability, and correlation were found in the automated 12SL method and the manual tangent method in lead V2. Conclusion: For the prediction of VT/VF, the utility of Tpe depends upon the measurement method, but for the prediction of mortality, most published Tpe measurement methods are similarly predictive. Heart rate correction improves predictive ability. The automated 12SL method performs as well as any manual measurement, and among manual methods, lead V2 is most useful.