Protective neutralizing antibodies from human survivors of Crimean-Congo hemorrhagic fever.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a World Health Organization priority pathogen. CCHFV infections cause a highly lethal hemorrhagic fever for which specific treatments and vaccines are urgently needed. Here, we characterize the human immune response to natural CCHFV infection to identify potent neutralizing monoclonal antibodies (nAbs) targeting the viral glycoprotein. Competition experiments showed that these nAbs bind six distinct antigenic sites in the Gc subunit. These sites were further delineated through mutagenesis and mapped onto a prefusion model of Gc. Pairwise screening identified combinations of non-competing nAbs that afford synergistic neutralization. Further enhancements in neutralization breadth and potency were attained by physically linking variable domains of synergistic nAb pairs through bispecific antibody (bsAb) engineering. Although multiple nAbs protected mice from lethal CCHFV challenge in pre- or post-exposure prophylactic settings, only a single bsAb, DVD-121-801, afforded therapeutic protection. DVD-121-801 is a promising candidate suitable for clinical development as a CCHFV therapeutic.

Pan-protective anti-alphavirus human antibodies target a conserved E1 protein epitope.

Alphaviruses are emerging, mosquito-transmitted pathogens that cause musculoskeletal and neurological disease in humans. Although neutralizing antibodies that inhibit individual alphaviruses have been described, broadly reactive antibodies that protect against both arthritogenic and encephalitic alphaviruses have not been reported. Here, we identify DC2.112 and DC2.315, two pan-protective yet poorly neutralizing human monoclonal antibodies (mAbs) that avidly bind to viral antigen on the surface of cells infected with arthritogenic and encephalitic alphaviruses. These mAbs engage a conserved epitope in domain II of the E1 protein proximal to and within the fusion peptide. Treatment with DC2.112 or DC2.315 protects mice against infection by both arthritogenic (chikungunya and Mayaro) and encephalitic (Venezuelan, Eastern, and Western equine encephalitis) alphaviruses through multiple mechanisms, including inhibition of viral egress and monocyte-dependent Fc effector functions. These findings define a conserved epitope recognized by weakly neutralizing yet protective antibodies that could be targeted for pan-alphavirus immunotherapy and vaccine design.

Systematic Analysis of Monoclonal Antibodies against Ebola Virus GP Defines Features that Contribute to Protection.

Antibodies are promising post-exposure therapies against emerging viruses, but which antibody features and in vitro assays best forecast protection are unclear. Our international consortium systematically evaluated antibodies against Ebola virus (EBOV) using multidisciplinary assays. For each antibody, we evaluated epitopes recognized on the viral surface glycoprotein (GP) and secreted glycoprotein (sGP), readouts of multiple neutralization assays, fraction of virions left un-neutralized, glycan structures, phagocytic and natural killer cell functions elicited, and in vivo protection in a mouse challenge model. Neutralization and induction of multiple immune effector functions (IEFs) correlated most strongly with protection. Neutralization predominantly occurred via epitopes maintained on endosomally cleaved GP, whereas maximal IEF mapped to epitopes farthest from the viral membrane. Unexpectedly, sGP cross-reactivity did not significantly influence in vivo protection. This comprehensive dataset provides a rubric to evaluate novel antibodies and vaccine responses and a roadmap for therapeutic development for EBOV and related viruses.

Antibodies from a Human Survivor Define Sites of Vulnerability for Broad Protection against Ebolaviruses.

Experimental monoclonal antibody (mAb) therapies have shown promise for treatment of lethal Ebola virus (EBOV) infections, but their species-specific recognition of the viral glycoprotein (GP) has limited their use against other divergent ebolaviruses associated with human disease. Here, we mined the human immune response to natural EBOV infection and identified mAbs with exceptionally potent pan-ebolavirus neutralizing activity and protective efficacy against three virulent ebolaviruses. These mAbs recognize an inter-protomer epitope in the GP fusion loop, a critical and conserved element of the viral membrane fusion machinery, and neutralize viral entry by targeting a proteolytically primed, fusion-competent GP intermediate (GPCL) generated in host cell endosomes. Only a few somatic hypermutations are required for broad antiviral activity, and germline-approximating variants display enhanced GPCL recognition, suggesting that such antibodies could be elicited more efficiently with suitably optimized GP immunogens. Our findings inform the development of both broadly effective immunotherapeutics and vaccines against filoviruses.

Design and characterization of protective pan-ebolavirus and pan-filovirus bispecific antibodies.

Monoclonal antibodies (mAbs) are an important class of antiviral therapeutics. MAbs are highly selective, well tolerated, and have long in vivo half-life as well as the capacity to induce immune-mediated virus clearance. Their activities can be further enhanced by integration of their variable fragments (Fvs) into bispecific antibodies (bsAbs), affording simultaneous targeting of multiple epitopes to improve potency and breadth and/or to mitigate against viral escape by a single mutation. Here, we explore a bsAb strategy for generation of pan-ebolavirus and pan-filovirus immunotherapeutics. Filoviruses, including Ebola virus (EBOV), Sudan virus (SUDV), and Marburg virus (MARV), cause severe hemorrhagic fever. Although there are two FDA-approved mAb therapies for EBOV infection, these do not extend to other filoviruses. Here, we combine Fvs from broad ebolavirus mAbs to generate novel pan-ebolavirus bsAbs that are potently neutralizing, confer protection in mice, and are resistant to viral escape. Moreover, we combine Fvs from pan-ebolavirus mAbs with those of protective MARV mAbs to generate pan-filovirus protective bsAbs. These results provide guidelines for broad antiviral bsAb design and generate new immunotherapeutic candidates.

Probing differences among Aß oligomers with two triangular trimers derived from Aß.

The assembly of the ß-amyloid peptide (Aß) to form oligomers and fibrils is closely associated with the pathogenesis and progression of Alzheimer's disease. Aß is a shape-shifting peptide capable of adopting many conformations and folds within the multitude of oligomers and fibrils the peptide forms. These properties have precluded detailed structural elucidation and biological characterization of homogeneous, well-defined Aß oligomers. In this paper, we compare the structural, biophysical, and biological characteristics of two different covalently stabilized isomorphic trimers derived from the central and C-terminal regions Aß. X-ray crystallography reveals the structures of the trimers and shows that each trimer forms a ball-shaped dodecamer. Solution-phase and cell-based studies demonstrate that the two trimers exhibit markedly different assembly and biological properties. One trimer forms small soluble oligomers that enter cells through endocytosis and activate capase-3/7-mediated apoptosis, while the other trimer forms large insoluble aggregates that accumulate on the outer plasma membrane and elicit cellular toxicity through an apoptosis-independent mechanism. The two trimers also exhibit different effects on the aggregation, toxicity, and cellular interaction of full-length Aß, with one trimer showing a greater propensity to interact with Aß than the other. The studies described in this paper indicate that the two trimers share structural, biophysical, and biological characteristics with oligomers of full-length Aß. The varying structural, assembly, and biological characteristics of the two trimers provide a working model for how different Aß trimers can assemble and lead to different biological effects, which may help shed light on the differences among Aß oligomers.

A Powassan virus domain III nanoparticle immunogen elicits neutralizing and protective antibodies in mice.

Powassan virus (POWV) is an emerging tick borne flavivirus (TBFV) that causes severe neuroinvasive disease. Currently, there are no approved treatments or vaccines to combat POWV infection. Here, we generated and characterized a nanoparticle immunogen displaying domain III (EDIII) of the POWV E glycoprotein. Immunization with POWV EDIII presented on nanoparticles resulted in significantly higher serum neutralizing titers against POWV than immunization with monomeric POWV EDIII. Furthermore, passive transfer of EDIII-reactive sera protected against POWV challenge in vivo. We isolated and characterized a panel of EDIII-specific monoclonal antibodies (mAbs) and identified several that potently inhibit POWV infection and engage distinct epitopes within the lateral ridge and C-C' loop of the EDIII. By creating a subunit-based nanoparticle immunogen with vaccine potential that elicits antibodies with protective activity against POWV infection, our findings enhance our understanding of the molecular determinants of antibody-mediated neutralization of TBFVs.

The dermatopathologist-patient consultation program: A pilot study on patient perspectives and interest.

BACKGROUND: Despite the integral contribution of dermatopathologists in diagnosing skin lesions, their role often remains unclear to patients, likely due to little face-to-face interaction. More healthcare systems have begun introducing patient-pathologist consultation programs that allow patients to discuss results with a pathologist and view tissue under a microscope. To our knowledge, only one study has been published exploring patient perspectives of these programs and no studies exist regarding interest in dermatopathology. METHODS: An anonymous survey was distributed via online support groups for various dermatologic diagnoses. RESULTS: Patients demonstrated a high level of interest in the dermatopathologist-patient consultation program, with 81.3% expressing at least moderate interest in discussing their diagnosis with a dermatopathologist and 79.2% expressing at least moderate interest in examining their tissue under the microscope with a dermatopathologist. The rationale for interest included various themes: (1) knowledge/understanding, (2) empowerment, (3) emotional support, (4) general interest, and (5) improved trust. CONCLUSIONS: Patients with cancerous and non-cancerous dermatologic diagnoses demonstrate high interest in a dermatopathologist-patient consultation program. Efforts to pilot this type of program can build upon the infrastructure of current pathologist consultation programs. Future efforts should be taken by hospital leadership, clinicians, and dermatopathologists to determine physician interest and address logistical challenges to the implementation of these programs.

Protocadherin-1 is essential for cell entry by New World hantaviruses.

The zoonotic transmission of hantaviruses from their rodent hosts to humans in North and South America is associated with a severe and frequently fatal respiratory disease, hantavirus pulmonary syndrome (HPS)1,2. No specific antiviral treatments for HPS are available, and no molecular determinants of in vivo susceptibility to hantavirus infection and HPS are known. Here we identify the human asthma-associated gene protocadherin-1 (PCDH1)3-6 as an essential determinant of entry and infection in pulmonary endothelial cells by two hantaviruses that cause HPS, Andes virus (ANDV) and Sin Nombre virus (SNV). In vitro, we show that the surface glycoproteins of ANDV and SNV directly recognize the outermost extracellular repeat domain of PCDH1-a member of the cadherin superfamily7,8-to exploit PCDH1 for entry. In vivo, genetic ablation of PCDH1 renders Syrian golden hamsters highly resistant to a usually lethal ANDV challenge. Targeting PCDH1 could provide strategies to reduce infection and disease caused by New World hantaviruses.

Predictor Variables Associated With Dermatology Referral Completion and the Impact on Surgical Treatment: A Retrospective Cohort Study.

BACKGROUND: Delays or failure to complete a dermatologic referral may affect health care outcomes. Factors associated with these delays remain understudied. OBJECTIVE: This study investigated socioeconomic and demographic factors associated with delays or failure to complete dermatology referrals and potential impact on surgical outcomes. METHODS: A retrospective chart review was performed for 400 patients internally referred to an academic dermatology center from 19 primary-care clinics from July 2018 to June 2019. Only patients referred after an in-person primary-care visit in which the provider documented a specific concerning lesion were included. Multivariate analyses were performed to explore variables associated with delays or failure to complete dermatology referrals. RESULTS: Patients were more likely to complete their referral if they had a personal history (adjusted odds ratio [aOR] = 7.843, 95% CI 1.383-14.304) or family history (aOR = 11.307, 95% CI 2.344-20.27) of skin cancer. Patients were more likely to delay referral completion past 30 days if they were ages 18 to 34 (aOR = 6.665, 95% CI 1.285-12.044) and less likely to delay referral past 30 days if they had a previous history of skin cancer (aOR = 0.531, 95% CI 0.181-0.882). LIMITATIONS: Single institution, retrospective study, limited surgical patients. CONCLUSION: Understanding factors associated with delays in dermatology referral completion can help identify at-risk patient populations.

Management of tinea capitis in infants and children in the United States: A national survey of pediatric dermatologists.

This study aimed to evaluate the current management of tinea capitis in the United States, specifically focusing on patients aged 0-2 months, 2 months to 2 years, and 2 years to 18 years. An online survey, distributed through the Pediatric Dermatology Research Alliance and the Society of Pediatric Dermatology, revealed the following preferences: fluconazole for those under 2 months, griseofulvin for those aged 2 months to 2 years, and terbinafine for those aged 2 years and older. There exists inter-provider variation in tinea capitis treatment regimens within the pediatric dermatology community.

Near-germline human monoclonal antibodies neutralize and protect against multiple arthritogenic alphaviruses.

Arthritogenic alphaviruses are globally distributed, mosquito-transmitted viruses that cause rheumatological disease in humans and include Chikungunya virus (CHIKV), Mayaro virus (MAYV), and others. Although serological evidence suggests that some antibody-mediated heterologous immunity may be afforded by alphavirus infection, the extent to which broadly neutralizing antibodies that protect against multiple arthritogenic alphaviruses are elicited during natural infection remains unknown. Here, we describe the isolation and characterization of MAYV-reactive alphavirus monoclonal antibodies (mAbs) from a CHIKV-convalescent donor. We characterized 33 human mAbs that cross-reacted with CHIKV and MAYV and engaged multiple epitopes on the E1 and E2 glycoproteins. We identified five mAbs that target distinct regions of the B domain of E2 and potently neutralize multiple alphaviruses with differential breadth of inhibition. These broadly neutralizing mAbs (bNAbs) contain few somatic mutations and inferred germline-revertants retained neutralizing capacity. Two bNAbs, DC2.M16 and DC2.M357, protected against both CHIKV- and MAYV-induced musculoskeletal disease in mice. These findings enhance our understanding of the cross-reactive and cross-protective antibody response to human alphavirus infections.

Effect of exercise interventions on hospital length of stay and admissions during cancer treatment: a systematic review and meta-analysis.

OBJECTIVE: To assess the effect of participating in an exercise intervention compared with no exercise during cancer treatment on the duration and frequency of hospital admissions. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, EMBASE, PEDro and Cochrane Central Registry of Randomized Controlled Trials. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised studies published until August 2023 evaluating exercise interventions during chemotherapy, radiotherapy or stem cell transplant regimens, compared with usual care, and which assessed hospital admissions (length of stay and/or frequency of admissions). STUDY APPRAISAL AND SYNTHESIS: Study quality was assessed using the Cochrane Risk-of-Bias tool and Grading of Recommendations Assessment, Development and Evaluation assessment. Meta-analyses were conducted by pooling the data using random-effects models. RESULTS: Of 3918 screened abstracts, 20 studies met inclusion criteria, including 2635 participants (1383 intervention and 1252 control). Twelve studies were conducted during haematopoietic stem cell transplantation regimens. There was a small effect size in a pooled analysis that found exercise during treatment reduced hospital length of stay by 1.40 days (95% CI: -2.26 to -0.54 days; low-quality evidence) and lowered the rate of hospital admission by 8% (difference in proportions=-0.08, 95% CI: -0.13 to -0.03, low-quality evidence) compared with usual care. CONCLUSION: Exercise during cancer treatment can decrease hospital length of stay and admissions, although a small effect size and high heterogeneity limits the certainty. While exercise is factored into some multidisciplinary care plans, it could be included as standard practice for patients as cancer care pathways evolve.

Whole-Slide Imaging, Mutual Information Registration for Multiplex Immunohistochemistry and Immunofluorescence.

Multiplex immunohistochemistry/immunofluorescence (mIHC/mIF) is a developing technology that facilitates the evaluation of multiple, simultaneous protein expressions at single-cell resolution while preserving tissue architecture. These approaches have shown great potential for biomarker discovery, yet many challenges remain. Importantly, streamlined cross-registration of multiplex immunofluorescence images with additional imaging modalities and immunohistochemistry (IHC) can help increase the plex and/or improve the quality of the data generated by potentiating downstream processes such as cell segmentation. To address this problem, a fully automated process was designed to perform a hierarchical, parallelizable, and deformable registration of multiplexed digital whole-slide images (WSIs). We generalized the calculation of mutual information as a registration criterion to an arbitrary number of dimensions, making it well suited for multiplexed imaging. We also used the self-information of a given IF channel as a criterion to select the optimal channels to use for registration. Additionally, as precise labeling of cellular membranes in situ is essential for robust cell segmentation, a pan-membrane immunohistochemical staining method was developed for incorporation into mIF panels or for use as an IHC followed by cross-registration. In this study, we demonstrate this process by registering whole-slide 6-plex/7-color mIF images with whole-slide brightfield mIHC images, including a CD3 and a pan-membrane stain. Our algorithm, WSI, mutual information registration (WSIMIR), performed highly accurate registration allowing the retrospective generation of an 8-plex/9-color, WSI, and outperformed 2 alternative automated methods for cross-registration by Jaccard index and Dice similarity coefficient (WSIMIR vs automated WARPY, P < .01 and P < .01, respectively, vs HALO + transformix, P = .083 and P = .049, respectively). Furthermore, the addition of a pan-membrane IHC stain cross-registered to an mIF panel facilitated improved automated cell segmentation across mIF WSIs, as measured by significantly increased correct detections, Jaccard index (0.78 vs 0.65), and Dice similarity coefficient (0.88 vs 0.79).

Longitudinally monitored immune biomarkers predict the timing of COVID-19 outcomes.

The clinical outcome of SARS-CoV-2 infection varies widely between individuals. Machine learning models can support decision making in healthcare by assessing fatality risk in patients that do not yet show severe signs of COVID-19. Most predictive models rely on static demographic features and clinical values obtained upon hospitalization. However, time-dependent biomarkers associated with COVID-19 severity, such as antibody titers, can substantially contribute to the development of more accurate outcome models. Here we show that models trained on immune biomarkers, longitudinally monitored throughout hospitalization, predicted mortality and were more accurate than models based on demographic and clinical data upon hospital admission. Our best-performing predictive models were based on the temporal analysis of anti-SARS-CoV-2 Spike IgG titers, white blood cell (WBC), neutrophil and lymphocyte counts. These biomarkers, together with C-reactive protein and blood urea nitrogen levels, were found to correlate with severity of disease and mortality in a time-dependent manner. Shapley additive explanations of our model revealed the higher predictive value of day post-symptom onset (PSO) as hospitalization progresses and showed how immune biomarkers contribute to predict mortality. In sum, we demonstrate that the kinetics of immune biomarkers can inform clinical models to serve as a powerful monitoring tool for predicting fatality risk in hospitalized COVID-19 patients, underscoring the importance of contextualizing clinical parameters according to their time post-symptom onset.

Predictors of patient satisfaction with Mohs micrographic surgery at time of surgery and 3 months postsurgery: A prospective cohort study.

BACKGROUND: Despite the importance of patient satisfaction in ensuring high-quality care, studies investigating patient satisfaction in Mohs micrographic surgery (MMS) are limited. OBJECTIVE: We investigated the factors associated with patient satisfaction in MMS for nonmelanoma skin cancer and how patient satisfaction changes in the postoperative period. METHODS: In this prospective cohort study including 100 patients, patient satisfaction surveys were administered at the time of surgery and at 3 months postsurgery. Sociodemographic characteristics, medical history, and surgical parameters were collected by chart review. Univariate linear and logistic regression models were created to examine these relationships. RESULTS: Decreased satisfaction was observed in patients requiring 3 or more MMS stages both at the time of surgery (P = .047) and at 3 months post-surgery (P = .0244). Patients with morning procedures ending after 1:00 pm had decreased satisfaction at the time of surgery (P = .019). A decrease in patient satisfaction between the time of surgery and 3 months postsurgery was observed in patients with surgical sites on the extremities (P = .036), larger preoperative lesion sizes (P = .012), and larger defect sizes (P = .033). LIMITATIONS: Single-institution data, self-selection bias, and recall bias. CONCLUSION: Patient satisfaction with MMS is impacted by numerous factors and remains dynamic over time.

Applying behaviour change models to policy-making: development and validation of the Policymakers' Information Use Questionnaire (POLIQ).

BACKGROUND: The purpose of this study was to develop and validate the Policymakers' Information Use Questionnaire (POLIQ) to capture the intention of individuals in decision-making positions, such as health policy-makers, to act on research-based evidence in order to inform theory and the application of behaviour change models to decision-making spheres. METHODS: The development and validation comprised three steps: item generation, qualitative face validation with cognitive debriefing and factorial construct validation. Confirmatory factor analysis was applied to estimate item-domain correlations for five predefined constructs relating to content, beliefs, behaviour, control and intent. Cronbach's alpha coefficient was calculated to assess the overall consistency of questionnaire items with the predefined constructs. Participants in the item generation and face validation were health and policy researchers and two former decision-makers (former assistant deputy ministers) from the Canadian provincial level. Participants in the construct validation were 39 Canadian decision-makers at various positions of municipal, provincial and federal jurisdiction who participated in a series of policy dialogues focused on childhood disability. RESULTS: Cognitive debriefing allowed for small adjustments in language for clarity, including simultaneous validation of the English and French questionnaires. Participants found that the questions were clear and addressed the domains being targeted. Internal consistency of items belonging to the respective questionnaire domains was moderate to high, with estimated Cronbach's alpha values ranging from 0.67 to 0.84. Estimated item-domain correlations indicated moderate to high measurement performance for the domains norm, control and beliefs, whereas weak to moderate correlations resulted for the constructs content and intent. Estimated imprecision of factor loadings (95% confidence interval widths) was considerable for the questionnaire domains content and intent. CONCLUSION: Measuring decision-makers' behaviour in relation to research evidence use is challenging. We provide initial evidence on face validity and appropriate measurement properties of the POLIQ based on a convenience sample of decision-makers in social and health policy. Larger validation studies and further psychometric property testing will support further utility of the POLIQ.

Wischnewski Spots in a Case of Hyperosmolar Hyperglycemic State.

ABSTRACT: Wischnewski spots were first described as a common finding in gastric mucosa of decedents exposed to hypothermic environmental conditions. In recent literature, they were also reported in cases of diabetic ketoacidosis, pancreatitis, and fatal burns. Although Wischnewski spots are not specific to cases of hypothermia, we present a case that further supports this contention. We report a case of a middle-aged woman with type 2 diabetes who died of complications of hyperosmolar hyperglycemic state. Although there were no features of hypothermia, she presented with Wischnewski spots in the gastric mucosa. On histology, the gastric mucosa contained brown-black pigmentations with no neutrophilic infiltration. Biochemical analysis from vitreous humor and femoral blood showed marked elevation of glucose levels, low concentration of ketone bodies, pseudohyponatremia, and prerenal azotemia. The autopsy findings in this case discussion shed light to the possible genesis and pathophysiology of Wischnewski spots and highlight an additional differential diagnosis for these lesions.

Using ultrasound and angiogenic markers from a 19- to 23-week assessment to inform the subsequent diagnosis of preeclampsia.

BACKGROUND: A definition of preeclampsia that incorporates the assessment of maternal, fetal, and uteroplacental status would optimize the identification of pregnancies at risk of complications at term gestational age. This definition would include "carrying forward" angiogenic test results from 35 to 36 weeks of gestation to term gestational age. Would this approach still be useful if testing is performed earlier or at a routine midgestation scan and the result is used to inform the diagnosis of preeclampsia that developed thereafter? OBJECTIVE: This study aimed to evaluate whether fetoplacental assessment at a 19- to 23-week scan could be "carried forward" to contribute to the classification of preeclampsia and improve the detection of women and fetuses at risk of adverse outcomes associated with hypertension. STUDY DESIGN: In this prospective cohort study of singleton pregnancies at 2 maternity hospitals in England (October 2011 to March 2020), women attending a routine hospital visit at 19 to 23 weeks of gestation underwent an assessment that included history, ultrasonographic estimated fetal weight, Doppler measurements of the pulsatility index in uterine arteries, and serum placental growth factor. Preeclampsia was defined according to various definitions: (1) traditional, based on new-onset proteinuria at ≥20 weeks of gestation; (2) 2013 American College of Obstetricians and Gynecologists; (3) 2018 International Society for the Study of Hypertension in Pregnancy maternal factor; (4) 2018 International Society for the Study of Hypertension in Pregnancy maternal-fetal factor (death or growth restriction), based on ultrasound scans at the 19 0/7 to 23 6/7 week of gestation (an estimated fetal weight of <3rd percentile or estimated fetal weight between the 3rd and 10th percentiles with a uterine artery pulsatility index of >95th percentile); and (5) 2021 International Society for the Study of Hypertension in Pregnancy maternal-fetal factor plus placental growth factor (with abnormal placental growth factor defined as an estimated fetal weight of <5th percentile for gestational age). The detection rates for outcomes of interest (ie, severe maternal hypertension, major maternal morbidity, perinatal mortality or major neonatal morbidity, neonatal intensive care unit admission ≥48 hours, and birthweight of <3rd percentile) ascertained by health record review were compared using the chi-square test. A P value of <.05 was considered statistically significant. RESULTS: Among 40,241 singleton pregnancies, preeclampsia incidence varied by definition, from lows of 2.6% (traditional) and 3.0% (American College of Obstetricians and Gynecologists) to a high of 3.8% (International Society for the Study of Hypertension in Pregnancy maternal-fetal factor plus placental growth factor). The International Society for the Study of Hypertension in Pregnancy maternal-fetal factor plus placental growth factor definition (vs the traditional) best identified women who developed adverse outcomes: severe hypertension (detection rate: 70.6% vs 52.8%; P<.001), major maternal morbidity (detection rate: 100% vs 87.5%; P=.027), perinatal mortality or major morbidity (detection rate: 84.6% vs 69.5%; P=.004), neonatal intensive care unit admission ≥48 hours (detection rate: 76.6% vs 63.2%;, P=.0002), and birthweight of <3rd percentile (detection rate: 81.3% vs 61.9%; P<.0001]. The detection rates improved, going from the American College of Obstetricians and Gynecologists definition to the International Society for the Study of Hypertension in Pregnancy maternal-fetal factor plus placental growth factor definition, for severe hypertension (11.4%; P=.003), perinatal mortality or major morbidity (10.6%; P=.03), neonatal intensive care unit admission ≥48 hours (8.6%; P=.01), and birthweight of <3rd percentile (16.2%; P<.001). However, going from the International Society for the Study of Hypertension in Pregnancy maternal-fetal factor definition to the International Society for the Study of Hypertension in Pregnancy maternal-fetal factor plus placental growth factor definition, the detection of fetuses with a birthweight of <3rd percentile improved by 7.0% (P=.01), but no other improvement was seen for severe hypertension (1.7%; P=.33), major maternal morbidity (0%), perinatal mortality or major morbidity (4.0%; P=.20), and neonatal intensive care unit admission ≥48 hours (3.2%; P=.17). CONCLUSION: The criteria for uteroplacental dysfunction (including placental growth factor) from the 19- to 23-week assessment can be used in the assessment of women who are later suspected of having PE, to best identify pregnancies at risk of adverse outcomes.

Peptide-Based Vaccines: Current Progress and Future Challenges.

Vaccines have had a profound impact on the management and prevention of infectious disease. In addition, the development of vaccines against chronic diseases has attracted considerable interest as an approach to prevent, rather than treat, conditions such as cancer, Alzheimer's disease, and others. Subunit vaccines consist of nongenetic components of the infectious agent or disease-related epitope. In this Review, we discuss peptide-based vaccines and their potential in three therapeutic areas: infectious disease, Alzheimer's disease, and cancer. We discuss factors that contribute to vaccine efficacy and how these parameters may potentially be modulated by design. We examine both clinically tested vaccines as well as nascent approaches and explore current challenges and potential remedies. While peptide vaccines hold substantial promise in the prevention of human disease, many obstacles remain that have hampered their clinical use; thus, continued research efforts to address these challenges are warranted.