Asymmetric Hydrative Aldol Reaction (HAR) via Vinyl-Gold Promoted Intermolecular Ynamide Addition to Aldehydes.

Herein, we reported an intermolecular asymmetric hydrative aldol reaction through vinyl-gold intermediate under ambient conditions. This tandem alkyne hydration and sequential nucleophilic addition afforded a "base-free" approach to ß-hydroxy amides with high efficiency (up to 95 % yields, >50 examples). Vinyl gold intermediate was applied as reactive nucleophile and Fe(acac)3 was used as the critical co-catalyst to prevent undesired protodeauration, allowing this transformation to proceed under mild conditions with good functional group tolerance and excellent stereoselectivity (>20 : 1 d.r. and up to 99 % ee).

"I Would Report It Even If They Have Not Committed Anything": Social Service Students' Attitudes Toward Minor-Attracted People.

This study explores future mental health providers' assumptions about minor-attracted people, using data from a survey of 200 students preparing for entry into social service professions at a public university in the state of Utah. Survey results show that more than half of the students believe clients who identify themselves as pedophiles must be automatically reported to the police, which has implications for providers' understandings about the term "pedophile," as well as their knowledge of guidelines for when clinicians may break client confidentiality. This belief was not significantly affected by taking ethics courses, nor courses that discussed mandated reporting guidelines. Despite this finding, 91% of students did not believe that they would need to report a client who had attractions to children, but who had never committed a sexual offense against a child. The majority of students indicated a willingness to work with minor-attracted clients, and commonly indicated in comments that they wanted more information about MAPs and when to break client confidentiality in their programs of study. Study results indicate a need for education among social service students about these issues.

Community-Based Testing Sites for SARS-CoV-2 - United States, March 2020-November 2021.

Immediately following the March 13, 2020 declaration of COVID-19 as a national emergency (1), the U.S. government began implementing national testing programs for epidemiologic surveillance, monitoring of frontline workers and populations at higher risk for acquiring COVID-19, and identifying and allocating limited testing resources. Effective testing supports identification of COVID-19 cases; facilitates isolation, quarantine, and timely treatment measures that limit the spread of SARS-CoV-2 (the virus that causes COVID-19); and guides public health officials about the incidence of COVID-19 in a community. A White House Joint Task Force, co-led by the Department of Health and Human Services (HHS) and the Federal Emergency Management Agency (FEMA), created the Community-Based Testing Sites (CBTS) program working with state and local partners (2). This report describes the timeline, services delivered, and scope of the CBTS program. During March 19, 2020-April 11, 2021, the CBTS program conducted 11,661,923 SARS-CoV-2 tests at 8,319 locations across the United States and its territories, including 402,223 (3.5%) administered through Drive-Through Testing, 10,129,142 (86.9%) through Pharmacies+ Testing, and 1,130,558 (9.7%) through Surge Testing programs. Tests administered through the CBTS program yielded 1,176,959 (10.1%) positive results for SARS-CoV-2. Among tested persons with available race data,* positive test results were highest among American Indian or Alaska Native (14.1%) and Black persons (10.4%) and lowest among White persons (9.9%), Asian persons (7.3%), and Native Hawaiian or Other Pacific Islanders (6.4%). Among persons with reported ethnicity, 25.3% were Hispanic, 15.9% of whom received a positive test result. Overall, 82.0% of test results were returned within 2 days, but the percentage of test results returned within 2 days was as low as 40.7% in July 2020 and 59.3% in December 2020 during peak testing periods. Strong partnerships enabled a rapid coordinated response to establish the federally supported CBTS program to improve access to no-charge diagnostic testing, including for frontline workers, symptomatic persons and close contacts, and persons living in high-prevalence areas. In April 2021, the CBTS Pharmacies+ Testing and Surge Testing programs were expanded into the Increasing Community Access to Testing (ICATT) program. As of November 12, 2021, the CBTS and ICATT programs conducted approximately 26.6 million tests with approximately 10,000 active testing sites. Although the CBTS program represented a relatively small portion of overall U.S. SARS-CoV-2 testing, with its successful partnerships and adaptability, the CBTS program serves as a model to guide current community-based screening, surveillance, and disease control programs, and responses to future public health emergencies.

Evaluation of approaches to strengthen civil registration and vital statistics systems: A systematic review and synthesis of policies in 25 countries.

BACKGROUND: Civil registration and vital statistics (CRVS) systems play a key role in upholding human rights and generating data for health and good governance. They also can help monitor progress in achieving the United Nations Sustainable Development Goals. Although many countries have made substantial progress in strengthening their CRVS systems, most low- and middle-income countries still have underdeveloped systems. The objective of this systematic review is to identify national policies that can help countries strengthen their systems. METHODS AND FINDINGS: The ABI/INFORM, Embase, JSTOR, PubMed, and WHO Index Medicus databases were systematically searched for policies to improve birth and/or death registration on 24 January 2017. Global stakeholders were also contacted for relevant grey literature. For the purposes of this review, policies were categorised as supply, demand, incentive, penalty, or combination (i.e., at least two of the preceding policy approaches). Quantitative results on changes in vital event registration rates were presented for individual comparative articles. Qualitative systematic review methodology, including meta-ethnography, was used for qualitative syntheses on operational considerations encompassing acceptability to recipients and staff, human resource requirements, information technology or infrastructure requirements, costs to the health system, unintended effects, facilitators, and barriers. This study is registered with PROSPERO, number CRD42018085768. Thirty-five articles documenting experience in implementing policies to improve birth and/or death registration were identified. Although 25 countries representing all global regions (Africa, the Americas, Southeast Asia, the Western Pacific, Europe, and the Eastern Mediterranean) were reflected, there were limited countries from the Eastern Mediterranean and Europe regions. Twenty-four articles reported policy effects on birth and/or death registration. Twenty-one of the 24 articles found that the change in registration rate after the policy was positive, with two supply and one penalty articles being the exceptions. The qualitative syntheses identified 15 operational considerations across all policy categories. Human and financial resource requirements were not quantified. The primary limitation of this systematic review was the threat of publication bias wherein many countries may not have documented their experience; this threat is most concerning for policies that had neutral or negative effects. CONCLUSIONS: Our systematic review suggests that combination policy approaches, consisting of at least a supply and demand component, were consistently associated with improved registration rates in different geographical contexts. Operational considerations should be interpreted based on health system, governance, and sociocultural context. More evaluations and research are needed from the Eastern Mediterranean and Europe regions. Further research and evaluation are also needed to estimate the human and financial resource requirements required for different policies.

Household Transmission of Ebola Virus: Risks and Preventive Factors, Freetown, Sierra Leone, 2015.

Background: Knowing risk factors for household transmission of Ebola virus is important to guide preventive measures during Ebola outbreaks. Methods: We enrolled all confirmed persons with Ebola who were the first case in a household, December 2014-April 2015, in Freetown, Sierra Leone, and their household contacts. Cases and contacts were interviewed, contacts followed prospectively through the 21-day incubation period, and secondary cases confirmed by laboratory testing. Results: We enrolled 150 index Ebola cases and 838 contacts; 83 (9.9%) contacts developed Ebola during 21-day follow-up. In multivariable analysis, risk factors for transmission included index case death in the household, Ebola symptoms but no reported fever, age <20 years, more days with wet symptoms; and providing care to the index case (P < .01 for each). Protective factors included avoiding the index case after illness onset and a piped household drinking water source (P < .01 for each). Conclusions: To reduce Ebola transmission, communities should rapidly identify and follow-up all household contacts; isolate those with Ebola symptoms, including those without reported fever; and consider closer monitoring of contacts who provided care to cases. Households could consider efforts to minimize risk by designating one care provider for ill persons with all others avoiding the suspected case.

The WHO 2016 verbal autopsy instrument: An international standard suitable for automated analysis by InterVA, InSilicoVA, and Tariff 2.0.

BACKGROUND: Verbal autopsy (VA) is a practical method for determining probable causes of death at the population level in places where systems for medical certification of cause of death are weak. VA methods suitable for use in routine settings, such as civil registration and vital statistics (CRVS) systems, have developed rapidly in the last decade. These developments have been part of a growing global momentum to strengthen CRVS systems in low-income countries. With this momentum have come pressure for continued research and development of VA methods and the need for a single standard VA instrument on which multiple automated diagnostic methods can be developed. METHODS AND FINDINGS: In 2016, partners harmonized a WHO VA standard instrument that fully incorporates the indicators necessary to run currently available automated diagnostic algorithms. The WHO 2016 VA instrument, together with validated approaches to analyzing VA data, offers countries solutions to improving information about patterns of cause-specific mortality. This VA instrument offers the opportunity to harmonize the automated diagnostic algorithms in the future. CONCLUSIONS: Despite all improvements in design and technology, VA is only recommended where medical certification of cause of death is not possible. The method can nevertheless provide sufficient information to guide public health priorities in communities in which physician certification of deaths is largely unavailable. The WHO 2016 VA instrument, together with validated approaches to analyzing VA data, offers countries solutions to improving information about patterns of cause-specific mortality.

Civil registration and vital statistics: progress in the data revolution for counting and accountability.

New momentum for civil registration and vital statistics (CRVS) is building, driven by the confluence of growing demands for accountability and results in health, improved equity, and rights-based approaches to development challenges, and by the immense potential of innovation and new technologies to accelerate CRVS improvement. Examples of country successes in strengthening of hitherto weak systems are emerging. The key to success has been to build collaborative partnerships involving local ownership by several sectors that span registration, justice, health, statistics, and civil society. Regional partners can be important to raise awareness, set regional goals and targets, foster country-to-country exchange and mutual learning, and build high-level political commitment. These regional partners continue to provide a platform through which country stakeholders, development partners, and technical experts can share experiences, develop and document good practices, and propose innovative approaches to tackle CRVS challenges. This country and regional momentum would benefit from global leadership, commitment, and support.

Improving mortality data in Jordan: a 10 year review.

PROBLEM: Before 2003 there was substantial underreporting of deaths in Jordan. The death notification form did not comply with World Health Organization (WHO) guidelines and information on the cause of death was often missing, incomplete or inaccurate. APPROACH: A new mortality surveillance system to determine the causes of death was implemented in 2003 and a unit for coding causes of death was established at the ministry of health. LOCAL SETTING: Jordan is a middle-income country with a population of 6.4 million people. Approximately 20 000 deaths were registered per year between 2005 and 2011. RELEVANT CHANGES: In 2001, the ministry of health organized the first meeting on Jordan's mortality system, which yielded a five-point plan to improve mortality statistics. Using the recommendations produced from this meeting, in 2003 the ministry of health initiated a mortality statistics improvement project in collaboration with international partners. Jordan has continued to improve its mortality reporting system, with annual reporting since 2004. Reports are based on more than 70% of reported deaths. The quality of cause-of-death information has improved, with only about 6% of deaths allocated to symptoms and ill-defined conditions - a substantial decrease from the percentage before 2001 (40%). Mortality information is now submitted to WHO following international standards. LESSONS LEARNT: After 10 years of mortality surveillance in Jordan, the reporting has improved and the information has been used by various health programmes throughout Jordan.

Can verbal autopsies be used on a national scale? Key findings and lessons from South Africa's national cause-of-death validation study.

BACKGROUND: Verbal autopsy (VA), though imperfect, serves as a vital tool to determine cause-of-death, particularly for out-of-facility deaths, but challenges persist in integrating VA into Civil Registration and Vital Statistics systems. OBJECTIVE: To describe the challenges and successes of collecting a national sample of verbal autopsy interviews in South Africa to obtain the cause of death profile in 2017/18. METHODS: We recruited next of kin from 27 randomly selected sub-districts (10.5%) across South Africa between September 2017 and April 2018. Trained fieldworkers conducted face-to-face interviews using the WHO2016 VA instrument, with physicians certifying underlying causes of death. Feasibility was evaluated based on response rates, participation, and data quality. RESULTS: Of the total 36,976 deaths registered, only 26% were identified during recruitment, with a 55% overall response rate for VA interviews. Physician-reviewed VA data were deemed of good quality for assigning underlying causes of death in 83% of cases. By comparing cause-specific mortality fractions, physician-reviewed VA identified 22.3% HIV/AIDS and InterVA-5 identified 18.5%, aligning with burden of disease estimates, while Statistics South Africa reported 4.9% HIV/AIDS. CONCLUSIONS: The study demonstrated the feasibility of using VA on a national scale, but immense challenges in identifying and recruiting next of kin highlight the importance of formalising VAs within the country's death notification system.

• Main findings: Next of kin of 9 730 decedents were approached at the time of registration of death and 55% consented to be approached later and agreed to do a VA interview by a trained field-worker; 83% of physician-reviewed VA data were considered high-quality for determining underlying causes and 22.3% of all the deaths were due to HIV/AIDS, much higher than the proportion reported in the national statistical office.• Added knowledge: Implementing the VA on a national scale was achievable but significant challenges in recruiting next of kin, emphasising a need to formalise VAs within the country's death notification system.• Global health impact for policy and action: Accurate cause-of-death data are crucial for policymakers to make informed decisions about the country's health system and could be supported by using VAs, particularly for the deaths that occur outside health facilities.

Implications of the WHO Child Growth Standards in rural Honduras.

OBJECTIVE: The present study analysed the impact of using the 2006 WHO Child Growth Standards ('the WHO standards') compared with the 1977 National Center for Health Statistics (NCHS) international growth reference ('the NCHS reference') on the calculated prevalence of chronic malnutrition in children aged 6·0-59·9 months. DESIGN: Anthropometric data were collected as part of a cross-sectional study exploring the association between household environments and nutritional status of children. Z-scores were computed for height-for-age (HAZ), weight-for-age (WAZ) and weight-for-height (WHZ) using each reference/standard. Results were compared using Bland-Altman plots, percentage agreement, kappa statistics, line graphs and proportion of children in Z-score categories. SETTING: The study was conducted in thirteen rural villages within Honduras's department of Intibucá. SUBJECTS: Children aged 6·0-59·9 months were the focus of the analysis, and households with children in this age range served as the sampling unit for the study. RESULTS: The WHO standards yielded lower means for HAZ and higher means for WAZ and WHZ compared with the NCHS reference. The WHO standards and NCHS reference showed good agreement between Z-score categories, except for HAZ among males aged 24·0-35·9 months and WHZ among males aged >24·0 months. Using the WHO standards resulted in higher proportions of stunting (low HAZ) and overweight (high WHZ) and lower proportions of underweight (low WAZ). The degree of difference among these measures varied by age and gender. CONCLUSIONS: The choice of growth reference/standard employed in nutritional surveys may have important methodological and policy implications. While ostensibly comparable, data on nutritional indicators derived with different growth references/standards must be interpreted cautiously.

Performance of iron spot test with Arabic bread made from fortified white wheat flour.

BACKGROUND: The iron spot test (IST) is a simple qualitative technique for determining the presence of added iron in fortified flour. IST performance in bread has never been investigated. If found to perform well, the IST has the potential to provide a field-friendly method for testing bread and thus support the monitoring and evaluation of flour fortification programs. OBJECTIVE: To assess the performance of the IST in Arabic bread made from white wheat flour. METHODS: Bread samples were collected from 1,737 households during a national micronutrient survey in Jordan. A subsample of Arabic bread (n = 44) was systematically selected for testing by both the IST and spectrophotometry (criterion reference). Performance measures (sensitivity, specificity, and positive and negative predictive values) were calculated using five cutoffs to define the presence of added iron, including > or = 15.0 ppm (approximate level of natural iron in Arabic bread) and four additional cutoffs based on test performance. RESULTS: The iron contents of samples testing negative by IST ranged from 10.4 to 18.4 ppm, with one outlier at 41.0 ppm, which was excluded from subsequent analyses. The iron contents of samples testing positive by IST ranged from 16.1 to 38.4 ppm. With the exception of negative predictive values for the two lowest cutoffs (> or = 15.0 and > or = 16.1 ppm), all performance measures exceeded 83.3%. CONCLUSIONS: These results show promise for the IST as an inexpensive, field-friendly method for testing bread that could have a useful role in the monitoring and evaluation process for flour fortification programs.

Bilateral dysthyroid compressive optic neuropathy responsive to teprotumumab.

Thyroid eye disease is an auto-immune mediated orbitopathy which can cause dysthyroid compressive optic neuropathy. Traditional management of active thyroid eye disease includes temporizing high-dose steroids, orbital radiation and surgical decompression, which each possess significant limitations and/or side effects. Teprotumumab is an IGF-IR inhibitor recently FDA-approved for active thyroid eye disease. The authors report reversal of bilateral dysthyroid compressive optic neuropathy managed medically utilizing teprotumumab.

Risk factors for Ebola virus disease among household care providers, Sierra Leone, 2015.

BACKGROUND: Household contacts who provide care to an Ebola virus disease (EVD) case have a 3-fold higher risk of EVD compared with contacts who do not provide care. METHODS: We enrolled persons with confirmed EVD from December 2014 to April 2015 in Freetown, Sierra Leone, and their household contacts. Index cases and contacts were interviewed, and contacts were followed for 21 days to identify secondary cases. Epidemiological data were analysed to describe household care and to identify risk factors for developing EVD. RESULTS: Of 838 contacts in 147 households, 156 (17%) self-reported providing care to the index case; 56 households had no care provider, 52 a single care provider and 39 multiple care providers. The median care provider age was 29 years, 68% were female and 32% were the index case's spouse. Care providers were more likely to report physical contact, contact with body fluids or sharing clothing, bed linens or utensils with an index case, compared with non-care providers (P <0.01). EVD risk among non-care providers was greater when the number of care providers in the household increased (odds ratio: 1.61; 95% confidence interval: 1.1, 2.4). In multivariable analysis, factors associated with care provider EVD risk included no piped water access and absence of index case fever, and protective factors included age <20 years and avoiding the index case. CONCLUSIONS: Limiting the number of care providers in a household could reduce the risk of EVD transmission to both care providers and non-care providers. Strategies to protect care providers from EVD exposure are needed.

Mixed-methods analysis of select issues reported in the 2016 World Health Organization verbal autopsy questionnaire.

BACKGROUND: Use of a standardized verbal autopsy (VA) questionnaire, such as the World Health Organization (WHO) instrument, can improve the consistency and reliability of the data it collects. Systematically revising a questionnaire, however, requires evidence about the performance of its questions. The purpose of this investigation was to use a mixed methods approach to evaluate the performance of questions related to 14 previously reported issues in the 2016 version of the WHO questionnaire, where there were concerns of potential confusion, redundancy, or inability of the respondent to answer the question. The results from this mixed methods analysis are discussed across common themes that may have contributed to the underperformance of questions and have been compiled to inform decisions around the revision of the current VA instrument. METHODS: Quantitative analysis of 19,150 VAs for neonates, children, and adults from five project teams implementing VAs predominately in Sub-Saharan Africa included frequency distributions and cross-tabulations to evaluate response patterns among related questions. The association of respondent characteristics and response patterns was evaluated using prevalence ratios. Qualitative analysis included results from cognitive interviewing, an approach that provides a detailed understanding of the meanings and processes that respondents use to answer interview questions. Cognitive interviews were conducted among 149 participants in Morocco and Zambia. Findings from the qualitative and quantitative analyses were triangulated to identify common themes. RESULTS: Four broad themes contributing to the underperformance or redundancy within the instrument were identified: question sequence, overlap within the question series, questions outside the frame of reference of the respondent, and questions needing clarification. The series of questions associated with one of the 14 identified issues (the series of questions on injuries) related to question sequence; seven (tobacco use, sores, breast swelling, abdominal problem, vomiting, vaccination, and baby size) demonstrated similar response patterns among questions within each series capturing overlapping information. Respondent characteristics, including relationship to the deceased and whether or not the respondent lived with the deceased, were associated with differing frequencies of non-substantive responses in three question series (female health related issues, tobacco use, and baby size). An inconsistent understanding of related constructs was observed between questions related to sores/ulcers, birth weight/baby size, and diagnosis of dementia/presence of mental confusion. An incorrect association of the intended construct with that which was interpreted by the respondent was observed in the medical diagnosis question series. CONCLUSIONS: In this mixed methods analysis, we identified series of questions which could be shortened through elimination of redundancy, series of questions requiring clarification due to unclear constructs, and the impact of respondent characteristics on the quality of responses. These changes can lead to a better understanding of the question constructs by the respondents, increase the acceptance of the tool, and improve the overall accuracy of the VA instrument.

Estimating causes of death where there is no medical certification: evolution and state of the art of verbal autopsy.

Over the past 70 years, significant advances have been made in determining the causes of death in populations not served by official medical certification of cause at the time of death using a technique known as Verbal Autopsy (VA). VA involves an interview of the family or caregivers of the deceased after a suitable bereavement interval about the circumstances, signs and symptoms of the deceased in the period leading to death. The VA interview data are then interpreted by physicians or, more recently, computer algorithms, to assign a probable cause of death. VA was originally developed and applied in field research settings. This paper traces the evolution of VA methods with special emphasis on the World Health Organization's (WHO)'s efforts to standardize VA instruments and methods for expanded use in routine health information and vital statistics systems in low- and middle-income countries (LMICs). These advances in VA methods are culminating this year with the release of the 2022 WHO Standard Verbal Autopsy (VA) Toolkit. This paper highlights the many contributions the late Professor Peter Byass made to the current VA standards and methods, most notably, the development of InterVA, the most commonly used automated computer algorithm for interpreting data collected in the WHO standard instruments, and the capacity building in low- and middle-income countries (LMICs) that he promoted. This paper also provides an overview of the methods used to improve the current WHO VA standards, a catalogue of the changes and improvements in the instruments, and a mapping of current applications of the WHO VA standard approach in LMICs. It also provides access to tools and guidance needed for VA implementation in Civil Registration and Vital Statistics Systems at scale.

Combination of PARP Inhibitor Olaparib, and PD-L1 Inhibitor Durvalumab, in Recurrent Ovarian Cancer: a Proof-of-Concept Phase II Study.

PURPOSE: Preclinical studies suggest PARP inhibition (PARPi) induces immunostimulatory micromilieu in ovarian cancer thus complementing activity of immune checkpoint blockade. We conducted a phase II trial of PARPi olaparib and anti-PD-L1 durvalumab and collected paired fresh core biopsies and blood samples to test this hypothesis. PATIENTS AND METHODS: In a single-center, proof-of-concept phase II study, we enrolled women aged ≥18 with recurrent ovarian cancer. All patients were immune checkpoint inhibitor-naïve and had measurable disease per RECISTv1.1, ECOG performance status 0-2, and adequate organ and marrow function. Patients received olaparib 300 mg twice daily and durvalumab 1,500 mg intravenously every 4 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. Primary endpoint was overall response rate (ORR). Secondary objectives were safety and progression-free survival (PFS). Translational objectives included biomarker evaluation for relationships with clinical response and immunomodulatory effects by treatment. RESULTS: Thirty-five patients with ovarian cancer [median, four prior therapies (IQR, 2-5.5), predominantly platinum-resistant (86%), BRCA wild-type (77%)] received at least one full cycle of treatment. ORR was 14% [5/35; 95% confidence interval (CI), 4.8%-30.3%]. Disease control rate (PR+SD) was 71% (25/35; 95% CI, 53.7%-85.4%). Treatment enhanced IFNγ and CXCL9/CXCL10 expression, systemic IFNγ/TNFα production, and tumor-infiltrating lymphocytes, indicating an immunostimulatory environment. Increased IFNγ production was associated with improved PFS [HR, 0.37 (95% CI, 0.16-0.87), P = 0.023], while elevated VEGFR3 levels were associated with worse PFS (HR, 3.22 (95% CI, 1.23-8.40), P = 0.017]. CONCLUSIONS: The PARPi and anti-PD-L1 combination showed modest clinical activity in recurrent ovarian cancer. Our correlative study results suggest immunomodulatory effects by olaparib/durvalumab in patients and indicate that VEGF/VEGFR pathway blockade would be necessary for improved efficacy of the combination.

A systematic review of vital events tracking by community health agents.

Background: Efforts to improve national civil registration and vital statistics (CRVS) systems are focusing on transforming traditionally passive systems into active systems that have the ability to reach the household level. While community health agents remain at the core of many birth and death reporting efforts, previous literature has not explored elements for their successful integration into CRVS efforts. Objective: To inform future efforts to improve CRVS systems, we conducted a systematic review of literature to understand and describe the design features, resulting data quality, and factors impacting the performance of community health agents involved in tracking vital events. Methods: We reviewed 393 articles; reviewers extracted key information from 58 articles meeting the eligibility criteria: collection of birth and/or death information outside of a clinic environment by a community agent. Reviewers recorded information in an Excel database on various program aspects, and results were summarized into key themes and topic areas. Results: The majority of articles described work in rural areas of Africa or South-East Asia. Nearly all articles (86%) cited some form of household visitation by community health agents. Only one article described a process in which vital events tracking activities were linked to official vital events registers. Other factors commonly described included program costs, relationship of community agents to community, and use of mobile devices. About 1/3 of articles reported quantitative information on performance and quality of vital events data tracked; various methods were described for measuring completeness of reporting, which varied greatly across articles. Conclusions: The multitude of articles on this topic attests to the availability of community health agents to track vital events. Creating a programmatic norm of integrating with CRVS systems the vital events information collected from existing community health programs has the potential to provide governments with information essential for public health decision-making.

A phase I study of the PD-L1 inhibitor, durvalumab, in combination with a PARP inhibitor, olaparib, and a VEGFR1-3 inhibitor, cediranib, in recurrent women's cancers with biomarker analyses.

BACKGROUND: Strategies to improve activity of immune checkpoint inhibitors are needed. We hypothesized enhanced DNA damage by olaparib, a PARP inhibitor, and reduced VEGF signaling by cediranib, a VEGFR1-3 inhibitor, would complement anti-tumor activity of durvalumab, a PD-L1 inhibitor, and the 3-drug combination would be tolerable. METHODS: This phase 1 study tested the 3-drug combination in a 3 + 3 dose escalation. Cediranib was taken intermittently (5 days on/2 days off) at 15 or 20 mg (dose levels 1 and 2, respectively) with durvalumab 1500 mg IV every 4 weeks, and olaparib tablets 300 mg twice daily. The primary end point was the recommended phase 2 dose (RP2D). Response rate, pharmacokinetic (PK), and correlative analyses were secondary endpoints. RESULTS: Nine patients (7 ovarian/1 endometrial/1 triple negative breast cancers, median 3 prior therapies [2-6]) were treated. Grade 3/4 adverse events include hypertension (1/9), anemia (1/9) and lymphopenia (3/9). No patients experienced dose limiting toxicities. The RP2D is cediranib, 20 mg (5 days on/2 days off) with full doses of durvalumab and olaparib. Four patients had partial responses (44%) and 3 had stable disease lasting ≥6 months, yielding a 67% clinical benefit rate. No significant effects on olaparib or cediranib PK parameters from the presence of durvalumab, or the co-administration of cediranib or olaparib were identified. Tumoral PD-L1 expression correlated with clinical benefit but cytokines and peripheral immune subsets did not. CONCLUSIONS: The RP2D is tolerable and has preliminary activity in recurrent women's cancers. A phase 2 expansion study is now enrolling for recurrent ovarian cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02484404. Registered June 29, 2015.

Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations.

BACKGROUND: Checkpoint inhibitors have not been effective for prostate cancer as single agents. Durvalumab is a human IgG1-K monoclonal antibody that targets programmed death ligand 1 and is approved by the U.S. Food and Drug Administration for locally advanced or metastatic urothelial cancer and locally advanced, unresectable stage 3 non-small cell lung cancer. Olaparib, a poly (ADP-ribose) polymerase inhibitor, has demonstrated an improvement in median progression-free survival (PFS) in select patients with metastatic castration-resistant prostate cancer (mCRPC). Data from other trials suggest there may be improved activity in men with DNA damage repair (DDR) mutations treated with checkpoint inhibitors. This trial evaluated durvalumab and olaparib in patients with mCRPC with and without somatic or germline DDR mutations. METHODS: Eligible patients had received prior enzalutamide and/or abiraterone. Patients received durvalumab 1500 mg i.v. every 28 days and olaparib 300 mg tablets p.o. every 12 h until disease progression or unacceptable toxicity. All patients had biopsies of metastatic lesions with an evaluation for both germline and somatic mutations. RESULTS: Seventeen patients received durvalumab and olaparib. Nausea was the only nonhematologic grade 3 or 4 toxicity occurring in > 1 patient (2/17). No patients were taken off trial for toxicity. Median radiographic progression-free survival (rPFS) for all patients is 16.1 months (95% CI: 4.5-16.1 months) with a 12-month rPFS of 51.5% (95% CI: 25.7-72.3%). Activity is seen in patients with alterations in DDR genes, with a median rPFS of 16.1 months (95% CI: 7.8-18.1 months). Nine of 17 (53%) patients had a radiographic and/or PSA response. Patients with fewer peripheral myeloid-derived suppressor cells and with alterations in DDR genes were more likely to respond. Early changes in circulating tumor cell counts and in both innate and adaptive immune characteristics were associated with response. CONCLUSIONS: Durvalumab plus olaparib has acceptable toxicity, and the combination demonstrates efficacy, particularly in men with DDR abnormalities. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02484404 .