Israel Cancer Research Articles

Recommendations from the Professional Advisory Committee on Nursing Practice When Caring for Adolescents and Young Adults with Cancer in Israel.

Recommendations from the Professional Advisory Committee on Nursing Practice When Caring for Adolescents and Young Adults with Cancer in Israel.

Implementing the first program of minimally invasive esophagectomy for cancer in Israel: shifting the paradigm in a high-volume center - a cohort study.

Esophagectomy is associated with significant perioperative morbidity. Limited data are available on the process of implementation of minimally invasive techniques in esophagectomy and related outcomes. The authors sought to describe implementation processes and outcomes following the implementation of the first minimally invasive esophagectomy (MIE) program at a high-volume center in Israel under the mentorship of American early adopters. Patients who underwent esophagectomy for esophageal carcinoma 2011-2022 were included. Early and late cohorts were created for learning curve analysis. Secondary analysis included patients who underwent open esophagectomy 1997-2011. Overall, 300 patients underwent MIE: three-field MIE (3F-MIE) was performed in 242 (80.7%) patients, two-field MIE (2F-MIE) in 58 (19.3%) patients. Following program implementation in 2012, the number of MIE performed increased during the first 3 years ( n =33, 86.8% in 2015). Among 3F-MIE patients, a higher number of retrieved lymph nodes was reported during later cases (median, IQR1-3 17, 12-23 vs. 12, 8-12, P <0.001) while surgeries required a longer time (median, IQR1-3 300min, 261-355 vs. 262.5, 239-300, P <0.001). Among 2F-MIE patients, the late cohort had lower rates of prolonged ICU admissions than earlier counterparts ( n =2, 6.9% vs. n =9, 31%, P =0.041), overall and severe 30-day complications ( n =12, 41.4% vs. n =23, 79.3%, P <0.001 and n =7, 24.1% vs. n =23, 79.3%, P =0.003). MIE was safely implemented. Nodal yield was higher among MIE patients than open esophagectomy. During the study years, open approach was gradually abandoned in favor of 3F-MIE procedures, while 2F-MIE increased over the course of the last years.

Context-Specific Estimation of Future Unrelated Medical Costs and Their Impact on Cost-Effectiveness Analyses.

This study constructed and applied procedures for the estimation of unrelated future medical costs (UFMC) of women with breast cancer in Israel (as a case study) and examined the influence of including UFMC in cost-effectiveness analyses (CEAs). Part I consisted of a retrospective cohort study based on patient-level claims data of both patients with breast cancer and matched controls during 14 years of follow-up. UFMC were estimated as (a) the annual average all-cause healthcare costs of the control subjects, and (b) as predicted values based on a generalized linear model (GLM) adjusted to patients' characteristics. Part II consisted of a CEA performed using a Markov simulation model comparing regimens of chemotherapy with/without trastuzumab, both excluding and including UFMC and for each of the UFMC estimates separately. All costs were adjusted to 2019 prices. Costs and QALYs were discounted at a yearly rate of 3%. The average annual healthcare costs in the control group were $2328 (± $5662). The corresponding incremental cost-effectiveness ratio (ICER) was $53,411/QALY and $55,903/QALY, when UFMC were excluded or included, respectively. Hence, trastuzumab was not considered cost-effective compared with a threshold of willingness-to-pay of $37,000 per QALY, regardless of the inclusion of UFMC. When UFMC were estimated on the basis of the prediction model, the ICERs were $37,968/QALY and $39,033/QALY, when UFMC were excluded or included, respectively. Thus, in this simulation, trastuzumab was not considered cost-effective, independent of the inclusion of UFMC. Our case study revealed that the inclusion of UFMC had modest effect on the ICERs, and thus did not alter the conclusion. Thus, we should estimate context-specific UFMC if they are expected to change the ICERs significantly, and transparently report the corresponding assumptions to uphold the integrity and reliability of the economic evaluation.

Disparities in Breast Cancer Mortality Rates in Israel among Urban and Rural Women

Breast cancer is a leading cause of death. There are a number of risk factors for breast cancer mortality including parity, age, ethnicity, genetic history, and place of residence. This study examined the disparities in breast cancer-related mortality rates among women from urban areas compared to rural areas in Israel. This was a retrospective, follow-up study on mortality from breast cancer among 894,608 Israeli women born between the years of 1940 and 1960. Data was collected from the Israeli Central Bureau of Statistics, the Population Authority, the Education Ministry, and the Health Ministry. Over 80% of women lived in urban areas. A higher incidence of mortality from breast cancer in Israel was found among urban women compared to rural women (1047.8/100,000 compared to 837/100,000, respectively). Even after adjusting for sociodemographic variables, higher mortality rates were found among women from urban areas in Israel compared to women from rural areas in Israel. It is believed that environmental factors can partially explain the geographic variation of breast cancer incidence, and that breast cancer incidence is likely a complex interaction between genetic, environmental, and health factors.

Thoracic surgery in Israel.

During the past 74 years since its establishment, Israel has evolved into a modernized country with well-established and effective public health care system. Thoracic surgeons in Israel play a central role in the diagnosis and treatment of patients with diseases of the chest wall, diaphragm, mediastinum, airways, Lung, and esophagus as well are taking part in designated trauma teams. Between 2,500-3,000 cases are being performed in 16 designated thoracic surgical units and departments across the country annually, the majority of them being performed in a minimally invasive fashion. Lung cancer is the leading cause of cancer related mortality in Israel and the second most common cancer in Israel. All types of thoracic oncologic cases are being presented routinely during designated multi-disciplinary conferences and treatment plans are designed according to the most up to date international guidelines. Each surgeon undergoes at least 6 years of formal training, followed by certifying exams. Advanced training is usually obtained overseas in centers of excellence. Israeli thoracic surgeons are part of an international societies and are actively involved in academic research. Despite the advancement of the Israeli health care system, thoracic surgeons in Israel are still facing few challenges that are limiting the early diagnosis of thoracic surgical malignancies such as lack of established national lung cancer screening program in Israel although a pilot program is being tested during these days. Tasked with taking care of diseases of the chest, and in order to remain at the forefront of diagnosis and treatment similar to our colleagues across the globe, Thoracic surgeons in Israel are continuously seeking to learn and evolve in order to improve and provide better care to our patients.

The association between geriatric assessment, muscle measures, and treatment-related toxicity in older adults with cancer: An Israeli prospective study

IntroductionWe investigated the associations among frailty, as determined via the comprehensive geriatric assessment (CGA), muscle measures (i.e., sarcopenia), and treatment-related toxicity in older adults with cancer in Israel. Materials and methodsThis prospective cohort study enrolled patients ≥65 years with newly-diagnosed stage IV lung, breast, or genitourinary cancer. Patients were enrolled and completed CGA before their first line of systemic therapy (chemotherapy, biologic therapy, immunologic therapy, or a combination thereof). CGA was used to classify patients as robust, pre-frail, or frail, and routine pre-treatment computed tomography (CT) images were used to quantify skeletal muscle index (SMI) and skeletal muscle density (SMD) at L3 cross-section. Two sarcopenia definitions were used: i. for women SMI <41 cm2/m2 regardless of body mass index (BMI), and for men SMI <43 cm2/m2 for those with BMI of <25 and < 53 cm2/m2 for those with BMI ≥25; and ii. SMI <38 cm2/m2 for women and < 41 cm2/m2 for men, regardless of BMI. The associations between frailty and muscle measures with the occurrence of at least one adverse event (AE) grade ≥ 2 were examined using the chi-square test, and logistic regression to determine odds ratio (OR) and 95% confidence interval (CI). ResultsIn total, 51 patients were included in the analysis. The median (interquartile range) age was 72 (68–76) years, 30 (59%) were male, and 26 (51%) had lung cancer. CGA data were available for 48 patients: fifteen (31%), thirteen (27%), and twenty (42%) were defined as robust, pre-frail, and frail, respectively. Overall, 33 (65%) were sarcopenic by the first aforementioned definition, and sixteen (31%) by the second. No statistically significant associations were identified between frailty and having at least one AE grade ≥ 2, or between frailty and sarcopenia. Statistically significant associations were found between having sarcopenia (the second definition) and having at least one AE grade ≥ 2 (P = 0.0217). The corresponding odds ratio (95% CI) was 4.2 (1.2–15.0), P = 0.026. DiscussionOur findings suggests that sarcopenia is significantly associated with treatment-related toxicity. Further studies with larger sample sizes are warranted.

Coeliac plexus radiosurgery for pain management in patients with advanced cancer : study protocol for a phase II clinical trial

IntroductionPancreatic cancer is characterised by severe mid-back and epigastric pain caused by tumour invasion of the coeliac nerve plexus. This pain is often poorly managed with standard treatments. This clinical...

Using COVID-19 Symbols in Anti-Smoking Fear Appeal Advertisements for Encouraging Smoking Cessation among Israeli Smokers.

The current study aims to reveal whether using COVID-19 as the threatening message in anti-smoking ads will influence smokers differently than other threat appeals. All ads that were chosen for this study were created by the Israel Cancer Association/the Israeli Ministry of Health. Since the coronavirus has proven to have far-reaching effects on the human respiratory system, it is directly connected to smoking. The present study included semi-structured in-depth interviews with experts, a pre-test (n = 106) and an online questionnaire including 721 participants (adults aged 18–30 versus 55+). The findings indicated that when using the COVID-19 symbol as the threatening message in an anti-smoking ad for the older participants, smoking cessation intentions were higher than when using a cigarette simulating a ‘gunpoint’ threat (p < 0.08). Additionally, when using the COVID-19 symbol, there was a positive relation between participants’ age and smoking cessation intentions. The average smoking cessation intention for the participants from the older age group (M = 3.05, SD = 1.07) was higher than the average for the participants from the young age group (M = 2.80, SD = 1.13). Finally, when using impotence (for men) and pregnancy risks (for women) as the threatening message in the ads for young respondents, smoking cessation intentions were higher than when using COVID-19 (p < 0.05). The results may help decision-makers and public health officials in choosing the marketing communication suited for conveying messages aimed to encourage people to reduce/quit smoking.

The Risk of Developing Tuberculosis in Cancer Patients Is Greatest in Lymphoma: A Large Population-Based Study

Introduction: Patients with cancer, especially those diagnosed with hematological malignancies, are considered at higher risk for tuberculosis (TB). Several studies reported that Hodgkin lymphoma (HL) patients have the highest risk for TB among patients with hematological malignancies. These data are relatively old and based mostly on series of patients with malignancies or with TB but often lack statistical rigor and not based on large population-based studies.According to the Israeli regulations, every new diagnosis of cancer must be reported to the Israel National Cancer Registry (INCR) and every new diagnosis of TB to the Israel National Tuberculosis Registry (INTR). We combined both databases and studied epidemiological features of TB among patients with cancer in Israel, in which the incidence of TB in the general population is relatively low. The study objectives were to examine whether patients with hematological malignancies are at increased risk to develop active TB, compared to patients with solid tumors, and to examine whether patients with HL have a higher risk of active TB than patients with other hematological malignancies.Methods: The study population consists of all newly diagnosed cancer cases reported to the INCR from 1993-2013. These data were linked with data from the INTR for the same period. HIV patients were excluded from both databases. Hematologic malignancies were categorized into 5 groups: acute leukemia, HL, non-Hodgkin lymphoma (NHL), myelodysplastic syndrome/myeloproliferative neoplasm and plasma cell dyscrasia. Incidence rates per 100,000 person-years were calculated. Logistic regression was used to analyze the risk of TB following cancer diagnosis among patients with different malignancies.Results: Of 465,429 patients who were diagnosed with cancer during 1993-2013, 676 patients were notified to have TB but in only 321 patients the diagnosis of TB followed cancer diagnosis. The cumulative incidence of TB following cancer diagnosis was 14.4 per 100,000 person-years (PY). The rate of TB incidence following cancer diagnosis was 27.2/100,000 PY for persons diagnosed with hematological malignancies, and 12.7/100,000 PY among those with non-hematological malignancies (p<0.001). The highest TB incidence was found among patients with lymphoma (30.1 TB cases per 100,000 PY). Among lymphoma patients, a higher incidence rate was found in NHL patients than among HL patients, however the difference was not significant (32.1 vs . 21.6, respectively, p=0.378). Accounting for sex, age at diagnosis and ethnicity in logistic regression, the risk of TB among lymphoma patients is significantly higher than in other malignancies (Odds ratio 2.61, p=0.002) and there is no added significant risk for patients with HL (Odds ratio 1.33, p=0.464).Conclusions: 1) In this population-based study of more than 450,000 patients diagnosed with cancer, the incidence of TB following a cancer diagnosis is higher among patients with hematological malignancies than in patients with solid tumors. 2) Lymphoma patients have the highest risk to develop TB. 3) In contrast to common perception, we did not find that patients with HL are at increased risk to develop TB relative to NHL patients. 4) These data suggest for a heightened awareness for latent TB among newly diagnosed patients with lymphoma and for active TB among patients with a background of lymphoma who present with fever or respiratory complains. DisclosuresNo relevant conflicts of interest to declare.

Real-world study of PD-L1 testing patterns and treatment distribution in patients with metastatic non-small-cell lung cancer in Israel.

Aim: We describe PD-L1testing patterns and first-linetreatment for patients with metastatic non-small-cell lung cancerin a 2.3million-member state-mandated health service in Israel. Materials & methods: Newly diagnosed stage IV non-small-cell lung cancer patients initiating systemic anticancer treatment from 1January 2017 until 31December 2018 were identified from the national cancer registry and Maccabi Healthcare Service database and followed until 30June 2019. Results: The cohort consisted of 410 patients; 58% males, median age 68years, 70% current/former smokers, 81% adenocarcinoma, 14% had brain metastases, and Eastern Cooperative Oncology Groupperformance status was 46/17/37% for 0-1/2-4/unknown, respectively. A total of 80%tested for PD-L1 expression, of which 47% had tumor proportion score (TPS) ≥50%. A total of95% with TPS≥ 50% and no known tumor aberrations (including EGFR mutations, and translocations in ALKand ROS1) received first-linePD-1/PD-L1-inhibitor monotherapy, and 80% of untested/TPS<50% received platinumdoublets. Conclusion: Fast uptake of testing was observed, and treatment patterns showed high adherence to guidelines.

P09.39 PD-L1 Testing Patterns and Treatment in Patients With Metastatic Non-Small Cell Lung Cancer in Israel – Analysis of Real-World Data

P09.39 PD-L1 Testing Patterns and Treatment in Patients With Metastatic Non-Small Cell Lung Cancer in Israel – Analysis of Real-World Data

Cancer risk and overall survival in APC I1307K carriers.

1592 Background: The germline variant APC I1307K is one of the most commonly identified pathogenic variants on germline genetic testing panels. The purpose of the Molecular Epidemiology of Colorectal Cancer study was to quantify the risk of colorectal cancer among carriers, characterize the clinical, pathologic, and molecular features of colorectal cancers arising in patients with APC I1307K, and to describe the overall and disease-specific survival of carriers with colorectal cancer. Here, the final results of the Molecular Epidemiology of Colorectal Cancer Study are reported with respect to APC I1307K. Methods: We consented 6,006 incident, pathologically confirmed cases of colorectal adenocarcinoma and 5,023 age, sex, and ethnicity matched controls without colorectal cancer between March 31, 1998 and July 1, 2017 within a geographically defined area of Northern Israel. Comprehensive, in-person epidemiologic interviews were conducted for cases and controls, with uniform histopathologic review, detailed molecular analysis, medical record review and clinical follow-up for up to 21 years. Results: The demographic and clinical features of incident colorectal cancer cases matched the population distribution of colorectal cancer in Israel. APC I1307K was identified in 429 (7.1%) of cases and 201 (4.0%) of controls. The estimated relative risk of colorectal cancer among carriers was 1.89 (95% confidence interval, 1.59 - 2.24), p &lt; 0.0001. The prevalence and odds ratios differed by ethnic group. Homozygous carriers were at especially high risk, with an odds ratio of 3.90 (95% confidence interval 1.11–13.71). APC I1307K carriers were significantly less likely to have microsatellite instable tumors (p = 0.04). Overall survival of APC I1307K carriers was not significantly different than survival of non-carriers, after adjustment for age, stage, sex, ethnicity, and microsatellite instability. Conclusions: APC I1307K is an actionable germline mutation that confers meaningful lifetime risk of colorectal cancer in heterozygous and homozygous carriers. APC I1307K is not an independent prognostic factor for overall survival or disease specific survival and is not associated with the MSI phenotype. Cumulative lifetime risk estimates inform genetic counseling and provide data for policies regarding the timing and frequency of screening and other preventive strategies.

Direct and indirect predictors of burden among Bedouin caregivers of family members with terminal cancer in Israel

Objective: The diverse demands of cancer care, which require time, psychological, physical, and material resources, often lead to caregiver burden. Studies with caregivers from ethnic minority groups suggest that they have unique beliefs and may experience different perceptions of role demands and caregiving. The aim of this study was to identify direct and indirect predictors of burden among Bedouin caregivers of family members with terminal cancer in Israel.Methods: A total of 101 Bedouin family caregivers of terminal cancer patients participated in this study. Participants were recruited from the oncology department of the largest medical center in southern Israel. The questionnaire battery included the Arabic version of the Zarit Burden Interview and other reliable measures validated for cancer caregiving. We performed path analyses on data allowing us to identify hypothesized, and un-hypothesized predictors of burden in this understudied population.Results: Most caregivers were adult children, followed by spouses, siblings and other family members. In our model, caregiver burden was directly predicted by depressive symptoms and (absence of) social support. Burden was indirectly predicted by quality of life (via depressive symptoms), optimism (via social support), emotional exhaustion (via quality of life and depressive symptoms) and mortality communication (via emotional exhaustion, quality of life and depressive symptoms).Conclusion: Social support and depression are the most important factors among all studied measures. Culturally-tailored intervention programs are required to foster community care and mitigate burden for Bedouin and other ethnic minority groups in Israel.

The effect of age at immigration on cervical cancer incidence: a population-based cohort study of 1 486 438 Israeli women.

To clarify the effect of mass migration from a high-risk area (former Soviet Union) to a low-risk area (Israel) on cervical cancer incidence and mortality in Israel and the modifying effect of age at immigration. All women who immigrated to Israel from the former Soviet Union between January 1, 1990 and December 31, 2000 (N=345 202) and all Jewish Israeli-born women who were 0-80 years old on January 1, 1990 (N=1 141 236) were included. Follow-up ended at December 31, 2010 or date of death or date of cervical cancer diagnosis, whatever occurred earlier. Crossing data from the computerized population registry of the Ministry of Interior, the Israel National Cancer Registry and the Central Bureau of Statistics, cervical cancer incidence and mortality and adjusted hazard ratios (aHR) with 95% confidence intervals (95% CI) were calculated. 1595 new cases (crude incidence rate 29.71: 100 000 person years) of cervical cancer were diagnosed in immigrants as compared with 6159 cases (crude incidence rate 27.21: 100 000 person years) diagnosed in Israel-born Jewish women. Immigration at an age older than 12 years was hazardous (aHR 1.27, 95% CI 1.19 to 1.35; P<0.001) while immigration at a younger age was protective (aHR 0.62, 95% CI 0.51 to 0.75; P<0.001) for cervical cancer incidence compared with native Israeli women. Cervical cancer mortality was also significantly higher in immigrants compared with Israel-born women with incidence density rates of 1.15 and 0.35 per 100 person years, respectively (P<0.0001). Factors related to the acquired causes of the disease at the country of origin are probably at the root of the low incidence of cervical cancer in Israel. Adult immigrants from the former Soviet Union should be managed as a high-risk group.

Constitutional mismatch repair deficiency and Lynch syndrome among consecutive Arab Bedouins with colorectal cancer in Israel.

We assessed the molecular characteristics and the frequency of mutations in mismatch-repair genes among Bedouin patients with colorectal cancer (CRC) in Israel. Bedouin patients with a diagnosis of CRC at a major hospital in the southern part of Israel were deemed eligible for this study. The primary screening method was immunohistochemical staining for mismatch-repair proteins (MLH1, MSH2, MSH6, and PMS2). For subjects with abnormal immunohistochemical staining, we performed microsatellite instability (MSI) analyses, and for tumors with a loss of MLH1 expression we also performed BRAF testing. In MSI high cases we searched further for germline mutations. Of the 24 patients enrolled, four subjects (16.7%) had MSI high tumors: one subject was found to harbor a biallelic PMS2 mutation, one subject had Lynch syndrome (LS) with MSH6 mutation and two subjects had a loss of MLH1/PMS2 proteins/BRAF wild type/normal MLH1 sequence. Ten patients (41.7%) were younger than 50 at the time of diagnosis and none had first degree relatives with CRC. In conclusion, in this cohort of 24 consecutive Arab Bedouins with CRC, one patient was found to harbor a constitutional mismatch repair deficiency, one patient had LS with MSH6 mutation, and two patients had unresolved loss of MLH1/PMS2 proteins/BRAF wild type phenotype.

Cancer in Israel: Incidence and Trends

Cancer in Israel: Incidence and Trends

Cancer in Israel: Incidence and Trends

Cancer in Israel: Incidence and Trends

Esophageal Cancer in Israel has Unique Clinico-Pathological Features: A Retrospective Study.

Introduction: Data regarding esophageal cancer (EC) in Israel are limited. The aim of this study was hence to characterize this entity in the Israeli population and to compare it to the literature.Patients/Methods: This is a retrospective study of all consecutive EC patients treated at our institution between 1997-2013. Data were retrieved from patients' medical files.Results: Two hundred patients were included. The median age at diagnosis was 70.5 years; 63.5% were males; 63% were Ashkenazi Jews, 29% were Sephardic Jews, and 0.5% were Arabs. Squamous cell carcinoma (SCC) was predominant: 52% versus 45.5% with adenocarcinoma (ADC). SCC was common even in the distal esophagus (45%). The overall 5-year survival rate was 25.5%. A temporal trend (2006-2013 vs 1997-2005) shows a decline in the proportion of SCC (47% vs 63%, p=0.061) and a rise in ADC (50% vs 33%, p=0.041), with a parallel decrease in patients' age (median: 68.5 vs 73 years, p=0.014). In the later period, patients received more treatment for localized and metastatic disease, with a trend for improved median survival (20.1 vs 14.9 months, p=0.658). Ashkenazi Jews were diagnosed at an older age than Sephardic Jews (median: 73 vs. 65 years, p=0.001), had a higher rate of family history of GI cancer (34% vs. 17%, p=0.026) and a higher rate of cardiovascular co-morbidity (41% vs. 24%, p=0.041).Conclusion: EC in Israel represents an intermediate entity between the Western and the endemic subtypes, showing some unique features. These included delayed reversal of the SCC/ADC ratio, commonness of SCC in the distal esophagus, prevalence of other malignancies and predominance of Ashkenazi ethnicity. The reason for these findings is unclear and its further evaluation is warranted.

O-023 Observational data outcomes of chemotherapy backbone for MSI – high metastatic colorectal cancer in molecular epidemiology of colorectal cancer in Israel

O-023 Observational data outcomes of chemotherapy backbone for MSI – high metastatic colorectal cancer in molecular epidemiology of colorectal cancer in Israel

Quality of life-related outcomes from a patient-tailored integrative medicine program: experience of Russian-speaking patients with cancer in Israel.

Complementary/integrative medicine (CIM) is increasingly being integrated with standard supportive cancer care. The effects of CIM on quality of life (QOL) during chemotherapy need to be examined in varied socio-cultural settings. We purpose to explore the impact of CIM on QOL-related outcomes among Russian-speaking (RS) patients with cancer. RS patients undergoing chemotherapy receiving standard supportive care were eligible. Patients in the treatment arm were seen by an integrative physician (IP) and treated within a patient-tailored CIM program. Symptoms and QOL were assessed at baseline, at 6, and at 12weeks with the Edmonton Symptom Assessment Scale (ESAS), the Measure Yourself Concerns and Wellbeing (MYCAW) questionnaire, and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Of 70 patients referred to the treatment arm, 50 (71.4%) underwent IP assessment and CIM treatments. Of 51 referred to the control arm, 38 (76%) agreed to participate. At 6weeks, CIM-treated patients reported improved ESAS scores for fatigue (P = 0.01), depression (P = 0.048), appetite (P = 0.008), sleep (P < 0.0001), and general wellbeing (P = 0.004). No improvement was observed among controls. Between-group analysis found CIM-treated patients had improved sleep scores on ESAS (P = 0.019) and EORTC (P = 0.007) at 6weeks. Social functioning improved between 6 and 12weeks (EORTC, P = 0.02), and global health status/QOL scale from baseline to 12weeks (EORTC, P = 0.007). A patient-tailored CIM treatment program may improve QOL-related outcomes among RS patients undergoing chemotherapy. Integrating CIM in conventional supportive care needs to address cross-cultural aspects of care. The study protocol was registered at ClinicalTrials.gov ( https://clinicaltrials.gov/ct2/show/NCT01860365 ).