Transforming Parkinson's Care in Africa (TraPCAf): protocol for a multimethodology National Institute for Health and Care Research Global Health Research Group project.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder and, according to the Global Burden of Disease estimates in 2015, was the fastest growing neurological disorder globally with respect to associated prevalence, disability, and deaths. Information regarding the awareness, diagnosis, phenotypic characteristics, epidemiology, prevalence, risk factors, treatment, economic impact and lived experiences of people with PD from the African perspective is relatively sparse in contrast to the developed world, and much remains to be learned from, and about, the continent. METHODS: Transforming Parkinson's Care in Africa (TraPCAf) is a multi-faceted, mixed-methods, multi-national research grant. The study design includes multiple sub-studies, combining observational (qualitative and quantitative) approaches for the epidemiological, clinical, risk factor and lived experience components, as appropriate, and interventional methods (clinical trial component). The aim of TraPCAf is to describe and gain a better understanding of the current situation of PD in Africa. The countries included in this National Institute for Health and Care Research (NIHR) Global Health Research Group (Egypt, Ethiopia, Ghana, Kenya, Nigeria, South Africa and Tanzania) represent diverse African geographies and genetic profiles, with differing resources, healthcare systems, health and social protection schemes, and policies. The research team is composed of experts in the field with vast experience in PD, jointly led by a UK-based and Africa-based investigator. DISCUSSION: Despite the increasing prevalence of PD globally, robust data on the disease from Africa are lacking. Existing data point towards the poor awareness of PD and other neurological disorders on the continent and subsequent challenges with stigma, and limited access to affordable services and medication. This multi-site study will be the first of its kind in Africa. The data collected across the proposed sub-studies will provide novel and conclusive insights into the situation of PD. The selected country sites will allow for useful comparisons and make results relevant to other low- and middle-income countries. This grant is timely, as global recognition of PD and the public health challenge it poses builds. The work will contribute to broader initiatives, including the World Health Organization's Intersectoral global action plan on epilepsy and other neurological disorders. TRIAL REGISTRATION: https://doi.org/10.1186/ISRCTN77014546 .

Case definitions for onchocerciasis-associated epilepsy and nodding syndrome: A focused review.

Onchocerciasis-associated epilepsy (OAE) is an important but neglected public health problem in onchocerciasis-endemic areas with insufficient or inadequate onchocerciasis control. Hence, there is a need for an internationally accepted, easy-to-use epidemiological case definition of OAE to identify areas of high Onchocerca volvulus transmission and disease burden requiring treatment and prevention interventions. By including OAE as a manifestation of onchocerciasis, we will considerably improve the accuracy of the overall onchocerciasis disease burden, which is currently underestimated. Hopefully, this will lead to increased interest and funding for onchocerciasis research and control interventions, notably the implementation of more effective elimination measures and treatment and support for affected individuals and their families.

Strategies to improve the implementation of infection control link nurse programmes in acute-care hospitals.

BACKGROUND: Infection control practitioners face several challenges when implementing infection control link nurse (ICLN) programmes. Identification of strategies to address these can improve the impact of current ICLN programmes and guide their future implementation. AIM: We aimed to identify implementation strategies for ICLN programmes in acute-care hospitals with the Consolidated Framework for Implementation Research (CFIR)-Expert Recommendations for Implementing Change (ERIC) Implementation Strategy Matching tool. METHODS: An expert panel matched 19 implementation and sustainment barriers, identified in our previous studies, to the most fitting CFIR constructs. Subsequently, we applied the CFIR-ERIC Matching Tool and generated a list of implementation strategies to address these barriers. FINDINGS: Barriers were predominantly found within the CFIR domains 'inner setting' (characteristics of the implementing organization) and 'process' (stages of implementation). With the ERIC Matching Tool, we identified the 10 most important strategies to address barriers of implementation of ICLN programmes: identify and prepare champions, conduct local consensus discussions, assess for readiness and identify barriers and facilitators, inform local opinion leaders, use facilitation, create a learning collaborative, conduct local needs assessments, develop a formal implementation blueprint, build a coalition, and identify early adopters. CONCLUSION: The CFIR domains 'inner setting' and 'process' appeared to be the most important to impede implementation of ICLN programmes in acute-care hospitals. Application of the CFIR-ERIC tool highlighted the identification and preparation of champions as the leading strategy for the successful implementation of these programmes. With this tool, strategies can be specifically tailored towards local implementation and sustainment barriers.

Lifetime risk of suicide among survivors of the atomic bombings of Japan.

AIMS: The long-term physical health effects of the atomic bombings of Hiroshima and Nagasaki are well characterised, but the psychological effects remain unclear. Therefore, we sought to determine whether measures of exposure severity, as indirect measures of psychological trauma arising from exposure to the atomic bombings, are associated with suicide mortality among atomic bomb survivors. METHODS: The Life Span Study is a prospective cohort study of 93 741 Japanese atomic bomb survivors who were located within 10 km of the hypocentre in Hiroshima or Nagasaki at the time of the bombings in 1945, and 26 579 residents of Hiroshima and Nagasaki who were not in either city at the time of the bombings, matched to survivors on city, sex and age. Measures of exposure severity included: proximity to the hypocentre, type of shielding between the survivor and the blast and self-reported occurrence of acute radiation and thermal injuries. Date of death was obtained from the Japanese National Family Registry system. Cause of death was obtained from death certificates. Adjusted hazard ratios (HRs) were estimated from Cox regression models overall and stratified by sex and age. RESULTS: During the 60-year follow-up period (1950-2009), 1150 suicide deaths were recorded among 120 231 participants (23.6 per 100 000 person-years): 510 among 70 092 women (17.2 per 100 000 person-years) and 640 among 50 139 men (33.6 per 100 000 person-years). Overall, there was no association of proximity, type of shielding or the occurrence of acute injuries with suicide mortality. Among those <25 years of age at the time of the bombings, increased suicide risk was observed for survivors outside v. shielded inside any structure (HR: 1.24; 95% confidence interval (CI): 1.03, 1.48; interaction p = 0.054) and for those who reported flash burns (HR: 1.32; 95% CI: 1.00, 1.73; interaction p = 0.025). Sex-stratified analyses indicated that these associations were limited to men. Among women, closer proximity to the hypocentre was associated with a non-significant increase in suicide risk, with a positive association between proximity and suicide risk observed among women <15 years of age (HR: 1.09 per km; 95% CI: 1.00, 1.18; interaction p = 0.067). CONCLUSIONS: Proximity to the hypocentre, shielding and acute injury presence do not generally appear to influence suicide mortality among atomic bomb survivors. However, heterogeneity may exist by age and sex, with younger survivors potentially more sensitive to psychological trauma. Coupled with other studies, our results suggest the importance of long-term monitoring of mental health among young populations exposed to catastrophic events or mass trauma.

Recognition of child maltreatment in emergency departments in Europe: Should we do better?

OBJECTIVES: To evaluate the different policies to recognize child maltreatment in emergency departments (EDs) in Europe in order to define areas of improvement. METHODS: A survey was conducted on the recognition of child maltreatment in EDs in European countries with a focus on screening methods, parental risk factors, training and hospital policies. The survey was distributed through different key members from the EUSEM, REPEM and the EuSEN. A summary score based on the NICE guideline (4 questions on child characteristics, 4 questions on parental characteristics and 5 questions on hospital policy) was calculated. RESULTS: We analysed 185 completed surveys, representing 148 hospitals from 29 European countries. Of the respondents, 28.6% used a screening tool, and 31.8% had guidelines on parental risk factors. A total of 42.2% did not follow training based on child characteristics, and 57.6% did not follow training on parental characteristics. A total of 71.9% indicated that there was a need for training. 50.8% of the respondents reported a standardized policy for the detection of child maltreatment. Translating the survey results to NICE summary scores of the EDs in Europe, we found that 25.6% (34/133) met most, 22.6% (30/133) met some and 51.9% (69/133) met few of the NICE guideline recommendations. More specifically, with respect to hospital policies, 33.8% (45/133) met most, 15.0% (20/133) met some and 51.1% (68/133) met few of the NICE guideline recommendations. CONCLUSION: There is high variability regarding policies for child maltreatment detection and only a quarter of the EDs met most of the NICE guideline recommendations for child maltreatment. There is a need for the use of screening tools, training of ED staff and implementation of local hospital policies.

The Coronary Sinus Reducer; 5-year Dutch experience.

BACKGROUND: Refractory angina is a growing and major health-care problem affecting millions of patients with coronary artery disease worldwide. The Coronary Sinus Reducer (CSR) is a device that may be considered for the relief of symptoms of refractory angina. It causes increased venous pressure leading to a dilatation of arterioles and reduced arterial vascular resistance in the sub-endocardium. This study describes the 5­year Dutch experience regarding safety and efficacy of the CSR. METHODS: One hundred and thirty-two patients with refractory angina were treated with the CSR. The primary efficacy endpoint of the study was Canadian Cardiovascular Society (CCS) class improvement between baseline and 6­month follow-up. The primary safety endpoint was successful CSR implantation in the absence of any device-related events. RESULTS: Eighty-five patients (67%) showed improvement of at least 1 CCS class and 43 patients (34%) of at least 2 classes. Mean CCS class improved from 3.17 ± 0.61 to 2.12 ± 1.07 after implantation (P < 0.001). The CSR was successfully implanted in 99% of the patients and only minor complications during implantation were reported. CONCLUSION: The CSR is a simple, safe, and effective option for most patients with refractory angina. However, approximately thirty percent of the patients showed no benefit after implantation. Future studies should focus on the exact underlying mechanisms of action and reasons for non-response to better identify patients that could benefit most from this therapy.

First familial Becker muscular dystrophy in Tanzania: Clinical and genetic features.

In African neurological practice, muscle disorders are either underdiagnosed or underrepresented. This may in part be due to the large burden of other more common neurological disorders. In this report we describe the first Tanzanian patient with genetically confirmed Becker muscular dystrophy. His phenotype and genotype were compatible with elsewhere in the world. Remarkably, this patient reported his progressive weakness of the legs with difficulty in walking only after a fall. We demonstrate that muscular dystrophies occur in sub-Saharan Africa. Neurologists must however be aware that patients are likely to delay seeking medical care for muscle disorders.

A Tanzanian Boy with Molecularly Confirmed X-Linked Adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder with classical features, which can be also recognised in a low resource setting. It had been described in various populations across the globe, but very few cases have been reported from Africa. In a boy with features of a progressive central nervous system condition and adrenal failure, ABCD1 gene screening was performed based on a clinical history and basic radiological features which were compatible with ALD. A common ABCD1 mutation was identified in this patient, which is the first report of genetically confirmed ALD in Sub-Saharan Africa. ALD is likely under recognised in those areas where there is no neurologist. This genetic confirmation widens geographical distribution of ABCD1-associated disease, and illustrates recognisability of this disorder, even when encountered in a low-resource environment.

BMI-for-age in South Asian children of 0-20 years in the Netherlands: secular changes and misclassification by WHO growth references.

BACKGROUND: South Asians are prone to cardiometabolic disease at lower BMI levels than most other ethnic groups, starting in childhood. The magnitude of BMI misclassifications is unknown. AIM: To compare the BMI distribution of contemporary South Asian 0-20 year olds in the Netherlands with: (1) The South Asian norm reference (secular trends); and (2) The WHO child growth standard and reference. SUBJECTS AND METHODS: The BMI-for-age distribution of 6677 routine measurements of 3322 South Asian children, aged 0-20 years, was described with the LMS method and BMI z-scores. RESULTS: The BMI distribution in South Asian 0-4 year olds was almost similar to the norm reference (mean BMI z-score = 0.11, skewness = 0.31, SD = 1.0), whereas in 5-19 year olds the distribution had shifted upwards (mean = 0.53) and widened (skewness = -0.12, SD = 1.08). Overweight (incl. obesity) and obesity peaked at 8-10 years, at 45-48% and 35-37%, respectively. Relative to the WHO references, the BMI distribution was left-shifted at ages 0-4 years (mean BMI z-score = -0.46, skewness = 0.23, SD = 0.98) and widened at ages 5-20 years (mean = 0.05; skewness = -0.02, SD = 1.40). At most ages, thinness rates were significantly higher and obesity rates lower than based on South Asian norms. CONCLUSIONS: A secular change of BMI-for-age in South Asian children mostly affected children >4 years. WHO references likely under-estimate overweight and obesity rates in South Asian children.

Non-invasive assessment of coronary artery geometry using coronary CTA.

AIM: To assess the association of coronary artery geometry with the severity of coronary artery disease (CAD). METHODS: 73 asymptomatic individuals at increased risk of CAD due to peripheral vascular disease (18 women, mean age 63.5 ±â€¯8.2 years) underwent coronary computed tomography angiography (coronary CTA) using first generation dual-source CT. Curvature and tortuosity of the coronary arteries were quantified using semi-automatically generated centerlines. Measurements were performed for individual segments and for the entire artery. Coronary segments were labeled according to the presence of significant stenosis, defined as >70% luminal narrowing, and the presence of plaque. Comparisons were made by segment and by artery, using linear mixed models. RESULTS: Overall, median curvature and tortuosity were, respectively, 0.094 [0.071; 0.120] and 1.080 [1.040; 1.120] on a per-segment level, and 0.096 [0.078; 0.118] and 1.175 [1.090; 1.420] on a per-artery level. Curvature was associated with significant stenosis at a per-segment (p < 0.001) and per-artery level (p = 0.002). Curvature was 16.7% higher for segments with stenosis, and 13.8% higher for arteries with stenosis. Tortuosity was associated with significant stenosis only at the per-segment level (p = 0.002). Curvature was related to the presence of plaque at the per-segment (p < 0.001) and per-artery level (p < 0.001), tortuosity was only related to plaque at the per-segment level (p < 0.001). CONCLUSION: Coronary artery geometry as derived from coronary CTA is related to the presence of plaque and significant stenosis.

Nudging to improve hand hygiene.

BACKGROUND: Hand hygiene is paramount to prevent healthcare-associated infections, but improving compliance is challenging. When healthcare workers seldom encounter healthcare-associated infections, they will consider the odds of causing infections through poor hand hygiene negligible. Cognitive biases such as these may induce non-compliance. Nudging, 'a friendly push to encourage desired behaviour', could provide an easily implemented, inexpensive measure to address cognitive biases and thus support hand hygiene interventions. AIM: To investigate whether behavioural nudges, displayed as posters, can increase the use of alcohol-based hand rub. METHODS: We developed nudges based on a systematic review of previously described cognitive biases, and tested these through a cross-sectional survey among the target audience. We then conducted a controlled before-after trial on two hospital wards, to assess the effect of these nudges on the use of alcohol-based hand rub, measured with electronic dispensers. FINDINGS: Poisson regression analyses adjusted for workload showed that nudges displayed next to dispensers increased their overall use on one ward [poster 1: relative risk: 1.6 (95% confidence interval: 1.2-2.2); poster 2: 1.7 (1.2-2.5)] and during doctor's rounds on both wards [poster 1: ward A: 1.7 (1.1-2.6); ward B: 2.2 (1.3-3.8)]. Use of dispensers without adjacent nudges did not increase. CONCLUSION: Nudges based on cognitive biases that play a role in hand hygiene, and displayed as posters, could provide an easy, inexpensive measure to increase use of alcohol-based hand rub. When applying nudges to change behaviour, it is important to identify the right nudge for the right audience.

Changes in regional body fat, lean body mass and body shape in trans persons using cross-sex hormonal therapy: results from a multicenter prospective study.

OBJECTIVE: Cross-sex hormonal therapy (CHT) in trans persons affects their total body fat and total lean body mass. However, it is unknown how separate body regions are affected and whether these changes alter body shape. Therefore, the aim of this study was to determine the effects on body fat and lean body mass in separate body regions and on body shape after one year of CHT. DESIGN AND METHODS: In a multicenter prospective study at university hospitals, 179 male-to-female gender dysphoric persons, referred to as transwomen, and 162 female-to-male gender dysphoric persons, referred to as transmen, were included. All underwent whole-body dual-energy X-ray absorptiometry and anthropometric measurements before and after one year of CHT. RESULTS: In transwomen, increases in body fat ranged from +18% (95% CI: 13%;23%) in the android region to +42% (95% CI: 37%;46%) in the leg region and +34% (95% CI: 29%;38%) in the gynoid region. In transmen, changes in body fat ranged from -16% (95% CI: -19;-14%) in the leg region and -14% in the gynoid region (95% CI: -16%;-12) to no change in the android region (+1%, 95% CI: -3%;5%). Waist-to-hip ratio (WHR) decreased in transwomen (-0.03, 95% CI: -0.04;-0.02) mainly due to an increase in hip circumference (+3.2 cm, 95% CI: 2.3;4.0). Transmen have a decrease in hip circumference (-1.9 cm, 95% CI: -3.1;-0.7) resulting in an increase in WHR (+0.01, 95% CI: 0.00;0.02). CONCLUSIONS: CHT causes a more feminine body fat distribution and a lower WHR in transwomen and a more masculine body fat distribution with a lower hip circumference in transmen.

[Palmar and axillary hyperhidrosis in children: endoscopic thoracic sympathectomy using clips for an underestimated problem]. / Hyperhidrosis palmaris en axillaris bij kinderen.

BACKGROUND: Palmar and axillary hyperhidrosis are defined as perspiration exceeding the body's 'normal' physiological need for thermal regulation. This condition affects about 1% of adolescents and children and may lead to psychosocial problems and poor school performance. CASE DESCRIPTION: We carried out an endoscopic thoracic sympathectomy (ETS) with clips in a 14-year-old girl and a 16-year-old girl who suffered from debilitating palmar and axillary hyperhidrosis. They were able to quickly resume their general daily activities and both were free of symptoms during an outpatient visit after 6 weeks. CONCLUSION: ETS using clips is a safe, relatively simple and effective technique, which may provide a permanent solution. ETS can be an option in case of therapy-resistant debilitating hyperhidrosis. This surgical procedure should be carefully considered, possible causes should be excluded and ETS should not be offered as the first treatment option for children.

Freeman-Sheldon Syndrome: First Molecularly Confirmed Case from Sub-Saharan Africa.

We report a case of a male baby who has characteristic signs of Freeman-Sheldon syndrome, a rare but recognizable, severe autosomal dominant form of distal arthrogryposis. Diagnosis was based on the distinctive clinical characteristics of the syndrome and confirmed by genetic analysis that showed a de novo missense mutation c.2015G>A (p.Arg672His) of the MYH3 gene. We highlight the different features present in our patient and describe the etiology of the Freeman-Sheldon phenotype and how its clinical complications can be dealt with. To the best of our knowledge, this is the first molecularly confirmed case of Freeman-Sheldon syndrome in sub-Saharan Africa.

[Thiamine in patients with alcohol use disorder and Wernicke's encephalopathy]. / Thiamine bij een alcoholstoornis en Wernicke-encefalopathie.

- Patients with alcohol use disorder frequently have a thiamine deficiency.- A potential life-threatening complication of thiamine deficiency is Wernicke's encephalopathy.- Since it is clinically difficult to recognize Wernicke's encephalopathy, this condition is often treated inadequately. - Early supplementation of thiamine is important to avoid irreversible neurological damage. - There are differences between the Dutch guidelines regarding the supplementation of thiamine for the treatment of alcoholic use disorder, and those for Wernicke's encephalopathy. - There are no solid evidence-based recommendations about the best dosage, route of administration and duration of thiamine supplementation for the treatment of alcohol use disorder and Wernicke's encephalopathy. - Based on the pharmacokinetic properties of thiamine, it is more appropriate to give patients with alcohol use disorder 25 mg four times a day rather than 50 mg twice a day. - Patients at high risk of Wernicke's encephalopathy should immediately receive an intravenous or intramuscular dose of thiamine; patients with suspected Wernicke's encephalopathy should preferably receive an intravenous dose.- Reports of anaphylactic reaction to parenteral administration of thiamine are rare and are not a reason to refrain from parenteral treatment.

Sulforaphane formation and bioaccessibility are more affected by steaming time than meal composition during in vitro digestion of broccoli.

Broccoli is a rich source of the glucosinolate glucoraphanin (GR). After hydrolysis of GR by the endogenous enzyme myrosinase, sulforaphane (SF) or sulforaphane nitrile (SFN) are produced, depending on environmental conditions. How the conversion of GR and bioaccessibility of released breakdown products are affected by steaming (raw, 1min, 2min and 3min steamed) and meal composition (protein or lipid addition) was studied with an in vitro digestion model (mouth, stomach, intestine, but not colonic digestion). The main formation of SF and SFN occurred during in vitro chewing. The contents of GR, SF and SFN did not change after further digestion, as the irreversible inactivated myrosinase under gastric conditions caused no further GR hydrolysis. SF concentrations were up to 10 times higher in raw and 1min steamed broccoli samples after digestion compared to longer-steamed broccoli. Protein or lipid addition had no influence on the formation and bioaccessibility of SF or SFN.

Cross-sex hormone therapy in transgender persons affects total body weight, body fat and lean body mass: a meta-analysis.

Weight gain and body fat increase the risk of cardiometabolic disease. Cross-sex hormone therapy in transgender persons leads to changes in body weight and body composition, but it is unclear to what extent. We performed a meta-analysis to investigate the changes in body weight, body fat and lean body mass during cross-sex hormone therapy in transgender persons. We searched the PubMed database for eligible studies until November 2015. Ten studies reporting changes in body weight, body fat or lean mass in hormone naive transgender persons were included, examining 171 male-to-female and 354 female-to-male transgender people. Pooled effect estimates in the male-to-female group were +1.8 kg (95% CI: 0.2;3.4) for body weight, +3.0 kg (2.0;3.9) for body fat and -2.4 kg (-2.8; -2.1) for lean body mass. In the female-to-male group, body weight changed with +1.7 kg (0.7;2.7), body fat with -2.6 kg (-3.9; -1.4) and lean body mass with +3.9 kg (3.2;4.5). Cross-sex hormone therapy increases body weight in both sexes. In the male-to-female group, a gain in body fat and a decline in lean body mass are observed, while the opposite effects are seen in the female-to-male group. Possibly, these changes increase the risk of cardiometabolic disease in the male-to-female group.

Prolactin levels during short- and long-term cross-sex hormone treatment: an observational study in transgender persons.

The cause of prolactin alterations in transgender persons is often assigned to oestrogens, but the precise cause and time course during different phases of cross-sex hormone treatment (CHT) remain unclear. In this study, we prospectively examined prolactin levels in 55 female-to-males (FtMs) and 61 male-to-females (MtFs) during the first year of CHT. Because long-term prolactin data were not available in this population, we studied these levels in a retrospective population of 25 FtMs and 38 MtFs who underwent gonadectomy. FtMs were treated with testosterone and MtFs with estradiol, with or without the anti-androgen cyproterone acetate (CPA) (after gonadectomy CPA is cessated). During the first year of CHT, prolactin decreased with 25% (95CI: -33%, -12%) in FtMs and increased with 193% (95CI: 156%, 219%) in MtFs. Eighteen MtFs developed hyperprolactinemia (≥0.6 IU L-1 ). In the retrospective population, post-gonadectomy levels in FtMs were lower than baseline levels (-39%; 95CI: -51%, -20%) while in MtFs post-gonadectomy levels and baseline levels were comparable (-6%; 95CI: -24%, 15%). No hyperprolactinemia was found after gonadectomy. In conclusion, in FtMs, prolactin decreased consistently during CHT and in MtFs, prolactin increased during pre-surgical CHT but normalised after gonadectomy. It is likely that CPA induces increasing prolactin levels in MtFs.

A European Network for the Investigation of Gender Incongruence: Endocrine Part.

INTRODUCTION: Cross-sex hormone therapy is an essential part of gender affirming treatment of transgender individuals. Studies systematically describing the physical and psychological effects of hormonal treatment of transgender persons are scarce. AIM: The aim of the current protocol is to evaluate clinical and side-effects of cross-sex hormonal treatment in trans persons. METHODS: The European Network for the Investigation of Gender Incongruence (ENIGI) is a multicenter prospective study. Because of the relatively low prevalence of the condition and small number of specialized centers, international collaboration is warranted. Four European treatment centers, Ghent, Oslo, Florence, and Amsterdam, developed a common study and treatment protocol. MAIN OUTCOME MEASURES: Outcome measures include hormonal and metabolic parameters, bone density, secondary sex and anthropometric characteristics, and physical and psychological well-being. RESULTS: Thus far, 333 trans women and 343 trans men have been included in the ENIGI Endocrine protocol. The study is still ongoing. CONCLUSION: In recent years, the number of trans persons seeking gender affirming treatment has increased. However, well-designed prospective studies evaluating safety and effectiveness of current hormonal treatment protocols are lacking. Therefore we started the ENIGI collaboration. In this article we give a detailed description of the study protocol, objectives, and design of the ENIGI Endocrine protocol.