Immunothrombosis and COVID-19 ‒ a nested post-hoc analysis from a 3186 patient cohort in a Latin American public reference hospital.

OBJECTIVE: COVID-19 is associated with an elevated risk of thromboembolism and excess mortality. Difficulties with best anticoagulation practices and their implementation motivated the current analysis of COVID-19 patients who developed Venous Thromboembolism (VTE). METHOD: This is a post-hoc analysis of a COVID-19 cohort, described in an economic study already published. The authors analyzed a subset of patients with confirmed VTE. We described the characteristics of the cohort, such as demographics, clinical status, and laboratory results. We tested differences amid two subgroups of patients, those with VTE or not, with the competitive risk Fine and Gray model. RESULTS: Out of 3186 adult patients with COVID-19, 245 (7.7%) were diagnosed with VTE, 174 (5.4%) of them during admission to the hospital. Four (2.3% of these 174) did not receive prophylactic anticoagulation and 19 (11%) discontinued anticoagulation for at least 3 days, resulting in 170 analyzed. During the first week of hospitalization, the laboratory most altered results were C-reactive protein and D-dimer. Patients with VTE were more critical, had a higher mortality rate, worse SOFA score, and, on average, 50% longer hospital stay. CONCLUSION: Proven VTE incidence in this severe COVID-19 cohort was 7.7%, despite 87% of them complying completely with VTE prophylaxis. The clinician must be aware of the diagnosis of VTE in COVID-19, even in patients receiving proper prophylaxis.

Immunothrombosis and COVID-19 ‒ a nested post-hoc analysis from a 3186 patient cohort in a Latin American public reference hospital

Abstract Objective COVID-19 is associated with an elevated risk of thromboembolism and excess mortality. Difficulties with best anticoagulation practices and their implementation motivated the current analysis of COVID-19 patients who developed Venous Thromboembolism (VTE). Method This is a post-hoc analysis of a COVID-19 cohort, described in an economic study already published. The authors analyzed a subset of patients with confirmed VTE. We described the characteristics of the cohort, such as demographics, clinical status, and laboratory results. We tested differences amid two subgroups of patients, those with VTE or not, with the competitive risk Fine and Gray model. Results Out of 3186 adult patients with COVID-19, 245 (7.7%) were diagnosed with VTE, 174 (5.4%) of them during admission to the hospital. Four (2.3% of these 174) did not receive prophylactic anticoagulation and 19 (11%) discontinued anticoagulation for at least 3 days, resulting in 170 analyzed. During the first week of hospitalization, the laboratory most altered results were C-reactive protein and D-dimer. Patients with VTE were more critical, had a higher mortality rate, worse SOFA score, and, on average, 50% longer hospital stay. Conclusion Proven VTE incidence in this severe COVID-19 cohort was 7.7%, despite 87% of them complying completely with VTE prophylaxis. The clinician must be aware of the diagnosis of VTE in COVID-19, even in patients receiving proper prophylaxis.

Juramento de Hipócrates: análise crítica / Hippocratic Oath: a critical analysis / Juramento de Hipócrates: un análisis crítico

Resumo O Juramento de Hipócrates é, talvez, o mais importante texto de ética médica do mundo ocidental. Amplamente discutido desde a Idade Média por estudantes e filósofos, mesmo com o dito fim da medicina hipocrática em favor do método científico, o documento suscita questões éticas essenciais e é adotado, com variações, em diversas instituições de ensino pelo mundo. Esta revisão procura analisar os textos transmitidos no original, apresentar algumas das interpretações que recebeu ao longo da história e suas leituras e versões em diferentes línguas, além de oferecer uma tradução moderna e comentada do original em grego. Por fim, discute-se sua adoção em escolas de medicina na atualidade.

Abstract The Hippocratic Oath is, perhaps, the most important text of medical ethics in the Western world. Widely discussed since the Middle Ages by students and philosophers, even with the so-called end of Hippocratic medicine in favor of the scientific method, the document still raises essential ethical questions and is adopted, with variations, in various educational institutions worldwide. This review analyzes the original texts, presents some of the interpretations it received throughout history and its readings and versions in different languages, and offers a modern and commented translation of the original in Greek. Finally, its adoption in medical schools today is discussed.

Resumen El Juramento de Hipócrates quizás sea el texto de ética médica más importante en el mundo occidental. Desde la Edad Media se viene discutiendo este documento entre estudiantes y filósofos, incluso con el objetivo de la medicina hipocrática a favor del método científico, además de plantear aspectos éticos esenciales, es utilizado con sus variaciones por diversas instituciones educativas. Esta revisión busca analizar los textos en el original, presentar algunas de las interpretaciones que había recibido a lo largo de la historia, sus lecturas y versiones en diferentes idiomas, así como exponer una traducción moderna y comentada del original en griego. Por último, se discute la actual utilización de este documento en las facultades de medicina.

Risk of osteoporotic fracture in women using the FRAX tool with and without bone mineral density score in patients followed at a tertiary outpatient clinic ‒ An observational study.

OBJECTIVES: Fragility fractures increase morbidity and mortality. Adding assessment of clinical risk factors independently or as a previous step to Bone Densitometry (BD) should provide better accuracy in fracture risk prediction. FRAX tool might be used to stratify patients in order to rationalize the need for BD and risk classification. The primary objective of this study is to describe and perform comparisons between the estimated risk of fractures in 10 years using the FRAX calculator based on clinical factors with and without BD results for women aged 40 or more with clinical diseases monitored in tertiary care service in internal medicine. METHODS: Cross-sectional. Women over 40 years with BD in the previous year. After medical chart review, identification of risk factors and risk estimations using FRAX-BRAZIL with (FRAX BDI) and without (FRAX BDNI) the inclusion of T-score. RESULTS: 239 women. Age 65 ± 10.35 years. BMI 29.68 ± 6.27kg/m2. RISK FACTORS: 32(13.4%) previous fractures; 23 (9.6%) current smoking; 78 (32.6%) corticosteroids use; 44 (18.4%) rheumatoid arthritis; 38 (15.9%) secondary causes; FRAX scores were higher when BD was not included. Spearman correlation coefficients between FRAX BDNI and FRAX BDI for major fractures r = 0.793 (95% CI 0.7388‒0.836). For hip fractures r = 0.6922 (95% CI 0.6174‒0.75446) CONCLUSION: Using FRAX to estimate 10-year fracture risk without BD data might be a reliable tool for screening, even for patients with a high prevalence of risk factors, improving accessibility and equity in health systems. The present study's data suggest an overestimation of fracture risk with FRAX BDNI, suggesting that it is safe to be widely used as a screening tool.

Risk of osteoporotic fracture in women using the FRAX tool with and without bone mineral density score in patients followed at a tertiary outpatient clinic ‒ An observational study

ABSTRACT Objectives: Fragility fractures increase morbidity and mortality. Adding assessment of clinical risk factors independently or as a previous step to Bone Densitometry (BD) should provide better accuracy in fracture risk prediction. FRAX tool might be used to stratify patients in order to rationalize the need for BD and risk classification. The primary objective of this study is to describe and perform comparisons between the estimated risk of fractures in 10 years using the FRAX calculator based on clinical factors with and without BD results for women aged 40 or more with clinical diseases monitored in tertiary care service in internal medicine. Methods: Cross-sectional. Women over 40 years with BD in the previous year. After medical chart review, identification of risk factors and risk estimations using FRAX-BRAZIL with (FRAX BDI) and without (FRAX BDNI) the inclusion of T-score. Results: 239 women. Age 65 ± 10.35 years. BMI 29.68 ± 6.27kg/m2. Risk factors: 32(13.4%) previous fractures; 23 (9.6%) current smoking; 78 (32.6%) corticosteroids use; 44 (18.4%) rheumatoid arthritis; 38 (15.9%) secondary causes; FRAX scores were higher when BD was not included. Spearman correlation coefficients between FRAX BDNI and FRAX BDI for major fractures r = 0.793 (95% CI 0.7388‒0.836). For hip fractures r = 0.6922 (95% CI 0.6174‒0.75446) Conclusion: Using FRAX to estimate 10-year fracture risk without BD data might be a reliable tool for screening, even for patients with a high prevalence of risk factors, improving accessibility and equity in health systems. The present study's data suggest an overestimation of fracture risk with FRAX BDNI, suggesting that it is safe to be widely used as a screening tool.

Use and misuse of biomarkers and the role of D-dimer and C-reactive protein in the management of COVID-19: A post-hoc analysis of a prospective cohort study.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is associated with high mortality among hospitalized patients and incurs high costs. Severe acute respiratory syndrome coronavirus 2 infection can trigger both inflammatory and thrombotic processes, and these complications can lead to a poorer prognosis. This study aimed to evaluate the association and temporal trends of D-dimer and C-reactive protein (CRP) levels with the incidence of venous thromboembolism (VTE), hospital mortality, and costs among inpatients with COVID-19. METHODS: Data were extracted from electronic patient records and laboratory databases. Crude and adjusted associations for age, sex, number of comorbidities, Sequential Organ Failure Assessment score at admission, and D-dimer or CRP logistic regression models were used to evaluate associations. RESULTS: Between March and June 2020, COVID-19 was documented in 3,254 inpatients. The D-dimer level ≥4,000 ng/mL fibrinogen equivalent unit (FEU) mortality odds ratio (OR) was 4.48 (adjusted OR: 1.97). The CRP level ≥220 mg/dL OR for death was 7.73 (adjusted OR: 3.93). The D-dimer level ≥4,000 ng/mL FEU VTE OR was 3.96 (adjusted OR: 3.26). The CRP level ≥220 mg/dL OR for VTE was 2.71 (adjusted OR: 1.92). All these analyses were statistically significant (p<0.001). Stratified hospital costs demonstrated a dose-response pattern. Adjusted D-dimer and CRP levels were associated with higher mortality and doubled hospital costs. In the first week, elevated D-dimer levels predicted VTE occurrence and systemic inflammatory harm, while CRP was a hospital mortality predictor. CONCLUSION: D-dimer and CRP levels were associated with higher hospital mortality and a higher incidence of VTE. D-dimer was more strongly associated with VTE, although its discriminative ability was poor, while CRP was a stronger predictor of hospital mortality. Their use outside the usual indications should not be modified and should be discouraged.

Perception of usefulness of laboratory tests ordering by internal medicine residents in ambulatory setting: A single-center prospective cohort study.

The demand for high value health care uncovered a steady trend in laboratory tests ordering and inappropriate testing practices. Residents' training in laboratory ordering practice provides an opportunity for quality improvement. We collected information on demographics, the main reason for the appointment, preexisting medical conditions and presence of co-morbidities from first-visit patients to the internal medicine outpatient service of our university general hospital. We also collected information on all laboratory tests ordered by the attending medical residents. At a follow-up visit, we recorded residents' subjective perception on the usefulness of each ordered laboratory test for the purposes of diagnosis, prognosis, treatment or screening. We observed that 17.3% of all ordered tests had no perceived utility by the attending resident. Tests were usually ordered to exclude differential diagnoses (26.7%) and to help prognosis estimation (19.1%). Age and co-morbidity influenced the chosen category to legitimate usefulness of tests ordering. This study suggests that clinical objectives (diagnosis, prognosis, treatment or prevention) as well as personalization to age and previous health conditions should be considered before test ordering to allow a more appropriate laboratory tests ordering, but further studies are necessary to examine this framework beyond this medical training scenario.

Use and misuse of biomarkers and the role of D-dimer and C-reactive protein in the management of COVID-19: A post-hoc analysis of a prospective cohort study

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is associated with high mortality among hospitalized patients and incurs high costs. Severe acute respiratory syndrome coronavirus 2 infection can trigger both inflammatory and thrombotic processes, and these complications can lead to a poorer prognosis. This study aimed to evaluate the association and temporal trends of D-dimer and C-reactive protein (CRP) levels with the incidence of venous thromboembolism (VTE), hospital mortality, and costs among inpatients with COVID-19. METHODS: Data were extracted from electronic patient records and laboratory databases. Crude and adjusted associations for age, sex, number of comorbidities, Sequential Organ Failure Assessment score at admission, and D-dimer or CRP logistic regression models were used to evaluate associations. RESULTS: Between March and June 2020, COVID-19 was documented in 3,254 inpatients. The D-dimer level ≥4,000 ng/mL fibrinogen equivalent unit (FEU) mortality odds ratio (OR) was 4.48 (adjusted OR: 1.97). The CRP level ≥220 mg/dL OR for death was 7.73 (adjusted OR: 3.93). The D-dimer level ≥4,000 ng/mL FEU VTE OR was 3.96 (adjusted OR: 3.26). The CRP level ≥220 mg/dL OR for VTE was 2.71 (adjusted OR: 1.92). All these analyses were statistically significant (p<0.001). Stratified hospital costs demonstrated a dose-response pattern. Adjusted D-dimer and CRP levels were associated with higher mortality and doubled hospital costs. In the first week, elevated D-dimer levels predicted VTE occurrence and systemic inflammatory harm, while CRP was a hospital mortality predictor. CONCLUSION: D-dimer and CRP levels were associated with higher hospital mortality and a higher incidence of VTE. D-dimer was more strongly associated with VTE, although its discriminative ability was poor, while CRP was a stronger predictor of hospital mortality. Their use outside the usual indications should not be modified and should be discouraged.

Improving serum calcium test ordering according to a decision algorithm.

AIM: To detect differences in the pattern of serum calcium tests ordering before and after the implementation of a decision algorithm. METHODS: We studied patients admitted to an internal medicine ward of a university hospital on April 2013 and April 2016. Patients were classified as critical or non-critical on the day when each test was performed. Adequacy of ordering was defined according to adherence to a decision algorithm implemented in 2014. RESULTS: Total and ionised calcium tests per patient-day of hospitalisation significantly decreased after the algorithm implementation; and duplication of tests (total and ionised calcium measured in the same blood sample) was reduced by 49%. Overall adequacy of ionised calcium determinations increased by 23% (P=0.0001) due to the increase in the adequacy of ionised calcium ordering in non-critical conditions. CONCLUSIONS: A decision algorithm can be a useful educational tool to improve adequacy of the process of ordering serum calcium tests.

Kidney injury and other complications related to colonoscopy in inpatients at a tertiary teaching hospital.

OBJECTIVES: To describe clinical complications related to colonoscopy in inpatients with multiple diseases. Among the known complications, acute kidney injury was the primary focus. METHODS: This was an observational retrospective study of 97 inpatients. Data relating to age; gender; comorbidities; current medication; blood tests (renal function, blood glucose and LDL cholesterol levels); length of hospital stay; indication, results, and complications of colonoscopies; and time to the development of kidney injury were collected between June 2011 to February 2012. RESULTS: A total of 108 colonoscopies (9 screening and 88 diagnostic) were conducted in 97 patients. Renal injury occurred in 41.2% of the patients. The univariate analysis revealed that kidney injury was related to the use of diuretics, statins, calcium channel blockers, and angiotensin converting enzyme inhibitor; however, the multivariate analysis showed that only the use of diuretics was associated with kidney injury. The occurrence of kidney injury and the time to its development were independent of the previous glomerular filtration rate as calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. CONCLUSIONS: The use of diuretics was the only independent variable associated with the development of kidney injury in inpatients with multiple comorbidities who underwent colonoscopy. The occurrence of kidney injury and the time to its development were independent of previous CKD-EPI-based assessments of renal function. These results highlight the increased risk of colonoscopy in such patients, and its indication should be balanced strictly and perhaps avoided as a screening test.

Kidney injury and other complications related to colonoscopy in inpatients at a tertiary teaching hospital

OBJECTIVES: To describe clinical complications related to colonoscopy in inpatients with multiple diseases. Among the known complications, acute kidney injury was the primary focus. METHODS: This was an observational retrospective study of 97 inpatients. Data relating to age; gender; comorbidities; current medication; blood tests (renal function, blood glucose and LDL cholesterol levels); length of hospital stay; indication, results, and complications of colonoscopies; and time to the development of kidney injury were collected between June 2011 to February 2012. RESULTS: A total of 108 colonoscopies (9 screening and 88 diagnostic) were conducted in 97 patients. Renal injury occurred in 41.2% of the patients. The univariate analysis revealed that kidney injury was related to the use of diuretics, statins, calcium channel blockers, and angiotensin converting enzyme inhibitor; however, the multivariate analysis showed that only the use of diuretics was associated with kidney injury. The occurrence of kidney injury and the time to its development were independent of the previous glomerular filtration rate as calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. CONCLUSIONS: The use of diuretics was the only independent variable associated with the development of kidney injury in inpatients with multiple comorbidities who underwent colonoscopy. The occurrence of kidney injury and the time to its development were independent of previous CKD-EPI-based assessments of renal function. These results highlight the increased risk of colonoscopy in such patients, and its indication should be balanced strictly and perhaps avoided as a screening test.

Laboratory Tests Ordering Pattern by Medical Residents From a Brazilian University Hospital.

OBJECTIVES: The adequacy of laboratory test orders by medical residents is a longstanding issue. The aim of this study is to analyze the number, types, and pattern of repetition of tests ordered by medical residents. METHODS: We studied all tests ordered over a 1-year period for inpatients of an internal medicine ward in a university hospital. Types, results, and repetition pattern of tests were analyzed in relation to patients' diagnoses. RESULTS: We evaluated 117,666 tests, requested for 1,024 inpatients. The mean number of tests was 9.5 per day. The test repetition pattern was similar, regardless of patients' diagnoses, previous test results, or duration of stay. The probability of an abnormal result after a sequence of three normal tests was lower than 25%, regardless of the diagnosis. CONCLUSIONS: Number of tests and repetition were both high, imposing costs, discomfort, and risks to patients, thus warranting further investigation.

Rational use of blood calcium determinations.

CONTEXT AND OBJECTIVE: This study was motivated by the recent excessive increase in requests for blood calcium determinations and laboratory tests in general, in the Hospital das Clínicas complex of Faculdade de Medicina, Universidade de São Paulo (HCFMUSP). Its aim was to suggest rules for the determination of total and ionized calcium in our intensive care units, emergency department, wards and outpatient services, thus contributing towards improving the quality of medical care and achieving more appropriate use of human and financial resources. DESIGN AND SETTING: Critical analysis on clinical and laboratory data and the pertinent scientific literature, conducted by the study group for rational clinical laboratory use, which is part of the Central Laboratory Division, HCFMUSP. METHODS: The study group reviewed scientific publications, statistics and clinical and laboratory data concerning requests for total and ionized calcium determinations in the settings of intensive care units, emergency department, wards and outpatient services. RESULTS: From this critical analysis, clinical decision flow diagrams aimed at providing guidance for ordering these tests were constructed. CONCLUSIONS: Use of the proposed flow diagrams may help to limit the numbers of inappropriate requests for ionized and total calcium determinations, with consequent reductions in the number of tests, risks to patients and unnecessary costs.

Rational use of blood calcium determinations / Uso racional da dosagem de cálcio no sangue

CONTEXT AND OBJECTIVE: This study was motivated by the recent excessive increase in requests for blood calcium determinations and laboratory tests in general, in the Hospital das Clínicas complex of Faculdade de Medicina, Universidade de São Paulo (HCFMUSP). Its aim was to suggest rules for the determination of total and ionized calcium in our intensive care units, emergency department, wards and outpatient services, thus contributing towards improving the quality of medical care and achieving more appropriate use of human and financial resources. DESIGN AND SETTING: Critical analysis on clinical and laboratory data and the pertinent scientific literature, conducted by the study group for rational clinical laboratory use, which is part of the Central Laboratory Division, HCFMUSP. METHODS: The study group reviewed scientific publications, statistics and clinical and laboratory data concerning requests for total and ionized calcium determinations in the settings of intensive care units, emergency department, wards and outpatient services. RESULTS: From this critical analysis, clinical decision flow diagrams aimed at providing guidance for ordering these tests were constructed. CONCLUSIONS: Use of the proposed flow diagrams may help to limit the numbers of inappropriate requests for ionized and total calcium determinations, with consequent reductions in the number of tests, risks to patients and unnecessary costs. .

CONTEXTO E OBJETIVO: Este trabalho foi motivado pelo recente aumento excessivo de solicitações de dosagem de cálcio no sangue, assim como de exames laboratoriais em geral, no complexo do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP). Seu objetivo foi sugerir regras para a determinação de cálcio total e iônico nas nossas unidades de terapia intensiva, pronto-socorro, enfermarias e ambulatórios e contribuir para a melhoria da qualidade da assistência médica, com utilização mais adequada dos recursos humanos e financeiros. TIPO DO ESTUDO E LOCAL: Análise crítica de dados clínicos, laboratoriais e da literatura médica pertinente, realizada pelo grupo de estudos para o uso racional do laboratório clínico, vinculado à Divisão de Laboratório Central do HCFMUSP. MÉTODOS: O grupo de estudos reviu publicações científicas, estatísticas e dados clínico-laboratoriais relativos às solicitações de cálcio total e iônico nos ambientes das unidades de terapia intensiva, prontos-socorros, enfermarias e ambulatórios. RESULTADOS: A partir dessa análise crítica, foram construídos fluxogramas de decisão clínica que visam orientar a requisição desses testes. CONCLUSÕES: A utilização dos fluxogramas propostos pode ajudar a limitar a solicitação inadequada das dosagens de cálcio total e iônico, com consequente redução do número de exames, de riscos para os pacientes e de custos desnecessários. .

Venous thromboembolism risk assessment in hospitalised patients: a new proposal.

OBJECTIVE: Cross-sectional studies have been conducted to evaluate the adequacy of prophylaxis for venous thromboembolism. However, these studies often evaluate prophylaxis on the data collection day, without analysing the prophylactic dose or duration and without reference to inappropriate use in patients without risk. A prospective, observational study was performed to assess the adequacy of prophylaxis in a general medicine ward of a university hospital. METHOD: In the analysis, the use of the proper prophylactic dose at the correct time, the use in patients with contraindications, and the misuse in patients without risk of venous thromboembolism were considered. RESULTS: A total of 245 patients were evaluated. Of these patients, 104 (42.4%) were considered to be at risk, and 82.7% either received adequate prophylaxis (i.e., the correct dose at the right time) or did not receive prophylaxis because it was contraindicated. Among the 141 patients who were not at risk, 81 (57.4%) incorrectly received prophylaxis, the majority (61/81) of whom presented with risk factors but did not demonstrate reduced mobility. Among the entire group, only 59.6% of patients were properly treated. CONCLUSIONS: The evaluation of prophylaxis adequacy should consider not only whether the correct dose is administered at the correct time but also whether it is used in patients with contraindications and whether it is inappropriately administered to patients who are not at risk.

Venous thromboembolism risk assessment in hospitalised patients: A new proposal

OBJECTIVE: Cross-sectional studies have been conducted to evaluate the adequacy of prophylaxis for venous thromboembolism. However, these studies often evaluate prophylaxis on the data collection day, without analysing the prophylactic dose or duration and without reference to inappropriate use in patients without risk. A prospective, observational study was performed to assess the adequacy of prophylaxis in a general medicine ward of a university hospital. METHOD: In the analysis, the use of the proper prophylactic dose at the correct time, the use in patients with contraindications, and the misuse in patients without risk of venous thromboembolism were considered. RESULTS: A total of 245 patients were evaluated. Of these patients, 104 (42.4%) were considered to be at risk, and 82.7% either received adequate prophylaxis (i.e., the correct dose at the right time) or did not receive prophylaxis because it was contraindicated. Among the 141 patients who were not at risk, 81 (57.4%) incorrectly received prophylaxis, the majority (61/81) of whom presented with risk factors but did not demonstrate reduced mobility. Among the entire group, only 59.6% of patients were properly treated. CONCLUSIONS: The evaluation of prophylaxis adequacy should consider not only whether the correct dose is administered at the correct time but also whether it is used in patients with contraindications and whether it is inappropriately administered to patients who are not at risk. .

Vitamin D: non-skeletal actions and rational use.

Recent years have witnessed a substantial increase in the number of seric determinations of vitamin D, in a worldwide basis. At Hospital das Clínicas of Faculdade de Medicina of Universidade de São Paulo that increase reached 700% over the last four years. Nevertheless there are many controversies on the literature about the role of vitamin D in conditions unrelated to the musculoskeletal system. In this study the metabolism, sources and actions of vitamin D on the body are reviewed. Observational studies, clinical trials, systematic reviews and metanalysis which focused on the relationship between the vitamin and conditions such as cancer, cardiovascular disease, diabetes and falls were searched on the literature, analyzed and discussed. Results are presented as quiz and answer, tables and a figure. The role of vitamin D on the above-mentioned conditions is discussed, and the controversial issues stressed.