Introduction: Prostate-specific antigen (PSA) is the main tool for early detection, risk stratification and monitoring of prostate cancer (PCa). However, there are controversies about the use of PSA as a population screening test because of the high potential for overdiagnosis and overtreatment associated. The net benefit of screening is unclear and according to the available recommendations, it should be offered to well-informed men with an adequate health status and a life-expectancy of at least 10 years or to men at elevated risk of having PCa. In addition, the factors that influence test results are unclear, as is impact of false positive or negative results on patient health. Our objective is to assess the clinical and analytical factors associated with the presence of false positive and false negative results and the diagnostic/therapeutic process followed by these patients. Methods and analysis: A prospective observational cohort study will be carried out. We will include a cohort of patients with a positive PSA result (1.081 patients) and a sample of patients with negative results (572 patients); both will be followed for 2 years by reviewing medical records to assess the variables associated with these results, as well as characteristics of patient management after a positive PSA value. We will include those patients with a PSA determination from 2 hospitals in the Valencian Community. Patients who have been previously diagnosed with prostate cancer or who are being followed for previous high PSA values will be excluded. Discussion: The study will estimate the frequency of false positive and false negative PSA results in routine clinical practice, and allow us to quantify the potential harm caused. Study registration: Clinicaltrials.gov (https://clinicaltrials.gov/): NCT03978299, June 7, 2019.

Objectives: Several studies have shown an inverse association between diabetes mellitus and prostate cancer (PCa). Some researchers suggest that this relationship is due to reduced PCa detection in diabetics due to lower prostate-specific antigen (PSA) levels compared to non-diabetics. Our objective is to analyze the impact of diabetes on PSA in asymptomatic men without known prostate pathology and without prior prostate intervention. Methods: We searched Medline (via PubMed), Embase and Scopus. We included studies that reported the relationship between serum PSA levels and diabetes or diabetes treatment in asymptomatic adult men without known prostate pathology, and without prior prostate intervention. Pooled mean differences were compared between diabetics and non-diabetics. Results: Of 2,392 screened abstracts, thirteen studies met the inclusion criteria and 8 (62%) reported appropriate measures that could be included in a meta-analysis. Eleven (85%) examined the influence of diabetes on PSA levels and 8 (62%) evaluated the influence of diabetes treatments on PSA levels. Overall diabetics had a significantly lower PSA level compared to non-diabetics (mean difference: −0.07 ng/mL; 95% CI −0.10, −0.04). Conclusions: Diabetes and related factors (such as disease duration, severity and treatment) were significantly associated with lower PSA levels among asymptomatic men, yet differences were small and are unlikely to influence PCa detection in a screening setting.

Background: Thyroxine (T4) to triiodothyronine (T3) deiodination in the hypothalamus/pituitary is mediated by deiodinase type-2 (D2) activity. Dio2 ^(−/−) mice show central resistance to exogenous T4. Patients with resistance to exogenous thyroxine (RETH) have not been described. The aim of this study was to identify hypothyroid patients with thyrotropin (TSH) unresponsiveness to levothyroxine (LT4) and to characterize the clinical, hormonal, and genetic features of human RETH. Methods: We investigated hypothyroid patients with elevated TSH under LT4 treatment at doses leading to clinical and/or biochemical hyperthyroidism. TSH and free T4 (fT4) were determined by chemiluminescence, and total T4, T3, and reverse T3 (rT3) by radioimmunoassay. TSH/fT4 ratio at inclusion and T3/T4, rT3/T4, and T3/rT3 ratios at follow-up were compared with those from patients with resistance to thyroid hormone (RTH) due to thyroid hormone receptor-β ( THRB ) mutations. DIO2, including the Ala92-D2 polymorphism, selenocysteine binding protein 2 ( SECISBP2 ), and THRB were fully sequenced. Results: Eighteen hypothyroid patients (nine of each sex, 3–59 years) treated with LT4 showed elevated TSH (15.5 ± 4.7 mU/L; reference range [RR]: 0.4–4.5), fT4 (20.8 ± 2.4 pM; RR: 9–20.6), and TSH/fT4 ratio (0.74 ± 0.25; RR: 0.03–0.13). Despite increasing LT4 doses from 1.7 ± 1.0 to 2.4 ± 1.7 μg/kg/day, TSH remained elevated (6.9 ± 2.7 mU/L). Due to hyperthyroid symptoms, LT4 doses were reduced, and TSH increased again to 7.9 ± 3.2 mU/L. In the euthyroid/hyperthyrotropinemic state, T3/T4 and T3/rT3 ratios were decreased (9.2 ± 2.4, RR: 11.3–15.3 and 2.5 ± 1.4, RR: 7.5–8.5, respectively) whereas rT3/T4 was increased (0.6 ± 0.2; RR: 0.43–0.49), suggesting reduced T4 to T3 and increased T4 to rT3 conversion. These ratios were serum T4-independent and were not observed in RTH patients. Genetic testing was normal. The Ala92-D2 polymorphism was present in 7 of 18 patients, but the allele dose did not correlate with RETH. Conclusions: Human RETH is characterized by iatrogenic thyrotoxicosis and elevated TSH/fT4 ratio. In the euthyroid/hyperthyrotropinemic state, it is confirmed by decreased T3/T4 and T3/rT3 ratios, and elevated rT3/T4 ratio. This phenotype may guide clinicians to consider combined T4+T3 therapy in a targeted fashion. The absence of germline DIO2 mutations suggests that aberrant post-translational D2 modifications in pituitary/hypothalamus or defects in other genes regulating the T4 to T3 conversion pathway could be involved in RETH.

Diabetes is a major public health problem, increasingly affecting low- and middle-income countries. The project CEAD (Contextualizing Evidence for Action in Diabetes in low-resource settings) aims to evaluate the implementation of comprehensive diabetes care in two low-resource settings in Ecuador and to stimulate context-led health systems innovations to improve diabetes care and reduce inequity. The mixed-methods approach includes a 24-month retrospective study to assess the current level of implementation of comprehensive diabetes care and participants will be followed up prospectively for two years to assess changes in healthcare and clinical outcomes from the outset of the research. We will include individuals diagnosed with type-2 diabetes aged over 18 years, who are accessing diabetes care in health facilities in the study districts. Varied stakeholders (patients and family members, community members, healthcare workers and decision-makers) will interpret the underlying causes of the observed weaknesses and propose solutions to strengthen diabetes-related healthcare in focus group discussions (FG). A second set of FG will analyze perceived improvements in healthcare based on prospective cohort findings and consider the success/failure of any context-led innovations occurring throughout the research. Our study will demonstrate how evidence can be contextualized to stimulate local innovations and overcome weaknesses of diabetes-related healthcare in low resource settings.

Scientific societies have provided guidelines to reduce PSA-specific harms. We studied the potential non-compliance of PSA testing with current guidelines in general practice. A cross-sectional study of a random sample of 1291 patients with a PSA test was performed between January and April 2018 in primary health care. Patients with a previous prostate cancer diagnosis or those who were being followed-up for previous high PSA values were excluded. Two independent researchers classified whether each test was potentially non-compliant with recommendations. We estimated frequencies of potentially non-compliant PSA determinations and calculated prevalence ratios (PR) to assess their relationship with possible explanatory variables. A total of 66% (95% CI: 62–69%) of PSA requests in asymptomatic patients were potentially non-compliant with the current guideline. This was associated with having a previous diagnosis of neoplasm (PR adjusted by age and life expectancy: 1.18; 95% CI: 1.02–1.37) as well as being a current consumer of tobacco, alcohol, or other drugs (PR: 0.80; 95% CI: 0.67–0.97). Real world data shows that patients are still frequently exposed to overdiagnosis risk with a PSA potentially non-compliant with recommendations. Patients diagnosed with another neoplasm or non-consumers of toxic substances were more exposed, probably due to increased contact with doctors or health-seeking behaviour.