Drug Utilisation Patterns of Alternatives to Ranitidine-Containing Medicines in Patients Treated with Ranitidine: A Network Analysis of Data from Six European National Databases.

INTRODUCTION: Ranitidine, a histamine H2-receptor antagonist (H2RA), is indicated in the management of gastric acid-related disorders. In 2020, the European Medicines Agency (EMA) recommended suspension of all ranitidine-containing medicines in the European Union (EU) due to the presence of N-nitrosodimethylamine (NDMA) impurities, which were considered to be carcinogenic. The aim of this study was to investigate the impact of regulatory intervention on use patterns of ranitidine-containing medicines and their therapeutic alternatives. OBJECTIVES: The aim was to study drug utilisation patterns of ranitidine and report discernible trends in treatment discontinuation and switching to alternative medications. METHODS: This retrospective, population-based cohort study was conducted using primary care records from six European countries between 2017 and 2023. To explore drug utilisation patterns, we calculated (1) incident use of ranitidine, other H2RAs, and other alternative drugs for the treatment of gastric ulcer and/or gastric bleeding; (2) ranitidine discontinuation; and (3) switching from ranitidine to alternative drugs (H2RAs, proton-pump inhibitors [PPIs], and other medicinal products for acid-related disorders). RESULTS: During the study period, 385,273 new ranitidine users were observed, with most users being female and aged 18-74 years. Ranitidine was the most commonly prescribed H2RA in the pre-referral period (September 2017-August 2019), with incidence rates between 0.8 and 9.0/1000 person years (PY). A steep decline to 0.3-3.8/1000 PY was observed in the referral period (September 2019-March 2020), eventually dropping to 0.0-0.4/1000 PY in the post-referral period (April 2020-March 2022). Switching from ranitidine to alternative drugs increased in the post-referral period, with the majority of patients switching to PPIs. Discontinuation of ranitidine use ranged from 270 to 380/1000 users in 2017 and decreased over time. CONCLUSIONS: Ranitidine was commonly used prior to referral, but it was subsequently discontinued and replaced primarily with PPIs.

Comorbidity in incident osteoarthritis cases and matched controls using electronic health record data.

BACKGROUND: Comorbidities are common in patients with osteoarthritis (OA). This study aimed to determine the association of a wide range of previously diagnosed comorbidities in adults with newly diagnosed OA compared with matched controls without OA. METHODS: A case-control study was conducted. The data were derived from an electronic health record database that contains the medical records of patients from general practices throughout the Netherlands. Incident OA cases were defined as patients with one or more diagnostic codes recorded in their medical records that correspond to knee, hip, or other/peripheral OA. Additionally, the first OA code had to be recorded between January 1, 2006, and December 31, 2019. The date of cases' first OA diagnosis was defined as the index date. Cases were matched (by age, sex, and general practice) to up to 4 controls without a recorded OA diagnosis. Odds ratios were derived for each 58 comorbidities separately by dividing the comorbidity prevalence of cases by that of their matched controls at the index date. RESULTS: 80,099 incident OA patients were identified of whom 79,937 (99.8%) were successfully matched with 318,206 controls. OA cases had higher odds for 42 of the 58 studied comorbidities compared with matched controls. Musculoskeletal diseases and obesity showed large associations with incident OA. CONCLUSIONS: Most of the comorbidities under study had higher odds in patients with incident OA at the index date. While previously known associations were confirmed in this study, some associations were not described earlier.

Skinfold-based-equations to assess longitudinal body composition in children from birth to age 5 years.

BACKGROUND & AIMS: In order to identify children at risk for excess adiposity, it is important to determine body composition longitudinally throughout childhood. However, most frequently used techniques in research are expensive and time-consuming and, therefore, not feasible for use in general clinical practice. Skinfold measurements can be used as proxy for adiposity, but current anthropometry-based-equations have random and systematic errors, especially when used longitudinally in pre-pubertal children. We developed and validated skinfold-based-equations to estimate total fat mass (FM) longitudinally in children aged 0-5 years. METHODS: This study was embedded in the Sophia Pluto study, a prospective birth cohort. In 998 healthy term-born children, we longitudinally measured anthropometrics, including skinfolds and determined FM using Air Displacement Plethysmography (ADP) by PEA POD and Dual energy X-ray Absorptiometry (DXA) from birth to age 5 years. Of each child one random measurement was used in the determination cohort, others for validation. Linear regression was used to determine the best fitting FM-prediction model based on anthropometric measurements using ADP and DXA as reference methods. For validation, we used calibration plots to determine predictive value and agreement between measured and predicted FM. RESULTS: Three skinfold-based-equations were developed for adjoined age ranges (0-6 months, 6-24 months and 2-5 years), based on FM-trajectories. Validation of these prediction equations showed significant correlations between measured and predicted FM (R: 0.921, 0.779 and 0.893, respectively) and good agreement with small mean prediction errors of 1, 24 and -96 g, respectively. CONCLUSIONS: We developed and validated reliable skinfold-based-equations which may be used longitudinally from birth to age 5 years in general practice and large epidemiological studies.

Chronic Cough-Related Differences in Brain Morphometry in Adults: A Population-Based Study.

BACKGROUND: Individuals with cough hypersensitivity have increased central neural responses to tussive stimuli, which may result in maladaptive morphometric changes in the central cough processing systems. RESEARCH QUESTION: Are the volumes of the brain regions implicated in cough hypersensitivity different in adults with chronic cough compared with adults without chronic cough? STUDY DESIGN AND METHODS: Between 2009 and 2014, participants in the Rotterdam Study, a population-based cohort, underwent brain MRI and were interviewed for chronic cough, which was defined as daily coughing for at least 3 months. Regional brain volumes were quantified with the use of parcellation software. Based on literature review, we identified and studied seven brain regions that previously had been associated with altered functional brain activity in chronic cough. The relationship between chronic cough and regional brain volumes was investigated with the use of multivariable regression models. RESULTS: Chronic cough was prevalent in 9.6% (No. = 349) of the 3,620 study participants (mean age, 68.5 ± 9.0 years; 54.6% female). Participants with chronic cough had significantly smaller anterior cingulate cortex volume than participants without chronic cough (mean difference, -126.16 mm3; 95% CI, -245.67 to -6.66; P = .039). Except for anterior cingulate cortex, there were no significant difference in the volume of other brain regions based on chronic cough status. The volume difference in the anterior cingulate cortex was more pronounced in the left hemisphere (mean difference, -88.11 mm3; 95% CI, -165.16 to -11.06; P = .025) and in male participants (mean difference, -242.58 mm3; 95% CI, -428.60 to -56.55; P = .011). INTERPRETATION: Individuals with chronic cough have a smaller volume of the anterior cingulate cortex, which is a brain region involved in cough suppression. CLINICAL TRIAL REGISTRATION: The Netherlands National Trial Registry (NTR; www.trialregister.nl) and the World Health Organization's International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/network/primary/en/) under the joint catalogue number NTR6831.

Effects of Short-Term Potassium Chloride Supplementation in Patients with CKD.

BACKGROUND: Observational studies suggest that adequate dietary potassium intake (90-120 mmol/day) may be renoprotective, but the effects of increasing dietary potassium and the risk of hyperkalemia are unknown. METHODS: This is a prespecified analysis of the run-in phase of a clinical trial in which 191 patients (age 68±11 years, 74% males, 86% European ancestry, eGFR 31±9 ml/min per 1.73 m2, 83% renin-angiotensin system inhibitors, 38% diabetes) were treated with 40 mmol potassium chloride (KCl) per day for 2 weeks. RESULTS: KCl supplementation significantly increased urinary potassium excretion (72±24 to 107±29 mmol/day), plasma potassium (4.3±0.5 to 4.7±0.6 mmol/L), and plasma aldosterone (281 [198-431] to 351 [241-494] ng/L), but had no significant effect on urinary sodium excretion, plasma renin, BP, eGFR, or albuminuria. Furthermore, KCl supplementation increased plasma chloride (104±3 to 105±4 mmol/L) and reduced plasma bicarbonate (24.5±3.4 to 23.7±3.5 mmol/L) and urine pH (all P<0.001), but did not change urinary ammonium excretion. In total, 21 participants (11%) developed hyperkalemia (plasma potassium 5.9±0.4 mmol/L). They were older and had higher baseline plasma potassium. CONCLUSIONS: In patients with CKD stage G3b-4, increasing dietary potassium intake to recommended levels with potassium chloride supplementation raises plasma potassium by 0.4 mmol/L. This may result in hyperkalemia in older patients or those with higher baseline plasma potassium. Longer-term studies should address whether cardiorenal protection outweighs the risk of hyperkalemia.Clinical trial number: NCT03253172.

The interrelationship of chronic cough and depression: a prospective population-based study.

Background: Chronic cough is a debilitating medical condition that is often complicated by psychomorbidities such as depressive symptoms. Nevertheless, little is known about the impact of chronic cough on the risk of developing depression. Therefore, we investigated the association between chronic cough and prevalent, incident and recurrent depression in a population-based sample of middle-aged and older persons. Methods: Within the Rotterdam Study, a population-based cohort, we defined chronic cough as reporting daily coughing for ⩾3 months. Depression was assessed using the Center for Epidemiologic Studies Depression scale, clinical interviews and medical records. Associations between chronic cough and depression were determined with linear, logistic and Cox regression analyses. Results: The study included 5877 participants (mean±sd age 72±8 years, 59% female) who contributed 37 287 person-years of follow-up. At baseline, participants with chronic cough reported more depressive symptoms (adjusted standardised mean difference 0.15, 95% CI 0.07-0.22) compared to those without chronic cough. Over time, chronic cough was associated with an increased risk of depression in participants with a history of depression (hazard ratio (HR) 1.45, 95% CI 1.13-1.84), but not in those without a history of depression (HR 0.91, 95% CI 0.68-1.22). Conclusions: Adults with chronic cough have a disproportionate burden of depressive symptoms and an increased risk of recurrent depression. This highlights the importance of screening for depression in patients with chronic cough.

Trends in the conduct and reporting of clinical prediction model development and validation: a systematic review.

OBJECTIVES: This systematic review aims to provide further insights into the conduct and reporting of clinical prediction model development and validation over time. We focus on assessing the reporting of information necessary to enable external validation by other investigators. MATERIALS AND METHODS: We searched Embase, Medline, Web-of-Science, Cochrane Library, and Google Scholar to identify studies that developed 1 or more multivariable prognostic prediction models using electronic health record (EHR) data published in the period 2009-2019. RESULTS: We identified 422 studies that developed a total of 579 clinical prediction models using EHR data. We observed a steep increase over the years in the number of developed models. The percentage of models externally validated in the same paper remained at around 10%. Throughout 2009-2019, for both the target population and the outcome definitions, code lists were provided for less than 20% of the models. For about half of the models that were developed using regression analysis, the final model was not completely presented. DISCUSSION: Overall, we observed limited improvement over time in the conduct and reporting of clinical prediction model development and validation. In particular, the prediction problem definition was often not clearly reported, and the final model was often not completely presented. CONCLUSION: Improvement in the reporting of information necessary to enable external validation by other investigators is still urgently needed to increase clinical adoption of developed models.

Is the Depth of Invasion a Marker for Elective Neck Dissection in Early Oral Squamous Cell Carcinoma?

OBJECTIVE: The depth of invasion (DOI) is considered an independent risk factor for occult lymph node metastasis in oral cavity squamous cell carcinoma (OCSCC). It is used to decide whether an elective neck dissection (END) is indicated in the case of a clinically negative neck for early stage carcinoma (pT1/pT2). However, there is no consensus on the cut-off value of the DOI for performing an END. The aim of this study was to determine a cut-off value for clinical decision making on END, by assessing the association of the DOI and the risk of occult lymph node metastasis in early OCSCC. METHODS: A retrospective cohort study was conducted at the Erasmus MC, University Medical Centre Rotterdam, The Netherlands. Patients surgically treated for pT1/pT2 OCSCC between 2006 and 2012 were included. For all cases, the DOI was measured according to the 8th edition of the American Joint Committee on Cancer guideline. Patient characteristics, tumor characteristics (pTN, differentiation grade, perineural invasion, and lymphovascular invasion), treatment modality (END or watchful waiting), and 5-year follow-up (local recurrence, regional recurrence, and distant metastasis) were obtained from patient files. RESULTS: A total of 222 patients were included, 117 pT1 and 105 pT2. Occult lymph node metastasis was found in 39 of the 166 patients who received END. Univariate logistic regression analysis showed DOI to be a significant predictor for occult lymph node metastasis (odds ratio (OR) = 1.3 per mm DOI; 95% CI: 1.1-1.5, p = 0.001). At a DOI of 4.3 mm the risk of occult lymph node metastasis was >20% (all subsites combined). CONCLUSION: The DOI is a significant predictor for occult lymph node metastasis in early stage oral carcinoma. A NPV of 81% was found at a DOI cut-off value of 4 mm. Therefore, an END should be performed if the DOI is >4 mm.

Comparison of Illumina versus Nanopore 16S rRNA Gene Sequencing of the Human Nasal Microbiota.

Illumina and nanopore sequencing technologies are powerful tools that can be used to determine the bacterial composition of complex microbial communities. In this study, we compared nasal microbiota results at genus level using both Illumina and nanopore 16S rRNA gene sequencing. We also monitored the progression of nanopore sequencing in the accurate identification of species, using pure, single species cultures, and evaluated the performance of the nanopore EPI2ME 16S data analysis pipeline. Fifty-nine nasal swabs were sequenced using Illumina MiSeq and Oxford Nanopore 16S rRNA gene sequencing technologies. In addition, five pure cultures of relevant bacterial species were sequenced with the nanopore sequencing technology. The Illumina MiSeq sequence data were processed using bioinformatics modules present in the Mothur software package. Albacore and Guppy base calling, a workflow in nanopore EPI2ME (Oxford Nanopore Technologies-ONT, Oxford, UK) and an in-house developed bioinformatics script were used to analyze the nanopore data. At genus level, similar bacterial diversity profiles were found, and five main and established genera were identified by both platforms. However, probably due to mismatching of the nanopore sequence primers, the nanopore sequencing platform identified Corynebacterium in much lower abundance compared to Illumina sequencing. Further, when using default settings in the EPI2ME workflow, almost all sequence reads that seem to belong to the bacterial genus Dolosigranulum and a considerable part to the genus Haemophilus were only identified at family level. Nanopore sequencing of single species cultures demonstrated at least 88% accurate identification of the species at genus and species level for 4/5 strains tested, including improvements in accurate sequence read identification when the basecaller Guppy and Albacore, and when flowcell versions R9.4 (Oxford Nanopore Technologies-ONT, Oxford, UK) and R9.2 (Oxford Nanopore Technologies-ONT, Oxford, UK) were compared. In conclusion, the current study shows that the nanopore sequencing platform is comparable with the Illumina platform in detection bacterial genera of the nasal microbiota, but the nanopore platform does have problems in detecting bacteria within the genus Corynebacterium. Although advances are being made, thorough validation of the nanopore platform is still recommendable.

Depth of invasion in early stage oral cavity squamous cell carcinoma: The optimal cut-off value for elective neck dissection.

OBJECTIVES: Depth of invasion (DOI) is the most important predictor for lymph node metastasis (LNM) in early stage (T1-T2) oral cancer. The aim of this study is to validate the cut-off value of 4 mm on which the decision to perform an Elective Neck Dissection (END) is made. MATERIALS AND METHODS: We performed a retrospective study in patients with pathologically proven early stage oral cavity squamous cell carcinoma (OCSCC) without clinical or radiological signs of LNM, who were treated between 2013 and 2018. An END was performed when DOI was ≥ 4 mm and a watchful waiting protocol was applied in patients with DOI < 4 mm. RESULTS: Three hundred patients were included. END was performed in 77% of patients with DOI ≥ 4 mm, of which 36% had occult LNM (pN+). Patients in the watchful waiting group (48%) developed a regional recurrence in 5.2% for DOI < 4 mm and 24.1% for DOI ≥ 4 mm. For DOI ≥ 4 mm, regional recurrence free survival was higher for patients who were treated with END compared to watchful waiting (p = 0.002). A Receiver-Operator-Curve -analysis showed that a DOI cut-off value of 4.0 mm was the optimal threshold for the prediction of occult LNM (95.1% sensitivity, 52.9% specificity). CONCLUSION: A DOI of ≥ 4 mm is an accurate cut-off value for performing an END in early stage OCSCC. END results in higher survival rates and lower regional recurrence rates in patients with DOI ≥ 4 mm.

Incidence, risk factors and re-exacerbation rate of severe asthma exacerbations in a multinational, multidatabase pediatric cohort study.

BACKGROUND: There are sparse real-world data on severe asthma exacerbations (SAE) in children. This multinational cohort study assessed the incidence of and risk factors for SAE and the incidence of asthma-related rehospitalization in children with asthma. METHODS: Asthma patients 5-17 years old with ≥1 year of follow-up were identified in six European electronic databases from the Netherlands, Italy, the UK, Denmark and Spain in 2008-2013. Asthma was defined as ≥1 asthma-specific disease code within 3 months of prescriptions/dispensing of asthma medication. Severe asthma was defined as high-dosed inhaled corticosteroids plus a second controller. SAE was defined by systemic corticosteroids, emergency department visit and/or hospitalization all for reason of asthma. Risk factors for SAE were estimated by Poisson regression analyses. RESULTS: The cohort consisted of 212 060 paediatric asthma patients contributing to 678 625 patient-years (PY). SAE rates ranged between 17 and 198/1000 PY and were higher in severe asthma and highest in severe asthma patients with a history of exacerbations. Prior SAE (incidence rate ratio 3-45) and younger age increased the SAE risk in all countries, whereas obesity, atopy and GERD were a risk factor in some but not all countries. Rehospitalization rates were up to 79% within 1 year. CONCLUSIONS: In a real-world setting, SAE rates were highest in children with severe asthma with a history of exacerbations. Many severe asthma patients were rehospitalized within 1 year. Asthma management focusing on prevention of SAE is important to reduce the burden of asthma.

Impact and longevity of measles-associated immune suppression: a matched cohort study using data from the THIN general practice database in the UK.

OBJECTIVE: To test the hypothesis that measles infection increases the incidence of non-measles infectious diseases over a prolonged period of time. DESIGN: A population-based matched cohort study. DATA SOURCES: This study examined children aged 1-15 years in The Health Improvement Network UK general practice medical records database. Participants included 2228 patients diagnosed with measles between 1990 and 2014, which were matched on age, sex, general practitioner practice and calendar year with 19 930 children without measles. All controls had received at least one measles vaccination. Children with a history of immune-compromising conditions or with immune-suppressive treatment were excluded. PRIMARY OUTCOME MEASURES: Incidence rate ratio (IRR) of infections, anti-infective prescriptions and all-cause hospitalisations following measles in predetermined periods using multivariate analysis to adjust for confounding variables. RESULTS: In children with measles, the incidence rate for non-measles infectious disease was significantly increased in each time period assessed up to 5 years postmeasles: 43% in the first month (IRR: 1.43; 95% CI 1.22 to 1.68), 22% from month one to the first year (IRR: 1.22; 95% CI 1.14 to 1.31), 10% from year 1 to 2.5 years (IRR: 1.10; 95% CI 1.02 to 1.19) and 15% (IRR: 1.15; 95% CI 1.06 to 1.25) in years 2.5 to 5 years of follow-up. Children with measles were more than three times as likely to receive an anti-infective prescription in the first month and 15%-24% more likely between the first month and 5 years. The rate of hospitalisation in children with measles was increased only in the month following diagnosis but not thereafter (IRR: 2.83; 95% CI 1.72 to 4.67). CONCLUSION: Following measles, children had increased rates of diagnosed infections, requiring increased prescribing of antimicrobial therapies. This population-based matched cohort study supports the hypothesis that measles has a prolonged impact on host resistance to non-measles infectious diseases.

Are proton-pump inhibitors harmful for the semen quality of men in couples who are planning pregnancy?

OBJECTIVE: To determine associations between proton-pump inhibitor (PPI) use and semen parameters in young men of couples who are planning pregnancy. DESIGN: Case-control study of a population-based registry. SETTING: Not applicable. PATIENT(S): General practitioner patients comprising 2,473 men from couples planning pregnancy with a recorded semen analysis: 241 with a low total motile sperm count (TMSC ≤1) and 714 with TMSC >1 as matched controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Exposure to PPI; PPI dosage. RESULT(S): The study of data from between 1996 and 2013 from the Integrated Primary Care Information database in the Netherlands, which incorporates the medical records of 1.5 million patients from 720 general practitioners, found that the use of PPIs in the period between 12 and 6 months before semen analysis was associated with a threefold higher risk of low TMSC (odds ratio 2.96; 95% confidence interval 1.26-6.97) adjusted for age and other medication. Use of PPIs during the 6 months immediately before the semen analysis was not statistically significantly associated with low TMSC. CONCLUSION(S): The use of PPIs in the period 12 to 6 months preceding semen analysis is associated with a threefold higher risk of low TMSC, which suggests that a long-term increase in gastric pH results in a decline of sperm quality. This finding emphasizes the need for more preconceptional research and counseling on the potential effects of medication use on semen quality.

Time trends in the incidence, prevalence and age at diagnosis of asthma in children.

BACKGROUND: Current knowledge on the prevalence of asthma is mainly based on cross-sectional questionnaire data. Current population-based data on the incidence of asthma in children are scarce. OBJECTIVE: To study the incidence, prevalence, and age at diagnosis of asthma in children in the Netherlands over the study period 2000-2012. METHODS: A population-based cohort study was conducted in the Integrated Primary Care Information database. The cohort consisted of 176,516 children (379,536 personyears (PY) of follow-up), aged 5-18 years between 2000 and 2012. All medical records of children with physician diagnosed asthma were validated. Incidence rates, annual percent change (APC), and prevalence for asthma were calculated. Influence of age and gender on incidence rates and change in age at diagnosis were studied. RESULTS: We identified an asthma cohort of 14,303 children with 35,118 PY. The overall incidence rate was 6.7/1000 PY (95% CI, 6.45-6.97). Until 2008, the incidence rate was significantly increasing (APC 5.79 (95% CI 1.43-10.34); from 2008 onwards, a non-significant decrease was observed (APC -12.16 (95% CI -23.07 to 0.28). Incidence for girls was lower than for boys, this difference decreased with increasing age. (p < 0.001) Overall, the age at diagnosis increased over calendar time and was lower for boys. (linear trend p < 0.001). CONCLUSION: Our population-based cohort study observed an incidence rate of 6.7 per 1000 PY of physician-diagnosed asthma in children in the Netherlands over 2000-2012. The asthma incidence rate was increasing until 2008. Further studies are needed to confirm the decrease in asthma incidence rate from 2008 onwards.

Rheumatoid arthritis during pregnancy and postnatal catch-up growth in the offspring.

OBJECTIVE: Active rheumatoid arthritis (RA) during pregnancy and the presence of rheumatoid factor (RF) or anti-citrullinated protein antibodies (ACPAs) are associated with lower birth weight of the child. Moreover, treatment of the mothers with prednisone may shorten the gestational age at birth. Rapid catch-up in weight for length during the first year of life has been related to a worse cardiovascular and metabolic profile in early adulthood. This study was therefore undertaken to assess the influence of RA disease activity, medication use, and presence of RF or ACPAs during pregnancy on the growth of the child in the first year of life. METHODS: Among 180 children born to mothers with RA, the tempo of catch-up in weight during the first year of life was studied. Independent variables were the extent of RA disease activity (according to the Disease Activity Score in 28 joints [DAS28]), medication use, and presence of RF or ACPAs during pregnancy. RESULTS: Of 167 children with available data, 52 (31%) showed catch-up in weight in the first year of life, of whom 90% (47 of 52) showed rapid catch-up. An elevated DAS28 score in the mother was associated with rapid catch-up in weight of the offspring, independent of maternal medication use or the presence of RF or ACPAs during pregnancy (odds ratio 1.44 [95% confidence interval 1.07-1.95] per 1-point increase in the DAS28). Use of medications during pregnancy had no influence on postnatal growth. CONCLUSION: Elevated RA disease activity during pregnancy should be avoided because it is associated with rapid postnatal catch-up in weight, a risk factor for a worse cardiovascular and metabolic profile in adults. Medication for RA during pregnancy, including prednisone, had no effect on growth. Continuation or extension of medication will not only improve maternal health during pregnancy, but could be beneficial for the future health of the unborn child.

Cognitive development in congenital hypothyroidism: is overtreatment a greater threat than undertreatment?

BACKGROUND: Optimal treatment of children with congenital hypothyroidism (CHT) is still debated. Our objective was to evaluate whether early undertreatment (UT) and overtreatment (OT) influence cognitive development at age 11 years. METHODS: Sixty-one patients (27 severe CHT, 34 mild CHT) were psychologically tested at ages 1.8 (Mental Development Index), 6 [intelligence quotient (IQ) 6], and 11 years (IQ11). Scores for cognitive development were related to initial levels of TSH normalization (fast, moderate, or slow) and to total durations of the UT and OT episodes within the first 2 years of life (no, short, or long UT/OT). UT and OT were defined as a free T4 (fT4) concentration below or above the individual fT4 steady-state concentration range (±2 SD). RESULTS: Patients with fast and moderate TSH normalization had higher Mental Development Index scores than patients with slow TSH normalization; 14.2 and 7.7 points higher, respectively (P = .001). TSH normalization had no significant effect on IQ11. Patients with long and short overtreatment had IQ11s that were -17.8 and -13.4 points lower, respectively, than the IQ11s of patients with no overtreatment (P = .014). UT without OT was associated with normal development scores, but UT with OT was associated with -14.7 points lower IQ11s than UT without OT (P = .005). CONCLUSIONS: Our study suggests that CHT overtreatment during the first 2 years leads to lowered cognitive outcomes at 11 years, whereas undertreatment, if not complicated by overtreatment, results in a normal cognitive development. Fast TSH normalization at initial treatment leads to above-normal development scores at a young age but does not affect IQ at age 11 years.

Experience in treating congenital hypothyroidism: implications regarding free thyroxine and thyrotropin steady-state concentrations during optimal levothyroxine treatment.

BACKGROUND: A major problem in the treatment of patients with congenital hypothyroidism (CHT) is that the optimal individual target values of thyrotropin (TSH) and free thyroxine (fT(4)) are unknown. We investigated whether patients with CHT have during treatment considered optimal stable fT(4) and TSH steady-state concentrations (SSCs) that can be used as target values, and whether TSH or fT(4) is more useful in guiding decisions regarding therapy. METHODS: From 60 early-treated patients with CHT, TSH and fT(4) follow-up samples within the age interval 1.5-132 months (postinitial period) and within TSH interval 0.5-10 mU/L were selected. TSH and fT(4) SSCs were estimated by taking the individual mean values of a series of determinations, under the most euthyroid conditions possible (n=1257), for the whole age and TSH intervals, as well as for the age intervals 1.5-24, 25-72, and 73-132 months, as well as, for fT(4), for the two split TSH intervals 0.5-4.49 and 4.5-10 mU/L. For all SSCs, the within-subject coefficient of variation (CV(w)) was determined. Further, fT(4) SSCs were assessed for the first 6 weeks after therapy initiation. RESULTS: For both TSH and fT(4), individual SSCs differed significantly (p<0.001). The 95% confidence interval for TSH SSCs was 1.1-5.7 mU/L and for fT(4) SSCs 16.6-28.7 pmol/L. Mean CV(w) values for TSH and fT(4) SSCs were 60.9% and 13.1%, respectively. Individual fT(4) and TSH SSCs were reproducible when assessed for the three age intervals, both slightly decreasing with age (p≤0.033), and fT(4) SSCs were reproducible for the two split TSH intervals, with a slight fT(4) difference (p<0.001). fT(4) SSCs were largely independent of the administered LT(4) dosage (range 2.4-6.1 µg/kg). fT(4) SSCs of the initial period were comparable to those of postinitial period with a mean±SD difference of 1.0±3.5 pmol/L, p=0.07. CONCLUSIONS: Our study suggests that in CHT during therapy considered optimal, stable TSH and fT(4) SSCs can be found slightly decreasing with age and largely independent of the administered LT(4) dosage (range 2.4-6.1 µg/kg). In clinical follow-up, fT(4) SSCs may be more valuable as individual target values than TSH SSCs.

Effective strategy for improving instructions for analgesic use in the emergency department.

Pain is a common presenting complaint of emergency department patients. Providing instructions that can be easily recalled by patients is an important step in enabling patients to manage their pain following discharge. The effect of the introduction of written discharge instructions for pain medication on patients' recall of instructions was evaluated in this study. A patient-control study within a prospective follow-up study was performed. In the first phase, no written discharge instructions were available. Patients discharged on analgesics filled in a digital questionnaire regarding correct analgesics use. In the second phase, patients were discharged with additional written instructions and completed the same questionnaire. In the first phase, 40% of patients correctly recalled instructions for taking analgesics. In the second phase, significantly more patients, 71% (P<0.01), were able to recall the instructions correctly. Results of this study support the hypothesis that it makes sense to provide patients with written instructions about the appropriate use of analgesics, and that emergency departments that are not yet doing this should consider introducing this policy. It is a relatively low-cost measure that could lead to a significant improvement in quality of care.