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Ana Lozano-Blázquez,1 Cecilia Calvo-Pita,2 Mónica Carbajales-Álvarez,1 Patricio Suárez-Gil,3 Fernando Martínez-Martínez,4 Miguel Ángel Calleja-Hernández51Pharmacy Department, Hospital de Cabueñes, Gijón, Spain; 2Pharmacy Department, Primary Health Care, Servicio Madrileño de Salud, Dirección Asistencial Oeste, Madrid, Spain; 3Research Unit Área V, Hospital de Cabueñes, Gijón, Spain; 4Responsable del Grupo de Investigación en Atención Farmacéutica, Universidad de Granada, 5UGC Provincial de Farmacia de Granada Instituto de Biomedicina de Granada, Hospital Virgen de las Nieves, Granada, SpainBackground: In Spain, hospital medicines are assessed and selected by local Pharmacy and Therapeutics committees (PTCs). Of all the drugs assessed, cancer drugs are particularly important because of their budgetary impact and the sometimes arguable added value with respect to existing alternatives. This study analyzed the PTC drug selection process and the main objective was to evaluate the degree of compliance of prescriptions for oncology drugs with their criteria for use.Methods: This was a retrospective observational study (May 2007 to April 2010) of PTC-assessed drugs. The variables measured to describe the committee's activity were number of drugs assessed per year and number of drugs included in any of these settings: without restrictions, with criteria for use, and not included in formulary. These drugs were also analyzed by therapeutic group. To assess the degree of compliance of prescriptions, a score was calculated to determine whether prescriptions for bevacizumab, cetuximab, trastuzumab, and bortezomib were issued in accordance with PTC drug use criteria.Results: The PTC received requests for inclusion of 40 drugs, of which 32 were included in the hospital formulary (80.0%). Criteria for use were established for 28 (87.5%) of the drugs included. In total, 293 patients were treated with the four cancer drugs in eight different therapeutic indications. The average prescription compliance scores were as follows: bevacizumab, 83% for metastatic colorectal cancer, 100% for metastatic breast cancer, and 82.3% for non-small-cell lung cancer; cetuximab, 62.0% for colorectal cancer and 50% for head and neck cancer; trastuzumab, 95.1% for early breast cancer and 82.4% for metastatic breast cancer; and bortezomib, 63.7% for multiple myeloma.Conclusion: The degree of compliance with criteria for use of cancer drugs was reasonably high. PTC functions need to be changed so that they can carry out more innovative tasks, such as monitoring conditions for drug use.Keywords: decision-making, drug selection, drug utilization, formulary, neoplasm, Pharmacy and Therapeutics committee

Abstract Background The null hypothesis significance test (NHST) is the most frequently used statistical method, although its inferential validity has been widely criticized since its introduction. In 1988, the International Committee of Medical Journal Editors (ICMJE) warned against sole reliance on NHST to substantiate study conclusions and suggested supplementary use of confidence intervals (CI). Our objective was to evaluate the extent and quality in the use of NHST and CI, both in English and Spanish language biomedical publications between 1995 and 2006, taking into account the International Committee of Medical Journal Editors recommendations, with particular focus on the accuracy of the interpretation of statistical significance and the validity of conclusions. Methods Original articles published in three English and three Spanish biomedical journals in three fields (General Medicine, Clinical Specialties and Epidemiology - Public Health) were considered for this study. Papers published in 1995-1996, 2000-2001, and 2005-2006 were selected through a systematic sampling method. After excluding the purely descriptive and theoretical articles, analytic studies were evaluated for their use of NHST with P-values and/or CI for interpretation of statistical "significance" and "relevance" in study conclusions. Results Among 1,043 original papers, 874 were selected for detailed review. The exclusive use of P-values was less frequent in English language publications as well as in Public Health journals; overall such use decreased from 41% in 1995-1996 to 21% in 2005-2006. While the use of CI increased over time, the "significance fallacy" (to equate statistical and substantive significance) appeared very often, mainly in journals devoted to clinical specialties (81%). In papers originally written in English and Spanish, 15% and 10%, respectively, mentioned statistical significance in their conclusions. Conclusions Overall, results of our review show some improvements in statistical management of statistical results, but further efforts by scholars and journal editors are clearly required to move the communication toward ICMJE advices, especially in the clinical setting, which seems to be imperative among publications in Spanish.

Introduction: Consumption of antibiotics is high in Spain, primarily in children. Excessive use of then contributes to the development of antimicrobial resistance. The aim of our study is to analyse the evolution of antibiotic consumption at the Primary Health Care in the paediatric population of Asturias, Spain, from 2014 to 2021, and to evaluate the impact of COVID-19 pandemic on it., Methods: Retrospective and observational study using data about antibacterial agents for systemic use dispensed for official prescriptions to children under 14 years in Primary Care. Antibiotic consumption is expressed as defined daily dose (DDD) per 1000 inhabitants per day (DID)., Results: The antibiotic consumption rate dropped from 13.9 DID in 2014 to 4.0 in 2021 (β=-1,42, p=0,002), with and inflection point in 2019. From 2019 to 2020 antibiotic use dropped by 47.1%. Antibiotic consumption remained very low from April 2020 to September 2021, and then moderately increased from October 2021. Prevalence of antibiotic use dropped from 39.9% in 2014 to 17.5% in 2021 (β=-3,64, p=0,006). Relative consumption of amoxicillin/clavulanic acid decreased, while those of amoxiciline and third-generation cephalosporins increased., Conclusions: Paediatric antibiotic consumption collapsed in Asturias in 2020, coinciding with COVID-19 pandemic. Monitoring of antimicrobial usage indicators will allow to check if these changes are sustained over time., (Copyright © 2022 Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: To evaluate the effect of COVID-19 lockdown on the prescription of benzodiazepines by gender, age and district health departments., Design: Longitudinal observational study., Location: Primary care. Asturias (Spain) health district V., Participants: People over 15 years of age with filled benzodiazepine prescriptions in between 2017 and 2020., Main Measurements: Benzodiazepine DHD (defined daily dose per 1000 habitants) mean difference between the period defined as pre-lockdown and lockdown. Additionally, the difference was adjusted for gender, sex and district health department and also with the interaction among them., Results: DHD mean pre-lockdown was 131.3 and 139.5 in the lockdown; this difference was significant in the global analysis (95% CI: 4.1-12.1). There was an increase in the DHD mean in the 60-74 age group (95% CI: 2.28-21.42), in the group over 90 years old (95% CI: 21.31-40.63) and in women (95% CI: 3.51-14.59). Finally, a decrease in the DHD mean of V11 (95% CI: -29 to -0.66) and V14 (95% CI: -54.28 to -25.04) district health departments was observed., Conclusions: Certain subgroups show a change in the pattern of benzodiazepine prescription without being able to relate this to the lockdown. We believe that there could be some inertia in the prescription of psychiatric medication according to the biopsychosocial characteristics of the patients; it is important to detect this in order to avoid the medicalization of psychological disorders., (Copyright © 2022 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.)

Trend study of the consumption of systemic antibiotics in the adult population in of Primary Care of the Health Service of the Principality of Asturias (SESPA) during the period 2014̶2020. Retrospective observational study. SESPA, Primary Care. Population from the Individual Health Card database. Data were collected on the prescription of antibiotics, carried out in the family medicine consultations, dispensed in the pharmacy offices with charge of SESPA. Antibiotic use and consumption variables were analyzed using linear regression models. Prevalence of antibiotic use (population percentage); consumption rate of systemic antibiotics (DTD), relative consumption of narrow-spectrum antibiotics (percentage DDD). The average prevalence of the use of antibiotics for the 2014̶2019 period was 32.2% and 23.9% in 2020. The rate of consumption of systemic antibiotics decreased from 21.4 DTD in 2014 to 12.7 DTD in 2020. The consumption of narrow-spectrum antibiotics remained stable (19.4% DDD in 2014 and 19.3% DDD in 2020) (CI95: -0.10, 0.26). In the period from March to December 2020, the consumption of antibiotics decreased by 28.6% compared to the same period in 2019. In 2014̶2020, the consumption of antibiotics decreased, especially since the COVID-19 pandemic, with stabilization of the consumption of narrow-spectrum antibiotics compared to the total. There is variability in consumption by therapeutic subgroups., (Copyright © 2021 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objective: In view of the unfavourable results of the HLS-EU Project in Spain and given that there are hardly any studies about health literacy (HL) in adolescents, it was proposed as main objective to determine the degree of HL of adolescents after Obligatory Secondary Education (OSE) and the educational necessities which they perceive in Health Education (HE)., Methods: Observational descriptive cross-sectional study with students in their first year of Upper Secondary Education for the academic year 2018/2019 from Healthcare Area V (Asturias). It was an equi-probabilistic one-stage cluster sampling, selecting 12 classrooms with 323 students. The HLS-EU-Q16 questionnaire was used to measure the HL and a self-designed one about educational necessities, which was validated by the Regional Ministry of Education and Culture. A descriptive and Bayesian inference analysis was performed in R 3.5.2., Results: 206 individuals were studied. HL proved sufficient in 55.8%, problematic in 40.3% and inadequate in 3.9%. A 98.6% considered training in HE necessary, preferring workshops and one-time talks (58.7%). HL only showed relation with self-perceived health, and not with sex, mothers'/fathers'/guardians' educational level nor having received HE., Conclusions: Almost half of adolescents got problematic or inadequate HL, which relates with health risk behaviours and worse use of health resources, according to the evidence. Having received HE did not associated with better HL, which suggests that currently their educational necessities are not covered., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objectives: The purpose of this study was to assess the effectiveness of ultrasound (US)-guided aspiration for the management of low-risk adnexal cysts., Methods: A longitudinal cohort of women with a low-risk adnexal cyst who underwent transvaginal US-guided aspiration from January 2012 to April 2018 were included. All procedures were performed on an outpatient basis, without anesthesia, sedation, or antibiotics. The posttreatment follow-up protocol included transvaginal US at 3 and 12 months. Potential risk factors for recurrence (ie, age, menopausal status, comorbidities, symptoms, cyst diameter, incomplete emptying, and location) were analyzed by multiple logistic regression., Results: A total of 156 patients were included. The median (interquartile range) cyst diameter was 66 (58-80) mm. Fifty-seven (36.5%) cases were resolved by US-guided aspiration. The median follow-up time was 556.5 (344-1070.25) days. The complication rate of the procedure was 2.6% (n = 4), with 3 cases of a major complication due to a pelvic abscess and 1 case of a minor complication due to self-limited vaginal spotting. A larger cyst size (odds ratio, 1.01; 95% confidence interval, 1.04-1.07; P = .002) and an older age (odds ratio, 1.01; 95% confidence interval, 1.03-1.05; P = .007) at diagnosis were independent factors related to recurrence., Conclusions: Based on the low resolution rate, US-guided aspiration is not an effective option for the treatment of low-risk adnexal cysts. Risk factors associated with recurrence were age and cyst size at diagnosis. Larger randomized studies are necessary to assess predictive factors for cyst recurrence., (© 2020 by the American Institute of Ultrasound in Medicine.)

Objective: Neurotic disorders are one of the main health problems of Western societies. Its impact on labor productivity grows exponentially with an increase in its incidence and the duration of temporary disability (TD) processes. To know the characteristics of the patients belonging to a mutual of work accidents who had transient disability due to neurotic disorders, their temporal and geographic distribution, their comorbidities and those variables that affected their duration., Methods: Retrospective descriptive study of the workers protected from a mutual of work accidents, national scope, who studied a disability period between 2006-2016 with diagnoses included between codes 300 and 300.9 of the CIE-9-CM, corresponding to Neurotic Disorders. We analyze clinical-demographic variables of patients, comorbidities during studied period and distributions by year and province, by Bayesian inference. We performed a logistic regression for the dependent variable duration of the TD adjusted for age, sex, toxic consumption, consultations, year, regulatory base and payment type., Results: We registered 56,619 processes in Spain, which corresponded to 1.5% of the total TD processes served in the period. The highest percentage of cases was grouped between 2007 and 2009, when 11% of the population were registered annually. The variables associated with an increase in this duration were: older age, male sex, psychiatric and psychological consultations, diagnostic year, regulatory base (whose average was 50.5 euros) and type of payment (delegate in 78.2% of cases and direct in 21.8%). The prevalence by provinces was more marked in the north and the islands (Barcelona, Lleida, Las Palmas, Islas Baleares, Coruña, Cantabria, Girona, Álava, Tarragona, Pontevedra y Asturias they have more than 6%).The durations of the disability were greater in the east of the country. The most prevalent comorbidities during the study period were low back pain (with an average of 65.1 days of IT anxiety), cervical pain (with an average of 67 days) and digestive disorders (with an average of 59.4 days)., Conclusions: There are comorbidities and variables associated with the temporary disability derived from neurotic disorders, with geographical differences. Deepening their knowledge and impact could promote better preventive and therapeutic approaches that allow an earlier functional recovery., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objective: To know the level of anxiety and knowledge of childcare and lactation of the current pregnant women, and the clinical-demographic variables with which they are related., Design: Cross-sectional study., Setting: Seven health centers of Area V (Asturias)., Participants: First-time pregnant women who completed preparatory courses from 01.06.2015 to 31.10.2015, excluding multiple gestation, risk pregnancy, contraindicated breastfeeding and language problems., Interventions: Sociodemographic variables questionnaire, STAI state anxiety questionnaire and 23 questions about childcare and lactation., Main Measurements: We performed descriptive and multivariate analysis (program R) of the variables of the questionnaire., Results: We captured 104 pregnant women; average age 34.2(SD: 4.5), 94.2% Spanish, 61.5% university, 17.3% smokers in pregnancy, 23.1% with psychopathological antecedents; 88.4% planned to give breastfeeding. The mean STAI-S was 18.1(SD: 7.4) and scored 4.5(SD: 2.3) mean errors. The most faulty ones were on causes of fever (56.7%), fever measurement (54.8%) and physiological stools (55.7%). The multivariate analysis between knowledge and profile showed statistically significant associations with: being foreign, university, pregnancy planning and matron. In relation to the STAI-S was significant for being a smoker, receiving breastfeeding, psychopathological antecedents and matron., Conclusions: The current pregnant women who complete preparatory courses are mainly mature, university and Spanish. They have good concepts about breastfeeding but many are unaware of basic concepts of fever and stool of the infant. Foreign mothers with unwanted pregnancy and primary education seem to have more confusing concepts. Smoking mothers with psychopathological antecedents and who have not received breastfeeding present more anxiety. The matron significantly influences anxiety and acquired concepts., (Copyright © 2018 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objective: To determine the usefulness of ultrasound examination in Primary Care (PC) for the detection of abdominal aortic aneurysm (AAA) in male patients from 65-75 years old, as well as the consistency between observers on the diagnosis between general practitioners and the reference specialty in this area, Vascular Surgery. To estimate the prevalence of AAA in that population and its association with risk factors., Design: Cross-sectional descriptive study., Location: Healthcare Centres of Coto and Calzada II (Gijón, Spain)., Participants: Males born between 1 January 1939 and 31 December 1950., Interventions: From the 2,511 males found, 407 were selected using stratified random sampling. Aortic diameter was measured, with those ≥3cm and 20% from the <3cm being referred for a second measurement by a vascular surgeon., Variables: Dependent: presence/absence of aneurism. Independent: age, abdominal perimeter, smoking, arterial hypertension, diabetes, dyslipidaemia, familial cases of AAA, cerebrovascular accident, and coronary disease. The analysis was performed using Bayesian inference with models for proportions and a multivariate logistic regression., Results: From 304 ultrasound scans performed, 13 were referred with suspicion of AAA, and 63 with were within normal. The sensitivity was 93.3% and specificity 98.5% with a 95% credibility interval (CredI) of 75.4-99.9%, and 94.3-100%, respectively. The prevalence was 4.6% (95% CredI: 2.5-7.2%, and the intraclass correlation coefficient between PC and Vascular Surgery was 0.88 (95% CredI: 0.79-0.94). Age, smoking, dyslipidaemia, and diabetes tended to increase the odds of prevalence of AAA., Conclusion: The ultrasound performed by GPs for the detection of AAA had high diagnostic validity. Further studies on the effectiveness should be conducted in order to assess the appropriateness of introducing a system of early detection of AAA in the risk population., (Copyright © 2017 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Negative symptoms represent the main cause of disability in schizophrenia, having recently been grouped into two general dimensions: avolition and diminished emotional expression, which includes affective flattening and alogia. The aim of this study was to explore the response of these two symptoms to a set of behavioral interventions based on contingency management, performed in an interdisciplinary context., Method: Behaviors of interest were monitored and evaluations before and after the treatment were performed on 9 schizophrenic inpatients with persistent negative symptoms. The program included 12 group double sessions aimed at developing facial expression and verbal communication, and a nursing care plan to generalize and strengthen these behaviors synergistically., Results: there were appreciable differences in facial expression, which were less clear for alogia. The clinical evaluation using PANSS-N did not find notable differences at group level, but the nursing assessment using NOC indicators did., Conclusions: although difficult to modify, negative symptoms are not insensitive to the influence of behavioral interventions. Specific psychological interventions that address negative symptoms as a priority focus of attention and care need to be promoted and developed, particularly when considering the crucial role of context in their progression.

Objective: To assess whether the economic crisis of 2008 has changed the consumption of anxiolytics, hypnotics-sedatives and antidepressants in Asturias (Spain)., Method: We conducted a descriptive study of drug use from 2003 -2013. The defined daily doses of 1000 inhabitants per day (DHD) were calculated for anxiolytics, hypnotics-sedatives and antidepressants. Linear regression coefficients (b) of the DHD were obtained for the pre-crisis period (2003-2008) and the crisis period (2009-2013)., Results: The consumption of anxiolytics increased by 40.25%, that of hypnotics by 88.11% and that of antidepressants by 80.93%. For anxiolytics: b-(2003-2008)=4.38 DDI/year and b-(2009-2013)=1.08 DDI/year. For hypnotics-sedatives: b-(2003-2008)=2.30 DDI/year and b-(2009-2013)=0.40 DDI/year. For antidepressants: b-(2003-2008)=5.79 DDI/year and b-(2009-2013)=2.83 DDI/year., Conclusions: The rise in consumption of the three subgroups during the crisis period was lower than that of the pre-crisis period. This study does not confirm the influence of the economic crisis on the rise in consumption of these drugs., (Copyright © 2016 SESPAS. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objetive: To evaluate the effectiveness of providing an educational intervention in primary care (PC) alongside a pharmacological treatment for insomnia., Design: Single blinded non randomised clinical trial., Location: Two urban primary health centers in Gijón (Asturias, Spain)., Participants: Patients who consulted for insomnia between July 2012-January 2013 and met the inclusion criteria (n=50) were assigned systematically to the control group (CG) or intervention group (IG). All patients initiated treatment with lorazepam 1mg in the evenings and had four weekly 15 min visits plus a follow-up visit after another month., Interventions: The IG received training for control of stimuli, sleep hygiene and respiration and relaxation techniques in the four visits. The CG had only non invasive measures taken., Measurements: Considering as cured those who reached a Pittsburgh Sleep Quality Index PSQI <6 or a 50% reduction from baseline level. It was also analyzed the change in the PSQI from baseline to final visit and to follow-up visit, and voluntary interruption of lorazepam. Analysis by Bayesian inference., Results: Twelve out of recoveries after intervention against one out of 24 among control group. Mean change in PSQI to final visit and follow-up visit was: -4.7 (95%CrI:-5.9 to -3.5) and -6,3 (95%ICred: -7.5 to -5.1) in IG; -1.8 (95%ICred: -3 to -0.5) and -1.7 (95%ICred: -2.9 to -0.4) in CG. Interruption of lorazepan: in 4 controls (16,7%) and 9 (34,6%) in IG. Twenty nine patients in GI and 17 in GC completed the trial. Per protocol analysis showed similar results., Conclusions: The educational intervention in PC improves sleep quality and reduces the need of treatment with benzodiacepines., (Copyright © 2013 Elsevier España, S.L.U. All rights reserved.)

Objectives: To evaluate the use of Internet as a source of health information by adolescents, its reliability and the acceptability of an email service for their questions., Design: Cross-sectional study., Setting: Secondary schools. Gijón (Asturias)., Participants: 475 students (1st and 4th Secondary, and 1st High School) selected by two-stage cluster sampling., Main Outcome Measures: Self-administered questionnaire of ten items., Variables: Age, sex, availability of Internet at home, daily time use, subjects consulted, source health consultation, information obtained reliability, willingness to use e-mail health consultations., Results: A total of 468 valid questionnaires, of which 88.5% had Internet at home, 42.5% use more than one hour daily on weekdays and 74% during the weekend. The most accessed topics were physical exercise (29.5%), self-image (23.3%) and piercing, and tattoos (18.4%). Internet is the fourth resource used for health concerns (13.9%), behind family, doctor and friends. The majority, 56%, gave a very low reliability to health information obtained on Internet. A total of 70.5% would use an email address that provided answers to health questions., Conclusions: Availability of Internet at home is above the national average. High usage but low for health information, which gives low credibility. It would be advisable to start a mail service for adolescents treated by a multidisciplinary team from Primary Care., (Copyright © 2009 Elsevier España, S.L. All rights reserved.)

Introduction: Several epidemiological studies have demonstrated that there is a genetic factor of susceptibility in Multiple Sclerosis (MS) and that the environmental factors play an important important role in their development. Smoking is among the environment factors studied. In fact, several studies have established a relationship between smoking and multiple sclerosis, although most of them did not find significant results or found that these were contradictory., Objective: To evaluate the influence of the smoking habit on the risk of suffering MS., Methods: This was a case-control matched study with 138 patients diagnosed of MS according to the McDonald criteria who were paired with the same number of controls of the same gender, residents in the same city and having the same age +/-2 years. Demographic data, smoking status (never, always smokers, ex-smokers), Kurtzke disability status scale (EDSS) and type of MS were collected., Results: Out of a total of 138 MS patients (93 women, 43 men), 110 had relapsing-remitting MS, 20 secondary progressive MS and 7 primary progressive MS. Most of the patients were smokers and ex-smokers (63%). In the control group, only the 41,3% were smokers/ex-smokers. Moreover, the age of onset for smoking was earlier in the case group., Conclusion: Being a smoker/ex-smoker implies a 27% greater risk of developing MS compared to those who have never smoked. This risk is statistically significant for women but not for men due to the low number of them in the sample.

Objectives: To assess in two General Medicine clinics the use of the formula "Was there anything else?" in connection with patients' additional requests and the question's possible association with other variables., Design: Quasi-experimental., Setting: Urban Health Centre., Patients: Patients from two lists attending over a two-month period, with the exclusion of scheduled patients without appointments., Measurements and Interventions: For one of the months patients were asked: "Was there anything else?" (intervention group) and for the other month, they were not (control group). On each visit variables were recorded: list, doctor (tutor/intern), age, gender, reason for consultation (pathology/burocratic), whether accompanied, waiting time and additional requests (new problems raised at the end of the visit). A bivariant analysis of each of the variables with the variable 'intervention' was made and, after a prior transformation of the variable 'additional requests' into two, was adjusted to a multiple logistic regression model in order to control the confusion., Results: 2,657 attendances were analysed. The variables which were significant for the prediction of additional requests were: intervention, list, age, gender and reason for consultation., Conclusions: The intervention of the doctor may generate additional requests, although whether this means that the consultation is better organised remains to be assessed.

8 cases of dementia associated with cortical Lewy bodies are dealt with, that were diagnosed in 1993 in examinations for dementia, using the Nottingham's clinical criteria. They make up 15.4% of primary degenerative dementias diagnosed in this examination. All developed a predominantly cortical dementia with variable bradiphrenia and a parkinsonian syndrome which was predominantly of the rigid-bradikinetic type. The dementia established itself rapidly -between 1 and 3 weeks- in 3 cases (37.5%). 50% of patients (4 cases) showed marked psychiatric symptoms. In 2 cases stiffness was predominantly axial and another had supranuclear paralysis of vertical gaze. 3 patients had no tremor, and 2 of the 5 remaining patients showed postural tremor. CT and axial MR images of the encephalon were similar to those observed in dementia of the Alzheimer type. The coronal MR carried out on 3 patients revealed less atrophy of the hypocampus than is normally observed in patients with dementia of the Alzheimer type who are at the same stage of development.