Sleep disorders during the COVID-19 pandemic: Results from the second phase of web-based EPICOVID19 study.

The COVID-19 pandemic has induced significant impairments, including sleep disturbances. The present study aimed to explore the impact of fear in relation to stress on sleep disorders among Italian adults and older participants in the second phase of the EPICOVID19 web-based survey (January-February 2021). Sleep disturbances during the pandemic were evaluated using the Jenkins Sleep Scale, perceived stress through the 10-item Perceived Stress Scale and fear of contagion and about economic and job situation with four ad hoc items. The strength of the pathways between stress, sleep disturbances and fear was explored using structural equation modelling, hypothesising that stress was related to sleep disturbances and that fear was associated with both stress and sleep problems. Out of 41,473 participants (74.7% women; mean age 49.7 ± 13.1 years), 8.1% reported sleep disturbances and were more frequently women, employed in a work category at risk of infection or unemployed, and showed higher deprivation scores. Considering an a priori hypotheses model defining sleep and stress scores as endogenous variables and fear as an exogenous variable, we found that fear was associated with sleep problems and stress, and stress was associated with sleep problems; almost half of the total impact of fear on sleep quality was mediated by stress. The impact of stress on sleep quality was more evident in the younger age group, among individuals with a lower socioeconomic status and healthcare workers. Fear related to COVID-19 seem to be associated with sleep disturbances directly and indirectly through stress.

Alcohol versus combined alcohol and energy drinks consumption: Risk behaviors and consumption patterns among European students.

INTRODUCTION: Recent research found that drinking alcohol mixed with energy drinks (AmED) could be riskier than drinking alcohol alone. Our aim was to compare rates of risk behaviors in consumers of AmED versus exclusive alcohol drinkers, matching them based on their drinking frequency. METHODS: Data about 16-year-old students who reported the number of occasions on which they had drunk AmED or alcohol only in the preceding 12 months (n = 32,848) were drawn from the 2019 ESPAD study. After matching for consumption frequency, the sample consisted of 22,370 students (11,185 AmED consumers and 11,185 exclusive alcohol drinkers). Key predictors comprised substance use, other individual risk behaviors, and family characteristics (parental regulation, monitoring, and caring). RESULTS: The multivariate analysis showed significantly higher odds of being AmED consumers compared to being exclusive alcohol drinkers in the majority of the investigated risk behaviors, including: daily tobacco smoking, illicit drug use, heavy episodic drinking, truancy at school, engaging in physical fights and serious arguments, having troubles with the police, and having unprotected sexual intercourse. Instead, lower odds were found for reporting high parents' educational level, medium and low family economic status, perceived possibility to freely talk about problems to family members, spending free time reading books or other hobbies. CONCLUSIONS: Our study shows that, given the same consumption frequency in the past year, AmED consumers typically reported higher associations with risk-taking behaviors compared to exclusive alcohol drinkers. These findings advance past research that failed to control for the frequency of AmED use versus exclusive alcohol consumption.

Long-term effects of a combination of isoflavones, agnus castus and magnolia extracts on climacteric symptoms and cardiometabolic risk profile in postmenopausal women.

OBJECTIVE: To evaluate the long-term effects of a combination of isoflavones, agnus castus and magnolia extracts (combined isoflavone compound [CIC]) on climacteric symptoms and cardiometabolic risk in symptomatic postmenopausal women. METHODS: This interventional, prospective study evaluated climacteric symptoms, mood and sleep disorders using the 21-item Greene Climacteric Scale (GCS) and 7-item Insomnia Severity Index (ISI) questionnaires; and cardiovascular, metabolic and thrombotic risk markers at baseline (T0) and after 12 months of CIC treatment (T1). RESULTS: In healthy postmenopausal women (N = 71), 12-month CIC treatment significantly reduced patient-reported vasomotor symptoms (100% vs. 17%), mood disorders (67% vs. 25%) and sleep disorders (89% vs. 19%%) (all p < .001) compared with baseline; and significantly improved GCS psychological, somatic, and vasomotor domain scores and ISI sleep disturbance scores (all p < .05). CIC significantly reduced systolic (p = .022) and diastolic blood pressure (p < .001), and heart rate (p < .001); glucose concentrations (p = .018), HOMA index (p = .013), and ALT (p = .035), homocysteine (p = .005) and NT-proBNP (p = .003) levels. CONCLUSIONS: Long-term CIC therapy improved vasomotor symptoms, mood disorders, sleep disorders, hemodynamic measurements and cardiometabolic risk markers in healthy postmenopausal women. CLINICALTRIALS.GOV IDENTIFIER: NCT03699150.

Fear of COVID-19 for Individuals and Family Members: Indications from the National Cross-Sectional Study of the EPICOVID19 Web-Based Survey.

The study analyzed the association of the fear of contagion for oneself and for family members (FMs) during the first wave of the COVID-19 pandemic, with demographic and socioeconomic status (SES) and health factors. The study was performed within the EPICOVID19 web-based Italian survey, involving adults from April-June 2020. Out of 207,341 respondents, 95.9% completed the questionnaire (60% women with an average age of 47.3 vs. 48.9 years among men). The association between fear and demographic and SES characteristics, contacts with COVID-19 cases, nasopharyngeal swab, self-perceived health, flu vaccination, chronic diseases and specific symptoms was analyzed by logistic regression model; odds ratios adjusted for sex, age, education and occupation were calculated (aORs). Fear for FMs prevailed over fear for oneself and was higher among women than men. Fear for oneself decreased with higher levels of education and in those who perceived good health. Among those vaccinated for the flu, 40.8% responded they had feelings of fear for themselves vs. 34.2% of the not vaccinated. Fear increased when diseases were declared and it was higher when associated with symptoms such as chest pain, olfactory/taste disorders, heart palpitations (aORs > 1.5), lung or kidney diseases, hypertension, depression and/or anxiety. Trends in fear by region showed the highest percentage of positive responses in the southern regions. The knowledge gained from these results should be used to produce tailored messages and shared public health decisions.

Rapid COVID-19 Screening Based on Self-Reported Symptoms: Psychometric Assessment and Validation of the EPICOVID19 Short Diagnostic Scale.

BACKGROUND: Confirmed COVID-19 cases have been registered in more than 200 countries, and as of July 28, 2020, over 16 million cases have been reported to the World Health Organization. This study was conducted during the epidemic peak of COVID-19 in Italy. The early identification of individuals with suspected COVID-19 is critical in immediately quarantining such individuals. Although surveys are widely used for identifying COVID-19 cases, outcomes, and associated risks, no validated epidemiological tool exists for surveying SARS-CoV-2 infection in the general population. OBJECTIVE: We evaluated the capability of self-reported symptoms in discriminating COVID-19 to identify individuals who need to undergo instrumental measurements. We defined and validated a method for identifying a cutoff score. METHODS: Our study is phase II of the EPICOVID19 Italian national survey, which launched in April 2020 and included a convenience sample of 201,121 adults who completed the EPICOVID19 questionnaire. The Phase II questionnaire, which focused on the results of nasopharyngeal swab (NPS) and serological tests, was mailed to all subjects who previously underwent NPS tests. RESULTS: Of 2703 subjects who completed the Phase II questionnaire, 694 (25.7%) were NPS positive. Of the 472 subjects who underwent the immunoglobulin G (IgG) test and 421 who underwent the immunoglobulin M test, 22.9% (108/472) and 11.6% (49/421) tested positive, respectively. Compared to NPS-negative subjects, NPS-positive subjects had a higher incidence of fever (421/694, 60.7% vs 391/2009, 19.5%; P<.001), loss of taste and smell (365/694, 52.6% vs 239/2009, 11.9%; P<.001), and cough (352/694, 50.7% vs 580/2009, 28.9%; P<.001). With regard to subjects who underwent serological tests, IgG-positive subjects had a higher incidence of fever (65/108, 60.2% vs 43/364, 11.8%; P<.001) and pain in muscles/bones/joints (73/108, 67.6% vs 71/364, 19.5%; P<.001) than IgG-negative subjects. An analysis of self-reported COVID-19 symptom items revealed a 1-factor solution, the EPICOVID19 diagnostic scale. The following optimal scores were identified: 1.03 for respiratory problems, 1.07 for chest pain, 0.97 for loss of taste and smell 0.97, and 1.05 for tachycardia (ie, heart palpitations). These were the most important symptoms. For adults aged 18-84 years, the cutoff score was 2.56 (sensitivity: 76.56%; specificity: 68.24%) for NPS-positive subjects and 2.59 (sensitivity: 80.37%; specificity: 80.17%) for IgG-positive subjects. For subjects aged ≥60 years, the cutoff score was 1.28, and accuracy based on the presence of IgG antibodies improved (sensitivity: 88.00%; specificity: 89.58%). CONCLUSIONS: We developed a short diagnostic scale to detect subjects with symptoms that were potentially associated with COVID-19 from a wide population. Our results support the potential of self-reported symptoms in identifying individuals who require immediate clinical evaluations. Although these results come from the Italian pandemic period, this short diagnostic scale could be optimized and tested as a screening tool for future similar pandemics.

Self-Reported Symptoms of SARS-CoV-2 Infection in a Nonhospitalized Population in Italy: Cross-Sectional Study of the EPICOVID19 Web-Based Survey.

BACKGROUND: Understanding the occurrence of symptoms resembling those of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a large nonhospitalized population at the peak of the epidemic in Italy is of paramount importance; however, data are currently scarce. OBJECTIVE: The aims of this study were to evaluate the association of self-reported symptoms with SARS-CoV-2 nasopharyngeal swab (NPS) test results in nonhospitalized individuals and to estimate the occurrence of symptoms associated with coronavirus disease (COVID-19) in a larger nontested population. METHODS: EPICOVID19 is a self-administered cross-sectional voluntary web-based survey of adults throughout Italy who completed an anonymous questionnaire in the period of April 13 to 21, 2020. The associations between symptoms potentially related to SARS-CoV-2 infection and NPS results were calculated as adjusted odds ratios (aORs) with 95% CIs by multiple logistic regression analysis controlling for age, sex, education, smoking habits, and number of comorbidities. Thereafter, for each symptom and for combinations of the symptoms, we calculated the sensitivity, specificity, accuracy, and areas under the curve (AUCs) in a receiver operating characteristic (ROC) analysis to estimate the occurrence of COVID-19-like infection in the nontested population. RESULTS: A total of 171,310 people responded to the survey, of whom 102,543 (59.9%) were women; mean age 47.4 years. Out of the 4785 respondents with known NPS test results, 4392 were not hospitalized. Among the 4392 nonhospitalized respondents, those with positive NPS tests (856, 19.5%) most frequently reported myalgia (527, 61.6%), olfactory and taste disorders (507, 59.2%), cough (466, 54.4%), and fever (444, 51.9%), whereas 7.7% were asymptomatic. Multiple regression analysis showed that olfactory and taste disorders (aOR 10.3, 95% CI 8.4-12.7), fever (aOR 2.5, 95% CI 2.0-3.1), myalgia (aOR 1.5, 95% CI 1.2-1.8), and cough (aOR 1.3, 95% CI 1.0-1.6) were associated with NPS positivity. Having two to four of these symptoms increased the aOR from 7.4 (95% CI 5.6-9.7) to 35.5 (95% CI 24.6-52.2). The combination of the four symptoms showed an AUC of 0.810 (95% CI 0.795-0.825) in classifying positive NPS test results and then was applied to the nonhospitalized and nontested sample (n=165,782). We found that 7739 to 20,103 of these 165,782 respondents (4.4% to 12.1%) had experienced symptoms suggestive of COVID-19 infection. CONCLUSIONS: Our results suggest that self-reported symptoms are reliable indicators of SARS-CoV-2 infection in a pandemic context. A nonnegligible number of symptomatic respondents (up to 12.1%) were undiagnosed and potentially contributed to the spread of the infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT04471701; https://clinicaltrials.gov/ct2/show/NCT04471701.

Paper-and-pencil versus computerized administration mode: Comparison of data quality and risk behavior prevalence estimates in the European school Survey Project on Alcohol and other Drugs (ESPAD).

PURPOSE: The aim of this experimental study was to investigate whether paper-and-pencil and computerized surveys administered in the school setting yield equivalent data quality indicators and risk behavior prevalence estimates. METHODS: Data were drawn from the European School Survey Project on Alcohol and Other Drugs (ESPAD®) carried out in Italy to monitor drug, alcohol, tobacco use and other risk-behaviors among Italian high school students aged 15-19 years. A sub-sample of schools was recruited for the study (1673 pupils). For each school, two entire randomly selected courses (from the first to the fifth grade) participated and were assigned randomly to the self-administered paper-and-pencil (N = 811) or computerized survey (N = 862). Differences in data quality were assessed using the following indicators: questionnaire completeness (missing gender and/or 50% of missing answers) and internal consistency (repetitive extreme response patterns). Separate logistic regression models were used to estimate the mode effect on the reporting of each risk behavior, controlling for gender and age. Finally, the prevalence estimates of the experimental study were compared to the results of the national ESPAD® study. RESULTS: The computerized administration mode produced a higher proportion of invalid questionnaires, but the prevalence estimates generated from responses to the paper-and-pencil and computerized surveys were generally equivalent. Nevertheless, comparing these results with those of the national ESPAD® study, some differences in the prevalence rates were found. CONCLUSIONS: The findings suggest that in a proctored school setting, the computerized survey mode yields almost the same results as the paper-and-pencil mode. However, because of the reliance on existing informatics facilities until when all schools in the country will be sufficiently equipped for the computerized data collection, they should be given the opportunity to choose between paper-and-pencil and computerized survey modes, in order to avoid a possible selection bias.

Prevalence of youth gambling and potential influence of substance use and other risk factors throughout 33 European countries: first results from the 2015 ESPAD study.

BACKGROUND AND AIMS: Although generally prohibited by national regulations, underage gambling has become popular in Europe, with relevant cross-country prevalence variability. This study aimed to estimate the prevalence of underage gambling in Europe stratified by type of game and on-/off-line mode and to examine the association with individual and family characteristics and substance use. DESIGN: Our study used data from the 2015 European School Survey Project on Alcohol and Other Drugs (ESPAD) cross-sectional study, a survey using self-administered anonymous questionnaires. SETTING: Thirty-three European countries. PARTICIPANTS: Sixteen-year-old-year-old students (n = 93 875; F = 50.8%). MEASUREMENTS: The primary outcome measure was prevalence of past-year gambling activity. Key predictors comprised individual behaviours, substance use and parenting (regulation, monitoring and caring). FINDINGS: A total of 22.6% of 16-year-old students in Europe gambled in the past year: 16.2% on-line, 18.5% off-line. High prevalence variability was observed throughout countries both for mode and types of game. With the exception of cannabis, substance use shows a higher association with gambling, particularly binge drinking [odds ratio (OR) = 1.46, 95% confidence interval (CI) = 1.39-1.53), life-time use of inhalants (OR = 1.57, 95% CI = 1.47-1.68) and other substances (OR = 1.78, 95% CI = 1.65-1.92)]. Among life habits, the following showed a positive association: truancy at school (OR = 1.26, 95% CI = 1.18-1.35), going out at night (OR = 1.32, 95% CI = 1.26-1.38), participating in sports (OR = 1.30, 95% CI = 1.24-1.37). A negative association was found with reading books for leisure (OR = 0.82%, 95% CI = 0.79-0.86), parents' monitoring of Saturday night activities (OR = 0.81, 95% CI = 0.77-0.86) and restrictions on money provided by parents as a gift (OR = 0.89, 95% CI = 0.84-0.94). CONCLUSIONS: Underage gambling in Europe appears to be associated positively with alcohol, tobacco and other substance use (but not cannabis), as well as with other individual behaviours such as truancy, going out at night and active participation in sports, and is associated negatively with reading for pleasure, parental monitoring of evening activities and parental restriction of money.

Integrated information for integrated care in the general practice setting in Italy: using social network analysis to go beyond the diagnosis of frailty in the elderly.

BACKGROUND: Frailty has been defined in different ways and several diagnostic tools exist, but most of them are not applicable in routine primary care. Nonetheless, general practitioners (GPs) have a natural advantage in identifying frailty, due to their continued access to patients, patient-centered approach and training. GPs have also an advantage in conducting population-based evaluation as consequence of their role of gatekeepers of the health care system. This paper aims to identify those socio-demographic and clinical profiles and the relative information sources that, from the GPs' perspective, act as frailty markers, not solely as a diagnosis of state but as the ability to identify a patient's trajectory, over time, through the aging process. METHODS: This study was performed as a survey within a population aged 75 and over, attending 148 GPs in Italy. A total of 23,996 patients were classified by GPs in distinct frailty status, without the use of a specific evaluation tool, but only referring to general indications. Co-morbidity was objectively assessed by a record-linkage with previous hospitalizations, in order to assess the occurrence of previous illnesses that could be associated with the likelihood of being identified as frails or at risk. The methodological approach is based on social network analysis (SNA), suited to explore relational aspects of complex phenomena. RESULTS: Our findings reveal that GPs are able to perform low cost population-based evaluation, by exploiting the advantages of their approach to patients, combined with the information derived from their daily practice and from other sources currently available. CONCLUSION: We believe that informative integration among different sources of available data can provide a comprehensive picture of the health state of patients in a shorter time and at lower cost. The identification of limited patient trajectories based on these observations can enable the development of critical biomarkers/diagnostics and prognostic indicators that will enhance patient care and potentially reduce inappropriate healthcare use. We also believe that network analysis is an extremely flexible research tool and a rich theoretical paradigm, and it may be used in the healthcare planning.

Poly-pharmacy among the elderly: analyzing the co-morbidity of hypertension and diabetes.

Clinical medicine faces many challenges, e.g. applying personalized medicine and genomics in daily practice; utilizing highly specialized diagnostic technologies; prescribing costly therapeutics. Today's population is aging and patients are diagnosed with more co-morbid conditions than in the past. Co-morbidity makes management of the elderly difficult also in terms of pharmacotherapy. The high prevalence of hypertension and diabetes as co-morbidities is indicative of the complexities that can impact accuracy in diagnosis and treatment, with poly-pharmacy being a significant component. It is essential to apply analytic methods to evaluate retrospective data to understand real world patients and medical practice. This study applies social network analysis, a novel method, to administrative data to evaluate the scope and impact of poly-pharmacy and reveal potential problems in management of elderly patients with diabetes and hypertension. Social Network Analysis (SNA) enables the examination of large patient data sets to identify complex relationships that may exist and go undetected either because of infrequent observation or complexity of the interactions. The application of SNA identifies critical aspects derived from over-connected portions of the network. These criticalities mainly involve the high rate of poly-pharmacy that results from the observation of additional co-morbid conditions in the study population. The analysis identifies crucial factors for consideration in developing clinical guidelines to deal with real-world patient observations. The analysis of routine health data, as analyzed using SNA, can be further compared with the inclusion/exclusion criteria presented in the current guidelines and can additionally provide the basis for further enhancement of such criteria.

The application of observational data in translational medicine: analyzing tobacco-use behaviors of adolescents.

BACKGROUND: Translational Medicine focuses on "bench to bedside", converting experimental results into clinical use. The "bedside to bench" transition remains challenging, requiring clinicians to define true clinical need for laboratory study. In this study, we show how observational data (an eleven-year data survey program on adolescent smoking behaviours), can identify knowledge gaps and research questions leading directly to clinical implementation and improved health care. We studied gender-specific trends (2000-2010) in Italian students to evaluate the specific impact of various anti-smoking programs, including evaluation of perceptions of access to cigarettes and health risk. METHODS: The study used, ESPAD-Italia® (European School Survey Project on Alcohol and other Drugs), is a nationally representative sample of high-school students. The permutation test for joinpoint regression was used to calculate the annual percent change in smoking. Changes in smoking habits by age, perceived availability and risk over a 11-year period were tested using a gender-specific logistic model and a multinomial model. RESULTS: Gender-stratified analysis showed 1) decrease of lifetime prevalence, then stabilization (both genders); 2) decrease in last month and occasional use (both genders); 3) reduction of moderate use (females); 4) no significant change in moderate use (males) and in heavy use (both genders). Perceived availability positively associates with prevalence, while perceived risk negatively associates, but interact with different effects depending on smoking patterns. In addition, government implementation of public policies concerning access to tobacco products in this age group during this period presented a unique background to examine their specific impact on behaviours. CONCLUSION: Large observational databases are a rich resource in support of translational research. From these observations, key clinically relevant issues can be identified and form the basis for further clinical studies. The ability to identify patterns of behaviour and gaps in available data translates into new experiments, but also impacts development of public policy and reveals patterns of clinical reality. The observed global decrease in use is countered by stabilization in number of heavy smokers. Increased cigarette cost has not reduced use. While perceived risk of smoking may prevent initial experimentation, how government policies impact the perception of risk is not easily quantifiable.

Characteristics of alcoholics attending 'clubs of alcoholics in treatment' in Italy: a national survey.

AIMS: To provide an overview of alcoholics attending a socio-ecological treatment programme [Clubs of Alcoholics in Treatment (CATs)] and to identify factors associated with abstinence and self-perceived improvement in lifestyle. METHODS: A national sample of 7522 subjects (76% males and 24% females, mean age 53.2 ± 11.3 years ± SD) attending CATs was evaluated using a self-administered questionnaire completed at a weekly meeting in 2006. RESULTS: Of participants, >70% reported no alcohol use in the last year and around 90% indicated no use in the previous month, whereas 4% of them declared no alcohol use before club attendance. Abstinence and lifestyle improvement were related positively to the number of years of club attendance but negatively to the presence of other problems in addition to the alcohol-related one. Moreover, being older or female was associated with more likely achievement of abstinence as well as with the perception of a better lifestyle. Finally, attending the club with one or more family members was associated with achievement of better lifestyle. CONCLUSION: These data provide an overview of alcoholics attending the CAT programme and are a first step toward developing a surveillance system. In addition, on the basis of this preliminary picture further research (notably longitudinal studies) can be planned considering this method and its effectiveness.

The association between overweight and illegal drug consumption in adolescents: is there an underlying influence of the sociocultural environment?

BACKGROUND: The aims of the study were to: a) Examine the distribution of gender-stratified body mass index (BMI), eating attitudes and use of addictive substances, under the hypothesis of a confluent prevalence of weight abnormalities, eating disorders and substance abuse. b) Demonstrate the extent to which family, peer-related and psychosocial factors are common elements in categories of compulsive behaviour. METHODOLOGY/PRINCIPAL FINDINGS: In the present cross-sectional study, data were collected through self reported questionnaires administered to a large sample of 33,185 15-19 years old adolescents (ESPAD®Italia), divided into weight categories based on the BMI percentile distribution. Multinomial analyses were adopted to address the influence of social, family, leisure time factors, Eating Attitude Test (EAT26) on the association between weight categories and drug use. Recent drugs use was more frequent in overweight and underweight adolescents (p<0.05), especially in females. An EAT26 score ≥20 was more common in overweight adolescents. Multinomial analysis abolished the relationship between overweight and the use of most drugs, implicating self-esteem, parents' educational level, and friendships as mediators of the association. Within the overweight category, adolescents reporting recent drug use, showed greater frequency of having drug-abusing friends (∼80%), and severe problems with parents and school (∼30%) compared to overweight adolescents without recent drug use. CONCLUSION: The frequent association of overweight and substance use and the presence of common underlying social factors, highlights the need for an interdisciplinary approach involving individual-focused treatment models as well as public health, social and environmental changes to reduce food- and substances-related problems.

High doses of intravenous calcitriol in the treatment of severe secondary hyperparathyroidism.

BACKGROUND: In hemodialysis (HD) patients, secondary hyperparathyroidism (HPTH) is a severe common disease. Calcitriol administration has been demonstrated as an effective therapy. In this prospective study, our aim was to determine the necessary calcitriol dose required to control severe HPTH preventing hypercalcemia or hyperphosphatemia and avoiding parathyroidectomy. METHODS: Eighteen dialysis patients suffering from severe HPTH during a 12-month period received intravenous (i.v.) calcitriol pulse doses (2-8 mcg/3x/week). Multislice helical computed tomography (CT) cardiac imaging was performed to measure coronary artery calcifications. RESULTS: Fourteen patients showed an improvement (parathyroid hormone (PTH) level < 400 pcg/mL), one patient an incomplete reduction, and three patients starting from PTH levels between 1100 and 2386 pcg/mL did not appear to benefit from the therapy. After a 6-month therapy in 15/18 patients PTH levels were significantly lower (p<0.05). In a large portion of the group, as well as in the control group, coronary calcification values were high when compared to the normal range. CONCLUSIONS: According to our data, we concluded that severe HPTH could be treated successfully by i.v. calcitriol pulse doses reaching high doses (up to 8 mcg/3x/week) and for a prolonged period of time (6 months). In such cases, close monitoring is necessary to prevent hyperphosphatemia and hypercalcemia episodes.