Prevalence of obesity and disturbances in glucose homeostasis in HIV-infected subjects and general population - missed diagnoses of diabetes?

OBJECTIVES: Comparative data on glucose disorders using fasting blood samples between people living with HIV (PLWH) and the general population are lacking. The objective of this study was to compare the prevalence and risk factors of obesity and disturbances in glucose homeostasis between PLWH treated with modern antiretroviral therapy and the general population. METHODS: Adjusted prevalence of obesity, features of insulin resistance (triglyceride:high-density lipoprotein cholesterol ratio and alanine aminotransferase), impaired fasting glucose (IFG), diabetes mellitus (DM) and combined dysglycaemia (presence of IFG or DM) were determined using fasting blood samples among 1041 PLWH and 7047 subjects representing the general population. RESULTS: People living with HIV had a lower prevalence of obesity [18.2%, 95% confidence interval (CI): 15.1-21.2 vs. 23.9%, 95% CI: 22.4-25.4], but a higher prevalence of insulin resistance and IFG (20.0%, 95% CI: 16.6-23.4 vs. 9.8%, 95% CI: 8.7-10.8) than the general population. Fasting glucose concentration was higher, but glycated haemoglobin (HbA1c) was lower, among PLWH. Prevalence of dysglycaemia for a given body mass index (BMI) was higher in PLWH than in the general population. The prevalence of DM did not differ between PLWH (13.2%, 95% CI: 10.2-15.9) and the general population (14.5%, 95% CI: 13.6-15.4). CONCLUSIONS: The prevalence of obesity was lower, but the risk of dysglycaemia for a given BMI was significantly higher, among PLWH, highlighting the importance of prevention and treatment of obesity among HIV-infected subjects. Regardless of the increased prevalence of insulin resistance and IFG, DM was surprisingly not more common among PLWH, raising concern about the under-diagnosis of DM, possibly due to low sensitivity of HbA1c in this patient population.

Population-based seroprevalence of Puumala hantavirus in Finland: smoking as a risk factor.

Puumala hantavirus (PUUV) causes hemorrhagic fever with renal syndrome in humans, that is an endemic disease in Finland. We estimated the seroprevalence of PUUV in Finland and explored risk factors and disease associations by using unique survey data with health register linkage. A total of 2000 sera from a nationwide health survey from 2011, representative of the adult population, were screened for PUUV IgG by immunofluorescence assay. We performed statistical analysis adjusting for stratified cluster design and taking into account sampling weights. In total, 254 sera among 2000 tested were PUUV-IgG-positive resulting in a weighted seroprevalence of 12.5%, (95% CI 10.9-14.4), mirroring known age and regional variation in reported incidence. No associations between PUUV-seropositivity and chronic diseases including cardiovascular (including hypertension), pulmonary, kidney disease and cancer were observed. Smoking was significantly associated with seropositivity (adjusted OR 1.54; 95% CI 1.16-2.04). In addition, significant dose-response relations were found for the number of cigarettes smoked daily (OR 1.14; 95% CI 1.12-1.28). The results are important for disease burden assessment and guide intervention strategies, highlighting also the role of smoking prevention.

Clostridium difficile infections in Finland, 2008-2015: trends, diagnostics and ribotypes.

We evaluated Clostridium difficile (CD) diagnostics in Finnish clinical microbiology laboratories during 2006-2011, with an update in 2015, in relation to CD surveillance data of the National Infectious Disease Register (NIDR) and ribotyping data from the national reference laboratory during the years 2008-2015. In 2011, diagnostic activity varied regionally more than three-fold and the positivity rate ranged between 7 and 21%. Nucleic acid amplification testing (NAAT) was implemented in the regions with high activity and NAAT users tested 30% more patients and found 15% more cases per population than those not using it. Culture was performed in 79% of laboratories, primary toxin testing by enzyme immunoassay (EIA) in 83% and by NAAT in 17%. In 2014, 12/19 laboratories used NAAT as the primary detection method and four as the secondary method, and ten cultured. Increasing usage of NAAT was not systematically related to various trends detected regionally in annual CD rates. Polymerase chain reaction (PCR) ribotyping of 1771 CD isolates (4.1% of CD cases) identified 146 distinct profiles, of which 37% were binary toxin positive. The most common ribotype was 027, but its proportion decreased, while 078 slightly increased. Transition from culture to NAAT in CD infection (CDI) diagnostics did not cause a significant increase in the observed CDI incidence. Major differences between diagnostic activity, methods and strategies in different regions have persisted over the years, which should be considered when comparing the regional epidemiology of CDI.

Regional differences in long-term cycles and seasonality of Puumala virus infections, Finland, 1995-2014.

Puumala hantavirus (PUUV) causes haemorrhagic fever with renal syndrome in humans, an endemic disease in Finland. We aimed to study recent trends in PUUV infections in Finland, to evaluate whether there are regional differences in seasonality and long-term cycles and whether the patterns have changed over time. We analysed serologically confirmed acute PUUV infections reported to the National Infectious Disease Register from 1 April 1995 to 31 March 2014. A total of 30 942 cases of PUUV infections were identified during the study period. The average annual incidence was 31 cases/100 000 person-years with the highest in Eastern Finland and the lowest in Southwestern Finland. Throughout Finland there was not an increasing trend in incidence but changes in incidence, seasonality and long-term cycles differed regionally. Long-term cycles supported by high Bayesian posterior probabilities (73-100%) differed between the south and the north, shifting from 3 to 4 years, respectively. Temporal changes in seasonality were most prominent in Southwestern Finland. The pattern of human PUUV infection epidemiology probably primarily reflects the spatio-temporal interaction between bank-vole population dynamics and climate.

Tuberculosis in immigrants in Finland, 1995-2013.

Increasing immigration from high tuberculosis (TB) incidence countries is a challenge for surveillance and control in Finland. Here, we describe the epidemiology of TB in immigrants by using national surveillance data. During 1995-2013, 7030 (84·7%) native and 1199 (14·4%) immigrant cases were identified. The proportion of immigrant cases increased from 5·8% in 1995 to 32·1% in 2013, consistent with increasing immigrant population (2·1-5·6%) and decreasing incidence of TB in the native population (from 12·1 to 3·5/100 000). TB cases in immigrants were significantly younger, more often female, and had extrapulmonary TB more often than native cases (P < 0·01 for all comparisons); multidrug resistance was also more common in immigrants than natives (P < 0·01). Immigrant cases were born in 82 different countries; most commonly in Somalia and the former Soviet Union/Russia. During 2008-2013, 433 Mycobacterium tuberculosis isolates from immigrants were submitted for spoligotyping; 10 different clades were identified. Clades were similar to those found in the case's country of birth. Screening immigrants from high-incidence countries and raising awareness of common characteristics and symptoms of TB is important to ensure early diagnosis and to prevent transmission.

Illness and injury of travellers abroad: Finnish nationwide data from 2010 to 2012, with incidences in various regions of the world.

The number of international tourist arrivals reached 1,000 million in 2012. Assessment of travellers' health problems has relied on proportionate morbidity data.Given the lack of data on number of visitors to each region, incidences have been impossible to calculate.This study, largest yet reporting travellers' health problems, is the first to present incidence of illness and injury. Data on Finnish travellers with health problems abroad during 2010 to 2012 were retrieved from the database of an assistance organisation,SOS International, covering 95% of those requiring aid abroad. The numbers were compared with those of Finnish travellers in the database of the Official Statistics of Finland. The SOS International database included 50,710 cases: infections constituted the most common health problem (60%), followed by injuries(14%), diseases of skin (5%), musculoskeletal system and connective tissue (5%), digestive tract (3%),and vascular system (2%). Gastroenteritis (23%) and respiratory infections (21%) proved the most frequent diagnoses. Overall incidence of illness or injury was high in Africa (97.9/100,000 travel days; 95% Bayesian credible interval (BCI): 53.1­145.5), southern Europe plus the eastern Mediterranean (92.3; 95% BCI: 75.4­110.1) and Asia (65.0; 95% BCI: 41.5­87.9). The data show significant differences between geographical regions, indicating the main risks and thus providing destination-specific tools for travelers' healthcare.

Incidence and seroprevalence of tularaemia in Finland, 1995 to 2013: regional epidemics with cyclic pattern.

We studied the incidence of reported tularaemia by year and region and the prevalence of antibodies against Francisella tularensis in the adult general population in Finland. Moreover, we assessed the correlation between vole population cycles and human tularaemia outbreaks. The seroprevalence study made use of serum samples from a nationwide population-based health survey (Health 2000). The samples of 1,045 randomly selected persons, representative for the Finnish population in each region, were screened with an enzyme-linked immunosorbent assay (ELISA) for the presence of IgG antibodies against F. tularensis, and positive results were further confirmed by immunoblotting. A serological response to F. tularensis was found in 2% (95% confidence interval: 1.1­3.5) of the population. Incidence and seroprevalence were highest in the same areas, and vole population peaks clearly preceded tularaemia outbreaks one year later.

Coincidental detection of the first outbreak of carbapenemase-producing Klebsiella pneumoniae colonisation in a primary care hospital, Finland, 2013.

In Finland, occurrence of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP) has previously been sporadic and related to travel. We describe the first outbreak of colonisation with KPC-KP strain ST512; it affected nine patients in a 137-bed primary care hospital. The index case was detected by chance when a non-prescribed urine culture was taken from an asymptomatic patient with suprapubic urinary catheter in June 2013. Thereafter, all patients on the 38-bed ward were screened until two screening rounds were negative and extensive control measures were performed. Eight additional KPC-KP-carriers were found, and the highest prevalence of carriers on the ward was nine of 38. All other patients hospitalised on the outbreak ward between 1 May and 10 June and 101 former roommates of KPC-KP carriers since January had negative screening results. Two screening rounds on the hospital's other wards were negative. No link to travel abroad was detected. Compared with non-carriers, but without statistical significance, KPC-KP carriers were older (83 vs 76 years) and had more often received antimicrobial treatment within the three months before screening (9/9 vs 90/133). No clinical infections occurred during the six-month follow-up. Early detection, prompt control measures and repetitive screening were crucial in controlling the outbreak.

Multinational outbreak of Salmonella Enteritidis infection during an international youth ice hockey competition in Riga, Latvia, preliminary report, March and April 2015.

A multinational outbreak of salmonellosis linked to the Riga Cup 2015 junior ice-hockey competition was detected by the Finnish health authorities in mid-April and immediately notified at the European Union level. This prompted an international outbreak investigation supported by the European Centre for Disease Prevention and Control. As of 8 May 2015, seven countries have reported 214 confirmed and suspected cases, among which 122 from Finland. The search for the source of the outbreak is ongoing.

Risk factors for pneumonic and ulceroglandular tularaemia in Finland: a population-based case-control study.

Few population-based data are available on factors associated with pneumonic and ulceroglandular type B tularaemia. We conducted a case-control study during a large epidemic in 2000. Laboratory-confirmed case patients were identified through active surveillance and matched control subjects (age, sex, residency) from the national population information system. Data were collected using a self-administered questionnaire. A conditional logistic regression model addressing missing data with Bayesian full-likelihood modelling included 227 case patients and 415 control subjects; reported mosquito bites [adjusted odds ratio (aOR) 9·2, 95% confidence interval (CI) 4·4-22, population-attributable risk (PAR) 82%] and farming activities (aOR 4·3, 95% CI 2·5-7·2, PAR 32%) were independently associated with ulceroglandular tularaemia, whereas exposure to hay dust (aOR 6·6, 95% CI 1·9-25·4, PAR 48%) was associated with pneumonic tularaemia. Although the bulk of tularaemia type B disease burden is attributable to mosquito bites, risk factors for ulceroglandular and pneumonic forms of tularaemia are different, enabling targeting of prevention efforts accordingly.

Telephone consultation cannot replace bedside infectious disease consultation in the management of Staphylococcus aureus Bacteremia.

BACKGROUND: Infectious disease specialist (IDS) consultation improves the outcome of Staphylococcus aureus bacteremia (SAB). Although telephone consultations constitute a substantial part of IDS consultations, their impact on treatment outcome lacks evaluation. METHODS: We retrospectively followed 342 SAB episodes with 90-day follow-up, excluding 5 methicillin-resistant S. aureus SAB cases. Patients were grouped according to bedside, telephone, or no IDS consultation within the first week. Patients with fatal outcome within 3 days after onset of SAB were excluded to allow for the possibility of death occurring before IDS consultation. RESULTS: Seventy-two percent of patients received bedside, 18% telephone, and 10% no IDS consultation. Patients with bedside consultation were less often treated in an intensive care unit during the first 3 days compared to those with telephone consultation (odds ratio [OR], 0.53; 95% confidence interval [CI], .29-.97; P = .037; 21% vs 34%), with no other initial differences between these groups. Patients with bedside consultation more often had deep infection foci localized as compared to patients with telephone consultation (OR, 3.11; 95% CI, 1.74-5.57; P < .0001; 78% vs 53%). Patients with bedside consultation had lower mortality than patients with telephone consultation at 7 days (OR, 0.09; 95% CI, .02-.49; P = .001; 1% vs 8%), at 28 days (OR, 0.27; 95% CI, .11-.65; P = .002; 5% vs 16%) and at 90 days (OR, 0.25; 95% CI, .13-.51; P < .0001; 9% vs 29%). Considering all prognostic markers, 90-day mortality for telephone-consultation patients was higher (OR, 2.31; CI, 95% 1.22-4.38; P = .01) as compared to bedside consultation. CONCLUSIONS: Telephone IDS consultation is inferior to bedside IDS consultation.

Antimicrobial prescribing in nursing homes in Finland: results of three point prevalence surveys.

PURPOSE: The purpose of this study was to analyse the Finnish European Surveillance of Antimicrobial Consumption (ESAC) nursing home (NH) point prevalence surveys' (PPSs) data in detail, i.e. to evaluate the variability in the prevalence of antimicrobial prescription between NHs and its relationship to resident characteristics. METHODS: All residents present in NHs for ≥ 24 h and receiving systemic antimicrobials on the day of the survey were included. Data on antimicrobials and their indications (prophylaxis or treatment, type of infection) were collected. RESULTS: Three PPSs were performed: eight NHs participated in April and November 2009 and nine in May-September 2010. In total, there were 5,691 eligible residents (range by survey, 1,706-2,320; range by NH, 60-688), 716 (12.6 %; range by NH, 3.2-33.3 %) of which received at least one antimicrobial and 40 residents received two. The most common indication was prophylaxis (487/5,691, 8.6 %), mainly for urinary tract infection (UTI) (460/487, 94.5 %). Of the residents, 269/5,691 (4.7 %, range by NH, 1.5-6.0 %) were on antimicrobial treatment. UTI (119/269; 44.2 %) was the most common indication for treatment. Methenamine (306/756, 40.5 %) was the most commonly used antimicrobial, followed by trimethoprim (13.6 %) and pivmecillinam (11.0 %). In the eight NHs participating in all three surveys, the prevalence of residents receiving antimicrobials decreased from 16.6 to 9.7 %. CONCLUSIONS: Antimicrobial use was common in NHs in Finland and most were used for UTI prophylaxis and treatment. The usage, however, varied among NHs and tended to decrease during the surveys. NHs may benefit from antimicrobial stewardship interventions focused on UTI.

Climatic, ecological and socioeconomic factors as predictors of Sindbis virus infections in Finland.

Mosquito-borne Sindbis virus (SINV) causes rash-arthritis syndrome in Finland. Major outbreaks with approximately 7-year cycles have caused substantial burden of illness. Forest dwelling grouse are suspected to be amplifying hosts, with the infection transmitted to humans by mosquito bites. SINV infection surveillance data for 1984­2010 were used to create a negative binomial hurdle model, with seasonality, long-term cycles, climatic, ecological and socioeconomic variables. Climatic factors during early summer and amount of snow in April described the occurrence and incidence of SINV infections. Regulated water shore and hatch-year black grouse density described the occurrence, while population working in agriculture, agricultural land(negative) and income (negative) described the incidence of the disease. The prediction for 2009 was 85 cases (95% prediction interval 2-1187), while the actual occurrence was 106. We identified novel and known risk factors. The prevention of SINV infections in regulated water areas by infected mosquito populations should be targeted.

Influenza-associated hospitalisations in Finland from 1996 to 2010: unexpected age-specific burden during the influenza A(H1N1)pdm09 pandemic from 2009 to 2010.

To assess the burden of influenza on the Finnish healthcare system, we analysed hospitalisations during 1996-2010 using the International Classification of Diseases codes potentially related to influenza and its complications from the national hospital discharge registry. To compare the influenza A(H1N1)pdm09 pandemic with previous influenza seasons in 1996-2009, we calculated hospitalisation rates by age- and diagnostic groups. We built a negative binomial regression model based on times series analysis to assess the impact of the pandemic. Influenza-associated hospitalisation rates were higher during the pandemic compared to pre-pandemic influenza seasons for 5-24 year-olds (incidence rate ratio (IRR): 1.52, 95% confidence interval (CI): 1.44-1.60) and 25-64 year-olds (IRR: 1.33, 95% CI: 1.29-1.36), but did not differ for persons aged ≥ 65 years (IRR: 0.98, 95% CI: 0.97-1.00). Hospitalisation rates exceeded the upper limit of the prediction line by 177% in 5-24 year-olds, 66% in 0-4 year-olds and 57% in 25-64 year-olds. During the influenza season of 2003/04, all age groups had higher-than-expected hospitalisation rates, whereas other seasonal peaks were only notable among persons aged ≥ 65 years. These age-specific differences in the hospital burden underscore the importance of the continuous surveillance of hospitalisations in order to evaluate immunisation priorities for seasonal influenza and pandemic preparedness including use of antiviral medication.

Low efficacy of three non-alcohol-based hand disinfectants utilizing silver polymer, lactic acid and benzalkonium chloride on inactivation of bacteria on the fingertips of healthcare workers.

BACKGROUND: Recently, new non-alcohol-based hand disinfection formulae have come to the market. Although they have passed the EN1500 test, data on their clinical efficacy compared with alcohol-based hand rubs are scarce, mainly covering benzalkonium chloride (BAC). AIM: To test the efficacy of silver-polymer-based, lactic-acid-based and BAC-based hand disinfectant foams and an alcohol-based hand rub gel to reduce bacterial counts on the fingertips of healthcare workers working on hospital wards. METHODS: Each of the 84 participants tested one of the four products during their morning shift on a hospital ward using the 'fingertips on Petri dish' method before and after rubbing their hands with the product. After incubation, two independent readers assessed bacterial counts on the culture plates. FINDINGS: The alcohol-based hand rub efficiently reduced bacteria on testers' fingertips in the test situation, whereas the lactic-acid- and BAC-based disinfectants did not have any detectable efficacy. The silver-polymer-based formula had some effect but requires further study. CONCLUSION: Non-alcohol-based hand rubs require careful consideration and further study before they can be accepted for clinical use.

Disease burden of Puumala virus infections, 1995-2008.

Puumala virus (PUUV) causes mild haemorrhagic fever with renal syndrome, a rodent-borne zoonosis. To evaluate the disease burden of PUUV infections in Finland, we analysed data reported by laboratories to the National Infectious Disease Registry during 1995-2008 and compared these with data from other national registries (death, 1998-2007; hospital discharge, 1996-2007; occupational diseases, 1995-2006). A total of 22,681 cases were reported (average annual incidence 31/100,000 population); 85% were in persons aged 20-64 years and 62% were males. There was an increasing trend in incidence, and the rates varied widely by season and region. We observed 13 deaths attributable to PUUV infection (case-fatality proportion 0.08%). Of all cases, 9599 (52%) were hospitalized. Only 590 cases (3%) were registered as occupational disease, of which most were related to farming and forestry. The wide seasonal and geographical variation is probably related to rodent density and human behaviour.

Risk factors for death in a cohort of patients with and without healthcare-associated infections in Finnish acute care hospitals.

We evaluated risk factors for death among hospitalised patients with healthcare-associated infections (HCAIs) using the McCabe classification and Charlson index to predict mortality. The study consisted of a cohort of 703 patients with HCAIs and 7531 patients without HCAI in acute care hospitals participating in the Finnish national prevalence survey in 2005. We used Centers for Disease Control and Prevention definitions for HCAIs and recorded the McCabe classification for comorbidity. We used the date from the prevalence survey and the patient's national identity code in order to retrieve data from the National Hospital Discharge Registry on discharge diagnoses (International Classification of Diseases-10 codes) for the Charlson index and the dates of death from the National Population Information System. Of all inpatients, 425 (5.2%) died within 28 days from the prevalence survey date; the death rate was higher in HCAI patients than in those without HCAI (9.8% vs 4.7%, P<0.001). In the multivariate regression analysis age >65 years, intensive care, McCabe classification and Charlson index, gastrointestinal system infection and pneumonia/other lower respiratory tract infections were independent predictors for death. The survival analysis, when adjusted by McCabe class or Charlson index, showed that HCAI reduced survival only among patients without severe underlying diseases. Certain types of HCAI increased the risk of death. The McCabe classification had advantages over the Charlson index as a predictor of death, because it was easier to collect from a prevalence survey.

Incidence rates of Guillain Barré (GBS), chronic fatigue/systemic exertion intolerance disease (CFS/SEID) and postural orthostatic tachycardia syndrome (POTS) prior to introduction of human papilloma virus (HPV) vaccination among adolescent girls in Finland, 2002-2012.

BACKGROUND: In Finland a vaccination programme against human papillomavirus (HPV) was introduced in November 2013 for girls aged 11-12 years with a catchup for girls 13-15 years. Allegations that HPV vaccine is causing Guillain Barré syndrome (GBS) and non-specific diagnostic entities, such as chronic fatigue syndrome/systemic exertion intolerance disease (CFS/SEID) and postural orthostatic tachycardia syndrome (POTS), continue to surface. We examined population register-based incidence rates of CFS/SEID, GBS and POTS to provide baseline data for future HPV vaccine safety evaluations. METHODS: First diagnosis of CFS/SEID, GBS and POTS in girls aged 11-15 years were obtained from the National Hospital Discharge Register during 2002-2012. We considered the following ICD-10 codes: G93.3 for CFS; G61.0 for GBS and G90.9, G90.8, G93.3, I49.8 for POTS. We calculated incidence rates per 100,000 person-years with 95% confidence intervals (CI). RESULTS: In total, 9 CFS/SEID, 19 GBS and 72 POTS cases were identified. The overall incidence rate was 0.53/100,000 (95% CI; 0.27-1.01) for CFS/SEID, 1.11 (95% CI; 0.71-1.74) for GBS and 4.21 (95%CI; 3.34-5.30) for POTS. Significant relative increase in annual incidence rate with a peak in 2012 was observed in CFS/SEID (33% (95% CI; 3.0-70.3: p=0.029) and POTS (16.5% (95% CI; 7.8-25.9: p<0.05), but not in GBS (5.4% (95% CI; -8.4-21.3: p=0.460). CONCLUSIONS: Our findings provide baseline estimates of CFS/SEID, GBS and POTS incidences in Finland. However, rates based on register data should be interpreted with caution, especially for non-specific diagnostic entities for which internationally and even nationally agreed criteria are still being discussed. To assess the associations with HPV vaccine, methods using register linkage for cohort and self-controlled case series should be explored in addition to factors contributing to patients seeking care, treating physicians setting the diagnoses, and their preference of using of codes for these clinical entities.

Population-based burden of bloodstream infections in Finland.

Bloodstream infections (BSI) are a major cause of mortality, morbidity and medical cost, but few population-based studies have concomitantly evaluated BSI incidence and mortality. Data on BSI episodes reported to national, population-based surveillance by all clinical microbiology laboratories in Finland during 2004-07 were linked to vital statistics. Age-, sex and microbe-specific incidence and mortality rates were calculated. During 2004-07, 33 473 BSI episodes were identified; BSI incidence increased from 147 to 168 per 100 000 population (average annual increase, 4.4%; p <0.001). Rates were highest among persons ≥65 years and <1 year, and higher among male patients than female patients (166 versus 152 per 100 000). The most common aetiologies were Escherichia coli (27%) and Staphylococcus aureus (13%). Among male patients, 52% of BSI were caused by gram-positive bacteria compared with 42% among female patients (p <0.001). The overall 30-day case-fatality was 13%. Of the deaths, 32% occurred within 2 days, 70% were among people aged 65 years or more and 33% were caused by E. coli or S. aureus infections. The BSI mortality rate increased from 19 to 22 per 100 000 (average annual increase: 4.0%, p 0.01). Among people aged 25 years or more, the mortality rate was 1.4-fold higher in men than women (34 versus 25 per 100 000 population). Overall excess annual mortality from BSI in the population was 18 per 100 000. The substantial BSI burden among the elderly and among adult men highlights the need for developing and implementing effective interventions, particularly for BSI caused by E. coli and S. aureus. One-third of BSI deaths occurred early, emphasizing the importance of early identification and treatment.