Association between atopic dermatitis and autoimmune diseases: a population-based case-control study.

BACKGROUND: Atopic dermatitis (AD) is a common chronic skin disorder and is well known to be associated with other atopic conditions. There is increasing evidence for an association also with nonatopic conditions, including autoimmune diseases, but data are limited about several autoimmune diagnoses. OBJECTIVES: To investigate the association between AD and autoimmune diseases. METHODS: This case-control study used Swedish national healthcare registers. The source population comprised the entire Swedish population aged ≥ 15 years from 1968 to 2016. Cases, including all those with an inpatient diagnosis of AD (from 1968) and/or a specialist outpatient diagnosis of AD (from 2001), were matched by sex and age to healthy controls (104 832 cases of AD, 1 022 435 controls). RESULTS: AD was significantly associated with one or more autoimmune diseases compared with controls - adjusted odds ratio (aOR) 1·97, 95% confidence interval (CI) 1·93-2·01 - and this association was significantly stronger in the presence of multiple autoimmune diseases compared with only one. The association was strongest for autoimmune disorders involving the skin (aOR 3·10, 95% CI 3·02-3·18), the gastrointestinal tract (aOR 1·75, 95% CI 1·69-1·82) or connective tissue (aOR 1·50, 95% CI 1·42-1·58). In the overall analysis, men with AD had a stronger association with rheumatoid arthritis and coeliac disease than did women with AD. In subanalyses, the findings remained stable in multivariable analyses after adjustment for smoking and parental autoimmune disease. CONCLUSIONS: This large population-based study indicates significant autoimmune comorbidity of adults with AD, especially between AD and autoimmune dermatological, gastrointestinal and rheumatological diseases. Having multiple autoimmune diseases resulted in a stronger association with AD than having only one autoimmune disease.

End-of-life care for hospitalized patients with metastatic melanoma in France: a nationwide, register-based study.

BACKGROUND: Although the aggressiveness of end-of-life cancer care has come under great scrutiny over the past two decades, little is known about the intensity of care and treatments in the last months of life of patients with metastatic melanoma. OBJECTIVES: To measure the prevalence of aggressive cancer care use, and to assess the frequency of palliative care referral over the course of the last 3 months of life of hospitalized patients who died from metastatic melanoma. METHODS: A nationwide register-based study in France was carried out, including all hospitalized adults aged ≥ 20 years who died from metastatic melanoma in metropolitan France between 2010 and 2013. RESULTS: Of 3889 patients who died from metastatic melanoma, 51·9% received chemotherapy in the last 3 months before death, 25·9% in the last month, 12·9% in the last 2 weeks and 7·6% in the last week. On average, patients were hospitalized for 31·7 days over the course of their last 3 months of life. During the final month before death, 12·0% of patients received radiation therapy, 14·0% received blood transfusion, 12·1% were transferred into an intensive care unit and 19·7% remained hospitalized continuously. Palliative care needs were identified in 78·4% of patients, with variations according to the type of facility. In total 17% of all patients died in palliative care inpatient units. CONCLUSIONS: Treatment intensity near the end of life of patients with metastatic melanoma raises concerns for the quality of care. There is a need for clinical guidelines and adequate support to facilitate patient-physician communication and to improve access to palliative care services.

Risk of basal cell carcinoma in Swedish organ transplant recipients: a population-based study.

BACKGROUND: Risk of basal cell carcinoma (BCC) has been reported to be several-fold increased among organ transplant recipients (OTRs). However, due to lack of reliable BCC registration, population-based risk estimates are scarce. OBJECTIVES: To characterize risk of BCC among OTRs compared with the general population, and contrast with risk of cutaneous squamous cell carcinoma (SCC). SUBJECTS AND METHODS: OTRs transplanted during 2004-2011 were identified through national healthcare registers and linked with the nationwide Swedish BCC Register initialized in 2004. Relative risk of BCC was expressed as standardized incidence ratios (SIR) with 95% confidence intervals (CI). RESULTS: Altogether, 4023 transplanted patients developed 341 BCCs during follow-up. Compared with the general population, the relative risk of BCC was increased sixfold (SIR 6·1, 95% CI 5·4-6·9). The risk was higher in kidney and heart/lung than in liver recipients (SIRkidney 7·2, 6·3-8·3; SIRheart/lung 5·8, 4·0-8·2; SIRliver 2·6, 1·7-4·0), and risk increased with time since transplantation (Ptrend < 0·01). The SCC to BCC ratio was 1 : 1·7 and BCC developed earlier after transplantation than SCC. Distribution of anatomical sites and histological types did not differ substantially between OTR- and population-BCCs. CONCLUSIONS: Risk of BCC was strikingly elevated in OTRs compared with the general population. Risk was higher in kidney recipients and increased with follow-up time. These findings support a tumour-promoting effect of immunosuppressive drugs in BCC development. The low SCC to BCC ratio was possibly attributed to short follow-up time.

Merkel cell carcinoma incidence is increasing in Sweden.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare aggressive neuroectodermal skin cancer with a high recurrence rate and a high mortality rate. Risk factors for MCC are reported to include high age, UV exposure, Caucasian skin type and immunosuppression. The incidence is reported to be increasing. OBJECTIVE: The purpose of this study was to describe a Swedish cohort and calculate incidence. METHODS: The study design is a retrospective cohort study of population-based data for MCC collected by the Swedish Cancer Registry to determine the incidence of MCC in Sweden and the clinical characteristics of these tumours including demographics, TNM classification, body part distribution and overall survival after diagnosis. De-identified data were collected from 1993 to 2012. RESULTS: A total of 606 cases of MCC were identified during the study period. The median age was 81 years (range 21-99) and a majority, 54.4% were women but age-adjusted incidence is higher in men. The incidence (per 100,000) of MCC in Sweden in 1993-2012 increased from 0.09 to 0.20 for men and 0.12-0.17 for women, adjusted for age to the world standard population. For the both sexes, the increase was from 0.11 to 0.19 per 100 000, an increase of 73%. The most common site of the primary tumour was the head and neck, with 51.8% of the cases. The size of the tumour was <5 cm in 82.1% of the cases. The majority of the tumours (90.7%) had no known lymphatic spread and only a few patients had confirmed distant metastases (2.9%) when diagnosed. CONCLUSIONS: MCC is a rare disease in Sweden, but the incidence is increasing. This study supports the finding that high age, male sex and UV exposure are risk factors for MCCs. Interventions are required to increase awareness of MCC among clinicians and the public.

Time trends in risk and risk determinants of non-Hodgkin lymphoma in solid organ transplant recipients.

Organ transplantation increases risk of non-Hodgkin lymphoma (NHL), but long-term risk and time trends have seldom been evaluated. Immunosuppressive drug load is an important risk determinant, but the details are unclear. We studied NHL risk in a nationwide Swedish cohort of 11 081 graft recipients transplanted 1970-2008. Relative risks (RRs) were estimated within the cohort and versus the general population by age, sex, follow-up time and calendar period. NHL risk was also assessed by cumulative and average doses of immunosuppressive treatments in a nested case-control design throughout 1997 using conditional logistic regression. We observed 153 NHL cases during 97 853 years of follow-up. Compared with the general population, NHL risk was eightfold increased (RR 7.9; 95% confidence interval [CI] 6.6-9.4), and increased risks persisted after ≥15 years of follow-up among kidney (6.1; 95% CI 3.5-10) and nonkidney recipients (44; 14-103). Among nonkidney recipients, NHL risk was lower in the 2000s compared with the 1990s (0.5; 95% CI 0.3-1.0; p = 0.04). A high average dose of antithymocyte immunoglobulin (ATG) conferred an eightfold increased risk of NHL (OR 8.5; 95% CI 1.9-38). To conclude, posttransplant NHL risk decreased during the last decade among nonkidney recipients, possibly because of a more careful use of ATG, the introduction of new drugs, or both.

Allergy and autoimmune disease: a registry-based study.

BACKGROUND: Allergy and autoimmunity are two potential outcomes of a dysregulated immune system, but the relationship between them is unclear. It has been hypothesized that they could be inversely associated because of different T helper cell reactivity patterns. However, both positive and negative associations have been reported. Therefore, our aim was to perform a large epidemiological study with a defined allergic disease cohort. METHODS: During the years 1990-2002, 68 770 subjects were tested for total serum IgE (Total-IgE) and 72 228 were tested with Phadiatop for diagnosing allergic disease at Karolinska University Hospital, Stockholm, Sweden. This cohort was then linked with the Swedish Inpatient Registry 1968-2004 for a follow-up with regard to recorded discharges for 28 autoimmune diseases. We then used Cox regression and logistic regression to estimate the risk of autoimmune diseases in general in the allergy-tested subjects. RESULTS: Subjects with positive Phadiatop test were at a statistically decreased risk of subsequent autoimmune disease in comparison with subjects with negative test; hazard ratio (HR): 0.80 [95% (Confidence interval) CI: 0.68-0.94). Prior autoimmune disease was associated with a decreased risk of positive Phadiatop test [odds ratio: 0.83 (95% CI: 0.72-0.96)] in comparison with negative test. Subjects with highly elevated Total-IgE were at a statistically increased risk of a subsequent autoimmune disease in comparison with subjects with normal levels [HR: 1.36 (95% CI: 1.09-1.70)], but no association was found between prior autoimmune disease and different Total-IgE levels. CONCLUSION: The study supports the hypothesis that allergy, defined as positive Phadiatop test, could be inversely related to autoimmune disease but this association is weak.

Cancer risk in a population-based cohort of patients hospitalized for psoriasis in Sweden.

Studies of clinical series of psoriasis patients have suggested an increased risk of nonmelanoma skin cancer and melanoma; the risk of other neoplasms has rarely been studied. In order to assess the incidence of cancer in a nationwide series of psoriasis patients from Sweden, we followed up, for the years 1965-89, 9773 patients with a hospital discharge diagnosis of psoriasis made during 1965-83, who were alive and free from malignancy 1 y after first discharge. We compared their incidence of neoplasms with that of the national population by computing standardized incidence ratios (SIR). We observed a total of 789 neoplasms [SIR 1.37, 95% confidence interval (CI) 1.28, 1.47]. There was an increase in the risk of cancers of the oral cavity and pharynx (SIR 2.80, 95% CI 1.96, 3.87), liver (SIR 1.91, 95% CI 1.28, 2.74), pancreas (SIR 1.56, 95% CI 1.02, 2.23), lung (SIR 2.13, 95% CI 1.71, 2.61), skin (squamous cell carcinoma, SIR 2.46, 95% CI 1.82, 3.27), female breast (SIR 1.27, 95% CI 1.00, 1.58), vulva (SIR 3.24, 95% CI 1.18, 7.06), penis (SIR 4.66, 95% CI 1.50, 10.9), bladder (SIR 1.43, 95% CI 1.03, 1.92), and kidney (SIR 1.56, 95% CI 1.04, 2.25). The risk of malignant melanoma was decreased (SIR 0.32, 95% CI 0.10, 0.74). Despite some limitations (possible diagnostic misclassification, lack of data on treatment, relatively short follow-up), our study provides evidence against an increased risk of melanoma among patients hospitalized for psoriasis. In addition to nonmelanoma skin and genital cancers, patients hospitalized for psoriasis were at increased risk of several malignancies, in particular those associated with alcohol drinking and tobacco smoking.

Is phototherapy in neonates a risk factor for malignant melanoma development?

OBJECTIVE: To determine whether phototherapy of the newborn's sensitive skin could be a risk factor for malignant melanoma. DESIGN: Retrospective study from 1973 to 1992. SETTING: The Swedish Medical Birth Registry and the Swedish Cancer Registry. PATIENTS: Thirty cases of childhood malignant melanoma and 120 matched controls. INTERVENTION: None. MAIN OUTCOME MEASURES: Data in birth and cancer reports and from death certificates in Sweden. RESULTS: None of the patients with childhood malignant melanoma had received phototherapy, in comparison with 11 of the controls. This difference was not significant (P = .08; Fisher exact test). CONCLUSION: This preliminary report shows no significant risk of developing childhood malignant melanoma after phototherapy of the skin in neonates with hyperbilirubinemia. However, the median follow-up time was only 18 years.

Risk of melanoma with psoralen/ultraviolet A therapy for psoriasis. Do the known risks now outweigh the benefits?

Since the introduction in the 1970s of treatment with oral psoralens with longwave ultraviolet radiation in the A range (PUVA), there has been an increasing concern about the long term carcinogenic effect of the therapy. The main indication for PUVA is psoriasis, a common, chronic and intractable skin disease that affects 1 to 3% of the world's population. The effectiveness of PUVA in inducing and maintaining the remission of severe psoriasis has been amply documented. Although psoriasis is not a life-threatening disorder, it may be associated with restriction of activities and days lost to hospitalisation. Therefore, a number of systemic treatments such as methotrexate and cyclosporin have been used. None of these treatments has been as carefully studied for long term adverse effects as PUVA. The short-term adverse effects of PUVA are generally well known and tolerated. The major mid-term adverse effect, squamous cell carcinoma of the skin, has been well documented in a number of large-scale epidemiological studies that have led to recommendations such as to restrict the lifetime number of treatments. Although squamous cell carcinoma is potentially life-threatening, it is usually slow growing and can be adequately managed by proper surveillance, treatment and follow-up. The situation is quite different for malignant melanoma, which is often fast growing and fatal. Except for anecdotal reports, malignant melanoma has not been observed in PUVA patients until recently. However, a report of a cohort of 1380 patients with psoriasis has concluded that about 15 years after the first treatment the risk of melanoma is increased approximately 5-fold in patients treated with high doses. Although this report needs to be confirmed by other multicentre trials, it is alarming since the association between exposure to ultraviolet light and development of melanoma is well established both in humans and in experimental animals. Until this study is validated, it is recommended that the guidelines for PUVA therapy should be rigorously followed and that the contra-indications should be extended to include history or family history of melanoma and patients who have already received > 200 treatments.

Lichen planus and malignancy. An epidemiologic study of 2071 patients and a review of the literature.

The literature contains 36 reports of squamous cell cancer associated with lichen planus, and several reports on increased frequency of oral cancer in patients with oral lichen planus. To examine the risk of malignant transformation, 2071 patients with lichen planus were followed up for an average of 9.9 years. Only eight squamous cell carcinomas were observed in this population after the first visit for lichen planus, producing a morbidity ratio of 1.0 (95% confidence interval, 0.9 to 1.2). Significant increase for oral cancer was observed in male subjects, with a morbidity ratio of 5.9 (95% confidence interval, 2.5 to 11.4). This study indicates that patients with cutaneous lichen planus do not carry an increased risk of malignant transformation of the skin lesions or internally; however, there is increased risk of oral cancer.

Incidence of malignant skin tumors in 14,140 patients after grenz-ray treatment for benign skin disorders.

During the years 1949 to 1975, 14,237 patients received therapeutic doses of grenz rays for the treatment of benign skin disorders such as chronic eczema, psoriasis, and warts. The records of 14,140 of these patients (99.3%) formed the basis for an epidemiologic study of the incidence of skin malignancies in this population. Information about the patients, diagnoses, doses, and sites of treatment was obtained from separate records. The follow-up time was 15 years on the average. We searched the Swedish Cancer Registry, Stockholm, for records reporting the incidence of malignant skin tumors in the study population (incidences of basal cell carcinoma are not registered). The expected number of malignancies was calculated on the basis of age- and sex-standardized incidence data from the Swedish Cancer Registry. In 58 patients, a malignant skin tumor was diagnosed more than five years after grenz-ray therapy had first been administered. Nineteen patients had malignant melanomas, and 39 patients had other malignant skin tumors. The expected number of melanomas was 17.8, and that of other malignant skin tumors was 26.9. None of the patients with melanomas, and only eight of the patients with other malignant skin tumors, had received grenz-ray therapy at the site of the tumor. Six of these eight patients had also been exposed to other known carcinogens. Four hundred eighty-one patients had received an accumulated high dose of grenz rays (greater than or equal to 10 000 rad [greater than or equal to 100 Gy]) on one and the same area. No malignancies were found on those areas. Although we cannot exclude grenz-ray therapy as a risk factor in the development of nonmelanoma skin malignancies, this risk, if any, is small, if recommendations for therapy are followed.

Differences in malignant melanoma between children and adolescents. A 35-year epidemiological study.

OBJECTIVE: To investigate whether there was an increase of malignant melanoma in children. Malignant melanomas are rare in people younger than 20 years. Although melanoma represents one of the most rapidly increasing neoplasm in adults, it is rarely studied in children. DESIGN: Retrospective study from 1958 through 1992. SETTING: The compulsory Swedish Cancer Registry in Stockholm, Sweden. PATIENTS: We present 287 cases of malignant melanoma in patients younger than 20 years during 35 years in Sweden. INTERVENTION: None. MAIN OUTCOME MEASURES: Data from cancer reports and death certificates in Sweden. RESULTS: The study shows a strong increase in malignant melanomas in puberty after a presumably constant prevalence before the age of 14 years. The melanomas are more common in females (162) than males (125). The distribution was the same as in adults. Of 287 cases, 44 patients died as a result of their tumors (15.3%), with a median survival time of 3 years after diagnosis. CONCLUSIONS: The incidence of malignant melanoma during adolescence has doubled in 10 years. This is not the case for the incidence of melanomas in children younger than 14 years, which seems to be unchanged. It is necessary to be aware of the risk of malignant melanomas in children after puberty.

Pemphigoid and cancer.

To evaluate the significance of the association of malignant disease with bullous pemphigoid, we reviewed 497 consecutive cases with positive immunofluorescence tests for circulating antibodies to basement membrane. We searched the Swedish Cancer Registry, Stockholm, Sweden, for records reporting malignancies in the study population (1958 to 1985), and the expected number of malignancies was calculated on the basis of age- and sex-standardized incidence data. In 61 patients, a total of 69 malignancies were diagnosed. The expected number of malignancies was 82.6. In 25 patients, a total of 27 malignancies appeared during the same year as the onset of pemphigoid, or later. The expected number was 35.8. The median titer of circulating antibodies in the 497 patients, in the 61 patients with malignancy, and in the 25 patients with malignancy preceded by the pemphigoid, were not significantly different. We conclude that pemphigoid is not statistically associated with malignancy, and that the former hypothesis of such an association was based on age only.

Human hair form. Morphology revealed by light and scanning electron microscopy and computer aided three-dimensional reconstruction.

The alleged relationship between the cross sectional shape of the hair shaft and the form of the hair, eg, curly or straight hair, has been challenged. By serial sections of human hair follicles from ten patients representing the three biological races, the relation between the follicle form and the hair form was studied. Using three-dimensional computer-aided reconstruction it was demonstrated that the follicle form determines the hair form, eg, the Negroid follicle has a helical form, whereas that of the Oriental follicle is completely straight. The caucasoid follicle represent variation between these extremes. However, even a straight caucasoid follicle may produce a hair shaft that has an oval cross section.

Comparison of the carcinogenic potential of trioxsalen bath PUVA and oral methoxsalen PUVA. A preliminary report.

BACKGROUND AND DESIGN: There is an increasing concern about the long-term carcinogenic effect of oral psoralen with long-wave UV radiation in the A range (PUVA). Most follow-up investigations indicate a definite risk of squamous cell carcinoma of the skin with long-term PUVA treatment. In a recently published study of 4799 Swedish patients who had received PUVA, it was noted that 833 patients who had received trioxsalen bath or oral trioxsalen did not show any increased risk of skin cancer in contrast to oral methoxsalen. This finding has been further investigated in this study. We compared four dermatologic university clinics in Sweden with regard to the carcinogenic potential of the PUVA regimen used. One clinic used trioxsalen bath PUVA exclusively and the other three used oral methoxsalen. Information on their PUVA-treated patients was collected and linked with information from the Swedish Cancer Registry to identify individuals with squamous cell carcinoma of the skin. RESULTS: A total of 18 squamous cell carcinomas of the skin were reported in 2975 PUVA-treated patients until 1987. The expected number was 3.1. The center using bath PUVA only had no increased risk of squamous cell carcinoma of the skin in contrast to the three centers using oral methoxsalen-PUVA. The increased risk for male subjects from those centers varied from six to 13 times that in the general population, but for female subjects a significant increased relative risk was found only at one center. CONCLUSION: In this preliminary report, PUVA treatment with trioxsalen bath seems to be less carcinogenic than the oral dosage. However, differences in the patient populations might also have affected the outcome of the study. More information on this field is needed.

Psoralen photochemotherapy (PUVA) and pregnancy.

BACKGROUND AND DESIGN: Psoralen photochemotherapy (PUVA) may carry a risk of mutagenesis and teratogenesis. Using a medical birth registry and other health registries, infants born to women who had been treated with PUVA were identified. Exposure information was obtained from treating hospitals and from the license-granting agency. A total of 504 infants were born of pregnancies occurring after PUVA treatment, and 689 infants were born of pregnancies occurring before such treatment. In another 14 cases, treatment occurred during pregnancy. RESULTS: No increase in infant or child mortality or in the presence of congenital malformations could be seen after PUVA treatment. There was a marked increase in low-birth-weight infants when pregnancy occurred after treatment, and this is probably not explained by maternal smoking, but could be an effect of the underlying disease. CONCLUSIONS: The theoretical mutagenic and teratogenic effect of PUVA treatment apparently does not carry any significant risk for abnormal delivery outcome.

DMSA administration to patients with alleged mercury poisoning from dental amalgams: a placebo-controlled study.

The present investigation was performed to determine the effect of 14-day oral administration of meso-2.3-dimercaptosuccinic acid (DMSA) on the urinary mercury excretion and the potential reduction of blood and plasma mercury concentrations, and also to relate these effects to possible decrease of symptoms, allegedly associated with amalgam fillings. Twenty subjects, relating their symptoms to mercury from amalgam fillings, received 20 mg/kg DMSA or placebo for 14 days. Their symptoms and mood states were recorded during the study and at a check-up 3 months later. Interpretation was based on intra-individual differences. DMSA-treatment resulted in an average increase in urinary mercury excretion by 65% and a decrease in blood mercury levels of 0.04 microgram/L/day. At the check-up after 3 months, urinary mercury excretion had returned to the pre-treatment level. No treatment effect of DMSA was apparent on subjective symptoms and mood state. One statistically significant treatment effect was noted-a decrease in fatigue-inertia in the DMSA-group-but there was no demonstrable correlation with increased urinary excretion or decreased blood concentration of mercury. Three subjects showed hypersensitive reactions, probably DMSA-specific, at the end of the treatment period. This placebo-controlled study provides no scientific support for diagnostic or therapeutic administration of DMSA for symptoms allegedly associated with chronic mercury exposition from dental amalgam fillings.

Influence of grenz rays and psychological factors on experimental pruritus induced by histamine and compound 48/80.

The interaction between grenz rays and experimentally induced pruritus was evaluated in 14 healthy subjects. Grenz rays were administered once weekly for 4 weeks on restricted areas of the upper arms. Pruritus was evoked by intradermal injection of histamine and the histamine liberator compound 48/80. The results were compared with unconditioned values and with those obtained following a placebo treatment procedure. The influence of psychosocial and psychosomatic factors was also evaluated. Grenz-ray therapy reduced itch but not flare responses. The influence of grenz rays was, however, not statistically different from that observed after placebo treatment. Psychosocial and psychosomatic factors were good predictors of individual skin responsiveness. The results indicate that grenz rays do not interfere with experimental histamine-induced pruritus more than placebo and emphasize the importance of knowing individual characteristics and coping strategies.

Absence of mutagenic response to radiation from a video display terminal.

The standard Ames Salmonella test (TA 100) was used to detect the mutagenicity of radiation from a video display terminal. The Ames test is a sensitive assay that detects the ability of a chemical to damage deoxyribonucleic acid. It has also been employed to detect the mutagenicity of electromagnetic radiation. An extremely short distance (62 mm) from a video display terminal and an extremely high electrostatic field strength (250 kv/m) was employed. No mutagenic response was found in this test system.

Grenz ray therapy in dermatology. An experimental, clinical and epidemiological study.

Grenz rays (ultrasoft X-rays, Bucky rays) have been used in the treatment of benign skin disorders for more than 60 years. The mechanism of action, the clinical effect, and the potential carcinogenic effect have been mainly unknown, and many of the reported studies are obsolete today. In the present work these concepts have been studied by means of immuno-histological methods, transmission electron microscopy, patch testing, clinical evaluation and epidemiological methods. The results can be summarized as follows. The number of Langerhans' cells (OKT-6 positive cells) decreases in human epidermis after grenz ray radiation and this reflects a true disappearance of the Langerhans' cells as shown by electron microscopy. Grenz ray treatment was found to--suppress the expression of nickel allergy in sensitive individuals--have a tendency to suppress irritant skin reactions--have a very good effect on psoriasis of the scalp. Grenz ray therapy cannot be excluded as a risk factor in the development of non-melanoma skin tumors, but this risk factor is small, if any, when certain therapy recommendations are followed.