Impact of caregiver burden on health-related quality of life and family functioning of carers of children with epilepsy at the Charlotte Maxeke Johannesburg Academic Hospital, South Africa

Background. The impact of caring for a child with a chronic disease on caregivers and their family functioning contributes to the child's adaptation to the disease.Objectives. To determine the impact of caregiver burden on the health-related quality of life (HRQOL) and family functioning of carers of children with epilepsy (CWE), and to determine factors associated with a high impact of caregiver burden.Method. A cross-sectional study was conducted among primary caregivers of CWE attending the Charlotte Maxeke Johannesburg Academic Hospital, South Africa. Participants had been involved in childcare for at least 6 months before study enrolment and all gave informed consent. Data regarding sociodemographic and epilepsy-related variables were obtained from questionnaires, including the 36-item family impact module of the Pediatric Quality of Life assessment tool. Scores in the lower quartile were considered indicative of a negative impact on HRQOL and poor family functioning.Results. Participants identified as experiencing a high impact of paediatric epilepsy care reported raw scores ≤31.3 for both caregiver burden and family functioning. The family functioning score correlated strongly with the caregivers' HRQOL score (p=0.78; p<0.001). Multivariate analysis identified a low level of education among caregivers and a high seizure frequency in patients as independent predictors of caregiver burden associated with a negative impact.Conclusion. Our findings suggest that the burden of caregiving in paediatric epilepsy among our study population impacts negatively on family functioning. The burden of care was associated with a low level of caregiver education and a high seizure frequency in their children

Phytotoxicity of polymetallic mine wastes from southern Tuscany and Saxony.

Restoration potential of mine wastes or approaches to improve soil conditions and to ameliorate phytotoxicity on these sites may be simulated in standardized greenhouse experiments. Plants can be cultivated side by side on materials from different origins in dilution series with defined admixtures of certain aggregates. Mine wastes used in the present study originated from Fenice Capanne (FC, Tuscany, Italy) and Altenberg (ALT, Saxony, Germany). Tailings of the Italian site contain high concentrations of lead, zinc, arsenic and sulphur while tin, wolfram, molybdenum and lithium are highly elevated in the German mine waste. We tested growth responses of five crop species and analyzed concentrations of various metals and nutrients in the shoot to evaluate the toxicity of the FC mine waste and found oilseed rape being the most and corn the least resistant crop. Interestingly, oilseed rape accumulated seven times higher levels of lead than corn without showing adverse effects on productivity. In a subsequent comparison of FC and ALT mine waste, we cultivated different species of buckwheat (Fagopyrum spec.), a fast growing genus that evolved in mountain areas and that has been shown to be tolerant to low pH and high concentrations of metals. We found that the FC mine waste was more toxic than the ALT substrate in F. tataricum and F. esculentum. However, lower admixtures of FC material (10%) resulted in stronger growth reductions than higher proportions (25%) of the mine waste which was primarily related to the slightly lower pH and higher availability of essential metals due to the admixture of sand. These results confirm the importance of managing the soil chemical and physical characteristics of wastelands and call for the development of assisted reclamation to prepare sites for regular biomass production.

Ordered nanopore arrays with large interpore distances via one-step anodization.

Preparation of pre-patterned alumina substrates using bottom-up techniques compatible with nanotechnology applications is still a challenge. We present a novel methodology to achieve superior order in 'anodic' alumina with large interpore distances by a convenient one-step anodization process. The use of transparent insulators renders such anodic layers applicable as templates for nanostructured photovoltaic or photoelectrochemical devices.

Significant performance enhancement of InGaN/GaN nanorod LEDs with multi-layer graphene transparent electrodes by alumina surface passivation.

Nanotextured surfaces provide an ideal platform for efficiently capturing and emitting light. However, the increased surface area in combination with surface defects induced by nanostructuring e.g. using reactive ion etching (RIE) negatively affects the device's active region and, thus, drastically decreases device performance. In this work, the influence of structural defects and surface states on the optical and electrical performance of InGaN/GaN nanorod (NR) light emitting diodes (LEDs) fabricated by top-down RIE of c-plane GaN with InGaN quantum wells was investigated. After proper surface treatment a significantly improved device performance could be shown. Therefore, wet chemical removal of damaged material in KOH solution followed by atomic layer deposition of only 10 [Formula: see text] alumina as wide bandgap oxide for passivation were successfully applied. Raman spectroscopy revealed that the initially compressively strained InGaN/GaN LED layer stack turned into a virtually completely relaxed GaN and partially relaxed InGaN combination after RIE etching of NRs. Time-correlated single photon counting provides evidence that both treatments-chemical etching and alumina deposition-reduce the number of pathways for non-radiative recombination. Steady-state photoluminescence revealed that the luminescent performance of the NR LEDs is increased by about 50% after KOH and 80% after additional alumina passivation. Finally, complete NR LED devices with a suspended graphene contact were fabricated, for which the effectiveness of the alumina passivation was successfully demonstrated by electroluminescence measurements.

A prospective comparison of times to presentation and treatment of regional and remote head and neck patients in North Queensland, Australia.

BACKGROUND/AIM: This study aims to examine differences between outer regional (OR) and remote/very remote (RVR) patients in northern Queensland, Australia in the times taken to receive various aspects of head and neck cancer management. METHODS: Our study prospectively recruited head and neck cancer patients presenting to three North Queensland regional hospitals from January 2009 to January 2011. Data on demographic and cancer-specific details, comorbidities and timing of presentation to various services, were collected using a self-administered questionnaire that included two questions in relation to possible reason for delays to health services. Multivariate linear regression analyses were conducted to assess the effects of various demographic characteristics on time delays. Survival and disease recurrence data were analysed in 2014. RESULTS: One hundred and fifty-eight patients participated. RVR patients had significantly longer median times between diagnosis and first treatment compared with OR patients (P = 0.015). Indigenous patients had significant delays from diagnosis to first treatment (P = 0.013) and visit to first specialist and treatment (P = 0.031) compared to non-Indigenous patients. Longer median times between symptoms and first treatment was associated with low income (P = 0.03) and lower education level (P = 0.04). Disease recurrence was higher for RVR patients compared with OR patients (P = 0.04), without significant differences in overall survival. Possible reasons for delays included patient and professional factors. CONCLUSION: Significant delays in various aspects of head and neck cancer management were associated with remoteness, Indigenous and socioeconomic status. While patient and professional factors could be addressed at local levels, sustainable improvement in outcomes requires a state and national level approach.

[Relationship Between General Cognitive Abilities and School Achievement: The Mediation Role of Learning Behavior]. / Zum Zusammenhang von allgemeinen kognitiven Fähigkeiten und schulischer Leistung: Welche Rolle spielt das Lernverhalten?

BACKGROUND: General cognitive abilities are still considered as the most important predictor of school achievement and success. Whether the high correlation (r=0.50) can be explained by other variables has not yet been studied. Learning behavior can be discussed as one factor that influences the relationship between general cognitive abilities and school achievement. METHODS: This study examined the relationship between intelligence, school achievement and learning behavior. Mediator analyses were conducted to check whether learning behavior would mediate the relationship between general cognitive abilities and school grades in mathematics and German. RESULTS: Statistical analyses confirmed that the relationship between general cognitive abilities and school achievement was fully mediated by learning behavior for German, whereas intelligence seemed to be the only predictor for achievement in mathematics. These results could be confirmed by non-parametric bootstrapping procedures. CONCLUSION: RESULTS indicate that special training of learning behavior may have a positive impact on school success, even for children and adolescents with low IQ.

Response of Australian veterinarians to the announcement of a Hendra virus vaccine becoming available.

DESIGN: A cross-sectional study of private veterinarians providing equine services in Queensland. RESULTS: The study revealed that a majority of veterinarians would support the introduction of a Hendra virus (HeV) vaccine. Moreover, almost half of the respondents intended to make vaccination a prerequisite to horse patient presentation. However, participants also responded that a vaccine would not reduce the risk sufficiently to cease or downgrade their HeV management plan and infection control measures. CONCLUSION: When devising promoting and marketing campaigns, government agencies and manufacturers should consider private veterinarians' intentions as a significant driver for the uptake of the HeV vaccine.

Functional relevance of genes implicated by obesity genome-wide association study signals for human adipocyte biology.

AIMS/HYPOTHESIS: Genome-wide association studies (GWAS) have identified numerous single-nucleotide polymorphisms associated with obesity, consequently implying a role in adipocyte biology for many closely residing genes. We investigated the functional relevance of such genes in human adipocytes. METHODS: We selected eight genes (BDNF, MAF, MTCH2, NEGR1, NPC1, PTER, SH2B1 and TMEM18) from obesity GWAS and analysed their effect in human adipogenesis using small interfering (si)RNA-mediated knockdown, their regulation by metabolic agents in adipocytes and pre-adipocytes, and gene expression in paired samples of human fat biopsies (68 non-obese, 165 obese) by quantitative real-time PCR. RESULTS: We show a two- to threefold upregulation of MAF, MTCH2 and NEGR1 and a two- to fourfold downregulation of BDNF and PTER during adipogenesis. Knockdown of BDNF (mean ± SEM; 83.8 ± 4.7% of control; p = 0.0002), MTCH2 (72.7 ± 9.5%; p = 0.0006), NEGR1 (70.2 ± 5.7%; p < 0.0001) and TMEM18 (70.8 ± 6.1%; p < 0.0001) significantly inhibited adipocyte maturation, while knockdown of the other proteins had no effect. Insulin slightly induced MAF (1.65-fold; p = 0.0009) and MTCH2 (1.72-fold; p < 0.0001), while it suppressed BDNF (59.6%; p = 0.0009), NEGR1 (58.0%; p = 0.0085) and TMEM18 (69.3%; p = 0.0377) in adipocytes. The synthetic glucocorticoid dexamethasone suppressed MAF (45.7%; p = 0.0022), BDNF (66.6%; p = 0.0012) and TMEM18 (63.5%; p = 0.0181), but induced NEGR1 (3.2-fold; p = 0.0117) expression. Furthermore, MTCH2, NEGR1 and TMEM18 were differentially expressed in subcutaneous and visceral adipose tissue. TMEM18 expression was decreased in the adipose tissue of obese patients, and negatively correlated with anthropometric variables and adipocyte size. CONCLUSIONS/INTERPRETATION: Our results imply a regulatory role for TMEM18, BDNF, MTCH2 and NEGR1 in adipocyte differentiation and biology. In addition, we show a variation of MAF expression during adipogenesis, while NPC1, PTER and SH2B1 were not regulated.

Serum markers lactate dehydrogenase and S100B predict independently disease outcome in melanoma patients with distant metastasis.

BACKGROUND: Established prognostic factors are of limited value to predict long-term survival and benefit from metastasectomy in advanced melanoma. This study aimed to identify prognostic factors in patients with distant metastasis. METHODS: We analysed overall survival of 855 institutional melanoma patients with distant metastasis by bivariate Kaplan-Meier survival probabilities and multivariate Cox hazard regression analysis. RESULTS: Serum lactate dehydrogenases (LDH), S100B, the interval between initial diagnosis and occurrence of distant metastasis, the site of distant metastases, and the number of involved distant sites were significant independent prognostic factors in both bivariate and multivariate analyses. Visceral metastases other than lung (hazard ratio (HR) 1.8), elevated S100B (HR 1.7) and elevated LDH (HR 1.6) had the highest negative impact on survival. Complete metastasectomy was likewise an independent prognostic factor in multivariate analysis. This treatment was associated with favourable survival for patients with normal LDH and S100B values (5-year survival, 37.2%). CONCLUSION: The serum markers LDH and S100B were both found to be prognostic factors in melanoma patients with distant metastasis. Furthermore, complete metastasectomy had an independent favourable prognostic impact in particular for the patient subgroup with normal LDH and S100B values.

Growth and risk factors for expansion of dilated popliteal arteries.

OBJECTIVES: The aims of this study were to investigate the change in maximum diameter of ectatic popliteal arteries during ultrasound surveillance and assess clinical predictors of their expansion. METHODS: Over a ten year period 67 patients with ectasia affecting one (n = 1) or both (n = 66) popliteal arteries entered this surveillance study. Patients were followed for a median of 3.1 years, at a median scan interval of 7.6 months. RESULTS: Growth of ectatic popliteal arteries was typically slow (<1 mm/yr). Initial artery diameter at entry to the study was not found to be predictive of subsequent growth. Seven patients followed for a median of 2 years had an expansion in popliteal artery diameter to >or=20 mm during follow-up. All of these patients had undergone aneurysm repairs at other arterial sites and none of them had diabetes. These participants also had a significantly higher rate of previous intervention of the contralateral popliteal artery in comparison to those that did not reach the 20 mm threshold (p < 0.001). Growth profiles of arteries that underwent significant expansion during surveillance were frequently characterised by a staccato pattern. CONCLUSIONS: Expansion of ectatic popliteal arteries is typically slow but difficult to predict. Trends observed in this study suggest that patients with extra-popliteal aneurysms, patients with previously treated contralateral popliteal artery ectasia and those who are not diabetics may be more prone to significant expansion. Further studies are required to validate these potential growth predictors.

Women with bulimic eating disorders: When do they receive treatment for an eating problem?

Variables associated with the use of health services were examined in a prospective, community-based study of women with bulimic-type eating disorders who did (n = 33) or did not (n = 58) receive treatment for an eating problem during a 12-month follow-up period. Participants who received treatment for an eating problem differed from those who did not in several respects, including higher body weight, higher levels of eating disorder psychopathology, general psychological distress, and impairment in role functioning, deficits in specific aspects of coping style, greater awareness of an eating problem, and greater likelihood of prior treatment for a problem with weight. However, the variables most strongly associated with treatment seeking were greater perceived impairment in role functioning specifically associated with an eating problem and greater perceived inability to suppress emotional difficulties. These were the only variables that were significantly associated with treatment seeking in multivariable analysis. The findings suggest that individuals' recognition of the adverse effects of eating-disordered behavior on quality of life may need to be addressed in prevention and early intervention programs for eating disorders.

Head lice prevalence in primary schools in Victoria, Australia.

OBJECTIVES: To determine the prevalence of and assess risk factors associated with head lice infections (pediculosis) in children from government primary schools in Victoria, Australia. METHODS: Between May and October 2001, children were selected by clustered random sampling of schools and classes, then examined for head lice using hair conditioner and a fine-toothed head lice comb. There were 1838 children screened from 16 primary schools. Risk factors evaluated included metropolitan or rural residence, school class, gender and hair length. RESULTS: Thirteen percent of children (239/1838) had an active infection (95% CI, 10.9-15.1) and 3.3% (61/1838) had an inactive infection (95% CI, 2.0-4.6). Prevalence of active pediculosis varied between schools from 0 to 28%. Our screening identified no more than one case per class in the majority of classes screened (58.5%). Females were 2.2 times more likely to have active infection than males (95% CI [1.7,2.9]) and there was no significant difference for the other risk factors investigated. CONCLUSIONS: Our study demonstrated the prevalence of head lice varied across Victoria and showed that risk factors commonly attributed to head lice infections did not hold true. Our findings support the premise that traditional ad hoc mass school-based screening may not be the best use of resources when controlling head lice. We suggest a more pragmatic community-based approach.

Do all fair-skinned Caucasians consider themselves fair?

BACKGROUND: Fair skin color is a risk factor for skin cancer. We aimed to determine whether Caucasians have an accurate perception of their skin color. METHODS: A convenience sample of 341 Caucasian adults in Townsville, Queensland, Australia was asked to categorize the color of their unexposed skin as fair, medium, or olive. Reflectance was measured on the inner upper arm (400-700 nm) for each subject to provide an objective measure of inherent skin pigmentation. RESULTS: The median skin reflectances at 685 nm for the olive (68.7%), medium (68.9%), and fair (71.9%) perception groups were very similar and were within the reflectance range generally associated with a fair/light complexion (>/=67%). Of those with a skin reflectance >/=67%, 46.6% considered their skin medium or olive. Agreement between perceived and measured skin color was poor (kappa = 0.113), with 36.4% over-estimating and 16.4% under-estimating their skin's natural pigmentation. CONCLUSIONS: Some Caucasians over-estimate their skin pigmentation and possibly the level of protection from sunlight this affords them. Skin cancer prevention campaigns that attempt to target those at greater risk of skin cancer, on the basis of fair/light skin color, are likely to fail, as many of these individuals don't consider themselves fair.

Sun exposure at school.

There is strong evidence that sun exposure during childhood and adolescence plays an important role in the etiology of skin cancer, in particular cutaneous melanoma. Between the age of 6 and 18, most children and adolescents will spend around 200 days per year at school and may receive a substantial fraction of their daily total solar ultraviolet radiation (UVR) exposure while at school. This study estimated the average daily erythemally effective dose of 70 grade 8 students from a high school in Townsville during 5 school days in July 1998. Through UV measurements of shade locations at the school and a combination of frequency counts and a questionnaire of grade 8 students, it was possible to determine the fraction of solar UVR reaching under the shade structures during lunch breaks and routine outdoor activities. Also, a routinely operating UV-Biometer provided the annual variation of the daily dose that was used to calculate exposure levels for the 70 students. Our results suggest that up to 47% of the daily total dose fell within the time periods where students were outdoors during school hours. For students not seeking shade structures during the breaks (which usually was the case when involved in sport activities such as basketball or soccer), the average daily dose could have been as high as 14 SED (standard erythemal dose). Using results from the questionnaire of 70 grade 8 students, their average annual dose while at school was 414 SED or 2 SED per school day. However, the distribution of average daily erythemal effective dose per grade 8 student over the whole year showed that on 31% of all school days in 1998, this dose was exceeded. Because most previous attempts to change arguably poor sun-protective behavior of young Australian children and adolescents at school showed little success, one way of decreasing the amount of harmful UVR reaching unprotected skin is the more careful design of shade structures at schools.

Ultraviolet light exposure, pigmentary traits and the development of melanocytic naevi and cutaneous melanoma. A case-control study of the German Central Malignant Melanoma Registry.

The present study firstly aimed at understanding the relationship between sun exposure, pigmentary traits and the history of sunburns. Secondly, the significance of UV-exposure for cutaneous melanoma and for melanocytic naevi was investigated. The case-controlled study comprised 513 patients with primary cutaneous melanoma and 498 controls matched by age and gender. Multivariate logistic regression analysis was used to study melanoma risk factors. The number of common melanocytic naevi was associated with age, gender, the history of sunburns and UV-exposure during holidays (odds-ratio = 1.9; 95% confidence interval = [1.1, 3.4]) for 3 weeks or more. The number of atypical melanocytic naevi was significantly related to age, gender, pigmentary traits, the history of sunburns and UV-exposure during holidays (odds-ratio = 3.5; 95% confidence interval = [1.4, 9.0]) for 2 months or more. The results of the present study showed that both the history of sunburn and intensive sun exposure during holidays were important for the development of melanocytic naevi and, therefore, indirectly for cutaneous melanoma. In addition, a particular type of pigmentation was found to be related to atypical melanocytic naevi.

Changes in abundance and behaviour of vector mosquitoes induced by land use during the development of an oil palm plantation in Sarawak.

Surveys were conducted of adult and immature mosquitoes in an area undergoing oil palm development in north Sarawak. Point prevalence data from 2 sites were collected annually, coinciding with annual phases of forest clearing, burning/cultivation, and maintenance. Major habitat perturbation during the forest/clearing transition shifted the major mosquito faunal equilibrium in terms of species composition, relative density and occurrence. Analyses of variance showed that the mean numbers of 4 species of Anopheles decreased significantly after forest clearing. Relative densities of immature stages decreased after forest clearing, but A. letifer and Culex tritaeniorhynchus remained relatively unchanged after the second year. Comparisons with the pre-development forest stage showed that the reductions in person-biting rates, adult survival and combined entomological inoculation rates (EIR) of A. donaldi and A. letifer decreased the risk of malaria transmission by 90% over the 4 years period. Concomitant reductions in EIR and annual malaria incidence were also correlated. This study highlighted the 'law of unintended consequences', since 2 contrasting effects were observed: reduction of malaria vectors but concomitant increase of dengue vectors.

Enhanced interaction of patients' lymphocytes with human dermal microvascular endothelial cell cultures in active Adamantiades-Behçet disease.

BACKGROUND AND DESIGN: To elucidate the role of lymphocyte/endothelial cell interactions in patients with Adamantiades-Behçet disease (ABD), we studied 16 patients of German and Turkish nationality (aged 18-57 years), all with active ABD, and 12 healthy volunteers (controls) of similar age and nationality. Peripheral blood lymphocytes (PBL) of patients were coincubated with human dermal microvascular endothelial cells (HDMEC) and human keratinocytes (HK) in vitro; interactions of PBL with HDMEC and HK were investigated using an established fluorometric assay. Interactions of patients' PBL with HDMEC, HK, or both were the main outcome measures. RESULTS: A significant increase of fluorescence with increasing PBL/HDMEC ratios was seen in patients and controls (P < .001); patients showed a significantly higher increase of fluorescence at higher PBL/HDMEC ratios (P < .05). The PBL/HK coincubation did not show significant alterations compared with the basal fluorescence signals of HK monolayers alone. Peripheral blood lymphocyte and HDMEC fluorescence values that were more than 2 SDs of controls (defined as positive result of assay) were found in a significantly higher number of patients with 2 or more active symptoms at the time of investigation (83%) compared with patients with only 1 active symptom (10%) (P = .008). Other clinical data did not correlate with the results of the PBL/HDMEC coincubation assay. CONCLUSIONS: Our results indicate enhanced in vitro interaction of PBL from patients with ABD with HDMEC, which was additionally shown to be a marker of the activity of the disease.

A colorimetric immunoassay for the detection of E-cadherin and carcinoembryonic antigen (CEA) expression on human colon carcinoma cell lines in vitro.

An immunohistochemical assay, using 96-well microtiter plates and based on the avidin-biotin peroxidase reaction, was developed for the quantitation of E-cadherin and CEA expression on HT-29 and SW620 colon carcinoma cells. The optical density of the generated dye was measured after solubilization with alkaline SDS solution. The staining procedure was evaluated with respect to reproducibility (coefficient of variation and intra-class correlation coefficient). On HT-29 cells the level of agreement for both E-cadherin and CEA were substantial, on SW620 cells almost perfect. The method allows testing compounds for their differentiation inducing capacity in screening programmes on the basis of protein marker expression.

[Elective lymph node dissection in primary malignant melanoma]. / Elektive Lymphknoten-dissektion bei primärem malignen Melanom.

The role of elective lymph node dissection (ELND) in primary malignant melanoma is controversial. Our purpose was to evaluate the benefit of ELND regarding survival and disease-free survival in malignant melanoma of the trunk and extremities. By matched-pair analysis, 375 patients treated by wide local excision (WLE) plus ELND were compared to 375 patients treated by WLE only. There was no difference in survival between the two treatment groups; however, the disease-free interval was significantly higher in the collective treated by WLE plus ELND (P < 0.05). Increased survival rates were noted for intermediate tumor thickness of 1.51-4.0 mm for the WLE+ELND group although the difference was not significant (P = 0.14), and disease-free survival was significantly improved in this group (P < 0.001). ELND elicited a higher benefit in male patients with intermediate thickness melanoma. Our results confirm the findings of several studies that ELND improves the outcome after primary treatment of malignant melanoma of intermediate tumor thickness.

[Management of primary malignant melanoma of the skin in German-speaking countries 1983-1993. A study of the Malignant Melanoma Central Register of the German Society of Dermatology]. / Die Versorgung des primären Malignen Melanoms der Haut im deutschen Sprachraum in den Jahren 1983 bis 1993. Eine Studie des Zentralregister Malignes Melanom der Deutschen Dermatologischen Gesellschaft.

During the past decade more than 90% of all melanoma patients in the German-speaking countries have been diagnosed with a primary tumour alone. Therefore, surgical intervention has been the most important element in the management of these patients. The present investigation was performed to analyse the different surgical procedures used in the treatment of primary melanoma during the years 1983-1993. The primary treatment of 15,054 patients with malignant melanoma and without recognizable metastasis has been examined. During the time period under investigation the percentage of cases treated with two-step surgical management increased from 30% to 60%. Primary excision was performed in local anaesthesia in 40% of all patients in 1983, whereas in 1993 surgical intervention under local anaesthesia had increased up to 80%. Over the same time, the average safety margin decreased from 33 mm to 21 mm for the final excision of primary melanomas, and this decrease was paralleled by marked decrease in the average thickness of the tumours excised from 2.1 to 1.5 mm. Elective node dissection was performed in 5% of all patients in 1983, whereas 9% of patients underwent elective node dissection in 1993. The different centres participating were found to differ noticeably in the therapeutic procedures applied for similar indications. In conclusion, the management of primary malignant melanoma has changed considerably during the years 1983-1993 in the German speaking area in favour of a two-step surgical procedure, local anaesthesia for the excision of the primary tumour and smaller safety margins. It seems that earlier diagnosis of the tumour and also ideas about treatment design may be responsible for these changes.