Although the consumption of vegetables and fruits is reported to influence the risk of cataract, no prospective study of this association from Asia has yet appeared. Here, we investigated the association between vegetable and fruit intake and cataract incidence in a large-scale population-based prospective cohort study in Japan.This study included 32,387 men and 39,333 women aged 45–74 years who had no past history of cataract and had completed a dietary questionnaire of the Japan Public Health Center-based Prospective Cohort Study. The incidence of cataract was evaluated after 5-year follow-up. We used multiple logistic regression analyses to estimate the sex-specific odds ratios (ORs), with adjustment for confounding factors.Q5 vs Q1, 0.77; 95% confidence interval [CI], 0.59–1.01; Ptrend across quartile categories = 0.03) and cruciferous vegetables . In contrast, the OR for cataract was increased with higher intake of vegetables among women . Green and yellow vegetable and fruit intake were not associated with cataract in either sex.We identified 1,836 incident cataracts in 594 men and 1,242 women. In men, the OR for cataract was decreased with higher intake of vegetables (ORThis study suggests that vegetables may reduce the risk of cataract in men, but not in women. Visual impairment due to cataract increases the risk of falling4,5 and is associated with decreased cognitive function6,7 in elderly people. These findings warrant ongoing and focused epidemiological research on lifestyle prevention of cataract in the elderly.Age-related cataract is the leading cause of visual loss and blindness globally, with almost 20 million people affected.8–15 A meta-analysis indicated that higher consumption of vegetables might reduce cataract risk, mainly in American and European populations.15 Prospective cohort studies reported that the intake of vegetables and fruits, which include lutein, vitamin C, and vitamin E, may reduce the risk of cataracts,9,10,13 and that vegetarians had lower risk of cataract than meat eaters among British residents.14Many studies have reported the association of cataract and foods, including vegetables.16 ultraviolet (UV) radiation exposure,17 steroid,18 diabetes mellitus,19,20 and high body mass index.21–23 Accordingly, it has been speculated that high doses of antioxidants, such as vitamin A, vitamin C, vitamin E, and β-carotene, may help prevent age-related cataract formation. Indeed, recent meta-analyses reported that such antioxidant intake might be associated with reduced cataract risk.24–26 Moreover, a recent study reported that cruciferous vegetables containing isothiocyanates protect lens cells against oxidative stress.27 Green and yellow vegetables are rich in carotenes and lutein, and a number of studies have reported an association between lutein and carotene and cataract risk.8–10 To date, however, no prospective study has reported the relationship between vegetables and fruits and cataract risk in Asia, although a previous case-control study in India reported that mean vegetable and fruit intakes were lower in cataract patients than in controls (P < 0.001).28Lens opacities in cataracts may occur as a result of lens protein damage by oxidative stress due to smoking,Here, we investigated the association between vegetable and fruit intake and incidence of cataract among middle-aged Japanese in a large-scale population-based prospective cohort study in Japan.29 Cohort I participants were residents aged 40–59 years in 1990 from five public health center areas , while those of cohort II included residents aged 40–69 years in 1993 from six public health center areas .The Japan Public Health Center-based Prospective (JPHC) Study was initiated in 1990 for cohort I and in 1993 for cohort II.A questionnaire survey was carried out at baseline and at 5- and 10-year follow-up. The questionnaire was self-administered and included information on medical history and lifestyle, such as smoking and drinking habits and diet and vitamin supplement use at the time of the survey. We used the 5-year follow-up survey in place of the baseline survey as starting point for the present analysis because it provided more comprehensive information on dietary intake.Ethics approval was obtained from the Institutional Review Board of the National Cancer Center and Keio University.Participant numbers were 103,880 in the 5-year (starting point) and 99,512 in the 10-year follow-up survey. Of these, 87,290 people participated in both surveys. We confirmed the diagnosis of age-related cataract using the following questions at the 5- and 10-year follow-up surveys: “Has a doctor ever told you that you had cataracts?”30We previously confirmed the validity of self-reported data on cataracts using a medical records review. We randomly selected 97 cases from 1,072 residents who self-reported a cataract diagnosis for cohort I. A total of 53 cases had permitted the review of medical records and had answers with regard to cataract diagnosis for validation study. We compared the self-reported response ‘I have been diagnosed as having cataracts’ with medical records and found that the positive predictive value of a self-reported diagnosis of age-related cataract was confirmed in 49 of 53 self-reporters (92.5%).We excluded 4,361 participants who had been diagnosed with cataract at the starting point. Of the remainder, 2,321 were diagnosed with age-related cataract at the 10-year follow-up survey  and confirmed to have age-related cataract. Of 82,929 participants, we excluded 1,308 who had missing information on the frequency of vegetable intake; 4,078 in either the upper or lower 2.5% of sex-specific total energy intake; and 5,823 with a history of cancer, cardiovascular diseases, and diabetes mellitus, leaving 71,720 for final analysis, consisting of 32,387 men and 39,333 women.31,32 including total fruits (16 fruit items), total vegetables (30 vegetable items), cruciferous vegetables (11 vegetable items), and green and yellow vegetables (16 vegetable items) during the previous year.The 5-year follow-up survey used food frequency questionnaires that were designed to estimate dietary habits. They included questions on the intake of 138 food items,33 and pickled Chinese radish, rape and leaf mustard, and Chinese leaves as pickled cruciferous vegetables. Green and yellow vegetables consisted of 10 green and yellow vegetables and one pickled green and yellow vegetable: broccoli, carrots, Chinese chives, chingensai, crown daisy, green beans, komatsuna, leaf mustard, mugwort, pickled green leafy vegetables, pumpkin, spinach, sweet pepper, Swiss chard, tomato, and tomato juice. Total fruits constituted of 16 fruits: papaya, mandarin oranges, other oranges, apples, persimmons, strawberries, grapes, melons, watermelon, peaches, pears, kiwifruit, pineapple, bananas, 100% orange juice, and 100% apple juice.The FFQ inquired about the usual consumption of 30 vegetables . Total cruciferous vegetables consisted of eight cruciferous vegetables and three pickled cruciferous vegetables: cabbage, Chinese radish, broccoli, komatsuna, Chinese leaves, pak choi, leaf mustard, and Swiss chard as cruciferous vegetables adopted in the IARC Handbooks of Cancer Prevention,Each food item was given nine options of consumption frequency, ranging from rarely (less than once a month) to seven or more times a day. Standard portion sizes for each food item were divided into the three options of small , medium (standard serving size), or large . The daily intake of each food was calculated by multiplying the daily consumption frequency and relative portion size for each food item.34 Food intakes were divided into quartiles. For the validity of food intake measurements from the FFQ and 28-day dietary records, Spearman’s rank correlation coefficients were 0.22 in men and 0.32 in women for vegetable intake and 0.41 in men and 0.23 in women for fruit intake in cohort I31; and 0.35 in men and 0.43 in women for vegetable intake and 0.50 in men and 0.30 in women for fruit intake in cohort II.32 These results reveal that the FFQ can be used to rank individuals according to food intake in the JPHC Study.The intake of each food item was adjusted for total energy intake using the residual method.Multiple logistic-regression analyses were used to calculate the sex-specific odds ratios (ORs) and 95% confidence intervals (CIs) of cataract incidence according to quartiles of total vegetables, cruciferous vegetables, green and yellow vegetables, and fruits.16,23,35 These were adjusted for age, area, and the following potential confounding factors: body-mass index (BMI), calculated as weight (kg)/height squared (m2) and grouped into four categories ; smoking status ; weekly alcohol intake (g/week), using four levels of consumption in men  and in women ; total fruit intake, which was an adjustment factor in the analysis of total vegetable, cruciferous vegetable, and green and yellow vegetable intake ; vitamin supplement intake (yes or no); and fundus photographic examination (yes or no). Furthermore, we calculated P interaction values using a likelihood-ratio test to compare logistic models with and without cross-product terms for smoking (non-smokers or smokers) and age (<60 or ≥60 years).Multivariate adjustment used covariates with risk factors known or suspected to affect cataract incidence.All statistical analyses were performed with SAS version 9.4 .Table P for trend = 0.03) and 0.74  (P for trend = 0.02), respectively. The multivariate ORs for the highest versus lowest quartile of green and yellow vegetable and total fruit intake were 0.85  and 1.13 , respectively. In women, in contrast, the results for total vegetable and cruciferous vegetable intakes showed the opposite results, with a multivariate OR for the highest quartile of energy-adjusted total vegetable intake compared with the lowest of 1.28  (P for trend = 0.01). Further, the multivariate OR of cruciferous vegetables was positively associated with cataract risk, albeit with no significant difference in trend analysis. A multivariate OR for the highest quartile of green and yellow vegetable intake was positively associated with cataract, but without statistical significance. Total fruit intake also tended to be positively associated, at 1.15 , but without statistical significance. Furthermore, we adjusted for vitamin C and vitamin E intake in the same model, but the results did not change. Additionally, we further adjusted for energy intake in the same model, and the results were not substantially changed.Table P values were not statistically significant.Table Q5 vs Q1, 0.66; 95% CI, 0.48–0.92) for total vegetable, P for interaction = 0.04 and ORQ5 vs Q1, 0.63; 95% CI, 0.46–0.85) for cruciferous vegetable, P for interaction = 0.007). Meanwhile, no significant differences by age were found for green and yellow vegetable and total fruit intake in men . Moreover, significant differences by age among women were also not found.Table These results for men and women did not change following stratification by vitamin supplement intake (data not shown).In this prospective cohort study of the relationship between vegetable and fruit intake and incidence of cataract, we found an inverse association between higher intake of total vegetables and cruciferous vegetables and cataract incidence in men, but not in women. Our findings also revealed that there was no association between green and yellow vegetable and fruit intake and cataract risk for Japanese. To our knowledge, this is the first study in an Asian population to report the association of vegetable, cruciferous vegetable, green and yellow vegetable, and fruit intake with cataract risk.15 In stratified analysis by study design, cohort studies from America and Europe showed inverse associations between vegetable consumption and cataract risk . Previous studies reported that intake of broccoli and spinach, included in cruciferous vegetables, reduced cataract risk,8–10 including a case-control study in Italy that found higher intake of cruciferous vegetables associated with decreased risk of cataract .8 Our finding of an inverse association between vegetable and cruciferous vegetable intake and cataract in men is consistent with these previous findings. Vegetables contain antioxidants, including vitamins, β carotene, phytoestrogens, folate and dietary fiber, which may prevent cataract progression.36,37 These components are involved in biological processes that may alter the structure of cataracts, such as DNA methylation, oxidative stress, and protection against DNA damage.38A meta-analysis of the association between vegetable consumption and risk of age-related cataract that included nine articles involving 6,464 cataract cases and 112,447 participants found that higher vegetable consumption decreased the risk of cataract.9,10,14,39,40 and showed that green and yellow vegetable intake reduced cataract risk.8–10 In this study, there was no significant difference between higher intake of green and yellow vegetables and the incidence of cataract. Brown et al reported that a high frequency of carrot and tomato intake was not related to cataract risk,9 whereas Tavani et al reported that high intake of spinach and tomatoes decreased cataract risk.8 The Blue Mountains Eye Study showed that there was no association between intake of green and yellow vegetables and cataract risk.11 In other words, not all green and yellow vegetables appear to reduce the risk of cataract.Previous studies showed an inverse or no association between carotene and lutein, which are abundant in green and yellow vegetables, and the risk of cataract,39–41 Theodoropoulou et al39 reported a significant inverse association between monthly frequency of fruit consumption and risk of cataract in a case-control study. Pastor-Valero et al40 and Christen et al41 reported that increasing quartiles of combined fruit and vegetable intake were related with a reduction in cataract risk. While these previous analyses of higher intake of all fruits or all vegetables separately were similarly shown to decrease the risk of cataract, albeit without significant differences, our present findings showed no obvious relation between total fruit intake and cataract incidence risk among subjects of either sex in our study, despite the relatively high antioxidant content of fruits.36,37 According to Food and Agriculture Organization of the United Nations data, fruit consumption in Japan (average 144.8 g/capita/day) is the lowest in developed countries, and one-third or less than that in the Netherlands (average 482.5 g/capita/day), the country with the highest fruit consumption.42 Since average Japanese fruit intake is low, there may have been no association between fruit intake and cataract incidence, although the average intake of fruits in our highest category was over 200 g.It has been reported that fruit intake might be associated with a decreased risk of cataract incidence.43–47 we stratified the results by smoking status. Results showed a clearer association between total cruciferous vegetable intake and cataract incidence among smoking men. Cruciferous vegetables, such as broccoli, are rich in carotenoids, vitamin C, vitamin E, vitamin K, folate, and minerals. A previous study showed that cruciferous vegetables contain isothiocyanates, such as sulforaphane, which protect lens cells against oxidative stress.27 Cruciferous vegetables have antioxidant activity and may act to antagonize the oxidative action of smoking, and possibly to inhibit cataract incidence.Because previous reports showed that smoking has effects on cataracts and is a cause of oxidative stress,However, the percentage of cataract incidence was lower in smokers (1.6% in men and 2.7% in women) than non-smokers (2.1% in men and 3.1% in women) in both sexes, as shown in Table 48 This result is consistent with the report by Simon et al.49 Accordingly, if participants visit a doctor, early lens opacities are also likely to be diagnosed. Since we had no information from consultations with doctors, we used information from fundus photographic examination at health check-ups as surrogate information. Although we adjusted data and stratified subjects by the presence of fundus photographic examination, the positive association in women was not changed. Correspondingly, the positive association between total vegetable and cruciferous vegetable intake and cataract risk for men in the <60 years age group is similar to the results in women. Like women, relatively younger men with a higher intake of vegetables might be more likely to consult a doctor at a health check-up or comprehensive medical examination due to increased health consciousness. Therefore, the results in women and men aged <60 years might be overestimated due to detection bias. Since we could not adjust by the number of persons who actually consulted doctors, we cannot remove this detection bias. A second consideration is that women generally have a higher incidence of cataract than men in the same age group due to the decrease in estrogen which follows menopause, which causes cataract progression.50,51 In other words, the lens is protected in women by the antioxidant action of estrogen until menopause. In our study, higher consumption of vegetables and cruciferous vegetables was associated with older age. We were, therefore, unable to eliminate the potential biases and confounding factors arising from this difference. Further study of the cause of these sex differences in the influence of vegetable and cruciferous vegetable intake and cataract incidence is anticipated.Contrary to our expectations, we found a positive association between total vegetable and cruciferous vegetable intake and cataract in women. Given the higher incidence of cataract in women than men in this study, this might be partly explained by the difference between sexes in the percentage of participants receiving medical advice. There are few subjective symptoms in the early development of cataracts, and many cataracts progress and develop symptoms slowly. Further, cataracts are often not diagnosed without a doctor visit. The Japanese Ministry of Health, Labour and Welfare reported in a patient survey of eligible persons using medical facilities throughout the country that women are more likely to consult a doctor than men.52 However, this study might be meaningful in revealing the relationship between vegetable and fruit intake and cataract risk in daily life.We agree that some randomized trials of antioxidant vitamin supplements have not shown protective effects against cataract, and further studies of antioxidant vitamins supplements have not been recommended.40,41 We might not be able to remove this detection bias. Second, evaluation of dietary intake occurred at only one time point: the second survey, which was the baseline of this study. Repeated assessment of long-term dietary intake before disease onset is more likely to predict exposure conditions. Third, the follow-up period of 5 years was relatively short for a disease with such a protracted natural history. Fourth, we analyzed the data after excluding subjects with a history of diabetes mellitus; however, we did not exclude cases having diabetic mellitus during follow-up, and did not adjust for glucose/HbA1c level because data on these variables was not available. Finally, we were unable to remove the possibility of unmeasured and residual confounding factors.The strengths of the present study include its large number of participants of both sexes; population-based prospective cohort design; limited localized bias, with inclusion of 11 public health center areas nationwide; use of a validated FFQ; and adjustment or stratification for potentially important confounding factors. However, the study also has several limitations. First, we had no source of information for cataract diagnosis other than the questionnaire, and might therefore have underestimated cataract incidence due to false-negative cases who had not visited an ophthalmology clinic and were not diagnosed with cataract. These sources of detection bias may have led to an underestimation of the overall incidence of age-related cataract. At the same time, this detection bias may have affected our results as mentioned above. In previous studies in which information on cataract was obtained using medical records or evaluation via ophthalmic examination, and not from self-report data, some reports showed an inverse association in women.In conclusion, the results of this prospective large-cohort study suggested that the intake of vegetables and cruciferous vegetables may reduce the risk of cataract incidence among Japanese men.


A significant difference in hospital admissions between 3 months before and post-TGJ insertion was noted . A significant amelioration of QoL after TGJ placement was also recorded; in particular, the biggest improvements were related to parents’ perceptions of the general health and emotional state of their babies (p < 0.001). Conclusions: The placement of TGJ as a temporary nutritional tool in selected cases of LGEA could improve nutritional conditions and parental QoL before fundoplication, allowing successful surgical treatment of GERD to be carried out.Background: Gastro-esophageal reflux disease (GERD), requiring surgical correction, and nutritional problems are reported after long-gap esophageal atresia (LGEA) repair and might jeopardize the postoperative course in some babies. We report an exploratory evaluation of the role of transgastric jejunostomy (TGJ) as a temporary nutritional tool before surgery for GERD in LGEA. Methods: Seven infant patients operated on for LGEA with intra-thoracic gastro-esophageal junction (GEJ) and growth failure, requiring improvement in their nutritional profile in anticipation of surgery, were retrospectively evaluated. Post-surgical follow-up, including growth evolution, complications, and parental quality of life (QoL), were considered. Results: The TGJ was placed at a mean age of 8.6 ± 5.6 months. The procedure was uneventful and well-tolerated in all seven cases. At 6.6 ± 2.0 months after TGJ placement, significant weight gain (weight z-score −2.68 ± 0.8 vs −0.9 ± 0.2,  Long-gap esophageal atresia (LGEA) occurs in 10% of patients with esophageal atresia , and repIt is still universally accepted that preserving the native esophagus is the best option for the patient ,4,5,6. HThe incidence of symptomatic GERD is reported in more than 50% of cases , and it An additional problem relates to nutritional aspects after restoring the esophageal continuity ; as a coWe report an exploratory evaluation on the role of transgastric jejunostomy (TGJ) as a temporary nutritional tool before surgical treatment of GERD in a case series of patients born with LGEA with an intra-thoracic gastro-esophageal junction (GEJ) and growth failure with the need to improve their nutritional profile in anticipation of surgery. Post-surgical follow-up, including growth evolution, complications, and parental quality of life (QoL), was considered.In this retrospective study, seven infant patients  operated on for LGEA (4 type A and 3 type C) were enrolled.All infants presented clinical and radiological signs of severe GERD  despiteThe study was performed in accordance with the Declaration of Helsinki principles and with the approval of the local Institutional Review Board . After receiving information about the nature of the study, the patients’ parents or guardians gave written consent for their child’s participation.In all patients with LGEA , a Stamm gastrostomy was performed at birth (with fistula closure when present) and esophageal anastomosis was carried out at a mean age of 4.6 months (age range 2.1–10.9 months), as reported in In selected cases with severe post-operative drug-resistant GERD and comorbidities, fundoplication was performed as the treatment of choice ,4,5. In The study was designed in order to evaluate the nutritional role of TGJ prior to fundoplication by the analysis of three parameters , as detailed below.The placement of the jejunal tube was performed in the operating room under general anesthesia with a 5 or 6 mm gastroscope inserted through the gastrostomy. When required, prior to endoscopy, progressive dilatation of the stoma was performed until the adequate caliber was reached. The gastroscope was directed through the pylorus, into the duodenum, and a guide-wire was passed up to the third duodenal portion. The endoscope was then retracted under direct vision and the jejunal tube was placed over the wire . The insertion of the tube over the guidewire, which is nitinol covered with hydrophilic Teflon and is provided by a hydrophilic coated soft tip, 230 cm in length, is straightforward with proper lubrification of the tube . On the other hand, the removal of the guidewire can be tricky because there is the risk of curling and pulling back the tube as well. The maneuver should be performed cautiously: the tube is anchored to the gastric wall by balloon filling and it is kept in place with one hand while the guidewire is pulled out with the other hand, using constant pressure and avoiding jerks. A fluoroscopic evaluation at the end of the procedure was required to clear up any doubts on the correct positioning of the tube.Approximately six months after gastro-jejunostomy placement, patients underwent Nissen fundoplication. At fundoplication, the gastro-jejunal tube was removed while the gastrostomy was maintained for about 1 month postoperatively in order to treat possible gas-bloating syndrome and dysphagia. Dietary schedules were tailored to every single patient following consultation with nutritional experts. The final planning included two bolus meals during the day and continuous night feeding with monomeric nutrient solutions. Meanwhile, oral stimulation and rehabilitation were strongly supported. Gastric venting from the gastric probe was employed at least two to three times per day to empty the stomach. After surgery, oral feeding was gradually introduced with good tolerance.Patients were closely monitored during follow-up at our outpatient clinic until the nutritional goals were reached , and then check-ups were arranged on the basis of individual needs.(1)weight increases after the placement of the jejunal tube, at the time of fundoplication surgery. Bodyweight was measured with a beam scale and it was used as the most sensitive parameter to detect short-term weight variations;(2)the number of hospital admissions during a period ranging from 3 months before to 3 months after TGJ positioning;(3)parental quality of life (QoL) before and after TGJ positioning (by administration of Short-Form 36 questionnaire version 1.6 to parents before fundoplication). The questionnaire is a common patient-reported survey to assess the patients’ health. It is based on the evaluation of eight items: physical activity, role and physical activity, physical pain, general health, vitality, social activities, emotional state and mental health. Each item is associated with a score with a maximum value of 100; the lower the score, the more severe the disability.As post-surgical parameters, we analyzed:In all the patients, a multidisciplinary approach with a dedicated team, including an otolaryngologist expert in swallowing re-education, a physiotherapist, and a speech therapist was performed.p-value < 0.05 was considered statistically significant.All analyses were performed using Stata 16 . Data were described with the mean, standard deviation (SD), median and 25th–75th percentiles if continuous and as counts and percent if categorical. Non-parametric correlations between continuous variables were assessed with the Spearman R test. The association of categorical variables was assessed by means of Fisher’s exact test. A The TGJ was placed at a mean age of 8.6 ± 5.6 months. The procedure was uneventful and well-tolerated in all seven cases.By 6.6 ± 2.0 months after TGJ placement, all patients had undergone GERD surgery. The procedures were performed smoothly with no intraoperative complications. The gastrostomy was removed after 4–6 weeks once oral feeding was successfully established. As indicated in p < 0.001). The clinical parameters during surgical stages are reported in At the time of TGJ insertion, we recorded a mean weight of 5.8 ± 1.1 kg (z-score −2.68 ± 0.8). The mean weight at fundoplication was 8.9 ± 1.1 kg (z-score −0.9 ± 0.2), with a significant increment compared to the TGJ stage . Before treatment, the patients were commonly admitted for respiratory infections, regurgitation, abdominal pain, and stoma care issues; in the 3 months following TGJ, admissions were mainly related to stoma care/tube malfunctioning. In particular, tube dislodgement occurred once in one patient and required endoscopic repositioning, stoma care was required in one patient with recurrent leaks , and one patient had a tube malfunction (he required tube replacement over a guidewire with no need for anesthesia). The remaining four patients had no problems with the TGJ tube . Physical activity (PA) and pain (PP) improved by 15 points but while PA reached high levels of satisfaction (65 vs. 80 after TGJ placement), PP remained a limiting factor for families . Likewise, social activities, which were very limited before TGJ placement (45 points), improved, reaching a mean score of 60 (p < 0.01). Vitality (V) and mental health (MH) were quite satisfactory before TGJ placement, but subsequently improved slightly (score of 70 vs. 75 p < 0.01).We recorded a significant improvement in QoL after TGJ placement, as recorded by higher scores in all 8 items considered. In particular, the biggest improvements were related to parents’ perception of the general health (GH) and emotional state (ES) of their babies, whose scores increased by 35 and 25 points respectively   occurs in approximately 10% of all infants with esophageal atresia and surgical repair is often difficult with significant postoperative complications. Classical management of patients with LGEA includes the placement of a gastrostomy tube for bolus feed in the neonatal period followed by delayed esophageal anastomosis . In receNutritional problems have been commonly reported after restoring esophageal continuity due to altered esophageal anatomy and motility (predisposition to GERD), as well as a delay in initiating oral intake, and parental anxiety ,12. MoreIn terms of functional aspects of the esophagus, the function of the lower esophageal sphincter (LES) and the motility propagation is often altered by upward traction ,15,16, cIndeed, GERD is a frequent occurrence after delayed repair of LGEA and, together with esophageal dysmotility, exposes patients to aspiration-induced airway infections, nutritional and global impairment, and affects the post-operative course .Different nutritional strategies have been proposed to overcome the above-mentioned problems such as parenteral nutrition, nasogastric tubes, and gastrostomy devices. In particular, gastrostomy feeding enables easy and effective nutritional intake and avoids some of the negative consequences of the other approaches . It alsoGastrostomy feeding may not be tolerated in the case of GERD-related symptoms  and brachy-esophagus ,20,21.In these patients, the placement of a TGJ tube is an efficient and safe solution. TGJ also permits gastric decompression using the dedicated port, thus reducing the risk of severe complications of GERD. However, the placement of a jejunal feeding tube should not be considered for widespread use; our experience over the last 10 years has shown that only a limited number of patients require this approach. TGJ appeared to be a possibility in those patients with a pre-existing gastrostomy and associated problems including intolerance to enteral feeding, moderate/severe undernutrition, diagnosis of GERD , and symptomatic GERD  due to intrathoracic EGJ co-morbidities , that may contraindicate long surgical procedures in the short term. Our series of patients also presented a high rate of prematurity and low birth rates, which are major factors of post-operative complications in the first months of life ,23.Each time these factors are identified, the multidisciplinary team caring for the patient should meet and discuss the clinical case in order to make a suitable decision.The concept of post-pyloric feeding by jejunal feeding tube (JFT) has been well described in children ,25,26,27This approach is less invasive than other anti-reflux procedures and it is generally considered a temporary nutritional strategy to limit long-term parenteral nutrition, when the use of gastrostomy is not possible ,29,30,31However, long-term outcomes and complications of JFT are unclear and reported complication rates vary widely, 1.6–20% ,30,31. MIndeed, in our hospital, there is a dedicated team of endoscopists (pediatric surgeons and pediatricians) who routinely perform this type of procedure. The jejunal tube is carefully selected on the basis of the child’s age, length, and weight. This is important not only to facilitate the endoscopic placement of JFT but also to reduce complications such as dislodgement and obstruction. Moreover, we can avail of pediatric and neonatal endoscopes: the use of a 5 mm endoscope was fundamental in smaller babies.We are also aware of the possibility of cramping, bloating, and dumping , but a wWe had positive results in managing seven patients with TGJ in terms of weight gain, reduced hospitalization, and high parental satisfaction. Regarding QoL, the nutrition plan based on two meals during the day and continuous night feeding was particularly welcomed by parents: it somehow reproduces the feeding mode of the family, avoiding the dependence involved in a continuous 24-hour nutrition regimen. We admit that this nutrition plan, specifically the continuous night feeding, is not optimal, but it may be used for a limited period to achieve specific nutritional goals. The number of hospitalizations was also significantly reduced, starting from the first weeks after TGJ placement. TGJ can successfully bridge the gap while waiting to perform a definitive surgical procedure to correct GER. Our data suggest that JPEG positioning could be performed as early as the infant’s first months when growth chart deflection appears. Indeed, fundoplication is essential in these patients and it is required in almost all cases .Some authors reported on the use of early anti-reflux procedures ,10,11, bWe are aware of the limitations of this study, mainly related to the small and heterogeneous sample of patients without a control group, which limits statistical analysis; further studies are mandatory to confirm our results. Moreover, we used only patients’ weight as an indicator of growth, because weight shift is usually the most sensitive variable to growth changes over short monitoring periods. Despite these limitations, this preliminary study indicates how TGJ is not the procedure of choice, but can be a bridge treatment option for nutritional problems in LGEA with a short esophagus.In conclusion, the placement of the TGJ as a temporary nutritional tool in selected cases of LGEA, with intrathoracic GEJ and growth failure, could improve nutritional conditions and parental QoL in the period before fundoplication, enabling successful surgical correction of GERD.


To investigate the mental health status of Chinese residents during the epidemic of COVID-19, as well as to identify the positive and negative factors and regulatory effect of negative cognitive processing bias on mental health.A total of 60,199 residents in China were surveyed via an internet-based survey containing a general questionnaire, such as the self-rating depression scale, the state anxiety inventory, and the negative cognitive processing bias questionnaire. An ordered multiple logistic regression analysis model was used to analyze the collected data.The survey revealed mild, moderate, and severe depressive symptoms in 62.65, 11.33, and 6.14% participants, respectively, and mild, moderate, and severe anxiety symptoms in 33.21, 41.27, and 22.99% participants, respectively. Multiple logistic regression analysis showed that factors, such as female gender, being older than 55 years, high school education level, medical staff, marital conflicts, negative attention bias, rumination, and death growth rate, positively affected depression and anxiety symptoms. The good family functionality, democratic working atmosphere, and a myriad of social activities negatively affected the level of depressive and anxiety symptoms.Chinese residents exhibited a high prevalence of anxiety and depressive symptoms during the epidemic. Thus, psychological interventions should focus on the vulnerable groups, and cognitive training should focus on reducing the negative cognitive processing bias. This might be an effective way to alleviate the mental stress of the general public during the COVID-19 pandemic. In late December 2019, the 2019 coronavirus disease (COVID-19) appeared in Wuhan City, Hubei Province, China . AccordiAs a result of the rapidly increasing numbers of confirmed cases and deaths, Chinese residents have been experiencing psychological problems, including anxiety and depression . The sevThus far, studies on depression and anxiety during COVID-19 have primarily focused on the medical staff. Only a few studies have examined the mental health of ordinary residents. Some previous studies have pointed out that the psychological impact caused by public health emergencies, such as the severe acute respiratory syndrome (SARS) epidemic in China in 2003  and the This cross-sectional study explores the effect of various factors on residents’ mental health under stress during public health emergencies. It provides accurate decision-making reference to the government departments with respect to the mental health of normal people.The current study used a snowball sampling approach to distribute questionnaires online in Mainland China between 23 and 29 February 2020. The questionnaires were distributed via WeChat, Tencent QQ, and other public platforms. When participants completed the questionnaire, they forwarded it to their own WeChat circle of friends or other public platforms to expand the sample size. Each IP address could only be used once. The inclusion criteria were as follows: (1) 18–65-years-old, (2) native Chinese residents able to complete the questionnaires on the cellphone or computer, (3) informed consent. The exclusion criteria were: (1) unable to read correctly or use a computer or cellphone to complete the questionnaires, (2) refused to participate in the research.In order to control bias, the questionnaires were initially distributed in the same number in each provincial capital city. The daily sample size was based on a national survey experience, and the sample size was set to be more than 1500 .A total of 66,152 questionnaires were returned. On February 26 and 27, only 5 individuals filled out the questionnaire. Therefore, the data of these 2 days were excluded. Five thousand nine hundred forty-eight questionnaires were excluded such due to missing data, incomplete information, or extreme data. After deleting these substandard responses, 60,199 valid questionnaires were analyzed, with an effective rate of 91%.The current study was approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University, China. All participants confirmed the informed consent before answering the questionnaires.Demographic data, work environment, family conditions, and social activities were covered by 13 items, including gender, age, education level, occupation, marital status, family structure in childhood, whether the participant was an only child, parenting style in childhood, whether the participant lived with his parents until the age of 10, number of close friends, the collective atmosphere in work/school, the management style of work/school, and social activities of last 2 weeks. According to Baumrind’s research , parentiThe self-rating depression scale (SDS)  containeThe state anxiety inventory (SAI) is a scale from the state-trait anxiety inventory , containNCPBQ is a 16-item self-report measure in Chinese, used for assessing the negative attention bias, negative memory bias, and rumination, using a 4-point Likert scale  [The confirmed growth rate was calculated as the ratio between the cumulative number of confirmed cases announced on the day and on the previous day to the cumulative number of confirmed cases announced on the previous day. The death growth rate was the ratio of the difference between the cumulative number of deaths announced on the day and on the previous day to the cumulative number of deaths announced on the previous day. The number of confirmed cases and deaths was provided by the National Health Commission of China .According to the SDS scoring criteria, the participants were divided into non-depressed, mild depressive symptoms, moderate depressive symptoms, and severe depressive symptom groups. They were also divided into non-anxiety, mild anxiety symptom, moderate anxiety symptom, and severe anxiety symptom groups according to the SAI scoring criteria.P < 0.05 on double sides was considered to be statistically significant. The analysis of the correlations between characteristics  and anxiety or depressive symptoms initially were assessed by the chi-square test. The correlations between negative cognitive processing bias , confirmed growth rate, death growth rate, and anxiety or depressive symptoms were initially assessed by one-way analysis of variance (ANOVA). The variables with P < 0.05 were entered in the ordered multiple logistic regression analysis models by the stepwise method.The data were analyzed using software SPSS 23.0 and SAS 9.4. Measurement data were expressed as mean ± standard deviation  females and 25,781 (42.8%) males among the 60,199 questionnaires, aged 18–65 (average: 34.66 ± 12.02)-years-old. The demographic characteristics of participants are shown in Table According to the cumulative numbers of confirmed cases and deaths of COVID-19 in China provided by the National Health Commission of the People’s Republic of China, we found that the confirmed growth rate fluctuated between 0.28 and 0.85%. The death growth rate fluctuated between 1.60 and 6.14% from February 23–29 .The SDS standard score of all the participants was 58.31 ± 8.46 points; among them, 19.89% were non-depressed, 62.65% were mildly depressed, 11.33% were moderately depressed, and 6.14% were severely depressed. The participants’ SAI score was 51.52 ± 7.52 points; 2.53% were non-anxious, 33.21% were mildly anxious, 41.27% were moderately anxious, and 22.99% were severely anxious . The one-way analysis of variance results showed significant differences in the scores of negative attention bias, negative memory bias, rumination, confirmed growth rate, and death growth rate associated with different degrees of depressive and anxiety symptoms (P < 0.001).Single-factor chi-square test results showed significant differences in the ratio of different degrees of depressive symptom and the ratio of different degrees of anxiety symptom with respect to gender, age, education level, occupation, family structure in childhood, whether the participant was an only child in the family, parenting style in childhood, whether the participant lived with parents until the age of 10, a number of close friends, collective atmosphere in work/school, the management style of work/school, marital status, and social activities of last 2 weeks  conducted a cross-sectional epidemiological survey in 2019, which revealed that 3.6% of Chinese adults had depressive disorder symptoms, while 5.0% had anxiety . The curThe death growth rate and the confirmed growth rate of COVID-19 reflect the severity of the epidemic. During our survey, the volatility trends of death growth rate and confirmed growth rate were not identical. Strikingly, the confirmed growth rate had a greater effect on depression severity, and only the death growth rate could positively affect the anxiety levels. During the pandemic of COVID-19, people could seek information from official channels to stay informed about the situation. Due to the transmission of COVID-19 and the continuous adjustment of diagnosis and treatment programs, the fluctuation of epidemic data may cause fluctuations in the public’s psychological pressure.Male respondents showed a significantly lower level of depressive and anxiety symptoms than their female counterparts. This phenomenon is consistent with previous research, which concluded that women are much more susceptible to stress and more likely to develop higher psychological distress during the COVID-19 outbreak than men . This maThe results also showed that education level and occupation were related to depression. People with a high school diploma were prone to develop severe depressive and anxiety symptoms compared to others. The education level may be related to the acquisition and identification of epidemic information; yet, this needs to be further investigated.During the outbreak, the medical staff had a higher level of depression and anxiety than individuals from other occupational sectors because they had to face a heavier workload and were at direct infection contact with patients infected with COVID-19. These pressures could be internalized, resulting in depression and anxiety . CollectThe family was another aspect that affects anxiety and depressive symptoms during the COVID-19 outbreak. Living with two parents led to lower depression than living with other groups. Having sisters or brothers and not being the only child in the family could decrease anxiety. The democratic parenting style and living with parents until the age of 10 years of age were also conducive to the epidemic’s response. Good family functionality was negatively correlated to stress and depressive symptoms . MaritalNegative cognitive processing bias, especially negative attention bias and rumination, had a negative role in regulating people’s mental health. People with negative attention, tending to reports such as death and confirmed cases, could easily succumb to negative stimuli. Lacking attention flexibility that engages with positive information and disengages from salient negative information might cause the failure of adaptive emotion regulation processes . The rumSince January 2020, the National Health Commission of China has published several guidelines for emergency psychological crisis intervention, established psychological assistance hotlines, and providing online mental health education for the COVID-19 epidemic , 45. AllThe present study has several limitations. First, this study used the method of cross-sectional design, this it is not possible to make causal inferences. Second, the study was limited to an online survey, which may lead to selection bias. We might overestimate the ratios of anxiety and depressive symptoms because people who voluntarily choose to participate in the survey might be more aware of their mental health issues than those who did not participate. Third, due to the web-based study design, we could not control the origin of the participants’ regions and guarantee the sample’s representativeness, which might affect the research results.In this study, we assessed Chinese residents’ mental health status during the COVID-19 outbreak and identified the related risk factors for anxiety and depressive symptoms. The elderly, females, medical staff, and people with high school education were at higher risk of developing psychological issues. Negative cognitive processing bias had a negative role in regulating mental health. Psychological interventions should focus on vulnerable groups. Moreover, cognitive training that focuses on reducing negative cognitive processing bias might help alleviate the general public’s mental stress during the COVID-19 pandemic.


CYP27A1 gene. Chronic diarrhea, tendon xanthomas, neurologic impairment, and bilateral cataracts are common symptoms of the disease. CTX is a rare congenital lipid-storage disorder, leading to a progressive multisystem disease. CTX with autosomal recessive inheritance is caused by a defect in the CYP27A1 gene was also studied for the number of pathogenic variants and their location. Three affected siblings with an initial diagnosis of non-syndromic intellectual disability were recruited for further molecular investigations. To identify the possible genetic cause(s), WES was performed on the proband. Sanger sequencing was applied to confirm the final variant. The clinical and molecular genetic features of the three siblings from the new CTX family and other patients with the same mutations, as previously reported, were analyzed. The CYP27A1 gene, which was confirmed by Sanger sequencing. Among the detected pathogenic variants, the splice site mutation had the highest prevalence, and the mutations were mostly found in exon 4. We found a homozygous splicing mutation, NM_000784: exon6: c.1184+1G>A, in This study is the first to report the c.1184+1G>A mutation in Iran. Our findings highlight the other feature of the disease, which is the lack of relationship between phenotype and genotype. Due to nonspecific symptoms and delay in diagnosis, CYP27A1 genetic analysis should be the definitive method for CTX diagnosis.  CYP27A1 gene, encoding the mitochondrial cytochrome P450 sterol 27-hydroxylase enzyme[1]. As a result of this deficiency, certain metabolites, such as cholesterol and cholestanol, accumulate in various tissues, particularly eye lenses and muscle tendons, as well as in the central nervous system. CTX has neurologic and systemic presentations[4-6], and its clinical symptoms include chronic diarrhea, cognitive impairment, intellectual disabilities, bilateral cataract, and tendon xanthomas. The clinical manifestation of CTX is highly heterogeneous, making CTX diagnosis difficult in the early stages. In this sense, the molecular detection of CYP27A1 mutations improves the robustness of diagnosis.Cerebrotendinous xanthomatosis is a rare autosomal recessive lipid storage disease caused by a defect in[9]. Although CTX is considered as a rare disorder, it may be less commonly diagnosed because it overlaps with other conditions with nonspecific symptoms. There is noticeable variability in the clinical presentations, severity, and age of onset among patients[9]. The prevalence of this disease in our country is unknown; we had only one case report without molecular diagnosis and one case with c.1476+2T>C mutation[12].CTX is more prevalent among female than male individuals (~55% vs. 45%) worldwideCYP27A1 gene, which is reported for the first time in Iran. This family is biologically unrelated but belongs to the same ethnic group. Such evidence indicates that the prevalence of CYP27A1 variant in this particular population is likely high and reminds the importance of carrier screening. The clinical and molecular features of CTX patients were analyzed and compared with other patients with the same mutation. Also, the CYP27A1 gene was analyzed for the number of pathogenic variants and their location.In the present study, we described three CTX siblings with c.1184+1G>A mutation in Patients’ dataIndex familyThis study recruited a non-consanguineous family from the same origin, with three affected children, a boy (proband) and two girls aged 38, 45, and 51 years, respectively . ParentsCase no. 1 (II.1)The 38-year-old male was proband and the result of a dizygotic twin normal pregnancy and delivery. The mother did not report a history of an accident or infection during pregnancy, and the twin brother was healthy. The proband initially had the history of seizures 15 years ago, which then repeated every four to five years. He also had a history of cataract in early childhood, which was operated a year ago and had normal psychomotor development during his childhood. At school, due to the lack of academic achievement, intellectual disability was diagnosed. At age 27, he was found to have tendinous masses at the metacarpophalangeal joint, which was operated five years ago. The muscle strength was satisfactory, but according to the patient’s report for the past two years, it had been weakening, accompanied by the loss of power in muscles. Upon admission, neurological examination revealed ataxia, mood change, and cognitive decline. Also, he had hemorrhoid surgery last year.Case no. 2 (II.4)The 51-year-old female was older sister of the proband. She was the result of a normal pregnancy and delivery. The mother did not report a history of an accident or infection during pregnancy. She also had normal psychomotor development during her childhood, and like her brother she was diagnosed with intellectual disability at school. She always had diarrhea. At age 30, she had an operation on cataract, and at age 35, she had a tendinous mass in the tendon of the Achilles, left knee, and finger joints. In addition, at age 45, she underwent another surgery for a blood clot on the brain. Added to these was a laser surgery carried out later to open up gallbladder outflow obstruction caused by gallstone. Three years ago, in 2017, she lost the ability to walk so that she needed help to get up and walk. She had experienced no seizures in her lifetime. At examination, her deep tendon reflexes were absent, and her muscle power was too weak to walk. She also had poor communication with those around her and suffered from ataxia and mood change.Case no. 3 (II.5)The 45-year-old female is the second sister of the proband. Like her brother and sister, she was the result of a normal pregnancy and delivery with no history of infection or accident during these periods. She also had normal psychomotor development and detected with intellectual disability at school. At age 30, she had a cataract surgery. Also, she underwent another surgery about six years ago because of the tendinous mass in the tendon of the Achilles. Like her sister, she had lost the ability to walk two years ago and could only get up and walk with help. She had no history of seizures but suffered from ataxia, which became more severe over time. At examination, she had ataxia, decreased muscle strength, and mood change.[15]. The DNA quality was evaluated by electrophorese on 1% agarose gel and quantified using Nanodrop2000C Spectrophotometer , The families had previously been excluded from chromosomal abnormalities (by karyotyping), Fragile X syndrome (by molecular methods or Southern blotting), and metabolic diseases (by tandem mass spectrometry).The present study was conducted in Shahid Beheshti University of Medical Sciences (SBUMS), Tehran, Iran in collaboration with Qazvin University of Medical Sciences, and University of Social Welfare and Rehabilitation Sciences, Qazvin, Iran. A non-consanguine family with three affected siblings with non-syndromic intellectual disability was recruited for further molecular investigation. The parents were from the same village in Qazvin Province, the northwest of Iran. To prepare participants for the complete clinical examination and genetic counseling, we first collected 10 ml of whole blood from each patient, parents, and unaffected siblings in EDTA anticoagulant. Thereafter, genomic DNA was extracted according to the standard proceduresWES[12]. In summary, FastQC 11.5 software (https://www.bioinformatics. babraham.ac.uk/projects/fastqc/) was applied to check and confirm the quality of the sequences and also Burrows–Wheeler Aligner (version 0.7.12-r1039) was employed for aligning the raw reads with the reference genome [16]. The Picard toolkit (https://broadinstitute.github.io/picard/) and GATK package[17] were used for trimming, filtering, base recalibration, coverage determination, and insertion/deletion realignment of the Sequence Alignment Map files, and then variants were called using the Unified Genotyper module of the GATK package. Variants with a frequency below 1% were selected based on different human population databases , Genome Aggregation Database )genomAD; https://gnomad.broadinstitute.org/), ExAC (http://exac.broadinstitute.org/), ESP6500 (http://evs. gs.washington.edu/EVS/) and in-house database of 800 Iranian control samples published in Iranome (http://www.iranome.com/). Then synonymous variants located outside the boundaries of 10 bp from the exons, and all non-coding regions were excluded. In the next step, variants belonging to the known genes in ID/DD were first considered, and then the pathogenicity of nonsynonymous, indels, deletions, and splice-site variants were examined. Besides, compound heterozygous/ homozygous variants were checked by in silico prediction algorithms, including Mutation Taster[19], CADD (https://cadd.gs. washington.edu/) and PROVEAN (http://provean.jcvi. org/index. php)[20], as well as in silico nucleotide conservation from GERP scores[21]. Finally, the selected variants were reviewed in OMIM database, ClinVar database (https://www.ncbi.nlm.nih.gov/ clinvar/), and locus/disease specific databases and evaluated for the relationship between phenotype and genotype and the causative agent of the disease. The final variant was confirmed by conventional Sanger sequencing. Co-segregation analysis was performed among family members, and variant analysis was carried out according to the patient's ethnicity.The affected boy (proband) was selected to perform whole-exome sequencing. DNA library preparation, DNA target enrichment, and capture were carried out by the Agilent SureSelectXT2 kit . Finally, the Illumina NextSeq 500 system  was used for the exome-sequencing, which uses 101-bp paired-end read with the mean depth of coverage 53× with 95.4% and 91.2% coverage at 10× and 20×, respectively. WES was analyzed according to our previous publicationEthical statementMethods for patient data and sample collection was approved by the Research Ethics Committee of Shahid Beheshti University of Medical Sciences, Tehran, Iran . Written informed consents were obtained from the parents of the three patients for molecular analysis and any patient images. CYP27A1 gene  and consisted of nine exons and eight introns[22]. The largest transcript is about 1895 bp long and encodes Sterol 27-hydroxylase, an enzyme protein with 531 amino acids. The mature enzyme contains 498 amino acids and carries a 33-amino acid mitochondrial signal sequence. Sterol 27-hydroxylase belongs to the mitochondrial cytochrome P450 family catalyzing the initial oxidation of the side chain of sterol intermediates during the hepatic bile acid synthesis. Adrenodoxin-binding site (residues 351–365) and the heme-binding site (residues 435–464) are two highly protected regions in the mature enzyme and interact with adrenodoxin and adrenodoxin reductase. Sterol 27-hydroxylase can also hydroxylate vitamin D3 at the C-1 and C-25 positions[25].The CYP27A1 is expressed in various tissues with the highest expression in the liver and then in the lung, followed by ileum and brain[27]. Defect in CYP27A1 gene causes a very rare disease, CTX. The clinical presentation of CTX is initially slow and then progressive process, including neurological and non-neurological symptoms. Some of these symptoms occur in childhood or adolescence and some in adulthood. The first clinical symptom to develop is neonatal cholestatic jaundice, which has been reported in numerous cases[28]. Other symptoms that begin in infancy or childhood are chronic diarrhea, bilateral cataracts, and xanthoma. Tendon xanthomas usually occur in the Achilles tendon, fingers, elbows, and knees as well as in the brain. Neurological presentations are the most debilitating factor in this disease and are present in many cases at diagnosis. Intellectual disability and gait disorders reflecting neurologic dysfunction are common symptoms. Developmental delay, cognitive impairment, and learning difficulties are other neurological symptoms that may be developed during childhood[9].CYP27A1 gene, of which about 85 variants are considered pathogenic or likely pathogenic. These variants are categorized as 14 frameshift (21.8%), 14 missense (21.8%), 17 nonsense (26%), and 19 splice site (29%) and by variant type: 15 are deletion (17%), 17 duplication (19%), 1 indel (1.1%), 3 insertion (3.4%), and 52 single nucleotide (59%). The distribution of these mutations in exons is as follows: exon 1 (7.8%), exon 2 (14%), exon 3 (15%), exon 4 (21%), exon 5 (3%), exon 6 (17%), exon 7 (10%), exon 8 (10%), and exon 9 (1.5%). Based on ClinVar database, this information indicates that the splice site mutation has the highest prevalence, and exon 4 has the highest amount of mutations.Currently, there are about 259 variants of ' half of exon 6 joins directly to exon 7. By changing the reading frame and creating a premature stop codon in this abnormal mRNA, a 348-amino acid truncated protein containing 16 new amino acids was formed at the end of its carboxy terminus. This truncated protein did not contain the three essential amino acids , which are supposed to play an important role in ferredoxin-binding domain. On the other hand, this shortened product, as iron–sulfur proteins, cannot be efficiently involved in a number of metabolic reactions in electron transfer[30]. Also, this truncated protein lacks the heme-binding domain. In the second abnormal product, following the complete removal of exon 6, exon 5 is connected directly to exon 7, leading to a frameshift and generation of a premature stop codon. This abnormal mRNA appears to encode a 322-amino-acid protein that contains 16 new amino acids at the end of carboxy and lacks the ferredoxin and heme-binding domain. In the third abnormal mRNA, exons 6 and 7 are both completely removed, and exon 5 is connected to exon 8. This event does not alter the reading frame, but the translated product is predicted to be a protein lacking 82 amino acids (from Thr307 to Ans388) and having a total length of 422 amino acids. This deletion of the amino acid eliminates the ferrodoxin-binding domain, and the final truncated protein, although found in very small amounts, appears to be inactive. Garuti et al. checked the activity of this enzyme in patients with c.1184+1G>A mutation and observed that the sterol 27-hydroxylase activity is undetectable. This variant was first reported by Garuti et al.[13] from Italy in 1997. It was reported to be heterozygous with another mutant allele in the patient indicated. Reported case was a 45-year-old female who at the age of seven developed symptoms such as cataracts, Tendon xanthomas, spastic paraparesis, mental deterioration, and psychiatric symptom, but no cerebellar signs like ataxia was observed. By comparing the symptoms of this patient with our patients, we found slight differences. For instance, ataxia is present in all of our patients, which gradually became more severe, but was not seen in the reported patient by Garuti et al.[13]. Another difference was that the c.1184+1G>A mutation has been reported as homozygous in our study and heterozygous in the study of Garuti et al.[13]. The variant c.1184+1G>A was also reported by Verrips et al.[9] from Netherlands in 2000[9]. The patient manifested the initial symptoms at childhood and was then diagnosed with the disease at age 36. Cataracts, intellectual disability, cerebellar and pyramidal signs, as well as dementia and peripheral neuropathy were other related symptoms in this patient; however, diarrhea and epilepsy were not detected. The genotype of this patient was homozygous as our patients. The manifestations were almost similar, but diarrhea was present in all the three of our patients in the early years of life[9]. Another case was reported by Lee et al.[14] in USA. The variant identified in that study was also heterozygote. These patients also had symptoms such as tendon xanthomas, cerebellar ataxia, and spastic paraparesis. Our patients also showed all these symptoms; however, the cataract, which was observed in all of our patients, was found in only one patient in the study of Lee et al.[14]. In our patients, there were phenotypic differences, though the genotype was quite similar. For instance, in case II.1, probands  had a history of seizures throughout their life, but no seizures were seen in female patients. In the proband, the pes cavus deformity was seen, but in female patients, the symptom was either absent or less severe. Moreover, the location of the xanthoma was present in the metacarpophalangeal joint in the male patient (proband), but in female patients, xanthoma was seen in the tendon of the Achilles. These discrepancies can possibly be due to dissimilarities in gender and genetic background. However, in this disease, there was phenotypic diversity between different patients, even those with the same genotype (sibling). All the clinical features of the cases with this variant are presented in the et al.[7] found that foot deformity (pes cavus) was the most common symptom, followed by cataracts, spastic paraparesis, ataxia, dementia, tendon xanthomas, cognitive impairment and diarrhea, respectively. By comparing the incidence of these phenotypes with the patients listed in The mutation c.1184+1G>A is located in the first nucleotide of intron 6. Its location at the intron-exon boundaries affects mRNA splicing, resulting in three abnormal transcripts. In the first transcript, by activating a cryptic donor splice site and skipping 89 bp of exon 6, the 5[7]. CTX is one of the rare lipid storage diseases, and increasing awareness about this condition can improve the process of diagnosis and treatment. CTX is a disease often diagnosed in adulthood with a long delay (~20 years), from the onset of symptoms and diagnosis of the actual disease. Timely diagnosis and initiation of treatment at the early age play a significant role in preventing the development of some symptoms. In some countries, the prevalence of carriers is high, and accordingly screening programs are carefully implementedCTX is a less diagnosed metabolic disorder. In our country, only two cases of CTX with genetic diagnosis have been reported. This study will acquaint readers with the clinical and genetic features of CTX, since this disease has a good clinical response to treatment, early detection and genetic diagnosis can help reduce the complications of this disease because timely treatment prevents the accumulation of cholestenol in the tissues and the progression of the disease.


Gastroesophageal cancers (GEC), combined, are the most prevalent type of gastrointestinal cancers worldwide. Esophageal cancer is a global health problem with an estimated annual incidence of 455,800 and 400,200 deaths occurring worldwide in 2012 . New treWe performed a phase II clinical trial of oxaliplatin combined with pralatrexate in metastatic or surgically inoperable, treatment naïve, GEC patients with a primary objective to assess the overall response rate (ORR). Our secondary objectives included the toxicity and tolerability of this regimen, time to progression, and overall survival. We also aimed to investigate whether functionally relevant polymorphisms of genes in the folate metabolism pathway were associated with the toxicity and efficacy of pralatrexate. As a correlative study, we wanted to assess whether microRNA expression profiling of the tumor's epithelial component can be used as a predictive biomarker to treatment response .In this study, a total of 35 patients were enrolled Four patients were treated at an initial dose level of Oxaliplatin 85 mg/m2 combined with pralatrexate 120 mg/m2, and two patients developed dose-limiting toxicities. Pralatrexate was dose reduced to 100 mg/m2 for the rest of the subjects (N=31). The median age of the overall population was 67 years, and adenocarcinoma was the predominant histology (83%). An ORR of 26%  was observed in 35 patients. The study did not achieve the defined primary endpoint of efficacy. The progression-free survival (PFS) was estimated at 5.1 (95% CI 3.4-6.4) months, and overall survival (OS) was 7.2 ( 95% CI 6.4-10.8) months. As for the toxicity profile of pralatrexate, the most common grade 3 or higher events were mucositis, neutropenia, and dehydration. Overall, the toxicities were manageable, and the therapy was well tolerated with the reduced pralatrexate dose.Pralatrexate differs from other antifolates, both structurally and mechanistically, which leads to differences in antitumor activity . It seleStudies have shown that loss of function mutations in the SLC19A1 gene make cancer cell lines resistant to antifolates in vitro . SeveralConventional serum biomarkers, such as CEA, are not useful in GEC. This study examined whether microRNA (miRNA)s can be used as a potential biomarker. MicroRNAs regulate cell proliferation, differentiation, and apoptosis, and depending on its mRNA target; a miRNA can function as a tumor suppressor or promoter of oncogenesis . BesidesIn conclusion, the treatment of advanced GEC remains a significant challenge, and many questions remain unresolved. There is an unmet need for intensive research to identify biomarkers of both predictive and prognostic significance. In this new era of pharmacogenomics research and precision medicine, the future is exciting.


Since the discovery of high-temperature superconductivity, significant progress in the fabrication of REBCO-based (Rare Earth Barium Copper mixed Oxides) thin-films superconductors has been achieved. In our review, we described the approaches and possibilities of the improvement of superconducting properties by the introduction of nanosized pinning centers. We focused on the synthesis and viability of the material for artificial pinning centers and methods used for the introduction of the pinning centers into superconducting REBCO-based thin-films. This article summarizes available materials and procedures regardless of the financial cost of the individual method. According to available literature, the most significant superconducting REBCO tapes can be obtained when a combination of 1D and 0D nanoparticles are used for nanoscale pinning. Materials that exhibit a superconducting state at temperatures of 30 K (commonly) and above are known as high-temperature superconductors (HTS). Such materials were first discovered in 1986 by J.G. Bednorz and K.A. Miiller in the Ba-La-Cu-O system [Superconductors are a group of materials that have unique properties within the range of their critical parameters, such as zero electrical resistance and expulsion of the magnetic flux field from the superconductor’s volume . The criO system . In pracO system ,5,6,7,8.c) [Superconductors are divided into type I and type II. For type I superconductors, it is typical that they exhibit sharp and rapid change between the non-superconducting state and the superconducting state without any mixed region. In the case of type II superconductors, the transition from non-superconducting to superconducting is more complicated, and it is seen as more of a gradual process as they exhibit an intermediate mixed state ,11,12,13c) ,21,22. T2Cu3O7–δ or REBCO (rare earth element (RE)) is a group of type II ceramic high-temperature superconductors. REBCO superconductors are used, for example, in thin layers and films [REBand films ,29, second films ,31,32, ond films . REBCO bnd films ,35, e.g.nd films  or supernd films .c of the final thin film-coated superconductors are lowered by a large margin [Coated conductors with a thin film of REBCO are currently produced on an industrial scale by various companies worldwide, whilst the demand for these materials is steadily rising ,40,41,42e margin ,45.2Cu3Ox), with a lower quantity of REBCO 211 (RE2BaCuO5). As the deposition of individual elements varies depending on the technique used, as well as on deposition parameters such as substrate temperature, quality of vacuum, acceleration voltage, etc. there can be a surplus of individual elements in the form of metal oxides or compounds which also belong to the individual REBCO system [3, LaAlO3, MgO, yttria-stabilized zirconia, or sapphire with buffer layers of CeO2, Ag, MgO [The phase composition of thin REBCO layers can differ significantly for different technologies. In general, the individual REBCO grains need to be properly aligned with very low relative angles at the grain boundaries in order to preserve the maximum critical current. Apart from that, the phase composition is mainly REBCO 123 , where M = Nb, Ta, Mo, W, Ru, Zr, Bi and Ag phase seems to be a promising material [3, Ba2RETaO6, Ba2Y O6 or BaTiO3 have been also reported as prospective candidates for inert pinning centers [Artificial pinning with the usage of noble metals, such as silver ,128,129,material ,141,142. centers ,145,146.c. To combat this issue, a combination of different artificial pinning centers has been developed. A synergy between 1D and 0D pinning centers had been shown for various perovskite-based phases (forming 1D nanorods) with nanoparticles at the same time [3 and Y2O3 [3 [3 [The design and development of superconducting REBCO-based coated wires is highly dependent on the method used. Techniques such as CVD or PVD are based on simultaneous growth, hence the orientation of individual phases tends to be determined by the growth mechanism, resulting in the overall defined orientation of artificial pinning centers ,152,153.ame time ,154,155.and Y2O3 ,157,158  Y2O3 [3  and BaHfO3 [3 [3 ). Nanoma3-doped YBCO films are shown for different BaSnO3 concentrations, at different temperatures in various fields [Although the vast majority of published articles deal with pinning properties at the temperature of boiling nitrogen, pinning has the biggest impact at low temperatures (4 K), which are achievable by using liquid helium. Nevertheless, an increase of the pinning effect is noticeable even for higher temperatures ,161 achis fields .In particular, the low temperature-high magnetic field operational interval is so important for high energy physics and nuclear fusion applications that it has drawn ever-increasing interest in recent years from both the scientific community and industry. High-field hybrid magnets, which use a very long YBCO tape can achieve impressive magnetic fields of up to 45 T .The addition of chemically inert material in the form of nano-objects of desired shapes by the optimized process which enables its preferred orientation is certainly one of the ways of introducing working pinning centers into the YBCO films. Purchasing the nanoparticles from commercial vendors is usually the first choice of any group dealing with research or commercial needs for REBCO thin-film synthesis. There are numerous commercial subjects that can supply a sufficiently large amount of broad spectrum of the desired nanomaterials. However, this approach has its limits. Some suitable materials are not available or are not available in sufficient quality or amount. Further, price and time of delivery may play a role. In any event, knowledge of the exact synthetic route and thoughtful characterization of the materials may be crucial in any material research. As a result, the synthesis of one’s own nanomaterials may be important. Few requirements are crucial for choosing synthetic procedures. To name a few: quality, particle size, morphology, purity of synthesized material and sufficient amount of prepared material. The chemical synthesis of nanomaterials by sol-gel processes is an effective method for producing high-quality metal oxide nanoparticles . The sol3 type, e.g., BaZrO3, can be prepared in following ways. Fine BaZrO3, BaTiO3, and LiNbO3 nanoparticles were synthesized in gram quantities by a soft chemistry route. The typical microstructure of fine BaZrO3 is shown in 3 nanoparticles is based on solvothermal and microwave-assisted synthesis [3 nanoparticles from approx. 40 nm further can be synthesized through the calcination of precursors prepared by the auto-combustion sol-gel method based on the citrate-nitrate approach [3 nanoparticles.More specifically, the perovskites of the BaMOynthesis . BaZrO3 approach . These mapproach  may be mIn conclusion, REBCO coated superconducting tapes technology has matured significantly over the last decades, both in terms of the technology itself and the global production of high-performance tapes. This advancement has allowed for steady growth in application areas that rely heavily on second generation coated superconducting tapes, most notably high-field hybrid magnets, which use miles of REBCO tapes in order to achieve fields of up to 45 T, with the potential for wide applications in other fields such as energy transport, research, and many more. In this review, we have focused on the mechanism, engineering, and results of artificial pinning centers in the field of high-performance thin-film coated superconducting tapes. While the general idea for artificial pinning is a simple one, the successful implementation of the theory behind the behavior of vortices and pinning centers still proves to be challenging. It is apparent that pinning centers of various sizes, morphology, and chemical compositions need to be employed, depending on the deposition techniques and intended use of the final product. The improvement for various pinning phases has been arranged into a table for a clear comparison. It seems that for superconducting REBCO tapes, the best overall approach is a combination of 1D (columnar defects and nanorods) and 0D (nanoparticles). This combination provides high-performance tapes whilst allowing for a slightly larger margin of error, given that the orientation of the 1D pinning centers is just one contribution of total pinning present in the REBCO layer. Finally, the methods of producing artificial pinning centers—most importantly, nanoparticles and nanorods—were discussed.


Adherence to treatment is a primary determinant of treatment success. Nonadherence attenuates clinical benefits to the recipients of the treatment. However, monitoring adherence to long treatment regimens is not given due emphasis in low-income contexts. This study aimed to assess adherence to antihypertensive treatment and factors associated with it in Central Ethiopia.  This is an institution-based cross-sectional study conducted in 4 public hospitals in Central Ethiopia from December 4, 2016, to September 25, 2017. The Morisky Medication Adherence Scale (MMAS-8) was used to assess the level of adherence. The Revised Illness Perception Questionnaire (IPQ-R) was used to assess illness perception. The MMAS-8 score ranges from 0 to 8, a score of 8 reflects high adherence, 6 to 7 medium adherence, and <6 low adherence.  A total of 989 hypertensive patients participated in the study, of which 36.0% were assessed to have high adherence, 31.7% medium adherence, and 32.3% low adherence. We found that treatment adherence was significantly and positively associated with having family support , high perception about consequences of hypertension , and high perception about the severity of the disease .  The treatment adherence to antihypertensive medications is low in Central Ethiopia. Engaging family members in the treatment plan and improving patients' understanding of the illness are critical in achieving high adherence to medication in this context. Hypertension (HTN) is one of the major public health problems globally , 2, in bMedication adherence is defined as “the extent to which the medication-taking behavior of a patient corresponds with agreed recommendations/prescriptions.” Patients receiving medication need to understand that the medications are critical to achieving blood pressure control , 9. ManyMultiple factors including patients' beliefs about health, illness, and treatment contribute to antihypertensive medication adherence therapy –23. In tAlthough the importance of treatment adherence has been recognized in Ethiopia by prior studies, the previous studies were conducted on a small number of patients often drawn from a single hospital and gave emphasis mostly only to sociodemographic factors –32. ImpoThis is a hospital-based cross-sectional study conducted from December 4, 2016, to September 25, 2017. The study was conducted in 4 public hospitals, namely, Bishoftu, Adama, Asella, and Shashemene. These hospitals are located in Oromia Regional State in Central Ethiopia. The hospitals provide a comprehensive healthcare service for both outpatient and inpatient clients. These hospitals also have specialty clinics where patients with specific chronic diseases are referred for follow-up. The hypertension clinic is one of those clinics. In Ethiopia, prescriptions are written by a physician in the follow-up clinics and patients get their medications from pharmacies from the same facility or pharmacies outside the healthcare facilities.All adults following their antihypertensive treatment in the four study hospitals were and who fulfilled the inclusion criteria were included in the study. The inclusion criteria include age at least 18 years or above, a diagnosis of hypertension confirmed by a physician, patients on antihypertensive medication for at least 3 months, patients who can give consent to participate in the study, and patients with no acute distress related to any disease during recruitment of study participants. Pregnant women, patients who cannot give consent, and patients who have hearing and/or speaking problems were excluded from the study.P1=28.7, OR = 0.64, 80% power, 95% confidence level, and 1 : 1 (n1 = n2) ratio. After adding 10% nonresponse, the calculated sample size was 1030 . Hypertensive patients who consented for the study were consecutively enrolled until the required sample was fulfilled.The sample size for determining the proportion of adherence to hypertensive treatment was determined with the following assumption: adherence to antihypertension treatment taken as 64.6% based on Ambaw et al. study , a 4% prData were collected using a uniform and pretested questionnaire by 12 trained nurses . The study nurses were not working at the hypertension clinic. Data were collected through a face-to-face interview. The data collectors were competent to do interviews either in Amharic  and Afaan Oromo (the state language). Additionally, one nurse was assigned to supervise the data collection process at each hospital. Patients were interviewed after they got their routine services at existing. Before collecting data, the data collectors explained the objective of the study and obtained informed verbal consent from each study participant. The data collection tool contained questions on sociodemographic information, lifestyle, health-related matters, illness perception (IPQ-R) , the MorThe Illness Representation (IR) component of the validated IPQ-R  had seveFor all these subscales, partial scores were defined as the mean of the scores for the items on each subscale . Then, responses of all items are summed according to the IR dimensions  and then dichotomized in to high and low by their mean. A higher score indicates stronger beliefs about the disease chronicity, cyclical course, impact and outcomes, personal influence, cure possibilities, perceived understanding, and emotional reactions to the disease. The internal consistency of Cronbach's alpha of the IPQ-R was checked and was 0.78, indicating satisfactory internal consistency.The questionnaire is generated by referring to previously published studies based on the constructs of the HBM . The HBMMedication adherence was measured using a validated eight-item self-reported Morisky Medication Adherence Scale (MMAS-8) . Each itThis scale is a questionnaire with high reliability and validity, which has been particularly useful in chronic conditions such as hypertension. Response choices were “Yes” or “No” for items 1 through 7, and item 8 has a four-point Likert response scale. Total scores on the MMAS-8 ranged from 0 to 8, with scores of 8 reflecting high adherence, 6 to <8 reflecting medium adherence, and <6 reflecting low adherence. The internal consistency of Cronbach's alpha of the MMAS was checked and was 0.72 , 36, 37.P. value of 0.25 in bivariate analysis entered into multivariable ordinal logistic regression analysis. The ordinal logistic regression model was used because the outcome variable had three ordered levels of adherence (low⁄ medium/high). This model compared adjacent levels: the odds ratio (OR) corresponded with the odds of adherence to the next lower level. The ORs are presented with their 95% confidence intervals (CIs). The level of significance was set at a P value of less than 0.05. STATA 12 software was used for data entry and analyses.Descriptive statistics were used to summarize sociodemographic, disease characteristics of the study population, and the nature and frequency of antihypertensive medications used. We examined sociodemographic, health-related variables, illness representation variables, and health belief items considering adherence as an outcome variable. The variables which have a A total of 989 study participants were interviewed from four public hospitals in Central Ethiopia. The response rate was 96.0%. The mean age of respondents was 57.6 years (SD = 11.8). Orthodox Christians and the Oromo ethnic group accounted for 64.6% and 51% of the respondents, respectively. More than three-fourth (76.8%) of the respondents were urban residents. Six hundred twenty-seven (63.4%) reported to be married, 34.6% were illiterate, and 32.9% were housewives .About three-fourth (73.8%) of the respondents reported that it takes half an hour or more for a single trip to reach the hospital where they are receiving antihypertensive treatment. More than half (55.7%) of the respondents visit the hospital once every month; about three-fourth (72.7%) did not have a family history of hypertension, and the majority (79.1%) reported getting support from their family or friends .n = 523). More than three-forth (81.3%) of the respondents sleep for more than 6 hours with an average of 6.95 hours (SD = 1.98). The mean values of systolic blood pressure were 139.56 (SD = 15.9) mmHg and 86.3 (SD = 8.32) mmHg for diastolic blood pressure  took their drugs more than once per day. Three-fourth (75.1%) of the respondents reported no side effects of medications, 70.7% reported never heard about the side effects of the drug from healthcare providers, only 38.2% reported the cost of the drug is high, and the rest reported either fair or low. About half (52.9%) of the respondents had comorbid chronic illnesses, and the most frequently reported comorbidity was diabetes mellitus by 80.1% , lower beliefs that potential factors might make it difficult to take the behavior (perceived barriers), and lower internal or external cues that prompt the action, whereas they had higher beliefs that the disease is severe and has serious consequences (perceived severity), higher beliefs that taking treatment is beneficial to reduce or prevent disease threat (perceived benefit), and relatively good confidence to tackle their illness (self-efficacy) .Considering the frequency distribution of the MMAS-8 items, the majority or more than three-fourth of the respondents reported positive responses for MMAS-8 items. However, MMAS-8 items sometimes forget taking their drugs and having some degree of remembering problem to take their medications reported less than three-fourth of the respondents, 63.3% and 52.3%, respectively .dmorisky@gmail.com.Use of the ©MMAS is protected by US copyright and registered trademark laws. Permission for use is required. A license agreement is available from MMAR, LLC., Donald E. Morisky, 294 Lindura Court, Las Vegas, NV 89138-4632, Overall, 32.3%  of participants demonstrated low adherence, 31.7%  medium adherence, and 36.0%  high adherence. About two-third (67.7%)  of participants were either moderate or high adherent for their antihypertensive medications removed .In bivariate regression analysis, sex, educational status, occupation, frequency of visit, family support, perception on a timeline, perception on a consequence, cyclical perception, perceived susceptibility, perceived benefit, perceived severity, and cues to action had a significant association with treatment adherence.After controlling possible confounding effects of other covariates, six factors remained as significant independent predictors of treatment adherence in the adjusted ordinal logistic regression model. These are farmer , family support , perceived consequences of hypertension , perceived cyclical nature of hypertension , perceived susceptibility , and perceived severity of the disease  had significant association with treatment adherence .This study found that only about one-third of the respondents had a high level of treatment adherence. Being a farmer, having family support, higher perceived consequences, perceived cyclical nature of hypertension, perceived susceptibility, and perceived severity of the disease had a significant association with treatment adherence.We collected the data for this study using an interviewer-administered questionnaire, which is a preferred method when conducting a fairly large survey among the community with substantial low literacy levels, to minimize cognitive burden and increase response rate . To miniIn our study, higher adherence to hypertensive medication as measured by MMAS-8 was only 36.0%, which is comparable to several reports from low- and middle-income countries –43. HoweThe findings of this research revealed that farmers were less likely to adhere to antihypertensive treatment compared to employed people. The Farmer is likely to be less educated and may have less information on the treatment adherence compared to the employed person , 45. TheIn this study, respondents who had family support were more likely to adhere to their treatment compared to those who have no family support. This finding is similar to the studies conducted in Northern Ethiopia, Mekele , and NigWhile there may be no clear symptoms of hypertension, understanding how patients perceive hypertension (their illness perceptions) is necessary because, without this, treatment may not be appropriately tailored to their needs and belief systems. Understanding individuals' perceptions about their illnesses provide a key for developing effective strategies to cope with chronic illnesses. Perception of a lower ability to control a health threat can be a barrier to one's behavioral actions, or cognitive and emotional changes in illness representations because of somatic experiences. Higher perception of illness control is associated with lower anxiety, lower avoidance/denial of coping strategies, and positive reappraisal , 49. In The respondent's perception of the consequences of the disease was also positively related to treatment adherence, which was consistent with reports by other researchers , 51. ThePatients' beliefs about how long their symptoms will last might impact their decisions to seek or not seek healthcare. Cyclical timeline refers to the belief of an individual that the expected symptoms will diminish after a certain period and then they might reappear at a certain time in the future. When the symptoms diminished, patients believe that it is cured and more likely to be nonadherent, including decreasing frequency and types of medication, taking medications intermittently, and deviating from the prescribed timing. In this regard, respondents who had higher cyclical perception were less likely to adhere to their treatment. The findings of this research were also supported by a study conducted by Chen et al.  indicateIn treating hypertension, understanding patient's beliefs about medication adherence is fundamental because hypertension is often silent and asymptomatic. Thus, patients might undermine its severity and the significance of its management , 30, 53,According to the Health Belief Model (HBM) people's perception of risk predicts their behaviors, low-risk perception leads to undesired behaviors . HyperteUnder the constructs of the HBM, those with a higher perceived susceptibility showed better adherence to antihypertensive medications , 56. A sThe importance of understanding treatment adherence to antihypertension medications in controlling the patient's blood pressure and reducing hypertension-related complications to clinical practice cannot be overemphasized. Healthcare providers have to be aware of and understand patient's beliefs about their illness and medications while caring for them and incorporating this belief in designing effective interventions to improve medication adherence through reducing barriers to taking medications.Overall, 67.7% of patients were reporting a medium or high level of adherence to antihypertensive medication in this research. Among the study participants, farmers by occupation, having family support, perceived consequences, perceived cyclical nature of hypertension, perceived susceptibility, and perceived severity of the disease showed a significant association with treatment adherence. Illness perceptions and other beliefs may influence the actions of the individual and negatively or positively affect his or her health and taking medication. Therefore, it is important before and during treatment to assess patients' views about their illness, symptoms, and treatments.