Full Responders Research Articles

Elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and rare mutations.

The triple combination of elexacaftor/tezacaftor/ivacaftor (ETI) has dramatically improved the outcome of people with Cystic Fibrosis (pwCF) with at least one F508del mutation. However, carriers of rare cystic fibrosis transmembrane conductance regulator (CFTR) variants are not candidates for this innovative treatment. In this observational study, we report the results of the compassionate use of ETI in 10 pwCF carriers of rare mutations after 2 months of treatment. Rectal organoids and short-term cultures of nasal epithelium obtained from rectal suction biopsies and nasal brushing were obtained from four subjects. After 2 months of ETI, all patients (4 males, mean age 30.1 ± 13.3 years) showed a significant increase of FEV1% predicted values [+8.0 (3.5-12.7) %, p < 0.010], body mass index [+0.85 (0-1.22) kg/m2, p < 0.020] and cystic fibrosis questionnaire-revised [+19.5 (6.3-29.2) points, p < 0.009]. A significant decrease of sweat chloride concentration [-11.2 (-1.7 to -34.0) mmol/L, p < 0.020] and exacerbations [-1.5 (-2 to -1), p < 0.008] was also recorded. Overall, 7 out of 10 participants were considered full responders. All patients reported cough disappearance (n = 3) or reduction (n = 7). Long-term oxygen was discontinued in two out of three patients and one also stopped noninvasive ventilation and was removed from the lung transplantation waiting list. Despite the limited number of cases, our results support the use of CFTR modulators in patients with rare CFTR variants that are not currently approved for ETI in Europe.

Sequential Peg-IFN after bepirovirsen may reduce post-treatment relapse in chronic hepatitis B

Bepirovirsen, an antisense oligonucleotide, induces sustained reductions in hepatitis B surface antigen (HBsAg) and HBV DNA to below the lower limit of quantification (<LLOQ) in a subset of patients. The B-Together study investigated if sequential bepirovirsen and pegylated interferon-α-2a (Peg-IFN) therapy can reduce relapse rates and improve response rates. In this phase IIb, multicentre, open-label trial, participants on stable nucleos(t)ide analogue (NA) therapy were randomised 1:1 to bepirovirsen 300mg once weekly (plus loading dose on Days 4 and 11) for 24 (Arm 1) or 12 (Arm 2) weeks followed by Peg-IFN 180μg once weekly for up to 24 weeks, with up to 36 weeks follow-up. Participants continued NA therapy throughout. The primary outcome was the proportion of participants with HBsAg <0.05 IU/ml and HBV DNA <LLOQ for 24 weeks after planned end of Peg-IFN treatment, in the absence of newly initiated antiviral therapy. The intent-to-treat population included 108 participants (Arm 1, n= 55; Arm 2, n= 53). The primary outcome was achieved by 5 (9%) participants in Arm 1 and 8 (15%) in Arm 2. All responders had baseline HBsAg ≤3,000 IU/ml. Indirect comparison with the phase IIb study B-Clear indicates that sequential addition of Peg-IFN may reduce the relapse rates previously observed with bepirovirsen alone. The proportions of participants with adverse events and treatment-related adverse events in both treatment windows were similar between treatment arms. Sequential therapy with bepirovirsen followed by Peg-IFN is tolerable and effective in participants with chronic HBV infection on stable NA therapy. This proof-of-concept trial demonstrates a potential strategy to extend responses to bepirovirsen by reducing relapse. This phase IIb study investigated whether sequential therapy with bepirovirsenfollowed by Peg-IFN could improve off-treatment response rates to bepirovirsen alone by converting partial bepirovirsen responders to full responders and/or reducing relapse rates in participants with chronic HBV. These data show that sequential therapy with bepirovirsen followed by Peg-IFN is tolerable and effective; in patients with a bepirovirsen response, sequential treatment with Peg-IFN may help to reduce off-treatment relapses in participants on stable NA. Participants had a similar response during bepirovirsen treatment as seen in B-Clear, with increased response rates in participants with lower baseline HBsAg; all responders to the sequential regimen had baseline HBsAg <3000 IU/mL. As the first study of antisense oligonucleotide-mediated RNA silencing followed by interferon immunomodulation in patients with chronic HBV infection, this study is an important proof-of-concept for sequential therapy, shedding light on the therapeutic potential of utilising immunomodulators following suppression of HBV antigens. NCT04676724.

Factors associated with chronic abdominal pain in patients with inflammatory bowel disease in remission: A pilot cross-sectional study.

Patients (20%-50%) with inflammatory bowel disease (IBD) experience chronic abdominal pain during remission. The clinical features of IBD patients with abdominal pain during remission remain poorly characterized. This cross-sectional pilot study aimed to assess patient recruitment, adherence, and feedback to optimize questionnaires for future use and to determine the clinical features that distinguish IBD patients in remission with and without abdominal pain. Online validated questionnaires about disease activity, symptoms, and psychological factors were sent to participants of the UK National Institute for Health and Care Research (NIHR) IBD BioResource, which is a national research platform consisting of re-callable IBD patients designed to expedite research into Crohn's and colitis. Inclusion/exclusion criteria of the IBD BioResource main cohort were applied. Descriptive and inferential statistics were applied to participants in remission. p-values ≤0.01 were considered significant. A total of 2050 patients were approached; 291 (14.2%) of these agreed to participate. In 35 patients, technical problems, length, and poor understanding of the relevance of some questionnaires affected completion as confirmed by feedback. In total, 244 patients were full responders with 122 (50%) in remission; 33 (27%) of these had chronic abdominal pain. Comparison of those with versus without (n = 89) chronic abdominal pain yielded higher scores in patients with pain for the following: somatization (p < 0.001); gastrointestinal symptoms rating scale score (p = <0.001); highly sensitive person scale (p = 0.007); catastrophizing score (p = 0.010). Trends were observed for azathioprine use (p = 0.021); coping resources inventory health in general (p = 0.046); neuroticism (p = 0.019); and poor sleep (p = 0.03). Differences in symptoms and psychological characteristics exist between IBD patients in remission with and without abdominal pain. Confirmation of findings in larger studies may facilitate development of personalized chronic pain treatments for IBD patients.

Illustrating the Financial Consequences of Outcome-Based Payment Models From a Payers Perspective: The Case of Autologous Gene Therapy Atidarsagene Autotemcel (Libmeldy®)

ObjectivesTo illustrate the financial consequences of implementing different managed entry agreements (managed entry agreements for the Dutch healthcare system for autologous gene therapy atidarsagene autotemcel [Libmeldy]), while also providing a first systematic guidance on how to construct managed entry agreements to aid future reimbursement decision making and create patient access to high-cost, one-off potentially curative therapies. MethodsThree payment models were compared: (1) an arbitrary 60% price discount, (2) an outcome-based spread payment with discounts, and (3) an outcome-based spread payment linked to a willingness to pay model with discounts. Financial consequences were estimated for full responders (A), patients responding according to the predicted clinical pathway presented in health technology assessment reports (B), and unstable responders (C). The associated costs for an average patient during the time frame of the payment agreement, the total budget impact, and associated benefits expressed in quality-adjusted life-years of the patient population were calculated. ResultsWhen patients responded according to the predicted clinical pathway presented in health technology assessment reports (scenario B), implementing outcome-based reimbursement models (models 2 and 3) had lower associated budget impacts while gaining similar benefits compared with the discount (scenario 1, €8.9 million to €6.6 million vs €9.2 million). In the case of unstable responders (scenario C), costs for payers are lower in the outcome-based scenarios (€4.1 million and €3.0 million, scenario 2C and 3C, respectively) compared with implementing the discount (€9.2 million, scenario 1C). ConclusionsOutcome-based models can mitigate the financial risk of reimbursing atidarsagene autotemcel. This can be considerably beneficial over simple discounts when clinical performance was similar to or worse than predicted.

The Impact of Steroid Responder Status on Long-Term Outcomes in Critically Ill Patients With Acute Respiratory Distress Syndrome Receiving High-Dose Glucocorticoids.

Background and objective High-dose intravenous pulsed glucocorticosteroids (GCS) are not part of the standard treatment in acute respiratory distress syndrome (ARDS), and the evidencesupporting their use is conflicting. In clinical practice, however, they are used in specialist settings when clinico-patho-radiological features suggest a potentially steroid-responsive pattern, or as a last resort in cases where patients are unable to be weaned off mechanical ventilation. This study aimed to investigate if an early objective response to high-dose GCS treatment in selected critically ill patients is predictive of survival in ARDS. Methods This study involved a case series of 63 patients treated at a tertiary specialist respiratory ICUbetween 2009 and 2017 who received high-dose GCS for ARDS following a multidisciplinary board agreement. Patients were stratified according to the change in their modified lung injury score (mLIS) between days 0 and 10 following GCS initiation. Changes in mLIS (range: 0-4)were grouped as follows - full responders: ≥2, partial responders: ≥1 and <2, and non-responders: <1. Mortality on discharge and at 6, 12, 18, and 24 months post-ICU discharge was assessed for each group. Data were analysed using logistic regression and a receiver operating curve (ROC) to determine a statistically significant association between the change in mLIS and survival. Results Of the 63 patients, there were seven full responders, 12 partial responders, and 44 non-responders to high-dose GCS. Overall mortality at ICU discharge and 6, 12, 18 and 24 months post-discharge was 29/63 (46.0%), 33/63 (52.4%), 34/63 (54.0%), 34/63 (54.0%), and 35/63 (55.6%) respectively. Mortality was significantly lower in the partial and full-response groups than in the non-response group at all time frames. Logistic regression showed a significant association between the change in mLIS and survival (p<0.001), and a ROC demonstrated that categorising the change in mLIS was a good predictive model for survival (c-statistic 0.86). Conclusions Measuring the change in mLIS by day 10 following high-dose GCS administration for ARDS may beclinically useful in prognosticating such patients. Further research using mLIS as a measure of response to GCS, and larger datasets to enable the evaluation of prognostic factors, may assist clinicians in predicting which patients with persistent ARDS are likely to respond to GCS therapy.

Effect of Luspatercept on Erythropoiesis and Fetal Hemoglobin in β-Transfusion-Dependent Thalassemia Patients: A Real-Life Experience

Background: Luspatercept is the first erythropoiesis-stimulating agent approved for transfusion-dependent β-thalassemia (TDT). In the BELIEVE trial, more than 70% of the patients had a hematological response defined as a reduction of ≥33% of transfusion burden in any 12-week interval. In our experience, some patients have a clinical benefit even if a response as defined by the clinical trial is not reached. Indeed, several aspects remain to be addressed, including its specific effects on erythropoiesis. Fetal hemoglobin (HbF) has been hypothesized as a potential marker in response evaluation. However, no results have been published, excluding an abstract presentation by Cappellini MD et al. at the European Hematology Association meeting in 2019, showing a greater HbF increase in responders vs. non-responders. Aim: This study aims to evaluate the effect of luspatercept on erythropoiesis and the hemoglobin (Hb) fractions in patients with β-TDT treated with luspatercept in a real-life setting at our Center in Milan, Italy. Methods: Inclusion criteria: age ≥18 years, β-TDT eligible for treatment with luspatercept, and signed informed consent. Exclusion criteria: unwilling to participate in the study. We assessed hematological parameters, Hb fractions, and erythropoiesis markers at baseline and over the treatment period of up to 48 weeks (Dose16). We also extracted mRNA from reticulocytes (RET) from peripheral blood at fixed doses and analyzed the expression of a panel of genes involved in erythropoiesis. We evaluated hematological variables dividing the patients into three groups of responses defined: Full responder (FR): reduction of transfusion burden ≥33% and ≥2 units of blood in any 12-week intervalIntermediate responder (IR): patients with a reduction in transfusion burden ≥25% and &amp;lt;33% in any 12-week intervalNon-responder (NR): reduction of the transfusion burden &amp;lt;25%. Statistical analysis at baseline was performed using Kruskal-Wallis test. We fitted linear random intercept regression models to evaluate time trends of hematological variables. Results: Thirty-seven patients have been enrolled in the study. 3/37 have been excluded from the analysis because they developed adverse events leading to drug interruption before completing 12 weeks of treatment. We herein present the data of the 29/34 subjects who reached at least 12 weeks of treatment as of July 20, 2023. The median age was 41 yrs (range 19-63 yrs), 15 were females (52%). 8/29 (28%) had a β0/β0 genotype; 12/29 (41%) patients underwent splenectomy. Twelve patients had a FR, 6 an IR, and 11 were NR. We found that the baseline median absolute value of HbF (g/dL) was different in the three groups (NR: 0.21, range 0.09-0.34; IR: 0.37, range 0.14-1.52; FR: 0.95, range 0.31-1.65, p=0.009) (Figure 1). In all subjects, HbF increased over time. However, the increase was different in the three groups (p-interaction: 0.0001). In the linear regression model (Figure 2), the HbF absolute increase per week was 0.004 g/dL (95% confidence interval (CI): 0.002-0.006) among NR, 0.015 (CI: 0.008-0.022) in the IR group and 0.03 g/dL (CI: 0.02-0.04) in the FR group. EPO baseline value was similar in the three groups, but unexpectedly we observed different increases over time (p-interaction: 0.0001). In the IR and FR groups, the regression slopes were 6.66 U/L (CI: 3.11-10-21) and 9.42 U/L (CI: 5.53-13.31) per week, respectively. In the NR group, there was no EPO increase. Interestingly, the baseline value of erythroblasts (EB) was different between the three groups, with FR having the highest value. EB increased in both IR and FR, with the IR group displaying a steeper increase and finally reaching the FR group. Preliminary results on gene expression in RET showed an upregulation of GATA-1 and its target genes involved in erythroid differentiation and heme biosynthesis, as shown in the murine model (Martinez PA et al. 2019), irrespective of the response group. Conclusions: Our findings identify baseline HbF as a possible predictor of response. Also, the HbF trend could represent a marker of response to luspatercept in β-TDT patients. Furthermore, HbF can be useful in identifying patients in the IR group with the best chance of becoming responders in long-term treatment. Our preliminary results also suggest that luspatercept acts by enhancing erythropoiesis and leads to an increase in EPO levels and EB. Studies on more patients are needed to confirm these findings.

Association of BDNF risk variant and dorsolateral cortical thickness with long-term treatment response to valproate in type I bipolar disorder: An exploratory study.

Valproate is among the most prescribed drugs for bipolar disorder; however, 87% of patients do not report full long-term treatment response (LTTR) to this medication. One of valproate's suggested mechanisms of action involves the brain-derived neurotrophic factor (BDNF), expressed in the brain areas regulating emotions, such as the prefrontal cortex. Nonetheless, data about the role of BDNF in LTTR and its implications in the structure of the dorsolateral prefrontal cortex (dlPFC) is scarce. We explore the association of BDNF variants and dorsolateral cortical thickness (CT) with LTTR to valproate in bipolar disorder type I (BDI). Twenty-eight BDI patients were genotyped for BDNF polymorphisms rs1519480, rs6265, and rs7124442, and T1-weighted 3D brain scans were acquired. LTTR to valproate was evaluated with Alda's scale. A logistic regression analysis was conducted to evaluate LTTR according to BDNF genotypes and CT. We evaluated CT differences by genotypes with analysis of covariance. LTTR was associated with BDNF rs1519480 and right dlPFC thickness. Insufficient responders with the CC genotype had thicker right dlPFC than TC and TT genotypes. Full responders reported thicker right dlPFC in TC and TT genotypes. In conclusion, different patterns of CT related to BDNF genotypes were identified, suggesting a potential biomarker of LTTR to valproate in our population.

Desmopressin in combination with anticholinergic agents in the treatment of nocturnal enuresis: a systematic review and meta-analysis.

The desmopressin combined with anticholinergic agents for the treatment of nocturnal enuresis (NE) remains controversial. This meta-analysis assesses the efficacy and safety of desmopressin compared with desmopressin plus anticholinergic agents for the treatment of NE. We searched MEDLINE, Embase, and Cochrane Controlled Trials Register databases for RCTs published for the treatment of NE. Systematic review was carried out using the Preferred Reporting Items for Systematic Reviews and Meta-analyses. This meta-analysis used RevMan v.5.1.0 to analyze data. Eight studies involving 600 patients (293 in the combination group and 307 in the desmopressin group) contained meaningful data. The results were as follows: after one month of treatment, compared with the desmopressin monotherapy group, the combination group was significantly better in treating NE in FR (full responders, P = 0.003), FR + PR (partial responders) (P < 0.0001), and the mean number of wet nights (P = 0.004); also, the combination group had a better effect in FR (P < 0.00001), FR + PR (P = 0.02) and the mean number of wet nights (P = 0.04) after 3 months' treatment. For side effects, combination therapy does not cause more adverse events in treating NE (P = 0.42). This study elucidates that desmopressin combined with the anticholinergic agent was demonstrated to be more effective in treating NE than desmopressin monotherapy, and the anticholinergic agent does not increase the risk of adverse events (AEs).

Association of vitamin D and polymorphisms of its receptor with antiviral therapy in pregnant women with hepatitis B.

The interruption of mother-to-child transmission (MTCT) is considered important to decrease the individual and population morbidity of hepatitis B virus (HBV) infection as well as the global burden of hepatitis B. Serum vitamin D (VD) is associated with hepatitis B. To assess whether baseline VD levels and single nucleotide polymorphisms of the VD receptor gene (VDR SNPs) are associated with the efficacy of tenofovir disoproxil fumarate (TDF) in the prevention of MTCT in pregnant women with high HBV viral loads. Thirty-eight pregnant women who were at high risk for MTCT of HBV (those with an HBV DNA level ≥ 2 × 105 IU/mL during 12-24 wk of gestation) receiving antiviral therapy of TDF between June 1, 2019 and June 30, 2021 in Mianyang were included in this retrospective study. The women received 300 mg TDF once daily from gestational weeks 24-28 until 3 mo after delivery. To further characterize the clinical relevance of maternal serum HBV DNA levels, we stratified patients according to HBV DNA level as follows: Those with levels < 2 × 105 (full responder group) vs those levels ≥ 2 × 105 IU/mL (partial responder group) at delivery. Serum levels of 25-hydroxyvitamin D [25(OH)D], liver function markers, virological parameters, VDR SNPs and other clinical parameters were collected to analyze their association with the efficacy of TDF. The Mann-Whitney U test or t test was used to analyze the serum levels of 25(OH)D in different groups. Multiple linear regressions were utilized to analyze the determinants of the maternal HBV DNA level at delivery. Univariate and multivariate logistic regression analyses were employed to explore the association of targeted antiviral effects with various characteristics at baseline and delivery. A total of 38 pregnant women in Mianyang City at high risk for MTCT of HBV were enrolled in the study. The MTCT rate was 0%. No mother achieved hepatitis B e antigen or hepatitis B surface antigen (HBsAg) clearance at delivery. Twenty-three (60.5%) participants were full responders, and 15 (39.5%) participants were partial responders according to antiviral efficacy. The present study showed that a high percentage (76.3%) of pregnant women with high HBV viral loads had deficient (< 20 ng/mL) or insufficient (≥ 20 but < 31 ng/mL) VD levels. Serum 25(OH)D levels in partial responders appeared to be significantly lower than those in full responders both at baseline (25.44 ± 9.42 vs 17.66 ± 5.34 ng/mL, P = 0.006) and delivery (26.76 ± 8.59 vs 21.24 ± 6.88 ng/mL, P = 0.044). Serum 25(OH)D levels were negatively correlated with maternal HBV DNA levels [log(10) IU/mL] at delivery after TDF therapy (r = -0.345, P = 0.034). In a multiple linear regression analysis, maternal HBV DNA levels were associated with baseline maternal serum 25(OH)D levels (P < 0.0001, β = -0.446), BMI (P = 0.03, β = -0.245), baseline maternal log10 HBsAg levels (P = 0.05, β = 0.285) and cholesterol levels at delivery (P = 0.015, β = 0.341). Multivariate logistic regression analysis showed that baseline serum 25(OH)D levels (OR = 1.23, 95%CI: 1.04-1.44), maternal VDR Cdx2 TT (OR = 0.09, 95%CI: 0.01-0.88) and cholesterol levels at delivery (OR = 0.39, 95%CI: 0.17-0.87) were associated with targeted antiviral effects (maternal HBV DNA levels < 2 × 105 at delivery). Maternal VD levels and VDR SNPs may be associated with the efficacy of antiviral therapy in pregnant women with high HBV viral loads. Future studies to evaluate the therapeutic value of VD and its analogs in reducing the MTCT of HBV may be justified.

Retinal vascular structure independently predicts the initial treatment response in neovascular age-related macular degeneration.

Prediction of the early treatment response is important in neovascular age-related macular degeneration (nAMD). Hence, we aimed to test if non-invasive measurements of the retinal vascular structure were able to predict a successful outcome of initial intravitreal treatment. In 58 eyes of 58 patients with treatment-naïve nAMD, advanced markers of retinal vascular structure were measured by Singapore I Vessel Assessment prior to initial intravitreal treatment with three monthly injections of aflibercept with subsequently categorization of patients as full treatment responders (FTR) or non/partial treatment responders (N/PR), with the former defined as loosing fewer than five Early Treatment Diabetic Retinopathy Study letters and having no residual intra- or subretinal fluid or macular haemorrhage. Of 54 eyes attending follow-up, 44.4% were categorized as FTR. Patients with FTR were older (81.5 vs. 77 years, p = 0.04), and prior to treatment those eyes had a lower retinal arteriolar fractal dimension (Fd) (1.21 vs. 1.24 units, p = 0.02) and venular length-diameter ratio (LDR) (7.3 vs. 15.9 units, p = 0.006), but did not differ with respect to other retinal vascular parameters. In multiple logistic regression models, a lower chance of FTR was independently predicted by a higher retinal venular LDR (odds ratio [OR] 0.91, 95% CI 0.82-0.99, p = 0.03, for each 1 unit increment) and marginally by a higher retinal arteriolar Fd (OR 0.83, 95% CI 0.68-1.00, p = 0.05, for each 0.01 unit increment). Retinal venular LDR independently predicted the initial treatment response in nAMD. If confirmed by long-term, prospective studies, this might help to guide treatment.

Gamma knife capsulotomy for intractable OCD: Neuroimage analysis of lesion size, location, and clinical response

Obsessive-compulsive disorder (OCD) affects 2–3% of the population. One-third of patients are poorly responsive to conventional therapies, and for a subgroup, gamma knife capsulotomy (GKC) is an option. We examined lesion characteristics in patients previously treated with GKC through well-established programs in Providence, RI (Butler Hospital/Rhode Island Hospital/Alpert Medical School of Brown University) and São Paulo, Brazil (University of São Paolo). Lesions were traced on T1 images from 26 patients who had received GKC targeting the ventral half of the anterior limb of the internal capsule (ALIC), and the masks were transformed into MNI space. Voxel-wise lesion-symptom mapping was performed to assess the influence of lesion location on Y-BOCS ratings. General linear models were built to compare the relationship between lesion size/location along different axes of the ALIC and above or below-average change in Y-BOCS ratings. Sixty-nine percent of this sample were full responders (≥35% improvement in OCD). Lesion occurrence anywhere within the targeted region was associated with clinical improvement, but modeling results demonstrated that lesions occurring posteriorly (closer to the anterior commissure) and dorsally (closer to the mid-ALIC) were associated with the greatest Y-BOCS reduction. No association was found between Y-BOCS reduction and overall lesion volume. GKC remains an effective treatment for refractory OCD. Our data suggest that continuing to target the bottom half of the ALIC in the coronal plane is likely to provide the dorsal–ventral height required to achieve optimal outcomes, as it will cover the white matter pathways relevant to change. Further analysis of individual variability will be essential for improving targeting and clinical outcomes, and potentially further reducing the lesion size necessary for beneficial outcomes.

When eating disorder attitudes and cognitions persist after weight restoration: An exploratory examination of non-cognitive responders to family-based treatment for adolescent anorexia nervosa.

Family-based treatment (FBT) is a well-established intervention for adolescent anorexia nervosa (AN). Although FBT is efficacious in promoting weight gain and improvements in psychological symptoms, for some adolescents, cognitive/attitudinal recovery lags behind weight gain. This study conducted an exploratory post hoc analysis of outcomes of adolescents who achieved weight gain by the end of FBT but continued to experience elevated psychological symptoms post-treatment. Data were drawn from two randomised controlled trials (RCTs) testing two forms of FBT (conjoint/whole family and parent-focussed). Descriptive statistics and generalised estimating equations were used to examine differences in treatment outcomes between non-cognitive responders (NCRs) (those who regained weight but continued to experience psychological symptoms) and full responders (FRs) (those who achieved both weight and cognitive restoration by the end of treatment) (n=80; 83.7% female, Agemean [SD]=14.66 [1.73]). By 12months post-treatment, there were no differences in weight between NCRs and FRs. However, NCRs had a slower trajectory of weight gain than FRs and continued to have elevated levels of psychological symptoms throughout the follow-up period. A subset of adolescents appear to continue to experience clinically significant levels of eating pathology up to 12months after FBT even when weight restoration is achieved.

A prospective and randomized study comparing the use of alarms, desmopressin and imipramine in the treatment of monosymptomatic nocturnal enuresis

Monosymptomatic enuresis (MNE) results from a pathogenic triad that may include lack of vasopressin secretion during sleep, reduced functional bladder capacity and inability to wake up during sleep. The treatment of MNE can be performed through behavioral therapy, use of alarms or medications such as desmopressin and imipramine. To compare the effectiveness of different treatments of MNE. Prospective and randomized study comparing different intervention and a control group (receiving only behavior therapy) for MNE. age between 5 and 16 years old, with MNE, evaluated at the pediatric urology outpatient clinic of Hospital Infantil Menino Jesus. At first visit children were submitted to behavior therapy (urotherapy) for 3 months, children were subsequently characterized according to the ICCS as non-responders, partial responders, or full responders. Those partial responders or non-responders received a patient ID and were randomized to four groups: Alarm Group (G1), Desmopressin Group - DDAVP (G2), Imipramine Group (G3) and Control (G4). All groups were monitored monthly, for a period of 6 months. After 6 months, the children were reevaluated for MNE. 93 patients were enrolled. Mean age was 10.96 years with a standard deviation of 2.28 years, 59,1% were male. All groups had improvement in the number of dry nights (Table). Taking in account success the population full responders and partial responders: Alarm Group (G1) achieve success in 100% of cases, Desmopressin Group - DDAVP (G2) in 63.6% of cases, Imipramine Group (G3) in 73.7% of cases (Table 3). No drugs side effects were observed in both groups (G2 and G3), there was no dropout in patients who used alarms. Our data suggests that the use of alarms is the most effective treatment of ENM with superior results when compared to imipramine and DDAVP. The small number of participants is a weakness of the study, as well as the lack of a voiding diary at the end of the study. All therapeutics options utilized in the treatment of MNE are safe, effective and has a low rate of abandonment.

A Proposal to Differentiate ACO, Asthma and COPD in Vietnam.

In low- and middle-income countries, such as Vietnam, the population is exposed to multiple risks, leading to frequent allergic asthma, COPD and their overlap (ACO). We aimed to differentiate asthma and COPD, so that recommended treatments can be applied. We hypothesized that during life, the cumulative exposure to noxious particles increases the relative prevalence of COPD, while due to immuno-senescence, the prevalence of allergic asthma decreases with age. Among 568 patients with chronic respiratory symptoms, five phenotypes were defined, based on responsiveness to a bronchodilator (BD), diffusion capacity and cumulative smoking. Then the relative prevalence of each phenotype was related with age. the smoker BD irreversible patients were considered "COPD", while the full BD responders and non-smoking BD incomplete responders were "asthmatics". The other patients were ACO, distributed as "like-COPD" or "like-asthma", based on decreased or normal diffusion capacity. The relative prevalence of asthma, COPD and ACO were 26, 42 and 32% (18% "like-asthma", 14% "like-COPD"). Vietnamese patients with chronic respiratory symptoms were considered as falling into asthma or COPD groups, based on cumulative smoking, spirometry with reversibility and diffusion capacity. The relative prevalence of asthma and COPD were 44 and 56%, respectively, most of which did not require corticosteroids.

Can enuresis alarm therapy be managed by the families without the support of a nurse? A prospective study of a real-world sample.

The alarm is the first-line treatment of nocturnal enuresis. However, the therapy is labour-intensive for both families and healthcare providers. Our aim was to see whether the treatment could be successfully used by the families, without support from healthcare providers. An alarm linked to an application on a parent's smartphone was used. The app recorded enuretic events and gave instructions. Group A were children supported by a nurse. Group B were patients whose families had bought the alarm and downloaded the app independently. There were 196 children in group A and 202 in group B. The percentages of full responders, partial responders, non-responders and dropouts were 18.4%, 20.4%, 22.4% and 38.8% in group A and 13.4%, 11.4%, 14.9% and 60.4% in group B. The risk for dropping out of therapy was higher in group B (p < 0.001), whereas the chance for adherent children to become dry did not differ between the groups (p=0.905). For families who are able to adhere to alarm therapy the chance of success is just as good when managed independently as when supported by a nurse. But the latter children will have a greater chance of adhering to the full treatment.

Trimodality Versus Surgery as Needed: Is Delayed or Salvage Esophagectomy Justified?

For advanced carcinomas of the esophagus multimodal therapies consisting of neoadjuvant treatment with chemo- and/or radiation followed by surgical resection are the standard of care in western countries. Still unknown remains the question if clinical full responders to neoadjuvant treatment should receive an esophagectomy with all its perioperative risks as they could be pathological full responders potentially without further oncologic benefit. In this article we discuss the possible benefits and disadvantages of an organ sparing approach in comparison of the standard of care for patients with esophageal cancer.

The value of case history and early treatment data as predictors of enuresis alarm therapy response

Two central problems with the enuresis alarm are the family workload and the lack of predictors of therapy response. We wanted to look at predictors of alarm response in a setting reflecting clinical reality. An alarm linked to a smartphone app was provided to enuretic children managed at pediatric outpatient wards. Baseline data (sex, age, daytime incontinence, urgency, previous therapies, arousal thresholds and baseline enuresis frequency) were recorded. Further information, such as enuretic episodes and actual alarm use, was gathered via the app during therapy. Therapy was given for 8-12 weeks or until 14 consecutive dry nights had been achieved. For the 196 recruited children the outcome was as follows: full responders (FR) 18.4%, partial responders (PR) 20.4%, nonresponders (NR) 22.4% and dropouts 38.8%. We found no clear predictors of response or adherence among baseline data. But as treatment progressed responders reduced their enuresis frequency as compared to NR (week two P=0.003, week three and onwards P<0.001). This is further illustrated in the Figurebelow. Furthermore, the children unable to complete the full treatment had more non-registered nights already from the second week (week two P=0.005, week three P=0.002 and so on). Anamnestic data give little predictive information regarding enuresis alarm response or adherence. Contrary to common belief neither daytime incontinence nor previous alarm attempts influenced treatment success. But after 2-4 weeks of therapy the children with a good chance of treatment success could be discerned by decreasing enuresis frequency, and the families that would not be able to comply with the full treatment showed incomplete adherence already during the first weeks. Maybe the enuresis alarm strategy should be changed so that the treatment is reassessed after one month and only children with a high chance of success continue. This way, unnecessary frustration for the families of therapy-resistant children may be reduced.

Deep brain stimulation in the ALIC-BNST region targeting the bed nucleus of stria terminalis in patients with obsessive–compulsive disorder: effects on cognition after 12 months

PurposeThe aim of this study was to evaluate cognitive effects 12 months after Deep Brain Stimulation (DBS) of the Bed Nucleus of Stria Terminalis (BNST) in patients with refractory Obsessive–Compulsive Disorder (OCD).MethodsEight patients (5 female; mean ± SD age 36 ± 15) with OCD were included. A neuropsychological test battery covering verbal and spatial episodic memory, executive function, and attention was administered preoperatively and 12 months after surgery. Medical records were used as a source for descriptive data to probe for any changes not covered by standardized checklists and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the primary outcome measure.ResultsAt 12 months, seven patients showed response to DBS: three were full responders (i.e., Y-BOCS ≥ 35% improvement), and four were partial responders (Y-BOCS 25–34% improvement). Relative to baseline, there was a slight decline on visuo-spatial learning (p = 0.027), and improved performance on the Color-Word Interference inhibition/switching subtest (p = 0.041), suggesting improvement in cognitive flexibility.ConclusionsDBS in the BNST for treatment refractory OCD generates very few adverse cognitive effects and improves cognitive flexibility after 12 months of stimulation. The improvement in Y-BOCS and the absence of major cognitive side effects support the BNST as a potential target for DBS in severe OCD.

Long-Term Outcomes of the Six-Food Elimination Diet and Food Reintroduction in a Large Cohort of Adults With Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is an immune-mediated inflammatory condition with tissue eosinophilia resulting in esophageal dysfunction. The six-food elimination diet (SFED) is an EoE treatment approach that removes milk, wheat, soy, eggs, tree nuts/peanuts, and fish/shellfish. After histologic remission, food reintroduction occurs to identify a food trigger. Outcomes from large series of adults undergoing SFED and food reintroduction as clinical care are not known. A retrospective review (2006-2021) of adult patients with EoE from an academic center was completed. Patients were classified as full responders (<15 eos/hpf) after SFED. If reintroduction was pursued, food triggers identified were recorded. Two hundred thirteen patients completed SFED. One hundred fifteen patients (54%) had response <15 eos/hpf after SFED. Seventy-seven percent of responders had symptom improvement. Thirty-two percent of initial nonresponders underwent repeat dietary elimination. Fifty-eight percent of patients (n = 123) achieved <15 eos/hpf after either initial or extended SFED. Seventy-eight percent of responders underwent food reintroduction. Sixty-nine percent had 1 food trigger identified, 24% had 2 allergens identified, and 4% had 3 allergens identified. The most common food triggers identified were milk, wheat, and soy. This study describes the largest cohort reported of adult patients with EoE completing SFED with food reintroduction. The overall SFED histologic response was 54%, which increased to 58% with 1 additional round of dietary therapy, suggesting that 31% may respond in a second attempt. Most patients who completed food reintroduction had a single food trigger identified. Dietary elimination with specific food trigger identification is a feasible alternative to medical therapy for adults with EoE.

Self-rated health of both US citizens and noncitizens is associated with state-level immigrant criminalization policies

Evidence shows that state-level restrictive immigrant policies are associated with health disparities between noncitizens and citizens. Most research has focused on Latinos and there is limited knowledge of the relationship between restrictive policies and citizenship status among other groups, particularly Asian and Pacific Islanders (API). We examined whether state-level criminalization policy contexts (e.g., law enforcement collaboration with immigration authorities, E-Verify employment authorization) were associated with self-rated health (SRH) by citizenship, with a focus on Latinos and APIs. We expected that criminalization policies would be associated with worse health for noncitizens and citizens, but with a more negative influence for noncitizens; and that this pattern would be the same for Latinos and APIs. We merged a state-level immigrant criminalization policy database with a multi-racial/ethnic sample from 2014 to 2015 National Health Interview Survey (NHIS, n = 70,335). We tested the association between SRH and the number of state-level criminalization policies and generated predicted probabilities of noncitizens and citizens reporting excellent health in states with the most and fewest criminalization policies for the full sample, Latino, and API respondents. In states with the most criminalization policies, all noncitizens had a higher and all US-born citizens had a lower probability of excellent health. In states with the fewest criminalization policies there were no differences by citizenship status. Findings provide new evidence that state-level immigrant policies may harm the health of US-born citizens. As immigrant policymaking at the state level continues, understanding the relationship between state-level immigrant policies and health inequities across citizenship statuses will continue to be critical to improving population health.