Prevalence of Malocclusion and Orthodontic Treatment Need in 9- to 12-Year-Old Schoolchildren in Ulaanbaatar, Mongolia.

Background The prevalence of malocclusion in Mongolia is increasing every year. Estimating the need for orthodontic treatment in the population is crucial for planning orthodontic care services and monitoring oral health programs. Therefore, the present study aimed to assess the need for orthodontic treatment among schoolchildren in Ulaanbaatar, Mongolia, using the Index of Orthodontic Treatment Need (IOTN). Methods A total of 656 schoolchildren aged 9-12 years were enrolled from 8 schools located in urban and suburban areas of 6 districts of Ulaanbaatar city. All the children were assessed according to the two components of the IOTN, the Dental Health Component (DHC) and the aesthetic component (AC). Statistical analyses were carried out using IBM SPSS Statistics for Windows, Version 28 (Released 2021; IBM Corp., Armonk, New York, United States). Results The prevalence of malocclusion was 561 (84.5%), consisting of 452 (68%) Angle Class I, 178 (26.8%) Angle Class II, and 34 (5.2%) Angle Class III malocclusion. For the DHC, the moderate need for treatment was 194 (29.3%) and the definite need was 53 (8.1%). For the AC, the moderate need was 148 (22.3%) and the definite need was 45 (6.9%). The association between the DHC and the AC was found to be statistically significant (p<0.001). The most common malocclusions were an increased overjet (maxillary protrusion), a contact point displacement (crowding), and an increased overbite (deep bite). The AC, Angle's molar relationship, an increased overjet, a contact point displacement, and an increased overbite were factors associated with the need for orthodontic treatment. Conclusion Approximately one-third of schoolchildren in Ulaanbaatar, Mongolia, require orthodontic treatment. This finding helps dental practitioners to better understand oral health problems, leading to an improvement in the overall quality of life of children.

Management challenges and the role of adjuvant chemotherapy in remnant gastric cancer: an analysis of 313 patients from the KEGG multicenter observational study.

BACKGROUND: Clinical findings and postoperative follow-up data on remnant gastric cancer (RGC) are limited due to its rarity. Additionally, the preoperative staging, radical surgery, and managing recurrence in RGC present significant clinical challenges. METHODS: We analyzed the clinicopathological findings, adjuvant chemotherapy, and patterns of postoperative recurrence of 313 consecutive patients who underwent curative surgery for RGC at 17 Japanese institutions. This study investigated the optimal management of RGC and the impact of adjuvant chemotherapy (AC) on recurrence-free survival (RFS). RESULTS: Pathological stages I, II, and III were observed in 55.9% (N = 175), 24.9% (N = 78), and 19.2% (N = 60) of the patients, respectively. The overall concordance rate between clinical and pathological T staging was 58.3%, with a clinical T4 sensitivity of 41.4% for diagnosing pathological T4. During the median follow-up period of 4.6 years, disease recurrence occurred in 24.3% of patients. Most recurrences (over 80%) occurred within 2.5 years, and 96.1% within 5 years after RGC surgery. Peritoneal recurrence was the most common in patients with advanced RGC, accounting for 14.1% in stage II and 28.3% in stage III. Multivariable regression analysis showed that AC was significantly associated with a longer RFS, with a hazard ratio of 0.45 (95% confidence interval: 0.26-0.76). CONCLUSIONS: Our study underscores the importance of early detection, accurate preoperative staging, and postoperative surveillance in managing advanced RGC cases. Despite some limitations, our findings indicate that AC may provide survival benefits comparable to those seen in primary gastric cancer.

Current insights on social media as a tool for the dissemination of research and education in surgery: a narrative review.

The purpose of our narrative review is to summarize the utilization of social media (SoMe) platforms for research communication within the field of surgery. We searched the PubMed database for articles in the last decade that discuss the utilization of SoMe in surgery and then categorized the diverse purposes of SoMe. SoMe proved to be a powerful tool for disseminating articles. Employing strategic methods like visual abstracts enhances article citation rates, the impact factor, h-index, and Altmetric score (an emerging alternative metric that comprehensively and instantly quantifies the social impact of scientific papers). SoMe also proved valuable for surgical education, with online videos shared widely for surgical training. However, it is essential to acknowledge the associated risk of inconsistency in quality. Moreover, SoMe facilitates discussion on specific topics through hashtags or closed groups and is instrumental in recruiting surgeons, with over half of general surgery residency programs in the US efficiently leveraging these platforms to attract the attention of potential candidates. Thus, there is a wealth of evidence supporting the effective use of SoMe for surgeons. In the contemporary era where SoMe is widely utilized, surgeons should be well-versed in this evidence.

Severe Maxillary Protrusion Treated with Surgically Assisted Rapid Maxillary Expansion.

In this case, surgically assisted rapid maxillary expansion (SARME) was successfully adopted to treat a skeletal maxillary protrusion with large overjet and severe crowding. The female patient, aged 25 years and 11 months, was diagnosed with skeletal maxillary protrusion with severe crowding and excessive overjet associated with labially inclined maxillary central incisors. After achieving sufficient space for surgical incision between bilateral maxillary central incisors, the SARME was performed. A total of 8.0 mm lateral expansion of the maxilla was completed. At 48 days after surgery, the Hyrax appliance was replaced with an Anchor-Lock system used as an external surgical stent and skeletal anchorage for maxillary group distalization, and the distal movement of the maxillary molars was initiated without waiting for bone healing of the separated midpalatal suture by SARME. Twenty-five months' treatment, including surgical preparation, achieved an acceptable and stable occlusion with adequate interincisal relationship. The occlusion was much more stable with a little relapse through more than 4 years' retention period. In conclusion, SARME followed by the Anchor-Lock system might lead to favorable occlusal outcome in the long term without any relapses.

Current Status of the Management of Idiopathic Condylar Resorption/Progressive Condylar Resorption-A Scoping Review.

The temporomandibular joint (TMJ) is a complex synovial joint shrouded in mystery, as the etiology of many TMJ disorders are unsolved. Idiopathic/progressive condylar resorption (ICR/PCR) is one such TMJ disorder characterized by a gradually deteriorating mandibular condylar mass, resulting in severe mandibular retrognathia, which often accompanied by clockwise rotation of mandible and an anterior open bite. Since the etiology of the ICR/PCR remains unclear, no definitive prevention or management options have been established. To date, various symptomatic non-surgical, surgical, and salvage management options have been developed and reported. To understand the current status of the ICR/PCR management options, this article provides an overview of the options presently reported in the literature to reduce its TMJ symptoms and improve mandibular function and form.

The efficacy of simple oral nutritional supplements versus usual care in postoperative patients with gastric cancer: study protocol for a multicenter, open-label, parallel, randomized controlled trial.

BACKGROUND: Body weight loss (BWL) after gastrectomy impact on the short- and long-term outcomes. Oral nutritional supplement (ONS) has potential to prevent BWL in patients after gastrectomy. However, there is no consistent evidence supporting the beneficial effects of ONS on BWL, muscle strength and health-related quality of life (HRQoL). This study aimed to evaluate the effects of ONS formulated primarily with carbohydrate and protein on BWL, muscle strength, and HRQoL. METHODS: This will be a multicenter, open-label, parallel, randomized controlled trial in patients with gastric cancer who will undergo gastrectomy. A total of 120 patients who will undergo gastrectomy will be randomly assigned to the ONS group or usual care (control) group in a 1:1 ratio. The stratification factors will be the clinical stage (I or ≥ II) and surgical procedures (total gastrectomy or other procedure). In the ONS group, the patients will receive 400 kcal (400 ml)/day of ONS from postoperative day 5 to 7, and the intervention will continue postoperatively for 8 weeks. The control group patients will be given a regular diet. The primary outcome will be the percentage of BWL (%BWL) from baseline to 8 weeks postoperatively. The secondary outcomes will be muscle strength (handgrip strength), HRQoL (EORTC QLQ-C30, QLQ-OG25, EQ-5D-5L), nutritional status (hemoglobin, lymphocyte count, albumin), and dietary intake. All analyses will be performed on an intention-to-treat basis. DISCUSSION: This study will provide evidence showing whether or not ONS with simple nutritional ingredients can improve patient adherence and HRQoL by reducing BWL after gastrectomy. If supported by the study results, nutritional support with simple nutrients will be recommended to patients after gastrectomy for gastric cancer. TRIAL REGISTRATION: jRCTs051230012; Japan Registry of Clinical Trails. Registered on Apr. 13, 2023.

Influence of Orthodontic Treatment on Changes in the Maxillary Sinus Dimensions.

Objective This study aimed to investigate the correlation of craniofacial morphology with maxillary sinus morphology and to evaluate whether orthodontic treatment facilitates maxillary sinus enlargement in adults. Materials and methods A total of 45 adult women underwent cephalography and computed tomography before and after orthodontic treatment. All participants were classified into three groups: skeletal class I, II, and III. The average dimensions and volume of the maxillary sinus were calculated in each subgroup. Furthermore, multiple regression analysis was used to analyze the correlations of maxillary sinus dimensions with 20 cephalometric variables. Results Before treatment, the maxillary sinus width, height, depth, and volume were 32.2 ± 3.9 mm, 39.5 ± 3.8 mm, 38.6 ± 1.8 mm, and 36,179.3 ± 5,454.0 mm3 in skeletal class I, 33.9 ± 6.2 mm, 37.3 ± 3.5 mm, 38.6 ± 2.4 mm, and 34,729.8 ± 6,686.6 mm3 in skeletal class II, and 32.0 ± 4.3 mm, 41.8 ± 5.0 mm, 38.0 ± 2.8 mm, and 35,592.3 ± 10,334.3 mm3 in skeletal class III, respectively. Despite no significant differences in maxillary sinus width, depth, or volume, the height was significantly lower in the skeletal class II than in the other two. Regardless of the skeletal pattern, maxillary sinus height and volume increased considerably after treatment. Moreover, the maxillary sinus width was substantially involved in pretreatment U1 to SN and overbite and posttreatment U1 to NA and overjet. Conclusion Except for the height, the maxillary sinus dimensions were almost similar, irrespective of the skeletal classification. The posttreatment sinus height and volume were significantly greater than the pretreatment values, although the sinus width and length showed no significant changes during orthodontic treatment. This implies that orthodontic treatment may facilitate the enlargement of the maxillary sinus even after physical growth.

A dual composite resin injection molding technique with 3D-printed flexible indices for biomimetic replacement of a missing mandibular lateral incisor.

PATIENTS: This case report presents a minimally invasive approach to replace a missing mandibular lateral incisor using a dual-injection molding technique with flowable composite resins. Integrated with a comprehensive digital workflow, this method achieves a structurally and esthetically biomimetic, bi-layered prosthetic solution. A 34-year-old woman with congenital absence of a mandibular lateral incisor was successfully rehabilitated using a direct composite resin-bonded fixed partial denture (RBFPD). DISCUSSION: Two specialized three-dimensional (3D)-printed flexible indices stabilized by a custom-designed 3D-printed rigid holder were employed to ensure the meticulous injection molding of flowable composite resins formulated to emulate the inherent chromatic gradations between dentin and enamel. The inherent flexibility of the indices, combined with the holder, facilitated accurate and seamless adaptation to the complex morphological features of the dental arch, thereby mitigating the challenges commonly associated with rigid 3D-printed resin indices. CONCLUSIONS: The bilayered direct composite RBFPD using 3D printed flexible indices prepared with a full digital workflow has several advantages over other dental prosthetic solutions, including noninvasiveness, cost-effectiveness, biomimetic esthetics, repairability, and shortened treatment times. Although the initial results are promising, further longitudinal studies with larger patient cohorts are required to confirm the long-term efficacy of this approach.

Conditioned Medium From Stem Cells of Human Exfoliated Deciduous Teeth Alleviates Mouse Osteoarthritis by Inducing sFRP1-Expressing M2 Macrophages.

Intravenous administration of conditioned medium from stem cells of human exfoliated deciduous teeth (SHED-CM) regenerates mechanically injured osteochondral tissues in mouse temporomandibular joint osteoarthritis (TMJOA). However, the underlying therapeutic mechanisms remain unclear. Here, we showed that SHED-CM alleviated injured TMJ by inducing anti-inflammatory M2 macrophages in the synovium. Depletion of M2 by Mannosylated Clodrosome abolished the osteochondral repair activities of SHED-CM. Administration of CM from M2-induced by SHED-CM (M2-CM) effectively ameliorated mouse TMJOA by inhibiting chondrocyte inflammation and matrix degradation while enhancing chondrocyte proliferation and matrix formation. Notably, in vitro, M2-CM directly suppressed the catabolic activities while enhancing the anabolic activities of interleukin-1ß-stimulated mouse primary chondrocytes. M2-CM also inhibited receptor activator of nuclear factor NF-κB ligand-induced osteoclastogenesis in RAW264.7 cells. Secretome analysis of M2-CM and M0-CM revealed that 5 proteins related to anti-inflammation and/or osteochondrogenesis were enriched in M2-CM. Of these proteins, the Wnt signal antagonist, secreted frizzled-related protein 1 (sFRP1), was the most abundant and played an essential role in the shift to anabolic chondrocytes, suggesting that M2 ameliorated TMJOA partly through sFRP1. This study suggests that secretome from SHED exerted remarkable osteochondral regeneration activities in TMJOA through the induction of sFRP1-expressing tissue-repair M2 macrophages.

Mycobiont identity and light conditions affect belowground morphology and physiology of a mixotrophic orchid Cremastra variabilis (Orchidaceae).

We have investigated whether mycobiont identity and environmental conditions affect morphology and physiology of the chlorophyllous orchid: Cremastra variabilis. This species grows in a broad range of environmental conditions and associates with saprotrophic rhizoctonias including Tulasnellaceae and saprotrophic non-rhizoctonian fungi from the family Psathyrellaceae. We cultured the orchid from seeds under aseptic culture conditions and subsequently inoculated the individuals with either a Tulasnellaceae or a Psathyrellaceae isolate. We observed underground organ development of the inoculated C. variabilis plants and estimated their nutritional dependency on fungi using stable isotope abundance. Coralloid rhizome development was observed in all individuals inoculated with the Psathyrellaceae isolate, and 1-5 shoots per seedling grew from the tip of the coralloid rhizome. In contrast, individuals associated with the Tulasnellaceae isolate did not develop coralloid rhizomes, and only one shoot emerged per plantlet. In darkness, δ13C enrichment was significantly higher with both fungal isolates, whereas Î´15N values were only significantly higher in plants associated with the Psathyrellaceae isolate. We conclude that C. variabilis changes its nutritional dependency on fungal symbionts depending on light availability and secondly that the identity of fungal symbiont influences the morphology of underground organs.

Impact of the coronavirus disease 2019 pandemic on gastric and colorectal cancer surgeries: a multicenter epidemiologic study from the Kinki region of Japan.

The coronavirus disease 2019 pandemic affected cancer surgeries and advanced cancer diagnoses; however, the trends in patient characteristics in medical institutions during this time, and the surgical approaches used are unclear. We investigated the impact of the pandemic on gastric and colorectal cancer surgeries in the Kinki region of Japan. We grouped 1688 gastric and 3493 colorectal cancer surgeries into three periods: "pre-pandemic" (April 2019-March 2020), "pandemic 1" (April 2020-March 2021), and "pandemic 2" (April 2021-September 2021), to investigate changes in the number of surgeries, patient characteristics, surgical approaches, and cancer progression after surgery. Gastric and colorectal cancer surgeries decreased from the pre-pandemic levels, by 20% and 4%, respectively, in pandemic 1, and by 31% and 19%, respectively, in pandemic 2. This decrease had not recovered to pre-pandemic levels by September, 2021. Patient characteristics, surgical approaches, and cancer progression of gastric and colorectal surgeries did not change remarkably as a result of the coronavirus disease 2019 pandemic.

FBXW7 regulates the sensitivity of imatinib in gastrointestinal stromal tumors by targeting MCL1.

BACKGROUND: Imatinib contributes to improving prognosis of high-risk or unresectable gastrointestinal stromal tumors (GISTs). As therapeutic efficacy is limited by imatinib resistance and toxicity, the exploration of predictive markers of imatinib therapeutic efficacy that enables patients to utilize more effective therapeutic strategies remains urgent. METHODS: The correlation between FBXW7 and imatinib resistance via FBXW7-MCL1 axis was evaluated in vitro and in vivo experiments. The significance of FBXW7 as a predictor of imatinib treatment efficacy was examined in 140 high-risk patients with GISTs. RESULTS: The ability of FBXW7 to predict therapeutic efficacy of adjuvant imatinib in high-risk GIST patients was determined through 5-year recurrence-free survival (RFS) rates analysis and multivariate analysis. FBXW7 affects imatinib sensitivity by regulating apoptosis in GIST-T1 cells. FBXW7 targets MCL1 to regulate apoptosis. MCL1 involves in the regulation of imatinib sensitivity through inhibiting apoptosis in GIST-T1 cells. FBXW7 regulates imatinib sensitivity by down-regulating MCL1 to enhance imatinib-induced apoptosis in vitro. FBXW7 regulates imatinib sensitivity of GIST cells by targeting MCL1 to predict efficacy of imatinib treatment in vivo. CONCLUSIONS: FBXW7 regulates imatinib sensitivity by inhibiting MCL1 to enhance imatinib-induced apoptosis in GIST, and predicts efficacy of imatinib treatment in high-risk GIST patients treated with imatinib.

Etiology and Diagnosis for Idiopathic Condylar Resorption in Growing Adolescents.

This article has been written in honor of the late professor emeritus Kazuo Tanne, who passed away on 4 March 2023 [...].

Microbially produced fertilizer provides rhizobacteria to hydroponic tomato roots by forming beneficial biofilms.

Hydroponic cultivation of Solanum lycopersicum (tomato) is important, and high tomato production depends on the use of nitrogen and phosphate fertilizers. We had developed a microbial fertilizer (MF), which is mainly composed of nitrate. To investigate the effect of MF on plant growth, hydroponic tomato was grown with MF or commercial inorganic fertilizer (IF), and the microbiomes of the rhizosphere and the liquid phase were analyzed by confocal microscopy and high-throughput sequencing. Plant biomass and biofilm formation were increased by growth in MF compared to IF. The microbial community structures of tomato roots and hydroponic water differed between the two conditions, and three operational taxonomic units (OTUs) dominated in plants grown with MF. The three OTUs were related to Rudaea spp., Chitinophaga spp., and Stenotrophobacter terrae, which are reported to be disease-suppressive epiphytic or endophytic microbes of plant roots. Because these three OTUs also predominated in the MF itself, they were likely provided to the rhizosphere or endophytic environments of tomato roots via hydroponic water. KEY POINTS: • Microbial fertilizer for hydroponic growth enhanced biofilm formation on tomato root. • Microbial fertilizer contains tomato-root epiphytic or endophytic microbes. • Microbial fertilizer provided beneficial microbes to the rhizosphere and endophytic environments of tomato roots via hydroponic water.

Efficacy of laser in re-osseointegration of dental implants-a systematic review.

Despite their high success rates, peri-implantitis can affect the stability and function of dental implants. Various treatment modalities have been investigated for the treatment of peri-implantitis to achieve re-osseointegration. An electronic literature search was performed supplemented by a manual search to identify studies published until January 2022. Articles that evaluated re-osseointegration in peri-implantitis sites in animal models following laser therapy or antimicrobial photodynamic therapy (aPDT) were included. Case reports, case series, systematic reviews, and letters to the editor were excluded. Risk of bias and GRADE assessment were followed to evaluate the quality of the evidence. Six studies out of 26 articles identified on electronic search were included in this review. The studies included animal studies conducted on canine models. Four out of six studies reported a higher degree of re-osseointegration following treatment of implants with laser therapy. The findings suggest that laser decontamination shows potential in enhancing re-osseointegration, particularly with the Er: YAG laser, which effectively decontaminated implant surfaces. However, conflicting outcomes and limitations in the evidence quality warrant caution in drawing definitive conclusions. Based on the limited available evidence, laser therapy may show a higher degree of re-osseointegration of implants than mechanical debridement.

Ability of minimally invasive surgery to decrease incisional surgical site infection occurrence in patients with colorectal cancer and other gastroenterological malignancies.

Background: Surgical site infection (SSI) is one of the most important complications of surgery for gastroenterological malignancies because it leads to a prolonged postoperative hospital stay and increased inpatient costs. Furthermore, SSI can delay the initiation of postoperative treatments, including adjuvant chemotherapy, negatively affecting patient prognosis. Identifying the risk factors for SSI is important to improving intra- and postoperative wound management for at-risk patients. Methods: Patients with gastroenterological malignancies who underwent surgery at our institution were retrospectively reviewed and categorized according to the presence or absence of incisional SSI. Clinicopathological characteristics such as age, sex, body mass index, malignancy location, postoperative blood examination results, operation time, and blood loss volume were compared between groups. The same analysis was repeated of only patients with colorectal malignancies. Results: A total of 528 patients (330 men, 198 women; mean age, 68 ± 11 years at surgery) were enrolled. The number of patients with diseases of the esophagus, stomach, small intestine, colon and rectum, liver, gallbladder, and pancreas were 25, 150, seven, 255, 51, five, and 35, respectively. Open surgery was performed in 303 patients vs. laparoscopic surgery in 225 patients. An incisional SSI occurred in 46 patients (8.7%). Multivariate logistic regression analysis showed that postoperative hyperglycemia (serum glucose level ≥140 mg/dl within 24 h after surgery), colorectal malignancy, and open surgery were independent risk factors for incisional SSI. In a subgroup analysis of patients with colorectal malignancy, incisional SSI occurred in 27 (11%) patients. Open surgery was significantly correlated with the occurrence of incisional SSI (P = 0.024). Conclusions: Postoperative hyperglycemia and open surgery were significant risk factors for SSI in patients with gastroenterological malignancies. Minimally invasive surgery could reduce the occurrence of incisional SSI.

Analysis of the Effects of Known Sleep-Support Supplements in Relation to Life Habits, Sleep Conditions, and Sleep Problems.

Sleep is a crucial component of health, and insomnia is among the most common and vexing of life-habit-related disorders. While dietary sleep-support supplements can improve sleep, choosing an effective dietary supplement can be challenging for users due to the wide variety of options available and the varying effects experienced by different individuals. In this study, to identify new criteria for estimating the effects of dietary supplements, we examined the relationships among the dietary supplements, the pre-conditions (PCs; defined as the life habits and sleep conditions before supplementation), and the sleep problems of subjects before supplementation. An open, randomized, cross-over intervention trial enrolling 160 subjects was conducted to test the efficacy of each dietary supplement (Analysis 1) and the relationships among dietary supplements, the PCs, and sleep problems (Analysis 2). To this end, l-theanine (200 mg/day), γ-aminobutyric acid (GABA) (111.1 mg/day), Apocynum venetum leaf extract (AVLE) (50 mg/day), and l-serine (300 mg/day) were administered to subjects. Before the first intervention period, life habits and sleep conditions were surveyed to identify each subject's PCs. For each combination of supplements and sleep problems, PCs were compared between subjects whose sleep problems were improved and subjects whose sleep problems were not improved via supplementation. All the tested supplements were found to ameliorate sleep problems significantly (Analysis 1). In Analysis 2, the PCs specific to improved subjects were found to differ depending on the dietary supplements and sleep problems. In addition, subjects who consumed dairy products often showed improvement in their sleep problems with all the tested supplements. This study suggests the possibility of personalizing sleep-support supplementation based on personal life habits, sleep conditions, and sleep problems, in addition to the known efficacy of dietary supplements.

Mechanisms of preferential bone formation in myeloma bone lesions by proteasome inhibitors.

Proteasome inhibitors (PIs) can preferentially restore bone in bone-defective lesions of patients with multiple myeloma (MM) who respond favorably to these drugs. Most prior in vitro studies on PIs used continuous exposure to low PI concentrations, although pharmacokinetic analysis in patients has shown that serum concentrations of PIs change in a pulsatile manner. In the present study, we explored the effects of pulsatile treatment with PIs on bone metabolism to simulate in vivo PI pharmacokinetics. Pulsatile treatment with bortezomib, carfilzomib, or ixazomib induced MM cell death but only marginally affected the viability of osteoclasts (OCs) with F-actin ring formation. Pulsatile PI treatment suppressed osteoclastogenesis in OC precursors and bone resorption by mature OCs. OCs robustly enhanced osteoblastogenesis in cocultures with OCs and MC3T3-E1 pre-osteoblastic cells, indicating OC-mediated coupling to osteoblastogenesis. Importantly, pulsatile PI treatment did not impair robust OC-mediated osteoblastogenesis. These results suggest that PIs might sufficiently reduce MM cell-derived osteoblastogenesis inhibitors to permit OC-driven bone formation coupling while suppressing OC differentiation and activity in good responders to PIs. OC-mediated coupling to osteoblastogenesis appears to be a predominant mechanism for preferential occurrence of bone regeneration at sites of osteoclastic bone destruction in good responders.