Miracle-dz/UniFAR-FTUs huggingface dataset:
The Effects of Oral Energy-Dense Supplements on Nutritional Status in Nondiabetic Maintenance Hemodialysis Patients

Visual Abstract Background and objectives Fat-based energy-dense nutritional supplements may offer benefits over protein- or carbohydrate-dense supplements for patients receiving dialysis because of the adverse metabolic consequences of the latter. We conducted a randomized controlled trial to assess the effects of the short-term use of a fat-based nutritional supplement on various measures of nutritional status in patients receiving maintenance hemodialysis who have low dietary energy intake. Design, setting, participants, & measurements We enrolled nondiabetic patients receiving hemodialysis for >3 months who had inadequate dietary energy intake (<30 kcal/kg per day). The participants were randomly assigned in a 1:1 ratio to receive an oral fat-based energy-dense supplement (300 kcal daily) or routine care for 12 weeks (n=120 per group). The primary outcome was the change in phase angle measured by bioelectrical impedance analysis, a marker of cell integrity and body cell mass, from the baseline to week 12. The secondary outcomes were changes in quality of life. Other outcomes included laboratory nutritional indicators and physical examinations. Results The average age of the total population was 47 (SD: 12) years, and 55% were men. The median of dialysis vintage was 43.4 (22.5–76.3) months; 240 participants were randomly assigned to the intervention (n=120) or control group (n=120). In total, 228 (95%) participants completed the trial. The change in phase angle did not differ significantly between the intervention and control groups (estimate, 0.0; 95% confidence interval, −0.1 to 0.1 versus estimate, 0.0; 95% confidence interval, −0.1 to 0.1; estimated difference, 0.0; 95% confidence interval −0.2 to 0.2; P=0.99). None of the 19 domains of quality of life differed between the groups. Adverse events were reported in 23 (19%) participants in the control group and 40 (33%) participants in the intervention group. Conclusions In nondiabetic patients on maintenance hemodialysis, short-term administration of fat-based energy-dense nutritional supplement has no clinically significant effect on nutritional status as measured by phase angle. Podcast This article contains a podcast at https://https://www.asn-online.org/media/podcast/CJASN/2021_08_03_CJN16821020. mp3
Effects of Translumbosacral Neuromodulation Therapy on Gut and Brain Interactions and Anorectal Neuropathy in Fecal Incontinence: A Randomized Study

Translumbosacral neuromodulation therapy (TNT) improves symptoms of fecal incontinence (FI), but its mechanism of action is unknown. We tested the hypothesis that TNT at one or more frequency will significantly improve underlying pathophysiology of FI through modulation of ascending and/or descending signaling pathways in the gut and brain axis and anorectal sensorimotor function.
Two cases of DCDC2‐related neonatal sclerosing cholangitis with developmental delay and literature review

Ciliopathies are a group of clinical and molecular heterogeneous conditions with pleiotropic manifestations affecting the central nervous system, renal, liver, skeletal, and ocular systems. Biallelic pathogenic variants in DCDC2 cause a ciliopathy primarily presenting with neonatal sclerosing cholangitis (NSC). Pathogenic variants in DCDC2 have further been reported in the context of nephronophthisis and non‐syndromic recessive deafness. Polymorphisms in DCDC2 have also been associated with dyslexia and DCDC2 has a role in neuronal development. We report on two unrelated patients with DCDC2‐related NSC with additional central nervous system impairment manifesting as microcephaly, global developmental delay, and axial hypotonia. Histological findings of our patients can mimic biliary atresia or congenital hepatic fibrosis. We further show that transmission electron microscopy in patients with NSC does not always show absence of primary cilia. Hence patients with DCDC2 pathogenic variants should also undergo an evaluation of neuromotor development. Review of all reported patients further reveals a risk for supra‐aortic arterial aneurysms.
Correction for Bernhard et al., Men and women candidates are similarly persistent after losing elections

Significance In this manuscript, we examine women’s reactions to electoral losses to show that women candidates are no more dissuaded from seeking office again after losing than men are. We analyze elections across a broad range of geographies in the United States, focusing on local and state races where most candidates run for office. These results add depth to mainstream news coverage of the surge in women’s candidacies following the 2016 presidential election, especially to more pessimistic coverage claiming the phenomenon would have little long-term impact. Contrary to those narratives, our results show that the surge in women candidates is unlikely to be a “flash in the pan” for women’s political representation. Are women more likely to quit politics after losing their first race than men? Women’s first-time candidacies skyrocketed in the wake of the 2016 presidential election. Yet we have little sense of the long-term impact of this surge in women candidates on women’s representation writ large: Inexperienced candidates are more likely to lose, and women might be especially discouraged by a loss. This might make the benefits of such a surge in candidacies fleeting. Using a regression discontinuity design and data that feature 212,805 candidates across 22,473 jurisdictions between 1950 and 2018, we find that women who narrowly lose these elections are no more likely to quit politics than men who narrowly lose. Drawing on scholarship on women’s lower political ambition, we interpret these findings to mean that women’s decision-making differs from men’s at the point of entry into politics—not at the point of reentry.
Brain variability in dynamic resting-state networks identified by fuzzy entropy: a scalp EEG study

Objective. Exploring the temporal variability in spatial topology during the resting state attracts growing interest and becomes increasingly useful to tackle the cognitive process of brain networks. In particular, the temporal brain dynamics during the resting state may be delineated and quantified aligning with cognitive performance, but few studies investigated the temporal variability in the electroencephalogram (EEG) network as well as its relationship with cognitive performance. Approach. In this study, we proposed an EEG-based protocol to measure the nonlinear complexity of the dynamic resting-state network by applying the fuzzy entropy. To further validate its applicability, the fuzzy entropy was applied into simulated and two independent datasets (i.e. decision-making and P300). Main results. The simulation study first proved that compared to the existing methods, this approach could not only exactly capture the pattern dynamics in time series but also overcame the magnitude effect of time series. Concerning the two EEG datasets, the flexible and robust network architectures of the brain cortex at rest were identified and distributed at the bilateral temporal lobe and frontal/occipital lobe, respectively, whose variability metrics were found to accurately classify different groups. Moreover, the temporal variability of resting-state network property was also either positively or negatively related to individual cognitive performance. Significance. This outcome suggested the potential of fuzzy entropy for evaluating the temporal variability of the dynamic resting-state brain networks, and the fuzzy entropy is also helpful for uncovering the fluctuating network variability that accounts for the individual decision differences.
Retargeting IL-2 Signaling to NKG2D-Expressing Tumor-Infiltrating Leukocytes Improves Adoptive Transfer Immunotherapy

Key Points Retargeting IL-2 delivery to CTLs improves immunotherapy. Regulatory lymphocytes hinder ex vivo expansion of CTLs. Tumor-infiltrating NK cells and γδ T cells facilitate adoptive transfer immunotherapy. Ex vivo expansion followed by reinfusion of tumor-infiltrating leukocytes (TILs) has been used successfully for the treatment of multiple malignancies. Most protocols rely on the use of the cytokine IL-2 to expand TILs prior to reinfusion. In addition, TIL administration relies on systemic administration of IL-2 after reinfusion to support transferred cell survival. The use of IL-2, however, can be problematic because of its preferential expansion of regulatory T and myeloid cells as well as its systemic side effects. In this study, we describe the use of a novel IL-2 mutant retargeted to NKG2D rather than the high-affinity IL-2R for TIL-mediated immunotherapy in a murine model of malignant melanoma. We demonstrate that the NKG2D-retargeted IL-2 (called OMCPmutIL-2) preferentially expands TIL-resident CTLs, such as CD8+ T cells, NK cells, and γδT cells, whereas wild-type IL-2 provides a growth advantage for CD4+Foxp3+ T cells as well as myeloid cells. OMCPmutIL-2–expanded CTLs express higher levels of tumor-homing receptors, such as LFA-1, CD49a, and CXCR3, which correlate with TIL localization to the tumor bed after i.v. injection. Consistent with this, OMCPmutIL-2–expanded TILs provided superior tumor control compared with those expanded in wild-type IL-2. Our data demonstrate that adoptive transfer immunotherapy can be improved by rational retargeting of cytokine signaling to NKG2D-expressing CTLs rather than indiscriminate expansion of all TILs.
Randomized Trial of Two Induction Therapy Regimens for High-Risk Neuroblastoma: HR-NBL1.5 International Society of Pediatric Oncology European Neuroblastoma Group Study

PURPOSE Induction therapy is a critical component of the therapy of high-risk neuroblastoma. We aimed to assess if the Memorial Sloan Kettering Cancer Center (MSKCC) N5 induction regimen (MSKCC-N5) would improve metastatic complete response (mCR) rate and 3-year event-free survival (EFS) compared with rapid COJEC (rCOJEC; cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C]). PATIENTS AND METHODS Patients (age 1-20 years) with stage 4 neuroblastoma or stage 4/4s aged < 1 year with MYCN amplification were eligible for random assignment to rCOJEC or MSKCC-N5. Random assignment was stratified according to national group and metastatic sites. Following induction, therapy comprised primary tumor resection, high-dose busulfan and melphalan, radiotherapy to the primary tumor site, and isotretinoin with ch14.18/CHO (dinutuximab beta) antibody with or without interleukin-2 immunotherapy. The primary end points were mCR rate and 3-year EFS. RESULTS A total of six hundred thirty patients were randomly assigned to receive rCOJEC (n = 313) or MSKCC-N5 (n = 317). Median age at diagnosis was 3.2 years (range, 1 month to 20 years), and 16 were younger than 1 year of age with MYCN amplification. mCR rate following rCOJEC induction (32%, 86/272 evaluable patients) was not significantly different from 35% (99/281) with MSKCC-N5 (P = .368), and 3-year EFS was 44% ± 3% for rCOJEC compared with 47% ± 3% for MSKCC-N5 (P = .527). Three-year overall survival was 60% ± 3% for rCOJEC compared with 65% ± 3% for MSKCC-N5 (P = .379). Toxic death rates with both regimens were 1%. However, nonhematologic CTC grade 3 and 4 toxicities were higher with MSKCC-N5: 68% (193/283) versus 48% (129/268) (P < .001); infection 35% versus 25% (P = .011); stomatitis 25% versus 3% (P < .001); nausea and vomiting 17% versus 7% (P < .001); and diarrhea 7% versus 3% (P = .011). CONCLUSION No difference in outcome was observed between rCOJEC and MSKCC-N5; however, acute toxicity was less with rCOJEC, and therefore rCOJEC is the preferred induction regimen for International Society of Pediatric Oncology European Neuroblastoma Group.
Water calorimetry-based k Q factors for Farmer-type ionization chambers in the SOBP of a carbon-ion beam

The dosimetry of carbon-ion beams based on calibrated ionization chambers (ICs) still shows a significantly higher uncertainty compared to high-energy photon beams, a fact influenced mainly by the uncertainty of the correction factor for the beam quality k Q . Due to a lack of experimental data, k Q factors in carbon-ion beams used today are based on theoretical calculations whose standard uncertainty is three times higher than that of photon beams. To reduce their uncertainty, in this work, k Q factors for two ICs were determined experimentally by means of water calorimetry for the spread-out Bragg peak of a carbon-ion beam, these factors are presented here for the first time. To this end, the absorbed dose to water in the 12C-SOBP is measured using the water calorimeter developed at Physikalisch-Technische Bundesanstalt, allowing a direct calibration of the ICs used (PTW 30013 and IBA FC65G) and thereby an experimental determination of the chamber-specific k Q factors. Based on a detailed characterization of the irradiation field, correction factors for several effects that influence calorimetric and ionometric measurements were determined. Their contribution to an overall uncertainty budget of the final k Q factors was determined, leading to a standard uncertainty for k Q of 0.69%, which means a reduction by a factor of three compared to the theoretically calculated values. The experimentally determined values were expressed in accordance with TRS-398 and DIN 6801-1 and compared to the values given there. A maximum deviation of 2.3% was found between the experiment and the literature.
The emerging role of robotics in upper and lower urinary tract reconstruction

Purpose of review Developments in robotic reconstructive urology have introduced novel treatments for complex upper and lower urinary tract disease. Short-term and mid-term data demonstrates excellent outcomes and minimal morbidity, suggesting the advanced instrumentation and visualization of robotics represent a new treatment paradigm in patients that are historically difficult to treat. Here we review recent developments in the robotically assisted surgical management of urethral and ureteral strictures. Recent findings The minimally invasive approach, enhanced precision and reach, and near-infrared fluorescence imaging capabilities of robotic platforms have proven to be valuable additions in reconstructive urology where perfusion is often compromised, or anatomy is distorted. These benefits are leveraged heavily in recent descriptions of robotic-assisted posterior urethroplasty and ureteroplasty. Short-term to mid-term follow-up data for these procedures show excellent patency rates with low morbidity and complication rates when compared with open approaches. Long-term data for these procedures are not yet available. Summary The role of robotics in reconstructive urology is being actively investigated. Initial findings demonstrate excellent results with low morbidity in the treatment of upper and lower urinary tract disease. Long-term data will ultimately determine the role of robotics in the reconstructive armamentarium.
Only the Co‐Transcriptional Activity of β‐Catenin Is Required for the Local Regulatory Effects in Hypertrophic Chondrocytes on Developmental Bone Modeling

In hypertrophic chondrocytes, β‐catenin has two roles. First, it locally suppresses the differentiation of osteoclasts at the chondro‐osseous junction by maintaining the pro‐osteoclastic factor receptor activator of NF‐κB ligand (RANKL) at low levels. Second, it promotes the differentiation of osteoblast‐precursors from chondrocytes. Yet, β‐catenin is a dual‐function protein, which can either participate in cell–cell adherens junctions or serve as a transcriptional co‐activator in canonical Wnt signaling interacting with T‐cell factor/lymphoid enhancer‐binding factor (TCF/LEF) transcription factors. Hence, whenever studying tissue‐specific requirements of β‐catenin using a conventional conditional knockout approach, the functional mechanisms underlying the defects in the conditional mutants remain ambiguous. To decipher mechanistically which of the two molecular functions of β‐catenin is required in hypertrophic chondrocytes, we used different approaches. We analyzed the long bones of newborn mice carrying either the null‐alleles of Lef1 or Tcf7, or mice in which Tcf7l2 was conditionally deleted in the hypertrophic chondrocytes, as well as double mutants for Lef1 and Tcf7l2, and Tcf7 and Tcf7l2. Furthermore, we analyzed Ctnnb1 mutant newborns expressing a signaling‐defective allele that retains the cell adhesion function in hypertrophic chondrocytes. None of the analyzed Tcf/Lef single or double mutants recapitulated the previously published phenotype upon loss of β‐catenin in hypertrophic chondrocytes. However, using this particular Ctnnb1 allele, maintaining cell adhesion function, we show that it is the co‐transcriptional activity of β‐catenin, which is required in hypertrophic chondrocytes to suppress osteoclastogenesis and to promote chondrocyte‐derived osteoblast differentiation. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Long-acting PGE2 and Lisinopril Mitigate H-ARS

Thrombocytopenia is a major complication in hematopoietic-acute radiation syndrome (H-ARS) that increases the risk of mortality from uncontrolled hemorrhage. There is a great demand for new therapies to improve survival and mitigate bleeding in H-ARS. Thrombopoiesis requires interactions between megakaryocytes (MKs) and endothelial cells. 16, 16-dimethyl prostaglandin E2 (dmPGE2), a longer-acting analogue of PGE2, promotes hematopoietic recovery after total-body irradiation (TBI), and various angiotensin-converting enzyme (ACE) inhibitors mitigate endothelial injury after radiation exposure. Here, we tested a combination therapy of dmPGE2 and lisinopril to mitigate thrombocytopenia in murine models of H-ARS following TBI. After 7.75 Gy TBI, dmPGE2 and lisinopril each increased survival relative to vehicle controls. Importantly, combined dmPGE2 and lisinopril therapy enhanced survival greater than either individual agent. Studies performed after 4 Gy TBI revealed reduced numbers of marrow MKs and circulating platelets. In addition, sublethal TBI induced abnormalities both in MK maturation and in in vitro and in vivo platelet function. dmPGE2, alone and in combination with lisinopril, improved recovery of marrow MKs and peripheral platelets. Finally, sublethal TBI transiently reduced the number of marrow Lin–CD45–CD31+Sca-1– sinusoidal endothelial cells, while combined dmPGE2 and lisinopril treatment, but not single-agent treatment, accelerated their recovery. Taken together, these data support the concept that combined dmPGE2 and lisinopril therapy improves thrombocytopenia and survival by promoting recovery of the MK lineage, as well as the MK niche, in the setting of H-ARS.
Increased diagnostic sensitivity of palpation‐guided thyroid nodule fine‐needle aspiration cytology by BRAF V600E‐mutation analysis

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer and its incidence is increasing. Preoperative diagnosis is warranted in order to avoid ‘two‐stage’ procedures that are associated with additional costs and higher radioactive iodine remnant uptake. In the setting of thyroid cancer, somatic BRAF V600E‐mutations are highly specific for PTC and can be analyzed in aspirates from fine‐needle aspiration cytology (FNAC). The ‘gold standard’ to perform FNAC is ultrasound guidance. Here, we analyze whether adding BRAF V600E‐mutation analysis could be of value in palpation‐guided FNACs. A total of 430 consecutive patients were included. Ultrasound‐guided FNACs were performed in 251 patients and 179 patients underwent palpation‐guided FNACs. BRAF V600E‐mutation analysis was performed using two methods, an allele‐specific polymerase chain reaction (PCR) analyzed by capillary gel electrophoresis (PCR/Qiaxcel), and a droplet digital PCR (ddPCR) assay. A total of 80 patients underwent surgery, and histology revealed 25 patients to have PTC. Of the 25 PTCs, 23 (92%) showed a BRAF V600E‐mutation. Both mutation analysis methods (PCR/Qiaxcel and ddPCR) produced concordant results. In the ultrasound‐guided group, the preoperative diagnostic sensitivity of FNAC using the Bethesda classification alone was very high and additional BRAF V600E‐mutation analysis added little to the preoperative diagnostic sensitivity. By contrast, in the palpation‐guided group, by adding BRAF V600E‐mutation analysis, eight instead of four patients were diagnosed of having PTC. This increase in the diagnostic sensitivity was statistically significant (p < 0.05). The costs per sample were as low as 62 USD (PCR/Qiaxcel and ddPCR) and 35 USD (PCR/Qiaxcel only). Ultrasound‐guided FNAC should be aimed for when dealing with thyroid nodules. However, if palpation‐guided FNAC cannot be avoided or may be required due to resource utilization, adding BRAF V600E‐mutation analysis using the methods described in this study might significantly increase the proportion of preoperatively diagnosed PTCs. The additional costs can be considered very reasonable.
Recruitment of release sites underlies chemical presynaptic potentiation at hippocampal mossy fiber boutons

Synaptic plasticity is a cellular model for learning and memory. However, the expression mechanisms underlying presynaptic forms of plasticity are not well understood. Here, we investigate functional and structural correlates of presynaptic potentiation at large hippocampal mossy fiber boutons induced by the adenylyl cyclase activator forskolin. We performed 2-photon imaging of the genetically encoded glutamate sensor iGluu that revealed an increase in the surface area used for glutamate release at potentiated terminals. Time-gated stimulated emission depletion microscopy revealed no change in the coupling distance between P/Q-type calcium channels and release sites mapped by Munc13-1 cluster position. Finally, by high-pressure freezing and transmission electron microscopy analysis, we found a fast remodeling of synaptic ultrastructure at potentiated boutons: Synaptic vesicles dispersed in the terminal and accumulated at the active zones, while active zone density and synaptic complexity increased. We suggest that these rapid and early structural rearrangements might enable long-term increase in synaptic strength.