Identification of SLC22A17 DNA methylation hotspot as a potential biomarker in cutaneous melanoma.

BACKGROUND: Cancer onset and progression are driven by genetic and epigenetic alterations leading to oncogene activation and the silencing of tumor suppressor genes. Among epigenetic mechanisms, DNA methylation (methDNA) is gaining growing interest in cancer. Promoter hypomethylation is associated with oncogene activation while intragenic methDNA can be involved in transcriptional elongation, alternative spicing, and the activation of cryptic start sites. Several genes involved in the modulation of the tumor microenvironment are regulated by methDNA, including the Solute Carrier Family 22 Member 17 (SLC22A17), which is involved in iron trafficking and extracellular matrix remodeling cooperating with the Gelatinase-Associated Lipocalin (NGAL) ligand. However, the exact role of intragenic methDNA in cancer has not been fully investigated. Therefore, the aim of the present study is to explore the role of methDNA in the regulation of SLC22A17 in cutaneous melanoma (CM), used as a tumor model. METHODS: Correlation and differential analyses between SLC22A17 expression and methDNA were performed using the data contained in The Cancer Genome Atlas and Gene Expression Omnibus databases. Functional studies on melanoma cell lines treated with 5-Azacytidine (5-Aza) were conducted to assess the correlation between methDNA and SLC22A17 expression. A validation study on the diagnostic potential of the in silico-identified SLC22A17 methDNA hotspot was finally performed by analyzing tissue samples obtained from CM patients and healthy controls. RESULTS: The computational analyses revealed that SLC22A17 was significantly downregulated in CM, and its expression was related to promoter hypomethylation and intragenic hypermethylation. Moreover, SLC22A17 overexpression and hypermethylation of two intragenic methDNA hotspots were associated with a better clinical outcome in CM patients. The correlation between SLC22A17 methDNA and expression was confirmed in 5-Aza-treated cells. In agreement with in silico analyses, the SLC22A17 promoter methylation hotspot showed higher methDNA levels in CM samples compared to nevi. In addition, the methDNA levels of this hotspot were positively correlated with advanced CM. CONCLUSIONS: The SLC22A17 methDNA hotspot could represent a promising biomarker for CM, highlighting the regulatory role of methDNA on SLC22A17 expression. These results pave the way for the identification of novel epigenetic biomarkers and therapeutic targets for the management of CM patients.

The effect of home-based neuromuscular electrical stimulation-resistance training and protein supplementation on lean mass in persons with spinal cord injury: A pilot study.

In persons with a spinal cord injury (SCI), resistance training using neuromuscular electrical stimulation (NMES-RT) increases lean mass in the lower limbs. However, whether protein supplementation in conjunction with NMES-RT further enhances this training effect is unknown. In this randomized controlled pilot trial, 15 individuals with chronic SCI engaged in 3 times/week NMES-RT, with (NMES+PRO, n = 8) or without protein supplementation (NMES, n = 7), for 12 weeks. Before and after the intervention, whole body and regional body composition (DXA) and fasting glucose and insulin concentrations were assessed in plasma. Adherence to the intervention components was ≥96%. Thigh lean mass was increased to a greater extent after NMES+PRO compared to NMES (0.3 (0.2, 0.4) kg; p < 0.001). Furthermore, fasting insulin concentration and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) were decreased similarly in both groups (fasting insulin: 1 [-9, 11] pmol∙L-1; HOMA-IR: 0.1 [-0.3, 0.5] AU; both p ≥ 0.617). Twelve weeks of home-based NMES-RT increased thigh lean mass, an effect that was potentiated by protein supplementation. In combination with the excellent adherence and apparent improvement in cardiometabolic health outcomes, these findings support further investigation through a full-scale randomized controlled trial.

Fitness to stand trial: 415 consecutive defendants assessed by a New Zealand forensic psychiatry service.

BACKGROUND: New Zealand defendants found unfit to stand trial following a Court-ordered forensic mental health assessment cannot be detained in prison and must either be released, or made subject to a mental health or intellectual disability order. There is increasing awareness of the need to identify these people and protect their rights. METHODS: Retrospective audit of 8 years of Court-ordered health assessor reports addressing fitness to stand trial prepared by a New Zealand regional forensic mental health service with a catchment area of around 850,000. RESULTS: Between 2014 and 2022, Courts referred 415 defendants for assessment of fitness to stand trial. The number of reports requested increased by 20% between 2014 and 2022. Report subjects were 81% male and had a median age of 31. Commonest primary diagnoses were psychotic disorders (37%), intellectual disability (13%) and acquired neurocognitive disorders (15%). Few people with foetal alcohol spectrum disorder were identified. Despite the increase in assessments, the number of defendants considered unfit by report writers remained stable over time. CONCLUSION: The increasing number of referrals for assessment of fitness to stand trial has resourcing implications for forensic mental health services.

Models and observations agree on fewer and milder midlatitude cold extremes even over recent decades of rapid Arctic warming.

An apparent increase in observed cold extremes over recent decades in the northern midlatitudes has been reported, in contrast to robust decreases predicted by climate models. This discrepancy has led to suggestions that models fail to accurately simulate changes in weather patterns caused by Arctic warming. Here, we show that the observed frequency and intensity of midlatitude cold extremes have strongly decreased since 1990 and are consistent with modeled trends. The previously reported increase in cold extremes was overestimated due to an artifact of changing data coverage. We also show that the fraction of land with observed cold extreme increases over recent decades is consistent with model internal variability on top of a near-uniform forced reduction in cold extremes across the midlatitudes. Our results provide strong evidence of a decrease in midlatitude cold extremes over recent decades and consistency between models and observations.

Worth the Pain? Comparing Pain Scores in Primary Furlow Palatoplasty With and Without Buccal Flap Augmentation.

OBJECTIVE: Pain following primary palatoplasty can adversely affect nutritional and quality of life following primary palatoplasty. The incorporation of buccal flaps during primary cleft palate (CP) repair provides additional tissue to reduce the risk of velopharyngeal insufficiency, though the additional donor site may alter pain levels in the postoperative period. This study sought to compare postoperative pain levels in patients undergoing primary CP repair with or without buccal flaps. DESIGN: A single-institution, retrospective cohort study. SETTING: An academic children's hospital with an affiliated comprehensive cleft care team. PATIENTS: Patients age 18 months or less with cleft palate undergoing primary palatoplasty from 2016 to 2021 were included. Patients were stratified by the number of buccal flaps utilized during repair. MAIN OUTCOME MEASURES: Primary outcome was 24-h postoperative pain score, measured using the FLACC pain scale. Secondary outcome was 24-h postoperative narcotic use, measured in morphine milligram equivalents (MME). RESULTS: A total of 106 patients (53 without buccal flaps, 53 with 1 + buccal flaps) were included. There was no significant difference in postoperative pain scores between the groups (p > 0.9). Both groups had similar postoperative narcotic utilization (p = 0.8). CONCLUSIONS: This study demonstrates no significant difference in postoperative pain levels or narcotic utilization between patients undergoing primary Furlow palatoplasty with or without buccal flaps. This information can help address parental concerns regarding pain in the context of a larger donor site for patients undergoing primary palatoplasty with buccal flaps. Larger, multi-institutional randomized trials are needed to confirm these findings.

Mechanochemical Synthesis, Characterization and Reactivity of a Room Temperature Stable Calcium Electride.

A new calcium-based Room temperature Stable Electride (RoSE), K[{Ca[N(Mes)(SiMe3)]3(e-)}2K3] (2), is successfully synthesized from the reaction of a calcium tris-amide, [Ca{N(Mes)(SiMe3)}3K] (1) (Mes = 2,4,6-trimethylphenyl), with potassium under mechanochemical treatment. The dimeric structure of K[{Ca[N(Mes)(SiMe3)]3(e-)}2K3] is calculated using ab initio random structure searching (AIRSS) methods. This shows the existence of highly localized anionic electrons (e-) and suggests poor electrical conductance, as confirmed via electroconductivity measurements. The two anionic electrons in 2 are strongly antiferromagnetically coupled, thus in agreement with the largely diamagnetic response from magnetometry. Reaction of 2 with pyridine affords 4,4'-bipyridine, while reaction with benzene gives C-H activation and formation of a calcium hydride complex, [K(η6-C6H6)4][{Ca[N(Mes)(SiMe3)](H)}2K3] (3). Computational DFT analysis reveals the crucial role played by the ligand framework in the stabilization of this new Ca-hydride complex.

Increased levels of extracellular matrix proteins associated with extracellular vesicles from brains of aged mice.

Extracellular vesicles (EVs) are secreted by all major cell types of the brain, providing a mode of intercellular communication and a pathway for disposal of cellular debris. EVs help maintain healthy brain function, but may also contribute to diseases affecting the brain. EVs might contribute to aging of the brain, as aging-related processes such as inflammation and cellular senescence may alter EV cargo, promoting further inflammation and senescence. However, the effects of aging on brain EVs and the function of EVs in the aging brain remain poorly understood. To address this question, we measured the levels and protein cargo of EVs isolated from the brains of 4-, 12-, and 22-month-old C57BL/6J mice. We detected no changes in EV levels, but observed age-dependent changes in EV proteins. EV fractions from aged (22 month old) brains contained higher levels of extracellular matrix proteins than EV fractions from young (4 month old) brains, with intermediate levels in 12-month-old brains. Specifically, EV fractions from aged mice contained elevated levels of hyaluronan and proteoglycan link proteins 1 and 2 and several chondroitin sulfate proteoglycans (CSPGs). Analysis of extracellular matrix in several brain regions of aged mice revealed increased immunolabeling for the CSPG aggrecan, but reduced labeling with Wisteria floribunda agglutinin, which binds to chondroitin sulfate side chains of CSPGs. These data are consistent with prior studies showing changes to the composition of extracellular matrix in aged brains, and indicate a novel association of EVs with changes in the extracellular matrix of the aging brain.

Voices From the Field: A Quality Improvement Project for Progressive Tinnitus Management 2.0.

PURPOSE: Tinnitus is a common health condition in the general population, with increased prevalence among military Veterans. Tinnitus is, in fact, the most prevalent military service-connected disability. There is no cure for tinnitus, but interventions are available to help patients manage their reactions to tinnitus and reduce its functional impact. Progressive tinnitus management (PTM) is a stepped-care protocol that involves coordinated audiological and behavioral health clinical services. PTM was endorsed by national Veterans Affairs (VA) audiology leadership in 2009. Given new clinical insights and research findings since the initial rollout of PTM, it remains necessary to improve and update the protocol in response to feedback from clinicians and patients. METHOD: This two-phase quality improvement project captured quantitative and qualitative feedback from VA and Department of Defense (DOD) clinicians and patients concerning PTM materials. A convergent parallel mixed-methods design was used to integrate the quantitative and qualitative data, and a consensus method was used to adjudicate any discrepant findings. RESULTS: In Phase 1, 21 VAs and DOD clinicians and patients completed semistructured interviews and quantitative measures on the PTM handbook and workbook revisions. Phase 1 findings were recommendations to modify content, format, and adaptations of content (e.g., electronic formats with a clickable index). In Phase 2, six non-Veteran patients assisted in pilot testing PTM PowerPoint slides used by clinicians for PTM skills education sessions. Phase 2 findings indicated that the revised PTM PowerPoint slides were useful and clinically acceptable. CONCLUSIONS: Findings from this study are being used to revise and update materials in the PTM skills education sessions. More generally, the study demonstrates the necessity of end-user input to inform and implement clinical updates. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.27057691.

[18F]TFB PET/CT misses intense [124I]iodine-avid metastases after redifferentiation therapy in metastatic thyroid cancer.

BACKGROUND: Fluorine 18-labelled tetrafluoroborate ([18F]TFB) is a substrate for the sodium/iodide symporter. In thyroid cancer, [18F]TFB-PET/CT may be an alternative to iodine imaging to evaluate the extent of disease, eligibility for radioiodine treatment, and success of redifferentiation therapies. We report the results of a pilot study to determine tumor uptake of [18F]TFB and compare its properties to [124I]IodinePET/CT in patients with metastatic thyroid cancer. METHODS: Five patients were included in a prospective study. All patients received PET/CT 1 h after injection of 356 ± 12 MBq [18F]TFB and were given 230 ± 9 MBq [124I]Iodine orally on the same day, followed by PET/CT after 48 h. Before redifferentiation therapy, patients underwent an additional baseline [124I]Iodine PET/CT. Cases were analyzed by two board-certified specialists. Detection rates and Spearman correlation for [18F]TFB and [124I]Iodine were calculated. RESULTS: Three patients had poorly differentiated thyroid cancer and received trametinib in a redifferentiation trial. Two patients had papillary thyroid cancer and did not receive redifferentiation therapy. Of the 33 lesions seen before/without redifferentiation therapy, 19 (58%) were visible on [18F]TFB and 30 (91%) on [124I]Iodine imaging. In the patients who underwent redifferentiation therapy, 48 lesions were newly seen on [124I]Iodine PET/CT with a median SUVmax of 3.3 (range, 0.4-285.0). All of these lesions were [18F]TFB-negative. CONCLUSION: [18F]TFB failed to predict radioactive iodine uptake in patients with poorly differentiated thyroid cancer who underwent redifferentiation therapy with trametinib. It is unclear whether such discrepancies may also occur in other redifferentiation therapies or may even be encountered in redifferentiation-naïve thyroid cancer. TRIAL REGISTRATION NUMBER: NCT03196518, registered on June 22, 2017.

Microbial Dormancy Supports Multi-Species Coexistence Under Resource Fluctuations.

The ability for microbes to enter dormant states is adaptive under resource fluctuations and has been linked to the maintenance of diversity. Nevertheless, the mechanism by which microbial dormancy gives rise to the density-dependent feedbacks required for stable coexistence under resource fluctuations is not well understood. Via analysis of consumer-resource models, we show that the stable coexistence of dormancy and non-dormancy strategists is a consequence of the former benefiting more from resource fluctuations while simultaneously reducing overall resource variability, which sets up the requisite negative frequency dependence. Moreover, we find that dormants can coexist alongside gleaner and opportunist strategies in a competitive-exclusion-defying case of three species coexistence on a single resource. This multi-species coexistence is typically characterised by non-simple assembly rules that cannot be predicted from pairwise competition outcomes. The diversity maintained via this three-way trade-off represents a novel phenomenon that is ripe for further theoretical and empirical inquiry.

Massive Tibial Defect Treated with Plate-assisted Bone Segment Transport and A Novel Internal Cable-Pulley System.

Aim: The treatment of massive diaphyseal tibial bone defects remains challenging with poor results seen from treatment modalities other than bone transport (BT). Current methods of BT require lengthy periods in a circular external fixator. Despite recent modifications in BT techniques via circular external fixator such as multifocal transport and immediate intramedullary nailing after docking, circular external fixation remains poorly tolerated with a high complication profile. Newer technologies such as magnetic lengthening nails have shown promise to provide alternatives to BT without resorting to long-term circular external fixation. Plate-assisted bone segment transport (PABST) has demonstrated success as an all-internal BT technique. Prior case reports have shown a modest ability to treat massive defects with varying success. Technique: A novel all-internal cable and pulley augmentation to a PABST technique for a massive (185 mm) tibial defect was utilised during a retrograde transport. The authors describe a patient scenario in which this augment allowed continued transport that could not be treated with an additional Precice nail recharge. Conclusion: Augmentation of PABST with a cable and pulley construct can successfully treat massive diaphyseal defects. Clinical significance: This cable and pulley modification to PABST allows for the treatment of massive tibial defects without the need for magnetic lengthening nail exchange or conversion to external fixation. How to cite this article: Lance D, Morpeth B, Faith H, et al. Massive Tibial Defect Treated with Plate-assisted Bone Segment Transport and A Novel Internal Cable-Pulley System. Strategies Trauma Limb Reconstr 2024;19(2):118-124.

Abdominal Ectopic Pregnancy: A Case Report of an Uncommon Complication of Pregnancy Without Prenatal Care.

Ectopic pregnancy (EP) is a life-threatening condition requiring a high clinical suspicion. This diagnosis must be considered in all female patients of reproductive age presenting with abdominal pain or discomfort who may possibly be pregnant. Ectopic pregnancies occur in a small percentage of all pregnancies and are a significant cause of maternal morbidity and mortality. Abdominal ectopic pregnancy (AEP) is a rare and potentially fatal form of ectopic pregnancy where the implantation occurs in the abdominal cavity. We present the following case of a 23-year-old female who was transferred following an initial workup for abdominal pain and subsequently found to have an abdominal ectopic pregnancy at 37 weeks gestation. After transferring to our emergency department, the patient continued to have abdominal pain and her presenting FAST exam was positive for free fluid concerning for active hemorrhage and hematoma. Her clinical presentation was consistent with ruptured abdominal ectopic pregnancy, and she was taken to the operating room for emergent exploratory laparotomy and delivery. Her clinical course was complicated by adherent placenta and re-bleeding with significant hemoperitoneum requiring re-entry laparotomy and transfusion. We present the details of this case along with the diagnostic imaging and management of the rarely seen and life-threatening condition of secondary abdominal ectopic pregnancy (AEP).

Development of Higher-Level Vision: A Network Perspective.

Most studies on the development of the visual system have focused on the mechanisms shaping early visual stages up to the level of primary visual cortex (V1). Much less is known about the development of the stages after V1 that handle the higher visual functions fundamental to everyday life. The standard model for the maturation of these areas is that it occurs sequentially, according to the positions of areas in the adult hierarchy. Yet, the existing literature reviewed here paints a different picture, one in which the adult configuration emerges through a sequence of unique network configurations that are not mere partial versions of the adult hierarchy. In addition to studying higher visual development per se to fill major gaps in knowledge, it will be crucial to adopt a network-level perspective in future investigations to unravel normal developmental mechanisms, identify vulnerabilities to developmental disorders, and eventually devise treatments for these disorders.

Vascular limitations in blood pressure regulation with age in women: Insights from exercise and acute cardioselective ß-blockade.

Younger women rely on altering cardiac output ( Q ̇ $\dot{Q}$ ) to regulate blood pressure (BP). In contrast, older women rely more on altering vascular tone. However, evidence suggests that the ability to alter systemic vascular conductance (SVC) is diminished in older women. In the present study, cardioselective ß-blockade was utilized to diminish the relative contribution of Q ̇ $\dot{Q}$ to BP regulation and thereby evaluate age-related vascular limitations in women at rest and during large muscle dynamic exercise. Younger (n = 13, mean age 26.0 years) and older (n = 14, mean age 61.8 years) healthy women performed submaximal bouts of semi-recumbent cycling exercise at varying intensities while receiving an intravenous infusion of esmolol, a ß1-antagonist, or saline control in a repeated-measures crossover design. Q ̇ $\dot{Q}$ was attenuated during esmolol infusion, with greater reductions during exercise (moderate, -1.0 (95% CI, -1.6 to -0.5) L/min, P < 0.001; heavy, -2.0 (95% CI, -2.6 to -1.5) L/min, P < 0.001) than seated rest (-0.5 (95% CI, -1.1 to 0.0) L/min, P = 0.048), and this reduction was not significantly different between age groups (P = 0.122). Older women exhibited a greater attenuation in mean arterial pressure (MAP) during esmolol (-7 (95% CI, -9 to -4) mmHg, P < 0.001) relative to younger women (-2 (95% CI, -5 to 0) mmHg, P = 0.071). These changes coincided with a greater reduction of SVC in the younger women during esmolol (-15 (95% CI, -20 to -10) mL/min/mmHg, P < 0.001) compared to older women (-3 (95% CI, -9 to 2) mL/min/mmHg, P = 0.242). Together, these findings provide evidence that older, postmenopausal women have a diminished ability to adjust SVC in order to regulate MAP.

Imaging in malignant peritoneal neoplasms.

Peritoneal malignancies encompass a diverse range of tumors originating within the peritoneum, including primary tumors such as mesothelioma and primary serous peritoneal carcinoma or secondary tumors resulting from the spread of cancers from gastrointestinal, gynecological, and extra-abdominal sources. The traditional approach of palliative care for these malignancies is being replaced by a multimodal strategies that integrates surgery with systemic or intraperitoneal chemotherapy. Notably, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy has shown significant improvements in survival rates. Imaging is crucial in the multidisciplinary management of these tumors, aiding in diagnosis, staging, restaging, and monitoring therapy response. It is also vital for appropriate patient selection, using the acronym "PAUSE", which involves assessing tumor burden via the peritoneal carcinomatosis index, evaluating patients pre- and post-therapy, detecting complications following therapy, and predicting treatment outcomes. This review explores the imaging manifestations of peritoneal malignancies, distinguishing them from various mimics, and underscores the importance of imaging modalities such as CT, MRI, PET/CT, and PET/MRI in effective decision-making and management.

High-Frequency 10-kHz Spinal Cord Stimulation Provides Long-term (24-Month) Improvements in Diabetes-Related Pain and Quality of Life for Patients with Painful Diabetic Neuropathy.

BACKGROUND: The SENZA-PDN study evaluated high-frequency 10-kHz spinal cord stimulation (SCS) for the treatment of painful diabetic neuropathy (PDN). Over 24 months, 10-kHz SCS provided sustained pain relief and improved health-related quality of life. This report presents additional outcomes from the SENZA-PDN study, focusing on diabetes-related pain and quality of life outcomes. METHODS: The SENZA-PDN study randomized 216 participants with refractory PDN to receive either conventional medical management (CMM) or 10-kHz SCS plus CMM (10-kHz SCS + CMM), allowing crossover after six months if pain relief was insufficient. Postimplantation assessments at 24 months were completed by 142 participants with a permanent 10-kHz SCS implant, comprising 84 initial and 58 crossover recipients. Measures included the Brief Pain Inventory for Diabetic Peripheral Neuropathy (BPI-DPN), Diabetes-Related Quality of Life (DQOL), Global Assessment of Functioning (GAF), and treatment satisfaction. RESULTS: Over 24 months, 10-kHz SCS treatment significantly reduced pain severity by 66.9% (P < .001; BPI-DPN) and pain interference with mood and daily activities by 65.8% (P < .001; BPI-DPN). Significant improvements were also observed in overall DQOL score (P < .001) and GAF score (P < .001), and 91.5% of participants reported satisfaction with treatment. CONCLUSIONS: High-frequency 10-kHz SCS significantly decreased pain severity and provided additional clinically meaningful improvements in DQOL and overall functioning for patients with PDN. The robust and sustained benefits over 24 months, coupled with high participant satisfaction, highlight that 10-kHz SCS is an efficacious and comprehensive therapy for patients with PDN.

Associations between Histo-Blood Group Antigen Status in Mother-Infant Dyads and Infant Oral Rotavirus Vaccine Immunogenicity in rural Zimbabwe.

INTRODUCTION: Histo-blood group antigen (HBGA) phenotypes may contribute to poor oral rotavirus vaccine (RVV) immunogenicity, since rotavirus binds intestinal epithelial HBGA glycans, while maternal HBGA status shapes breastmilk composition, which influences the composition of the infant microbiome. We investigated associations between maternal/infant HBGA phenotypes and RVV immunogenicity in rural Zimbabwe. METHODS: We undertook salivary FUT2/FUT3 phenotyping in mother-infant pairs. Serum anti-rotavirus IgA was measured by ELISA. We explored adjusted associations between FUT2/FUT3 status and RVV seroconversion (primary outcome, N=322), and seropositivity and geometric mean titre (secondary outcomes, N=776). RESULTS: Infants of FUT2-positive or FUT3-positive women were less likely to seroconvert post-RVV than infants of FUT2-negative or FUT3-negative women (FUT2-positive 20.1% versus FUT2-negative 27.5%, adjusted relative risk (aRR) 0.47, 95%CI 0.26, 0.82; P=0.008; FUT3-positive 18.1% versus FUT3-negative 30.0%, aRR 0.45, 95%CI 0.25, 0.78; P=0.005). Compared to FUT2-positive infants with FUT2-positive mothers, FUT2-positive infants with FUT2-negative mothers were twice as likely to seroconvert (36.8% versus 21.9%, aRR 2.12, 95%CI 1.23, 3.63; P=0.006). Compared to FUT3-positive infants with FUT3-positive mothers, FUT3-positive infants with FUT3-negative mothers were three times as likely to seroconvert (48.3% versus 18.2%, aRR 2.99, 95%CI 1.82, 4.90; P<0.001). CONCLUSIONS: Maternal and infant FUT2 and FUT3 status influences infant RVV immunogenicity.