Acoustic deep brain modulation: Enhancing neuronal activation and neurogenesis.

BACKGROUND: Non-invasive deep brain modulation (DBM) stands as a promising therapeutic avenue to treat brain diseases. Acoustic DBM represents an innovative and targeted approach to modulate the deep brain, employing techniques such as focused ultrasound and shock waves. Despite its potential, the optimal mechanistic parameters, the effect in the brain and behavioral outcomes of acoustic DBM remains poorly understood. OBJECTIVE: To establish a robust protocol for the shock wave DBM by optimizing its mechanistic profile of external stimulation, and to assess its efficacy in preclinical settings. METHODS: We used shockwaves due to their capacity to leverage a broader spectrum of peak intensity (10-127 W/mm2) in contrast to ultrasound (0.1-5.0 W/mm2), thereby enabling a more extensive range of neuromodulation effects. We established various types of shockwave pressure profiles of DBM and compared neural and behavioral responses. To ascertain the anticipated cause of the heightened neural activity response, numerical analysis was employed to examine the mechanical dynamics within the brain. RESULTS: An optimized profile led to an enhancement in neuronal activity within the hypothalamus of mouse models. The optimized profile in the hippocampus elicited a marked increase in neurogenesis without neuronal damage. Behavioral analyses uncovered a noteworthy reduction in locomotion without significant effects on spatial memory function. CONCLUSIONS: The present study provides an optimized shock wave stimulation protocol for non-invasive DBM. Our optimized stimulation profile selectively triggers neural functions in the deep brain. Our protocol paves the way for new non-invasive DBM devices to treat brain diseases.

Inflammation mediated by gut microbiome alterations promotes lung cancer development and an immunosuppressed tumor microenvironment.

Accumulating evidence indicates that the gut microbiome influences cancer progression and therapy. We recently showed that progressive changes in gut microbial diversity and composition are closely associated with tobacco-associated lung adenocarcinoma (LUAD) in a human-relevant mouse model. Furthermore, we demonstrated that the loss of the antimicrobial protein Lcn2 in these mice, exacerbates pro-tumor inflammatory phenotypes while further reducing microbial diversity. Yet, how gut microbiome alterations impinge on LUAD development remains poorly understood. Here, we investigated the role of gut microbiome changes in LUAD development using fecal microbiota transfer and delineated a pathway by which gut microbiome alterations incurred by loss of Lcn2 fostered the proliferation of pro-inflammatory bacteria of the genus Alistipes, triggering gut inflammation. This inflammation propagated systemically, exerting immunosuppression within the tumor microenvironment, augmenting tumor growth through an IL-6-dependent mechanism and dampening response to immunotherapy. Corroborating our preclinical findings, we found that patients with LUAD with a higher relative abundance of Alistipes species in the gut showed diminished response to neoadjuvant immunotherapy. These insights reveal the role of microbiome-induced inflammation in LUAD and present new potential targets for interception and therapy.

Do obese patients undergoing surgery for grade 1 spondylolisthesis have worse outcomes at 5 years' follow-up? A QOD study.

OBJECTIVE: The long-term effects of increased body mass index (BMI) on surgical outcomes are unknown for patients who undergo surgery for low-grade lumbar spondylolisthesis. The goal of this study was to assess long-term outcomes in obese versus nonobese patients after surgery for grade 1 spondylolisthesis. METHODS: Patients who underwent surgery for grade 1 spondylolisthesis at the Quality Outcomes Database's 12 highest enrolling sites (SpineCORe group) were identified. Long-term (5-year) outcomes were compared for patients with BMI ≥ 35 versus BMI < 35. RESULTS: In total, 608 patients (57.6% female) were included. Follow-up was 81% (excluding patients who had died) at 5 years. The BMI ≥ 35 cohort (130 patients, 21.4%) was compared to the BMI < 35 cohort (478 patients, 78.6%). At baseline, patients with BMI ≥ 35 were more likely to be younger (58.5 ± 11.4 vs 63.2 ± 12.0 years old, p < 0.001), to present with both back and leg pain (53.8% vs 37.0%, p = 0.002), and to require ambulation assistance (20.8% vs 9.2%, p < 0.001). Furthermore, the cohort with BMI ≥ 35 had worse baseline patient-reported outcomes including visual analog scale (VAS) back (7.6 ± 2.3 vs 6.5 ± 2.8, p < 0.001) and leg (7.1 ± 2.6 vs 6.4 ± 2.9, p = 0.031) pain, disability measured by the Oswestry Disability Index (ODI) (53.7 ± 15.7 vs 44.8 ± 17.0, p < 0.001), and quality of life on EuroQol-5D (EQ-5D) questionnaire (0.47 ± 0.22 vs 0.56 ± 0.22, p < 0.001). Patients with BMI ≥ 35 were more likely to undergo fusion (85.4% vs 74.7%, p = 0.01). There were no significant differences in 30- and 90-day readmission rates (p > 0.05). Five years postoperatively, there were no differences in reoperation rates or the development of adjacent-segment disease for patients in either BMI < 35 or ≥ 35 cohorts who underwent fusion (p > 0.05). On multivariate analysis, BMI ≥ 35 was a significant risk factor for not achieving minimal clinically important differences (MCIDs) for VAS leg pain (OR 0.429, 95% CI 0.209-0.876, p = 0.020), but BMI ≥ 35 was not a predictor for achieving MCID for VAS back pain, ODI, or EQ-5D at 5 years postoperatively. CONCLUSIONS: Both obese and nonobese patients benefit from surgery for grade 1 spondylolisthesis. At the 5-year time point, patients with BMI ≥ 35 have similarly low reoperation rates and achieve rates of satisfaction and MCID for back pain (but not leg pain), disability (ODI), and quality of life (EQ-5D) that are similar to those in patients with a BMI < 35.

Modeling Cortical Versus Hippocampal Network Dysfunction in a Human Brain Assembloid Model of Epilepsy and Intellectual Disability.

Neurodevelopmental disorders often impair multiple cognitive domains. For instance, a genetic epilepsy syndrome might cause seizures due to cortical hyperexcitability and present with memory impairments arising from hippocampal dysfunction. This study examines how a single disorder differentially affects distinct brain regions by using human patient iPSC-derived cortical- and hippocampal-ganglionic eminence assembloids to model Developmental and Epileptic Encephalopathy 13 (DEE-13), a condition arising from gain-of-function mutations in the SCN8A gene. While cortical assembloids showed network hyperexcitability akin to epileptogenic tissue, hippocampal assembloids did not, and instead displayed network dysregulation patterns similar to in vivo hippocampal recordings from epilepsy patients. Predictive computational modeling, immunohistochemistry, and single-nucleus RNA sequencing revealed changes in excitatory and inhibitory neuron organization that were specific to hippocampal assembloids. These findings highlight the unique impacts of a single pathogenic variant across brain regions and establish hippocampal assembloids as a platform for studying neurodevelopmental disorders.

Multiple intrinsic timescales govern distinct brain states in human sleep.

Human sleep exhibits multiple, recurrent temporal regularities, ranging from circadian rhythms to sleep stage cycles and neuronal oscillations during non-rapid eye movement (non-REM) sleep. Moreover, recent evidence revealed a functional role of aperiodic activity, which reliably discriminates different sleep stages. Aperiodic activity is commonly defined as the spectral slope χ of the 1/frequency (1/fχ) decay function of the electrophysiological power spectrum. However, several lines of inquiry now indicate that the aperiodic component of the power spectrum might be better characterized by a superposition of several decay processes with associated timescales. Here, we determined multiple timescales, which jointly shape aperiodic activity using human intracranial encephalography (iEEG). Across three independent studies (47 participants, 23 female), our results reveal that aperiodic activity reliably dissociated sleep stage-dependent dynamics in a regionally-specific manner. A principled approach to parametrize aperiodic activity delineated several, spatially- and state-specific timescales. Lastly, we employed pharmacological modulation by means of propofol anesthesia to disentangle state-invariant timescales that may reflect physical properties of the underlying neural population from state-specific timescales that likely constitute functional interactions. Collectively, these results establish the presence of multiple intrinsic timescales that define the electrophysiological power spectrum during distinct brain states.Significance Statement Sleep is characterized by prominent temporal regularities. In this study, we unveil a previously unrecognized principle that governs neural activity during human sleep. Our results shed light on the existence of a set of intrinsic timescales that fundamentally define the current state of the sleeping brain. These timescales serve as indicators of both physiological and functional interactions within the underlying neural population. Through pharmacological modulation, we differentiated state-specific functional interactions from state-invariant timescales, suggesting that the latter may reflect the inherent physical properties of the neural population at play.

Varying Supraglottic Pressure Using Controlled Supraglottic Pressure Phonation with a Straw-Shaped Mouthpiece in Healthy Subjects.

OBJECTIVE: The objective of this study is to expand on a novel method for semioccluded vocal tract therapy (SOVT) called controlled supraglottic pressure phonation, and investigate the mechanism that introduced supraglottic pressure mediates a decrease in impedance during SOVT therapy. Instead of the previously used CPAP mask, this study analyzes controlled supraglottic pressure phonation by use of a straw mouthpiece to deliver supraglottic pressure. METHODS: Twenty-six human subjects were randomly assigned to one of four supraglottic pressure levels: 0, 2, 4, and 6 cm H2O, which were controlled through a continuous positive airway pressure device. Subjects were asked to phonate during a SOVT task for one round (referred to as the "short-duration" task) and eight rounds (referred to as the "long-duration" task), in which acoustic and aerodynamic properties were measured before and after. Subjects were surveyed for the levels of discomfort experienced during controlled supraglottic pressure phonation therapy and subjective levels of improvement of vocal economy. RESULTS: Significant differences were observed between pre- and post-task measurement for phonation threshold pressure for the long-duration task for the 2 cmH2O group. Frequency measurement was not found to have statistically significant differences. The perceived phonatory effort was not significantly different at any pressure levels. CONCLUSIONS: Lower supraglottic pressure levels will improve ease of phonation for longer durations, however, shorter-duration tasks will not be effective. Controlled supraglottic pressure phonation coupled with straw phonation may produce an improved vocal economy for those who have access to an oppositional airflow setup.

Pediatric colonic adenocarcinoma: A deceptive case of gastroenteritis and constipation.

Adenocarcinoma of the colon is a rare diagnosis in pediatric patients. We present a previously healthy 15-year-old female who began experiencing escalating colicky abdominal pain and associated vomiting over 2 weeks in the setting of presumed acute gastroenteritis. A computed tomography scan revealed an obstruction in her descending colon. A multidisciplinary decision was made to perform a colonoscopy upon which a large, circumferential, friable lesion was discovered 40 cm from the anus. A colon decompression catheter was successfully inserted following controlled radial expansion (CRE) Balloon dilation to 13.5 mm beyond the mass, resulting in a significant discharge of fluid and gas. The patient underwent hemicolectomy with mass resection and colostomy. Biopsies confirmed poorly differentiated adenocarcinoma with "napkin-ring" morphology and positive lymph node metastasis with extranodal extension.

Multimodal, Longitudinal Profiling of SCA1 Identifies Predictors of Disease Severity and Progression.

OBJECTIVES: Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant neurodegenerative disease. Objective surrogate markers sensitive to detect changes in disease severity are needed to reduce sample sizes in interventional trials and identification of predictors of faster disease progression would facilitate patient selection, enrichment, or stratification in such trials. METHODS: We performed a prospective 1-year longitudinal, multimodal study in 34 ataxic SCA1 individuals and 21 healthy controls. We collected clinical, patient-reported outcomes, biochemical and magnetic resonance (MR) biomarkers at baseline and after 1 year. We determined 1-year progression and evaluated the potential predictive value of several baseline markers on 1-year disease progression. RESULTS: At baseline, multiple structural and spectroscopic MR markers in pons and cerebellum differentiated SCA1 from healthy controls and correlated with disease severity. Plasma and cerebrospinal fluid (CSF) neurofilament light (NfL) chain and CSF glial fibrillary acidic protein (GFAP) were elevated in SCA1. In longitudinal analysis, total brainstem and pontine volume change, inventory of non-ataxia signs (INAS) count, and SCA functional index (SCAFI) showed larger responsiveness compared to the Scale for Assessment and Rating of Ataxia (SARA). Longer disease duration, longer non-expanded CAG repeat length, and higher disease burden were associated with faster SARA increase after 1-year in the SCA1 group. Similarly, lower baseline brainstem, pontine, and cerebellar volumes, as well as lower levels of N-acetylaspartate and glutamate in the cerebellar white matter, were also associated with faster SARA increase. INTERPRETATION: Our results guide the selection of the most sensitive measures of disease progression in SCA1 and have identified features associated with accelerated progression that could inform the design of clinical trials. ANN NEUROL 2024.

Sirolimus for vascular anomalies associated with PTEN hamartoma tumor syndrome.

Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a rare condition associated with vascular anomalies and increased tumor risk. Sirolimus, an mTOR inhibitor used for managing vascular anomalies is underexplored in PHTS. A single-institution retrospective review of children with PHTS and vascular anomalies treated with sirolimus identified seven patients. Median age at sirolimus initiation was 10 years. After a median 2.5-year follow-up, six of seven patients (86%) showed significant clinical improvement. No significant adverse effects were observed, except mild buccal ulcers and acne. This study supports sirolimus as an effective and safe treatment for vascular anomalies in a small group of children with PHTS.

Growth and mineralization of fetal mouse long bones under microgravity and daily 1 g gravity exposure.

In a previous Space Shuttle/Spacelab experiment (STS-42), we observed direct responses of isolated fetal mouse long bones to near weightlessness. This paper aimed to verify those results and study the effects of daily 1×g exposure during microgravity on the growth and mineralization of these bones. Two experiments were conducted: one on an American Space Shuttle mission (IML-2 on STS-65) and another on a Russian Bio-Cosmos flight (Bion-10 on Cosmos-2229). Despite differences in hardware, both used 17-day-old fetal mouse metatarsals cultured for 4 days. Results showed reduced proteoglycan content under microgravity compared to 1×g conditions, with no main differences in other cellular structures. While the overall metatarsal length was unaffected, the length increase of the mineralized diaphysis was significantly reduced under microgravity. Daily 1×g exposure for at least 6 h abolished the microgravity-induced reduction in cartilage mineralization, indicating the need for long-duration exposure to 1×g as an in-flight countermeasure using artificial gravity.

A Retrospective External Validation of the Cleveland Clinic Malignancy Probability Prediction Model for Indeterminate Pulmonary Nodules.

Objective: To perform a retrospective, multicenter, external validation of the Cleveland Clinic malignancy probability prediction model for incidental pulmonary nodules. Patients and Methods: From July 1, 2022, to May 31, 2023, we identified 296 patients who underwent tissue acquisition at Mayo Clinic (MC) (n=198) and Loyola University Medical Center (n=98) with histopathology indicating malignant (n=195) or benign (n=101). Data was collected at initial radiographic identification (point 1) and at the time of intervention (point 2). Point 3 represented the most recent data. The areas under the receiver operating characteristics were calculated for each model per time point. Calibration was evaluated by comparing the predicted and observed rates of malignancy. Results: The areas under the receiver operating characteristics at time points 1, 2, and 3 for the MC model were 0.67 (95% CI, 0.61-0.74), 0.67 (95% CI, 0.58-0.77), and 0.70 (95% CI, 0.63-0.76), respectively. The Cleveland Clinic model (CCM) was 0.68 (95% CI, 0.61-0.74), 0.75 (95% CI, 0.65-0.84), and 0.72 (95% CI, 0.66-0.78), respectively. The mean ± SD estimated probability for malignant pulmonary nodules (PNs) at time points 1, 2, and 3 for the CCM was 64.2±25.9, 65.8±24.0, and 64.7±24.4, which resembled the overall proportion of malignant PNs (66%). The mean estimated probability of malignancy for the MC model at each time point was 38.3±27.4, 36.2±24.4, and 42.1±27.3, substantially lower than the observed proportion of malignancies. Conclusion: The CCM found discrimination similar to its internal validation and good calibration. The CCM can be used to augment clinical and shared decision-making when evaluating high-risk PNs.

What Is the Epidemiology of Cervical and Thoracic Spine Fractures?

BACKGROUND: Vertebral fractures are associated with enduring back pain, diminished quality of life, as well as increased morbidity and mortality. Existing epidemiological data for cervical and thoracic vertebral fractures are limited by insufficiently powered studies and a failure to evaluate the mechanism of injury. QUESTION/PURPOSE: What are the temporal trends in incidence, patient characteristics, and injury mechanisms of cervical and thoracic vertebral fractures in the United States from 2003 to 2021? METHODS: The United States National Electronic Injury Surveillance System-All Injury Program (NEISS-AIP) database collects data on all nonfatal injuries treated in US hospital emergency departments and is well suited to capture epidemiological trends in vertebral fractures. As such, the NEISS-AIP was queried from 2003 to 2021 for cervical and thoracic fractures. The initial search by upper trunk fractures yielded 156,669 injuries; 6% (9900) of injuries, with a weighted frequency of 638,999 patients, met the inclusion criteria. The mean age was 62 ± 25 years and 52% (334,746 of 638,999) of patients were females. Descriptive statistics were obtained. Segmented regression analysis, accounting for the year before or after 2019 when the NEISS sampling methodology was changed, was performed to assess yearly injury trends. Multivariable logistic regression models with age and sex as covariates were performed to predict injury location, mechanism, and disposition. RESULTS: The incidence of cervical and thoracic fractures increased from 2.0 (95% CI 1.4 to 2.7) and 3.6 (95% CI 2.4 to 4.7) per 10,000 person-years in 2003 to 14.5 (95% CI 10.9 to 18.2) and 19.9 (95% CI 14.5 to 25.3) in 2021, respectively. Incidence rates of cervical and thoracic fractures increased for all age groups from 2003 to 2021, with peak incidence and the highest rate of change in individuals 80 years or older. Most injuries occurred at home (median 69%), which were more likely to impact older individuals (median [range] age 75 [2 to 106] years) and females (median 61% of home injuries); injuries at recreation/sports facilities impacted younger individuals (median 32 [3 to 96] years) and male patients (median 76% of sports facility injuries). Falls were the most common injury mechanism across all years, with females more likely to be impacted than males. The proportion of admissions increased from 33% in 2003 to 50% in 2021, while the proportion of treated and released patients decreased from 53% to 35% in the same period. CONCLUSION: This epidemiological study identified a disproportionate increase in cervical and thoracic fracture incidence rates in patients older than 50 years from 2003 to 2021. Furthermore, high hospital admission rates were also noted resulting from these fractures. These findings indicate that current osteoporosis screening guidelines may be insufficient to capture the true population at risk of osteoporotic fractures, and they highlight the need to initiate screening at an earlier age. LEVEL OF EVIDENCE: Level III, prognostic study.

Interpersonal consequences of paranoid ideation, negative symptoms and sleep problems in a transdiagnostic sample of individuals with psychosis.

Paranoid ideation is a transdiagnostic construct that is associated with social impairment and often occurs in psychotic spectrum disorders. Little research has examined how paranoid ideation is related to social behaviors that underlie social impairment and may ultimately lead to social rejection. It is important to consider that negative symptoms and sleep problems also contribute to social impairment. No research has assessed the unique and combined influence of paranoid ideation, negative symptoms, and sleep problems on social impairment. Therefore, the current study examined how paranoid ideation, negative symptoms, and sleep problems contribute to poorer social skills and social rejection in a transdiagnostic sample of persons with psychosis and community members (N = 112). Assessments included diagnostic and symptom interviews, questionnaires, behavioral ratings of social skill and facial displays of affect, and naive observer reactions utilizing thin-slice methodology. Greater paranoid ideation, negative symptoms, and sleep problems were each related to poorer social skill and more negative reactions from observers. When considered in path analyses, negative symptoms were associated with observer reports of less willingness to interact with participants through poorer social skill. These findings demonstrate the symptom correlates of social rejection and how interpersonal behavior may contribute to social exclusion.

Pharmacological non-hormonal treatment options for male infertility: a systematic review and network meta-analysis.

BACKGROUND: Male factor infertility affect up to 50% of couples unable to conceive spontaneously. Several non-hormonal pharmacological treatments have been proposed to boost spermatogenesis and increase chances of conception in men with infertility. Still, no clear evidence exists on the most effective treatment strategy. OBJECTIVE: We aimed to compare the effectiveness of non-hormonal pharmacological treatment options for men with infertility using a systematic review and network meta-analysis. METHODS: We searched MEDLINE, EMBASE, and CENTRAL until October 2023 for randomised/quasi-randomised trials that evaluated any non-hormonal pharmacological treatment options for men with idiopathic semen abnormalities or those with hypogonadism. We performed pairwise and network meta-analyses using a random effect model. We assessed risk of bias, heterogeneity, and network inconsistency. We calculated the mean rank and the surface under the cumulative ranking curve (SUCRA) for each intervention the maximum likelihood to achieve each of reported outcomes. We reported primarily on sperm concentration and other important semen and biochemical outcomes using standardised mean difference (SMD) and 95% confidence-intervals(CI). RESULTS: We included 14 randomised trials evaluating four treatments (Clomiphene citrate, Tamoxifen, Aromatase inhibitors, anti-oxidants) and their combinations in 1342 men. The overall quality of included trials was low. Sperm concentration improved with clomiphene compared to anti-oxidants (SMD 2.15, 95%CI 0.78-3.52), aromatase inhibitor (SMD 2.93, 95%CI 1.23-4.62), tamoxifen (SMD - 1.96, 95%CI -3.57; -0.36) but not compared to placebo (SMD - 1.53, 95%CI -3.52- 0.47). Clomiphene had the highest likelihood to achieve the maximum change in sperm concentration (SUCRA 97.4). All treatments showed similar effect for sperm motility, semen volume, and normal sperm morphology. FSH levels showed significant improvement with clomiphene vs.anti-oxidant (SMD 1.48, 95%CI 0.44-2.51) but not compared to placebo. The evidence networks for LH and testosterone suffered from significant inconsistency (p = 0.01) with similar trend of improvement with clomiphene compared to other treatments but not compared to placebo. CONCLUSION: There is insufficient evidence to support the routine use of Clomiphene, tamoxifen, and aromatase inhibitors to optimise semen parameters in men with infertility. Future randomised trials are needed to confirm the efficacy of clomiphene in improving fertility outcomes in men. PROSPERO: CRD42023430179.

Structure-Activity Relationships of the Fentanyl Scaffold: Identification of Antagonists as Potential Opioid Overdose Reversal Agents.

Opioid-related overdoses account for almost half of all drug overdose deaths in the United States and cause more preventable deaths every year than car crashes. Fentanyl, a highly potent mu opioid receptor (MOR) agonist and its analogues (fentalogues) are increasingly found in illicit drug samples, both where the primary drug of abuse is an opioid and where it is not. The prevalence of fentalogues in the illicit drug market is thought to be the primary driver of the increased number of opioid-related overdose deaths since 2016. In fact, fentanyl and its analogues are involved in more than 70% of opioid-related overdoses. The standard opioid overdose rescue therapy naloxone is often insufficient to reverse opioid overdoses caused by fentalogue agonists under current treatment paradigms. However, the pharmacology of many fentalogues is unknown. Moreover, within the fentalogue series of compounds, it is possible that antagonists could be identified that might be superior to naloxone as opioid overdose reversal agents. In this report, we explore the pharmacology of 70 fentalogues and identify compounds that behave as MOR antagonists in vitro and demonstrate with one of these reversals of fentanyl-induced respiratory depression in the mouse. Such compounds could provide leads for the development of effective agents for the reversal of opioid overdose.

'Feeling Hot': Exploring the feasibility of nocturnal erection detection through penile temperature measurements.

Objectives: The observational 'Feeling Hot' study aims to evaluate the feasibility of employing overnight penile temperature measurements for the detection of nocturnal erections, thereby contributing to the advancement and modernization of a non-invasive diagnostic system for erectile dysfunction. Subjects/Patients and Methods: In this proof-of-concept study, 10 healthy men aged 20-25 were recruited, following the methodology outlined in the 'Staying Hot' study by Torenvlied et al. Participants underwent ambulatory overnight penile temperature measurements concurrent with RigiScan recordings. Key outcome measures included baseline and peak penile temperatures during RigiScan-annotated nocturnal erections. Reference measurements of the thigh temperature were also taken to assess nocturnal temperature variations. Results: Statistically significant penile temperature increases (p = 0.008, n = 9) were observed during nocturnal erections, with an average elevation of 1.47°C noted during the initial erections. This underscores the practical utility of penile temperature measurements in detecting erection onset. Challenges arose in accurately determining erection duration and subsequent erection onsets due to the persistence of elevated temperatures following initial erections, termed the 'Staying Hot effect'. Reference thigh temperature measurements aided in addressing this challenge. Conclusion: Examining overnight penile temperature alongside simultaneous RigiScan recordings has yielded valuable insights into the viability of using the temperature methodology for detecting nocturnal erections. The 'Feeling Hot' study findings demonstrate significant penile temperature elevation during nocturnal erections in healthy young men, highlighting the potential of integrating this measurement methodology into the design of a modernized tool for ambulatory erectile dysfunction diagnostics. Further development of an advanced sensor system to comprehensively assess erection duration and quality is essential for enhancing clinical applicability.

Acoustic Character Governing Variation in Normal, Benign, and Malignant Voices.

INTRODUCTION: Benign and malignant vocal fold lesions (VFLs) are growths that occur on the vocal folds. However, the treatments for these two types of lesions differ significantly. Therefore, it is imperative to use a multidisciplinary approach to properly recognize suspicious lesions. This study aimed to determine the important acoustic characteristics specific to benign and malignant VFLs. METHODS: The acoustic model of voice quality was utilized to measure various acoustic parameters in 157 participants, including individuals with normal, benign, and malignant conditions. The study comprised 62 female and 95 male participants (43 ± 10 years). Voice samples were collected at the Shanghai Eye, Ear, Nose, and Throat Hospital of Fudan University between May 2020 and July 2021. The acoustic variables of the participants were analyzed using Principal Component Analysis (PCA) to present important acoustic characteristics that are specific to normal vocal folds, benign VFLs, and malignant VFLs. The similarities and differences in acoustic factors were also studied for benign conditions including Reinke's edema, polyps, cysts, and leukoplakia. RESULTS: Using the PCA method, the components that accounted for the variation in the data were identified, highlighting acoustic characteristics in the normal, benign, and malignant groups. The analysis indicated that coefficients of variation in root mean square energy were observed solely within the normal group. Coefficients of variation in pitch (F0) were found to be significant only in benign voices, while higher formant frequencies and their variability were identified as contributors to the acoustic variance within the malignant group. The presence of formant dispersion (FD) as a weighted factor in PCA was exclusively noted in individuals with Reinke's edema. The amplitude ratio between subharmonics and harmonics (SHR) and its coefficients of variation were evident exclusively in the polyps group. In the case of voices with cysts, both pitch (F0) and coefficients of variation for FD were observed to contribute to variations. Additionally, higher formant frequencies and their coefficients of variation played a role in the acoustic variance among voices of patients with leukoplakia. CONCLUSION: Experimental evidence demonstrates the utility of the PCA method in the identification of vibrational alterations in the acoustic characteristics of voice affected by lesions. Furthermore, the PCA analysis has highlighted underlying acoustic differences between various conditions such as Reinke's edema, polyps, cysts, and leukoplakia. These findings can be used in the future to develop an automated malignant voice analysis algorithm, which will facilitate timely intervention and management of vocal fold conditions.

Feeder-free culture of human pluripotent stem cells drives MDM4-mediated gain of chromosome 1q.

Culture-acquired variants in human pluripotent stem cells (hPSCs) hinder their applications in research and clinic. However, the mechanisms that underpin selection of variants remain unclear. Here, through analysis of comprehensive karyotyping datasets from over 23,000 hPSC cultures of more than 1,500 lines, we explored how culture conditions shape variant selection. Strikingly, we identified an association of chromosome 1q gains with feeder-free cultures and noted a rise in its prevalence in recent years, coinciding with increased usage of feeder-free regimens. Competition experiments of multiple isogenic lines with and without a chromosome 1q gain confirmed that 1q variants have an advantage in feeder-free (E8/vitronectin), but not feeder-based, culture. Mechanistically, we show that overexpression of MDM4, located on chromosome 1q, drives variants' advantage in E8/vitronectin by alleviating genome damage-induced apoptosis, which is lower in feeder-based conditions. Our study explains condition-dependent patterns of hPSC aberrations and offers insights into the mechanisms of variant selection.

Optimizing automated detection of high frequency oscillations using visual markings does not improve SOZ localization.

OBJECTIVE: High frequency oscillations (HFOs) are a biomarker of the seizure onset zone (SOZ) and can be visually or automatically detected. In theory, one can optimize an automated algorithm's parameters to maximize SOZ localization accuracy; however, there is no consensus on whether or how this should be done. Therefore, we optimized an automated detector using visually identified HFOs and evaluated the impact on SOZ localization accuracy. METHODS: We detected HFOs in intracranial EEG from 20 patients with refractory epilepsy from two centers using (1) unoptimized automated detection, (2) visual identification, and (3) automated detection optimized to match visually detected HFOs. RESULTS: SOZ localization accuracy based on HFO rate was not significantly different between the three methods. Across patients, visually optimized detector settings varied, and no single set of settings produced universally accurate SOZ localization. Exploratory analysis suggests that, for many patients, detection settings exist that would improve SOZ localization. CONCLUSIONS: SOZ localization accuracy was similar for all three methods, was not improved by visually optimizing detector settings, and may benefit from patient-specific parameter optimization. SIGNIFICANCE: Visual HFO marking is laborious, and optimizing automated detection using visual markings does not improve localization accuracy. New patient-specific detector optimization methods are needed.

A Comparison of Rapid Rule-Learning Strategies in Humans and Monkeys.

Interspecies comparisons are key to deriving an understanding of the behavioral and neural correlates of human cognition from animal models. We perform a detailed comparison of the strategies of female macaque monkeys to male and female humans on a variant of the Wisconsin Card Sorting Test (WCST), a widely studied and applied task that provides a multiattribute measure of cognitive function and depends on the frontal lobe. WCST performance requires the inference of a rule change given ambiguous feedback. We found that well-trained monkeys infer new rules three times more slowly than minimally instructed humans. Input-dependent hidden Markov model-generalized linear models were fit to their choices, revealing hidden states akin to feature-based attention in both species. Decision processes resembled a win-stay, lose-shift strategy with interspecies similarities as well as key differences. Monkeys and humans both test multiple rule hypotheses over a series of rule-search trials and perform inference-like computations to exclude candidate choice options. We quantitatively show that perseveration, random exploration, and poor sensitivity to negative feedback account for the slower task-switching performance in monkeys.