Search

Introduction: Large cell neuroendocrine carcinoma (LCNEC) and atypical carcinoid (AC) tumor are two distinct types of pulmonary neuroendocrine tumors (NETs) that are considered genetically unrelated. AC is categorized as a well-differentiated NET, while LCNEC is considered a poorly differentiated NET with a significantly poorer prognosis. Case Presentation: In this case report, we present an 83-year-old male who presented with 2-day history of hemoptysis and subsequently diagnosed with a right upper lobe carcinoid tumor on pre-excision biopsy. After evaluation of the entire excised specimen, the tumor was subsequently reclassified as LCNEC. This case is rare as the tumor displayed pathologic features of AC (areas with low mitotic activity and punctate necrosis) alternating with areas of LCNEC (high mitotic activity with sheets of necrosis). Subsequent molecular studies were more characteristic of AC, with no mutations detected in Rb1 or p53. The patient underwent surgical resection (right upper lobectomy with bronchoplasty and mediastinal lymph node dissection) to remove the tumor. Conclusion: This report outlines the clinical presentation and the underlying pathology of this rare case, which underscores the complex molecular landscape of neuroendocrine neoplasms and the need for nuanced molecular analyses in refining diagnostic approaches.

Abstract Occipital nerve decompression is effective in reducing headache symptoms in select patients with migraine and occipital neuralgia. Eligibility for surgery relies on subjective symptoms and responses to nerve blocks and Onabotulinum toxin A (Botox) injections. No validated objective method exists for detecting occipital headache pathologies. The purpose of the study is to explore the potential of high-resolution Magnetic Resolution Imaging (MRI) in identifying greater occipital nerve (GON) pathologies in chronic headache patients. The MRI protocol included three sequences targeting fat-suppressed fluid-sensitive T2-weighted signals. Visualization of the GON involved generating 2-D image slices with sequential rotation to track the nerve course. Twelve patients underwent pre-surgical MRI assessment. MRI identified four main pathologies that were validated against intra-operative examination: GON entanglement by the occipital artery, increased nerve thickness and hyperintensity suggesting inflammation compared to the non-symptomatic contralateral side, early GON branching with rejoining at a distal point, and a connection between the GON and the lesser occipital nerve. MRI possesses the ability to visualize the GON and identify suspected trigger points associated with headache symptoms. This case series highlights MRI's potential to provide objective evidence of nerve pathology. Further research is warranted to establish MRI as a gold standard for diagnosing extracranial contributors in headaches.

Category: Sports; Trauma Introduction/Purpose: Artificial intelligence (AI) chatbots have recently gained popularity as a source of information that can be easily accessed by patients given their human-like responses to prompts and questions. Within orthopaedics, the treatment of acute Achilles tendon ruptures is not uniform due to varying surgical repair techniques, postoperative protocols, and nonoperative treatment options dependent on surgeon preference and patient factors. Given that patients are increasingly turning toward AI for questions about medical diagnoses and treatment options, our study looked to compare the adequacy of AI chatbot responses to frequently asked questions regarding acute Achilles tendon ruptures. Methods: Three popular AI platforms (ChatGPT, Google Gemini, and Microsoft Bing AI) were prompted for a concise response to ten commonly asked questions regarding Achilles tendon rupture management (Table 1). Four board-certified subspecialty-trained orthopaedic surgeons (two in foot and ankle, two in sports medicine) were asked to assess the value of the AI response using a four-point scale (1 – satisfactory; 2 – satisfactory requiring minimal clarification; 3 – satisfactory requiring substantial clarification; 4 – unsatisfactory). A Kruskal-Wallis test was used to compare the responses between the three AI platforms using the scores assigned by the surgeons. Results: All three AI chatbots provided comparable answers to 7 of 10 questions (70%). Of all the responses (30 total), only two (6.7%) had a mean rating of 3 or higher. Significant differences were noted between the AI systems for questions 4 [H(2) = 7.258, p = .027], 7 [H(2) = 6.308, p = .043], and 10 [H(2) = 6.796, p = .033]. Post hoc analyses revealed Bing AI had significantly worse scores as compared to ChatGPT for all three of these questions. Conclusion: AI chatbots can appropriately answer concise prompts about the diagnosis and management of acute Achilles tendon ruptures often sought out by patients prior to or after evaluation by an orthopaedic surgeon. The responses provided by the three AI chatbots analyzed in our study were uniform and satisfactory, with only one of the platforms scoring worse on three of the ten questions. As AI chatbots advance, they will become a valuable tool for patient education in orthopaedics. Future studies will be needed to assess performance as new AI chatbots develop and large language models continue to evolve. Table 1: List of 10 selected frequently asked questions regarding acute Achilles tendon ruptures

Abstract Ultrafast electron diffraction using MeV energy beams(MeV-UED) has enabled unprecedented scientific opportunities in the study of ultrafast structural dynamics in a variety of gas, liquid and solid state systems. Broad scientific applications usually pose different requirements for electron probe properties. Due to the complex, nonlinear and correlated nature of accelerator systems, electron beam property optimization is a time-taking process and often relies on extensive hand-tuning by experienced human operators. Algorithm based efficient online tuning strategies are highly desired. Here, we demonstrate multi-objective Bayesian active learning for speeding up online beam tuning at the SLAC MeV-UED facility. The multi-objective Bayesian optimization algorithm was used for efficiently searching the parameter space and mapping out the Pareto Fronts which give the trade-offs between key beam properties. Such scheme enables an unprecedented overview of the global behavior of the experimental system and takes a significantly smaller number of measurements compared with traditional methods such as a grid scan. This methodology can be applied in other experimental scenarios that require simultaneously optimizing multiple objectives by explorations in high dimensional, nonlinear and correlated systems.

In an effort to teach law students to “think like a lawyer” and develop their professional identities, attention has turned to helping students self-regulate their learning. To encourage self-regulated learning among her first-year law students, one of us (Tanner) adapted a self-regulated learning prompt developed by the other (Roderick) to assign The Legal Writing Manual—a capstone project in her first-year legal writing course, which tasks students with instructing others in processes and practices for composing legal memoranda and appellate briefs. Each student’s manual is built upon previous analytical and self-reflective work carried out in a first-year legal writing course. The experience of articulating instructions for legal writing encourages students to self-regulate their learning by re-thinking knowledge and practices for legal writing.

Realizing the full potential of ultrahigh-intensity lasers for particle and radiation generation will require multi-beam arrangements due to technology limitations. Here, we investigate how to optimize their coupling with solid targets. Experimentally, we show that overlapping two intense lasers in a mirror-like configuration onto a solid with a large preplasma can greatly improve the generation of hot electrons at the target front and ion acceleration at the target backside. The underlying mechanisms are analyzed through multidimensional particle-in-cell simulations, revealing that the self-induced magnetic fields driven by the two laser beams at the target front are susceptible to reconnection, which is one possible mechanism to boost electron energization. In addition, the resistive magnetic field generated during the transport of the hot electrons in the target bulk tends to improve their collimation. Our simulations also indicate that such effects can be further enhanced by overlapping more than two laser beams.

Introduction: Acute aortic syndrome (AAS) includes the disease processes of aortic dissection, penetrating atherosclerotic ulcer, and intramural hematoma. This case demonstrates an atypical presentation of the disease and offers approaches to potentially prevent missed diagnoses. Case Report: An 87-year-old female with hypertension and Alzheimer’s dementia presented to the emergency department with stable vital signs and a chief complaint of throat pain. Initial work-up was significant for ischemia on electrocardiogram and elevated troponin. Computed tomography of the soft tissue neck revealed evidence of a ruptured aorta. Conclusion: Aortic rupture is a fatal complication of AAS. In an elderly patient with a history of hypertension, ischemic changes on electrocardiogram, and nonspecific pain, AAS should be on the emergency physician’s differential even in the setting of a benign or limited history and exam.

Introduction: Cerebral air embolisms are a rare but potentially devastating event where air enters the vascular system. Although commonly associated with intravascular catheters, they can arise from a variety of mechanisms including endoscopic procedures. Case Report: We report the case of a 90-year-old woman who presented with focal neurologic deficits due to an air embolism after undergoing an esophagogastroduodenoscopy. Conclusion: Cerebral air embolisms should be considered in patients who present to the emergency department with acute neurologic changes, especially after an endoscopic procedure.

Next-generation accelerator concepts, which hinge on the precise shaping of beam distributions, demand equally precise diagnostic methods capable of reconstructing beam distributions within six-dimensional position-momentum spaces. However, the characterization of intricate features within six-dimensional beam distributions using current diagnostic techniques necessitates a substantial number of measurements, using many hours of valuable beam time. Novel phase space reconstruction techniques are needed to reduce the number of measurements required to reconstruct detailed, high-dimensional beam features in order to resolve complex beam phenomena and as a feedback in precision beam shaping applications. In this study, we present a novel approach to reconstructing detailed six-dimensional phase space distributions from experimental measurements using generative machine learning and differentiable beam dynamics simulations. We demonstrate that this approach can be used to resolve six-dimensional phase space distributions from scratch, using basic beam manipulations and as few as 20 two-dimensional measurements of the beam profile. We also demonstrate an application of the reconstruction method in an experimental setting at the Argonne Wakefield Accelerator, where it is able to reconstruct the beam distribution and accurately predict previously unseen measurements 75× faster than previous methods.

Accelerator physics relies on numerical algorithms to solve optimization problems in online accelerator control and tasks such as experimental design and model calibration in simulations. The effectiveness of optimization algorithms in discovering ideal solutions for complex challenges with limited resources often determines the problem complexity these methods can address. The accelerator physics community has recognized the advantages of Bayesian optimization algorithms, which leverage statistical surrogate models of objective functions to effectively address complex optimization challenges, especially in the presence of noise during accelerator operation and in resource-intensive physics simulations. In this review article, we offer a conceptual overview of applying Bayesian optimization techniques toward solving optimization problems in accelerator physics. We begin by providing a straightforward explanation of the essential components that make up Bayesian optimization techniques. We then give an overview of current and previous work applying and modifying these techniques to solve accelerator physics challenges. Finally, we explore practical implementation strategies for Bayesian optimization algorithms to maximize their performance, enabling users to effectively address complex optimization challenges in real-time beam control and accelerator design.

Beams with cross-plane coupling or extreme asymmetries between the two transverse phase spaces are often encountered in particle accelerators. Flat beams with large transverse-emittance ratios are critical for future linear colliders. Similarly, magnetized beams with significant cross-plane coupling are expected to enhance the performance of electron cooling in hadron beams. Preparing these beams requires precise control and characterization of the four-dimensional transverse phase space. In this study, we employ generative phase-space reconstruction techniques to rapidly characterize magnetized and flat-beam phase-space distributions using a conventional quadrupole-scan method. The reconstruction technique is experimentally demonstrated on an electron beam produced at the Argonne Wakefield Accelerator and successfully benchmarked against conventional diagnostics techniques. Specifically, we show that predicted beam parameters from the reconstructed phase-space distributions (e.g., as magnetization and flat-beam emittances) are in excellent agreement with those measured from the conventional diagnostic methods.

ObjectivesCongenital cytomegalovirus disease (cCMV) can have significant sensory and neurodevelopmental sequelae throughout childhood. Many of these sequalae are consistent with special education eligibility, but the special education needs of affected children have not been systematically studied.MethodsRetrospective chart reviews from two cohorts of cCMV children receiving care in a large tertiary care children's hospital were included in this study: a historical research cohort (N = 186, 41% symptomatic at birth) and a contemporary clinical cohort of cCMV patients (N = 112, 68% symptomatic at birth). SNOMED-CT was used to identify ICD-10 codes describing special education-qualifying health outcomes fitting the Individuals with Disabilities Education Act (IDEA) criteria. ICD-10 codes were retrospectively applied to the historical research cohort through manual chart review, whereas the ICD-10 billing codes were extracted from the electronic medical record for all encounters in the contemporary cohort.ResultsOf the 56 unique special education-qualifying ICD-10 codes we identified as pertinent to the IDEA, at least one was noted in 39% of those asymptomatic at birth (AcCMV) as compared to 94% of the patients symptomatic at birth (ScCMV). In the contemporary clinical cohort, at least one of these codes was noted in 67% of the AcCMV patients as compared to 95% for ScCMV patients. 61% of patients in the historical and 86% in the contemporary cohort had at least one special education-qualifying ICD-10 code. Developmental, mobility, physical therapy and hearing-related health outcomes were common in both ScCMV and AcCMV patients.ConclusionsHealth outcomes qualifying for special educational services occur commonly in children with cCMV, including those who are classified as asymptomatic at birth. The emergence of qualifying conditions beyond the neonatal period among these children suggests that continued surveillance of this vulnerable population throughout early childhood may facilitate the timely identification of health outcomes requiring special educational services.

Abstract Background Telehealth can improve access to evidence-based care at a lower cost for patients, especially those living in underserved and remote areas. The barriers to the widespread adoption of telehealth have been well documented in the literature. However, the barriers may not be the same for pediatric patients, who must rely on their parents or guardians to make healthcare decisions. This paper presents some of the leading barriers parents or guardians of pediatric patients report in using telehealth to meet their children’s healthcare needs. Methods This cross-sectional survey was conducted in a tertiary care pediatric Emergency Department (ED) at a children’s hospital in Alabama between September 2020 to December 2020. The parents or guardians of pediatric patients were asked about their reasons for not using telehealth despite having healthcare needs for their children, whether they canceled or rescheduled healthcare provider visits and facility visits, and whether the child’s health conditions changed over the past three months. Descriptive analyses were conducted that explored the distribution of telehealth use across the variables listed above. Results Five hundred ninety-seven parents or guardians of pediatric patients participated in the survey, and 578 answered the question of whether they used telehealth or not over the past three months. Of them, 33.1% used telehealth, 54.3% did not, and 12.6% did not have healthcare needs for their child. The leading reason for not using telehealth was that the doctor or health provider did not give them a telehealth option, the second main reason was that they did not know what telehealth is, and the third leading reason was that the parents did not think telehealth would help meet healthcare needs for their child. Conclusions This study highlights the telehealth utilization barriers among underserved pediatric populations, including the need for physicians to proactively offer telehealth options to parents or guardians of pediatric patients. Improving health literacy is of paramount importance, given that a substantial proportion of parents were not familiar with telehealth. Policymakers and healthcare organizations should raise awareness about the benefits of telehealth which can improve healthcare access for underserved pediatric patients.

Scholars under the Fulbright Foreign Language Teaching Assistant (FLTA) Program have three important roles: teach the Filipino language and culture, study two courses per semester, and serve as cultural ambassadors of the Philippines in the United States. Exploring the scholars’ journey is important in providing future scholars ideas on rewarding and challenging experiences. This qualitative-biographical study focuses on five scholars’ (2022-2023 cohort) personal embodied experiences and encounters of learning processes. Using reflective writing, introspection, and journal entries as data collection techniques, the researchers accounted for the journey of every scholar. Results show that scholars’ personal embodied experiences include a sense of fulfillment, challenges, and personal and professional growth while their encounters of learning processes are comprised of students’ challenges in learning the language, the presence of negative learning behavior, and appreciation of the language and culture taught. Scholars also see Fulbright as platform for global and cultural involvement and self-growth.

Upon its establishment for the treatment of metastatic breast cancer (mBC), continuing trastuzumab beyond disease progression was an important paradigm shift that became the recommendation by major guidelines. However, data supporting continuation of human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab beyond the second-line setting are limited, resulting in a lack of approval of, or access to, this therapeutic strategy in many countries. This study aimed to provide additional data on the continued use of trastuzumab and trastuzumab-based therapies in combination with chemotherapy (CT) as third-line treatment for patients with mBC. This open-cohort, retrospective, observational study used deidentified patient-level data from an electronic health record–derived database that included patients with mBC who initiated third-line treatment with trastuzumab-based therapy combined with CT (Tras + CT; n = 288) or CT alone (CT; n = 49). Patients who received Tras + CT had a longer weighted median overall survival vs those who received CT only: 20.6 months (95% CI, 18.3–26.4 months) vs 10.1 months (95% CI, 7.8–12.3 months), respectively (hazard ratio [HR], 0.29; 95% CI, 0.16–0.53). This study provides additional support for maintaining trastuzumab-based therapies for patients with HER2+ mBC beyond second-line treatment. This treatment option should be available for all patients with mBC worldwide.

Abstract The long-term impact of COVID-19 among those with mild infections is not well characterized. Among 81 adults who completed online assessments at 3- and 12-months following infection, quality of life scores did not significantly improve over time. Among 62 subjects who also completed telephone interviews, respiratory symptoms or exercise limitation were reported by 42% at a median follow-up of 387 days (IQR 251–402 days). Those with persistent respiratory symptoms scored lower on the EQ-5D visual analog score compared to those without. Persistent respiratory symptoms were associated with a lower likelihood of full-time employment at 1 year (aOR 0.09, 95%CI 0.01–0.91; P = 0.041). In an adjusted linear regression, persistent respiratory symptoms (P = 0.037) and female sex (P = 0.016) were both independent risks for increased visits to a primary care provider. This cohort study demonstrates that respiratory symptoms are frequent at 1 year following COVID-19 and more importantly, are associated with negative impacts on employment, quality of life, and health care utilization. Further research is needed to determine the pathophysiology and risk factors for persistent symptoms as well as optimal management strategies to improve the level of functioning and quality of life.

Abstract Leg movements during sleep occur in patients with sleep pathology and healthy individuals. Some (but not all) leg movements during sleep are related to cortical arousals which occur without conscious awareness but have a significant effect of sleep fragmentation. Detecting leg movements during sleep that are associated with cortical arousals can provide unique insight into the nature and quality of sleep. In this study, a novel leg movement monitor that uses a unique capacitive displacement sensor and 6-axis inertial measurement unit, is used in conjunction with polysomnography to understand the relationship between leg movement and electroencephalogram (EEG) defined cortical arousals. In an approach that we call neuro-extremity analysis, directed connectivity metrics are used to interrogate causal linkages between EEG and leg movements measured by the leg movement sensors. The capacitive displacement measures were more closely related to EEG-defined cortical arousals than inertial measurements. Second, the neuro-extremity analysis reveals a temporally evolving connectivity pattern that is consistent with a model of cortical arousals in which brainstem dysfunction leads to near-instantaneous leg movements and a delayed, filtered signal to the cortex leading to the cortical arousal during sleep.

Abstract Climate change poses a particular threat to the world’s unique built heritage—historic buildings, sites monuments, and museums. As preserving built heritage resources from climate change becomes a global priority, understanding the current inadequacies of legal frameworks designed to protect built heritage in coastal areas is essential. Only by identifying and examining these shortfalls can countries create resilient legal policies and tools that better protect coastal built heritage from the immediate and long-term effects of climate change. Building on previous comparative cultural heritage law scholarship, this article describes the legal frameworks that the United States, United Kingdom, and France use to protect their respective built heritage in coastal areas and identifies two critical challenges facing each country.

Abstract Rhabdomyosarcoma (RMS) is an aggressive pediatric tumor with a poor prognosis for metastasis and recurrent disease. Large-scale sequencing endeavors demonstrate that Rhabdomyosarcomas have a dearth of precisely targetable driver mutations. However, IGF-2 signaling is known to be grossly altered in RMS. The insulin receptor (IR) exists in two alternatively spliced isoforms, IR-A and IR-B. The IGF-2 signaling molecule binds both its innate IGF-1 receptor as well as the insulin receptor variant A (IR-A) with high affinity. Mitogenic and proliferative signaling via the canonical IGF-2 pathway is, therefore, augmented by IR-A. This study shows that RMS patients express increased IR-A levels compared to control tissues that predominantly express the IR-B isoform. We also found that Hif-1α is significantly increased in RMS tumors, portraying their hypoxic phenotype. Concordantly, the alternative splicing of IR adapts to produce more IR-A in response to hypoxic stress. Upon examining the pre-mRNA structure of the gene, we identified a potential hypoxia-responsive element, which is also the binding site for the RNA-binding protein CUG-BP1 (CELF1). We designed Splice Switching Oligonucleotides (SSO) against this binding site to decrease IR-A levels in RMS cell lines and, consequently, rescue the IR-B expression levels. SSO treatment resulted in a significant reduction in cell proliferation, migration, and angiogenesis. Our data shows promising insight into how impeding the IGF-2 pathway by reducing IR-A expression mitigates tumor growth. It is evident that Rhabdomyosarcomas use IR alternative splicing as yet another survival strategy that can be exploited as a therapeutic intervention in conjunction with already established anti-IGF-1 receptor therapies.

Previous neurofeedback research has shown training-related frontal theta increases and performance improvements on some executive tasks in real feedback versus sham control groups. However, typical sham control groups receive false or non-contingent feedback, making it difficult to know whether observed differences between groups are associated with accurate contingent feedback or other cognitive mechanisms (motivation, control strategies, attentional engagement, fatigue, etc.). To address this question, we investigated differences between two frontal theta training groups, each receiving accurate contingent feedback, but with different top-down goals: (1) increase and (2) alternate increase/decrease. We hypothesized that the increase group would exhibit greater increases in frontal theta compared to the alternate group, which would exhibit lower frontal theta during down- versus up-modulation blocks over sessions. We also hypothesized that the alternate group would exhibit greater performance improvements on a Go-NoGo shooting task requiring alterations in behavioral activation and inhibition, as the alternate group would be trained with greater task specificity, suggesting that receiving accurate contingent feedback may be the more salient learning mechanism underlying frontal theta neurofeedback training gains. Thirty young healthy volunteers were randomly assigned to increase or alternate groups. Training consisted of an orientation session, five neurofeedback training sessions (six blocks of six 30-s trials of FCz theta modulation (4–7 Hz) separated by 10-s rest intervals), and six Go-NoGo testing sessions (four blocks of 90 trials in both Low and High time-stress conditions). Multilevel modeling revealed greater frontal theta increases in the alternate group over training sessions. Further, Go-NoGo task performance increased at a greater rate in the increase group (accuracy and reaction time, but not commission errors). Overall, these results reject our hypotheses and suggest that changes in frontal theta and performance outcomes were not explained by reinforcement learning afforded by accurate contingent feedback. We discuss our findings in terms of alternative conceptual and methodological considerations, as well as limitations of this research.

Longitudinal, community-based sampling is important for understanding prevalence and transmission of respiratory pathogens. Using a minimally invasive sampling method, the FAMILY Micro study monitored the oral, nasal and hand microbiota of families for 6 months. Here, we explore participant experiences and opinions. A mixed methods approach was utilised. A quantitative questionnaire was completed after every sampling timepoint to report levels of discomfort and pain, as well as time taken to collect samples. Participants were also invited to discuss their experiences in a qualitative structured exit interview. We received questionnaires from 36 families. Most adults and children >5y experienced no pain (94% and 70%) and little discomfort (73% and 47% no discomfort) regardless of sample type, whereas children ≤5y experienced variable levels of pain and discomfort (48% no pain but 14% hurts even more, whole lot or worst; 38% no discomfort but 33% moderate, severe, or extreme discomfort). The time taken for saliva and hand sampling decreased over the study. We conducted interviews with 24 families. Families found the sampling method straightforward, and adults and children >5y preferred nasal sampling using a synthetic absorptive matrix over nasopharyngeal swabs. It remained challenging for families to fit sampling into their busy schedules. Adequate fridge/freezer space and regular sample pick-ups were found to be important factors for feasibility. Messaging apps proved extremely effective for engaging with participants. Our findings provide key information to inform the design of future studies, specifically that self-sampling at home using minimally invasive procedures is feasible in a family context.

Background and Aims: The recovery of sperm by assisted reproductive technology (ART) results in significant DNA damage. Elevated levels of DNA damage in sperm have been linked to poor-quality embryos and increased pregnancy loss after ART. Therefore, in this study, we aimed to investigate potential of the new mitochondrial activator BGP-15 to prevent sperm DNA damage in an in vitroejaculate over time. Additionally, we sought to determine whether BGP-15 can preserve sperm quality during various sperm recovery techniques used in ART. Method: We incubated donated human semen specimens untreated or treated with BGP-15, then examined sperm motility and DNA damage (DNA fragmentation and oxidation). Semen samples were then processed using different clinical sperm recovery methods: simple wash (SW), swim-up (SU) and density gradient centrifugation (DGC); and the purified sperm underwent further analysis including motility, vitality, ROS levels, mitochondrial membrane integrity and mitochondrial membrane potential (MMP), and DNA damage. Results: Semen samples incubated with BGP-15 demonstrated improved sperm motility and reduced DNA damage levels. SW samples had the highest sperm count, while SU had the highest vitality and DNA integrity, but the lowest MMP. DGC sperm had increased MMP after BGP-15 Treatment. Although BGP-15 treatment only reduced sperm DNA fragmentation in SW samples, it reduced DNA oxidation in all recovery methods. Conclusion: Our findings indicate that clinical manipulation of patient semen samples can negatively impact sperm quality, and different sperm recovery methods have unique effects. However, the addition of BGP-15 to clinical processes can preserve sperm quality, potentially leading to improved embryo quality and ART success.

Background and Aims: Aging and obesity are associated with female infertility, with mitochondrial dysfunction proposed as an underlying factor; but our understanding of energy metabolism within the ovary remains limited. Method: This study focused on the granulosa cells surrounding the oocyte and investigated mitochondrial function, glycolytic function, total ATP production, and fatty acid metabolism using real-time metabolic analysis (Seahorse XFe96) to understand the effects of obesity and aging on energy metabolism. Mouse models were used to precisely isolate the effects of aging and obesity, with parallel studies conducted on human granulosa cells. Results: In mice, aging impaired both mitochondrial function and glycolytic function, while obesity primarily reduced mitochondrial function. Mice with both aging and obesity showed massively impaired granulosa cell metabolism. Next, the metabolic profile of granulosa cells in the follicular fluid of a cohort of 130 women who underwent IVF/ICSI cycles was measured. Aging primarily impaired mitochondrial function, with ATP production biased towards glycolysis, and no correlation was found with glycolytic function. Obesity primarily affected ATP production efficiency in mitochondria. Correlations between granulosa cell energy metabolism and embryonic development were also found. Mitochondrial spare capacity was associated with more retrieved oocytes, glycolytic reserve capacity was associated with Day 3 embryo quality, and mitochondrial ATP production was associated with improved blastocyst formation rates. Analysis of patient diagnoses revealed that in patients with normal ovarian function, only ATP production efficiency was decreased by aging, whereas in patients diagnosed with conditions of impaired ovarian function, mitochondrial function was more important. Interestingly, patients with adequate mitochondrial function showed good embryonic development, whereas those with very high mitochondrial and glycolytic energy metabolism showed a negative correlation with embryonic development, which was also observed in patients with ovarian dysfunction. Conclusion: These results provide new insights into the underlying metabolic dysfunction that occurs with female infertility.

Embryo biopsy is a precise procedure, demanding adept manipulation skills and the finest instruments to ensure high-quality results. One of the most crucial elements to gain mastery over is the micromanipulator system. In this session attendees will delve into the practical facets of setting up and controlling a micromanipulator within the context of a blastocyst biopsy. The session will also cover the important aspects of system set-up, instrument alignment, and objective positioning, aimed to maximize control, precision, and stability during the biopsy procedure. Moreover, the discussion will touch on the common challenges faced during the set-up process, offering practical solutions, and troubleshooting tips to manage these effectively.

Autism spectrum disorder (ASD) is a type of neurodevelopmental disorder that has been diagnosed in an increasing number of children around the world. The existing data suggest that early diagnosis and intervention can improve ASD outcomes. The causes of ASD remain complex and unclear, and there are currently no clinical biomarkers for autism spectrum disorder. There is an increasing recognition that ASD might be associated with oxidative stress through several mechanisms including abnormal metabolism (lipid peroxidation) and the toxic buildup of reactive oxygen species (ROS). Glutathione acts as an antioxidant, a free radical scavenger and a detoxifying agent. This open-label pilot study investigates the tolerability and effectiveness of oral supplementation with OpitacTM gluthathione as a treatment for patients with ASD. The various aspects of glutathione OpitacTM glutathione bioavailability were examined when administered by oral routes. The absorption of glutathione from the gastrointestinal tract has been recently investigated. The results of this case series suggest that oral glutathione supplementation may improve oxidative markers, but this does not necessarily translate to the observed clinical improvement of subjects with ASD. The study reports a good safety profile of glutathione use, with stomach upset reported in four out of six subjects. This article discusses the role of the gut microbiome and redox balance in ASD and notes that a high baseline oxidative burden may make some patients poor responders to glutathione supplementation. In conclusion, an imbalance in redox reactions is only one of the many factors contributing to ASD, and further studies are necessary to investigate other factors, such as impaired neurotransmission, immune dysregulation in the brain, and mitochondrial dysfunction.

Introduction Patients with head and neck cancer (HNC) experience unique physical and psychosocial challenges that impact their health and quality of life. Early implementation of palliative care has been shown to improve various health care outcomes. Objective The aim of the present study was to evaluate the patterns of referral of patients with HNC to outpatient palliative care as they relate to utilization of resources and end-of-life discussions. Methods We performed a retrospective review of 245 patients with HNC referred to outpatient palliative care services at two Louisiana tertiary care centers from June 1, 2014, to October 1, 2019. The control group consisted of those that were referred but did not follow-up. Reasons for referral were obtained, and outcome measures such as emergency department (ED) visits, hospital readmissions, and advance care planning (ACP) documentation were assessed according to predictive variables. Results There were 177 patients in the treatment group and 68 in the control group. Patients were more likely to follow up to outpatient palliative care services if referred for pain management. Hospital system, prior inpatient palliative care, and number of outpatient visits were associated with an increased likelihood for ED visits and hospital readmissions. Those in the palliative care treatment group were also more likely to have ACP discussions. Conclusion Early implementation of outpatient palliative care among patients with HNC can initiate ACP discussions. However, there are discrepancies in referral reasons to palliative care and continued existing barriers to its effective utilization.

Characterizing an unknown, complex system, like an accelerator, in multi-dimensional space is a challenging task. Here the authors report a Bayesian active learning method - Constrained Proximal Bayesian Exploration - for the characterization of a complex, constrained measurement as a function of multiple free parameters.

In recent years, human serum albumin (HSA) has been characterized as an ideal drug carrier in the cancer arena. Caveolin-1 (Cav-1) has been established as the principal structural protein of caveolae and, thus, critical for caveolae-mediated endocytosis. Cav-1 has been shown to be overexpressed in cancers of the lung and pancreas, among others. We found that Cav-1 expression plays a critical role in both HSA uptake and response to albumin-based chemotherapies. As such, developing a novel albumin-based chemotherapy that is more selective for tumors with high Cav-1 expression or high levels of caveolar-endocytosis could have significant implications in biomarker-directed therapy. Herein, we present the development of a novel and effective HSA-SN-38 conjugate (SSH20). We find that SSH20 uptake decreases significantly by immunofluorescence assays and western blotting after silencing of Cav-1 expression through RNA interference. Decreased drug sensitivity occurs in Cav-1-depleted cells using cytotoxicity assays. Importantly, we find significantly reduced sensitivity to SSH20 in Cav-1-silenced tumors compared to Cav-1-expressing tumors in vivo. Notably, we show that SSH20 is significantly more potent than irinotecan in vitro and in vivo. Together, we have developed a novel HSA-conjugated chemotherapy that is potent, effective, safe, and demonstrates improved efficacy in high Cav-1-expressing tumors.

Transverse beam emittance plays a key role in the performance of high-brightness accelerators. Characterizing beam emittance is often carried out using a quadrupole scan, which fits beam matrix elements to experimental measurements using first-order beam dynamics. Despite its simplicity at face value, this procedure is difficult to automate due to practical limitations. Key issues that must be addressed include maintaining beam size measurement validity by keeping beams within the radius of diagnostic screens, ensuring that measurement fitting produces physically valid results, and accurately characterizing emittance uncertainty. We describe a demonstration of the Bayesian exploration technique towards solving this problem at the Argonne Wakefield Accelerator, enabling a turn-key, autonomous quadrupole scan tool that can be used to quickly measure beam emittances at various locations in accelerators with limited operator input.

In this retrospective study, we aimed to evaluate the performance of dried-blood-spot (DBS) testing as a diagnostic method for the congenital cytomegalovirus (cCMV). We reviewed the medical records and DBS test results of 89 patients who had also undergone diagnostic cCMV testing within the first 21 days of life. The DBS test had a sensitivity of 83.9%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 73%. Patients with a true-positive DBS had a higher median level of CMV in blood according to PCR than those with a false-negative result. Additionally, all patients with cCMV and hearing loss had a positive DBS test, with higher median viremia levels observed in those with hearing loss compared to those without a CMV PCR blood test. These results suggest that DBS-based testing is useful in the diagnosis of cCMV, and its performance may be related to levels of CMV viremia. DBS testing accurately identified those patients with congenital/early onset hearing loss and those at risk of developing late-onset hearing loss.

Background:. Carpal tunnel release is a life-changing procedure within hand surgery. Multiple factors may have an impact on the outcome following surgery. Methods:. In this retrospective cohort study, we reviewed all patients who underwent carpal tunnel release in our institutional database from 2018 to 2020. We included patients with a minimum of 6-week follow-up. Patient demographics were identified, including insurance status and comorbidities. Patients were categorized as “improved” or “not improved” based on two-point test differences. Results were analyzed using the Fisher exact test. We ran a logistic regression model to analyze the relationship between income status (operationalized by having Medicaid/Carelink) and preoperative scores, and inferential statistics were computed with appropriate t tests. Results:. Of the 125 patients who met the inclusion criteria, 47 (37.6%) had Medicaid or Carelink, and 79 (62.4%) had commercial insurance. Medicaid/ Carelink patients presented with worse two-point discrimination on initial presentation (P < 0.001). Compared to commercial insurance, Medicaid/Carelink patients were less likely to show improvement in postoperative two-point discrimination (P < 0.001). Male patients were also less likely to show improvement. Race, ethnicity, medical comorbidities, and age were not shown to have a significant effect on improvement in two-point discrimination. Conclusions:. Although medical comorbidities did not have a significant effect on postoperative two-point, patients with low-income status (Medicaid/Carelink) may have a less predictable outcome. These socioeconomic considerations are critical in appropriately risk stratifying surgical candidates, and counseling patients in whom tactile acuity may be less predictable.

Abstract Fusobacterium nucleatum (Fn) is frequently found in colorectal cancers (CRCs). High loads of Fn DNA are detected in CRC tissues with microsatellite instability-high (MSI-H), or with the CpG island hypermethylation phenotype (CIMP). Fn infection is also associated with the inflammatory tumor microenvironment of CRC. A subtype of CRC exhibits inflammation-associated microsatellite alterations (IAMA), which are characterized by microsatellite instability-low (MSI-L) and/or an elevated level of microsatellite alterations at selected tetra-nucleotide repeats (EMAST). Here we describe two independent CRC cohorts in which heavy or moderate loads of Fn DNA are associated with MSI-H and L/E CRC respectively. We also show evidence that Fn produces factors that induce γ-H2AX, a hallmark of DNA double strand breaks (DSBs), in the infected cells.

In the Small Island Developing States (SIDS), public sector infrastructure projects (PSIPs) fail to both meet targeted performance metrics and deliver on the intended benefits to society. In terms of the cost performance metric, cost overruns (COs) beyond the initial contract value are more of a norm than a unique occurrence. Therefore, to ensure economic sustainability for SIDS, and value for money on PSIPs, there is a need to investigate and evaluate the risk impacts on COs. The purpose of this research was to identify and evaluate the perceived cost overrun risk factors that are within the primary project stakeholders’ sphere of control, and to reduce the ongoing ambiguities that exist in the prioritization of these risks. This was achieved by extracting critical risk factors from selected comparative studies in developing countries to formulate a closed-ended questionnaire to be administered to construction professionals in Trinidad and Tobago. Thereafter, the process of fuzzy synthetic evaluation (FSE) was used to develop a risk model based on three tiers of risks: 11 critical risk factors, 3 critical risk groupings (CRGs) and an overall risk level (ORL). The results showed that the two highest-ranked critical risks were project funding problems and variations by client. The leading critical risk grouping was client-related risk (5.370), followed by professional-related risk (4.815) and physical risk (4.870). The ORL was 5.068. Based on the FSE’s linguistic scaling, the CRGs and the ORL are perceived to be high risks in PSIPs. This research adds to the CO body of knowledge in primarily three ways. Firstly, the study extends the comparative assessment previously undertaken in scholarship into the context of SIDS to build on the generalizability of this context-specific phenomenon. Secondly, the FSE evaluation undertaken provides a practical tool to be promoted for use in SIDS’ construction industry among practitioners to focus and prioritize the critical risks in the planning phases and improve on contemporary risk practices in the execution phases of projects. Finally, this quantitative model approach is recommended to supplement the traditional qualitative risk management practices adopted in SIDS, thus contributing towards the overall improved economic sustainability and viability of PSIPs.

Wildlife corridors are typically designed for single species, yet holistic conservation approaches require corridors suitable for multiple species. Modelling habitat linkages for wildlife is based on several modelling steps (each involving multiple choices), and in the case of multi-species corridors, an approach to optimize single species corridors to few or a single functional corridor for multiple species. To model robust corridors for multiple species and simultaneously evaluate the impact of methodological choices, we develop a multi-method approach to delineate corridors that effectively capture movement of multiple wildlife species, while limiting the area required. Using wildlife presence data collected along ground-based line transects between Lake Manyara and Tarangire National Parks, Tanzania, we assessed species-habitat association in both ensemble and stacked species distribution frameworks and used these to estimate linearly and non-linearly scaled landscape resistances for seven ungulate species. We evaluated habitat suitability and least-cost and circuit theory-based connectivity models for each species individually and generated a multi-species corridor. Our results revealed that species-habitat relationships and subsequent corridors differed across species, but the pattern of predicted landscape connectivity across the study area was similar for all seven species regardless of method (circuit theory or least-cost) and scaling of the habitat suitability-based cost surface (linear or non-linear). Stacked species distribution models were highly correlated with the seven species for all model outputs (r = 0.79 to 0.97), while having the greatest overlap with the individual species least-cost corridors (linear model: 61.6%; non-linear model: 60.2%). Zebra was the best single-species proxy for landscape connectivity. Overall, we show that multi-species corridors based on stacked species distribution models achieve relatively low cumulative costs for savanna ungulates as compared to their respective single-species corridors. Given the challenges and costs involved in acquiring data and parameterizing corridor models for multiple species, zebra may act as a suitable proxy species for ungulate corridor conservation in this system.

Fibro-osseous pseudotumors are lesions of calcification involving the subcutaneous tissues usually of the digits of the hands and more rarely seen in the lower extremity. A frequent differential diagnosis or misdiagnosis for these lesions is osteosarcoma. This case study is of a 26-year-old female who presented with a rapidly growing nodule along the dorsal aspect of her left hallux. Resection of the nodule with subsequent pathology confirmed that the lesion was benign and a rare fibro-osseous pseudotumor. This paper details the diagnosis, surgical management and follow up of resection of the pseudotumor and the importance in ruling out malignancy.

Brain abscesses represent a pathology with significant morbidity and mortality. An underlying predisposing condition may not be apparent or identifiable in some instances. We present a patient with cerebral abscess who was found to have, previously undiagnosed, pulmonary arteriovenous malformations (PAVMs). PAVMs are rare pulmonary vascular anomalies resulting in intrapulmonary right to left shunt. These have been implicated in the development of brain abscesses. Conventional cultures from the lesion were non-revealing; hence, sample was sent for next-generation sequencing (NGS) which revealed multiple organisms, with predominance of Mycoplasma faucium, a bacterium initially felt to be a commensal of the oropharynx, but recently implicated as a human pathogen. This case, along with other documented associations between brain abscesses and pulmonary AVMs, highlights that brain abscess could be an initial clinical presentation in asymptomatic PAVMs. Additionally, novel testing such as NGS should be utilized in select settings where microbiological diagnosis can be elusive. This will help institute pathogen-directed specific antimicrobial therapy for favorable clinical outcomes.

This paper proposes the CorpRank algorithm to extract social hierarchies from electronic communication data. The algorithm computes a ranking score for each user as a weighted combination of the number of emails, the number of responses, average response time, clique scores, and several degree and centrality measures. The algorithm uses principal component analysis to calculate the weights of the features. This score ranks users according to their importance, and its output is used to reconstruct an organization chart. We illustrate the algorithm over real-world data using the Enron corporation’s e-mail archive. Compared to the actual corporate work chart, compensation lists, judicial proceedings, and analyzing the major players involved, the results show promise.

Flare frequency distributions represent a key approach to addressing one of the largest problems in solar and stellar physics: determining the mechanism that counterintuitively heats coronae to temperatures that are orders of magnitude hotter than the corresponding photospheres. It is widely accepted that the magnetic field is responsible for the heating, but there are two competing mechanisms that could explain it: nanoflares or Alfvén waves. To date, neither can be directly observed. Nanoflares are, by definition, extremely small, but their aggregate energy release could represent a substantial heating mechanism, presuming they are sufficiently abundant. One way to test this presumption is via the flare frequency distribution, which describes how often flares of various energies occur. If the slope of the power law fitting the flare frequency distribution is above a critical threshold, α = 2 as established in prior literature, then there should be a sufficient abundance of nanoflares to explain coronal heating. We performed >600 case studies of solar flares, made possible by an unprecedented number of data analysts via three semesters of an undergraduate physics laboratory course. This allowed us to include two crucial, but nontrivial, analysis methods: preflare baseline subtraction and computation of the flare energy, which requires determining flare start and stop times. We aggregated the results of these analyses into a statistical study to determine that α = 1.63 ± 0.03. This is below the critical threshold, suggesting that Alfvén waves are an important driver of coronal heating.

Objectives Drug and biological products that treat rare, serious or life-threatening conditions can receive US Food and Drug Administration (FDA) orphan designation and expedited programme designations (accelerated approval, breakthrough therapy, fast track or priority review) meant to incentivise development. Timely recommendations from guidance documents may encourage more rapid and appropriate use and access to these medicines for serious conditions. We sought to determine time between FDA approval and inclusion in guidance documents for non-oncological orphan products overall and by number and type of expedited programme designations.Design and setting Retrospective survival analysis of non-oncological orphan products with ≥1 expedited designation approved since 1992. In June 2020, PubMed, Turning Research into Practice and Guideline Central databases were searched to identify guidance documents influencing US practice that included each product.Main outcomes and measures The primary outcome was time to guidance inclusion, defined as any recommendation on use provided within the recommendation framework used by the guidance document.Results Among 135 included non-oncological orphan products, 97.0% (n=131) were designated with priority review, 49.6% (n=67) fast track, 16.3% (n=22) breakthrough therapy and 14.1% (n=19) accelerated approval. Sixty per cent of products (n=81) received ≥2 designations. Overall, 74.1% (n=100) were included in a guidance document. The median time to inclusion was 2.87 years (IQR 2.21–4.18) for the entire cohort. In survival analyses, guidance inclusion was more likely to occur earlier for products with ≥2 designations (HR, 1.84; 95% CI 1.21 to 2.79) and for those with fast-track designation compared with priority review (HR 1.40; 95% CI 1.02 to 2.0). Of 35 products not included in a guidance document, 54.3% (n=19) were approved in 2018 or later.Conclusions Among non-oncological orphan products with priority designations, nearly 3 years had passed between FDA approval and inclusion in any guidance document. These findings suggest that despite efforts to expedite availability, appropriate access to these treatments may be delayed because of the lack of timely guidance on their use in clinical practice.