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Objective To compare racial differences in male fertility history and treatment. Design Retrospective review of prospectively collected data. Setting North American reproductive urology centers. Patient(s) Males undergoing urologist fertility evaluation. Intervention(s) None. Main Outcome Measure(s) Demographic and reproductive Andrology Research Consortium data. Result(s) The racial breakdown of 6,462 men was: 51% White, 20% Asian/Indo-Canadian/Indo-American, 6% Black, 1% Indian/Native, Conclusion(s) Racial differences exist for males undergoing fertility evaluation by a reproductive urologist. Better understanding of these differences in history in conjunction with societal and biologic factors can guide personalized care, as well as help to better understand and address disparities in access to fertility evaluation and treatment.

During mammalian development, differences in chromatin state coincide with cellular differentiation and reflect changes in the gene regulatory landscape1. In the developing brain, cell fate specification and topographic identity are important for defining cell identity2 and confer selective vulnerabilities to neurodevelopmental disorders3. Here, to identify cell-type-specific chromatin accessibility patterns in the developing human brain, we used a single-cell assay for transposase accessibility by sequencing (scATAC-seq) in primary tissue samples from the human forebrain. We applied unbiased analyses to identify genomic loci that undergo extensive cell-type- and brain-region-specific changes in accessibility during neurogenesis, and an integrative analysis to predict cell-type-specific candidate regulatory elements. We found that cerebral organoids recapitulate most putative cell-type-specific enhancer accessibility patterns but lack many cell-type-specific open chromatin regions that are found in vivo. Systematic comparison of chromatin accessibility across brain regions revealed unexpected diversity among neural progenitor cells in the cerebral cortex and implicated retinoic acid signalling in the specification of neuronal lineage identity in the prefrontal cortex. Together, our results reveal the important contribution of chromatin state to the emerging patterns of cell type diversity and cell fate specification and provide a blueprint for evaluating the fidelity and robustness of cerebral organoids as a model for cortical development., Analysis of chromatin state at a single-cell level in samples of developing human forebrain demonstrate both cell-type-specific and region-specific changes during neurogenesis.

As cost-effective measures become increasingly implemented in the US healthcare system, changes in patient-reported outcome measure (PROM) scores can be utilized to indicate patient satisfaction following procedures including total knee arthroplasty (TKA). The primary aim of this study was to develop and evaluate machine learning algorithms to predict achievement of the minimal clinically important difference (MCID) for the Knee Injury and Osteoarthritis Outcome Score-Physical Function Short Form (KOOS-PS) at 1-year following TKA. A retrospective review of primary TKA patients between 2016 and 2018 was performed. Variables considered for prediction included demographics and preoperative PROMs. The KOOS-PS MCID was calculated via a distribution-based method. Five machine learning algorithms were developed and tested by discrimination, calibration, Brier score, and decision curve analysis. Among the 744 patients who met the inclusion criteria, 385 (72.8%) patients achieved the MCID. The elastic-net penalized logistic regression model was selected as the best performing model (c-statistic 0.77, calibration intercept -0.02, calibration slope 1.15, and Brier score 0.14). The most important variables for MCID achievement were preoperative KOOS-PS score, preoperative VAS Pain, preoperative opioid use, preoperative PROMIS global mental health score, age, and sex. Algorithms were incorporated into an open-access digital application available at https://sorg-apps.shinyapps.io/tka_koos_mcid/. This study is the first to predict the probability of achieving the KOOS-PS MCID following TKA using a machine learning-based approach. The results were used to develop a clinical decision aid based on commonly collected predictive variables to preoperatively predict an individual patient's likelihood of attaining an acceptable outcome following TKA.

Introduction The aims of this study were to determine if increasing body mass index (BMI) is a risk factor for failure to attain the 1-year Patient Reported Outcomes Measurement Information System Physical Function (PROMIS PF-10a) minimal clinically important difference (MCID) following total joint arthroplasty (TJA) and to determine a possible BMI threshold beyond which this risk increases significantly. Methods This retrospective study was performed using 3506 TJAs sourced from a regional-based registry. An anchor-based MCID threshold of 7.9 was chosen. PROMIS PF-10a scores were collected at the preoperative and 1-year postoperative timepoints, and the change was used to determine failure to achieve the 1-year MCID. Demographic and surgical variables were also collected. The association between BMI and failure to achieve 1-year PROMIS PF-10 MCID was then evaluated using logistic regression. A BMI threshold was determined using receiver operating characteristic (ROC) curve analysis. Results Increasing BMI assessed continuously was a significant risk factor for failure to achieve the MCID (P 40 kg/m2) subgroups compared to “Normal BMI” ( Conclusion Our study showed that increasing BMI is a risk factor for failure to achieve the 1-year PROMIS PF-10a MCID following TJA. Among our patients, an increase in 1 kg/m2 increased the risk of failure to achieve the MCID by 2%. With these findings, surgeons will be better equipped to preoperatively advise patients with elevated BMIs considering TJA.

Objective To develop and validate a novel, mail-in semen analysis (SA) system. Design Prospective cohort. Setting Not applicable. Patient(s) Ejaculates from normospermic men. Intervention(s) One-hour SA, then repeat SAs (on same ejaculate) over 52 hours using a novel technique for maintaining sperm viability. Main Outcome Measure(s) World Health Organization SA parameters. Result(s) One-hour SA on 104 ejaculates in the validation phase of the study demonstrated normal semen parameters. With up to 52 hours of observation and four subsequent SA measurements/ejaculate, concentration remained stable, motility decreased by 0.39%/h, and normal morphology decreased by 0.1%/h. Measured 1-hour and calculated motility (correlation coefficients 0.87) and morphology (correlation coefficients 0.82) strongly were correlated. Conclusion This novel, mail-in, Clinical Laboratory Improvement Amendments–approved SA testing system demonstrates a strong degree of correlation between 1-hour and delayed SA testing. Given the linear motility and morphology decrease and stability of sperm concentration, this test may be used in clinical practice to evaluate semen quality for fertility evaluations. Furthermore, this approach significantly improves the ease, comfort, and efficiency of obtaining a SA, likely breaking down early barriers to accessing successfully a male fertility evaluation.

Background Anastrozole is a non-steroidal fourth generation aromatase inhibitor that stops the conversion of testosterone to estradiol and has been used as empiric medical therapy for the treatment of male infertility in men with an abnormal testosterone-to-estradiol ratio

Opioids are the most widely used therapy for pain during the postoperative period. It has been suggested by some that hydromorphone is clinically superior. Our primary objective was to determine if there is a difference in postoperative pain score ratings between adult patients receiving intravenous hydromorphone vs intravenous morphine on discharge from the post-anesthesia care unit (PACU).For this historical cohort study, convenience sampling was used to identify the first 605 patients ≥ 18 yr undergoing elective, non-cardiac surgery. Patients were categorized based on treatment in the PACU with hydromorphone (n = 326) or morphine (n = 279). Pain scores (scale of 0-10), nausea/vomiting (scale of 0-3), pruritis (scale of 0-3), and sedation (scale of 0-4), as well as total opioid dose administered from arrival in the PACU until readiness to discharge were evaluated.For the primary outcome of pain reported at discharge from the PACU, there was no significant difference between the mean (standard deviation) hydromorphone numeric rating scale (NRS) [2.8 (1.6)] and the morphine NRS [2.5 (1.5)] after adjusting for potential confounders (adjusted mean difference, 0.10; 95% confidence interval, -0.21 to 0.42; P = 0.53). Similarly, there were no significant between-group differences in length of stay in the PACU, satisfactory analgesia, nausea/vomiting, and sedation.This study serves to help guide the decision-making process for selecting either morphine or hydromorphone for acute postoperative analgesia. Overall, we found no significant difference for analgesia or for common opioid-related adverse effects between these two opioids in the postoperative period at the time of discharge from the PACU. Furthermore, according to this data, the equipotency ratio of hydromorphone to morphine is closer to 1:6.5 rather than the commonly employed 1:5 ratio.RéSUMé: OBJECTIF: Les opioïdes sont le traitement le plus fréquemment utilisé pour prendre en charge la douleur postopératoire. Certains auteurs suggèrent que l’hydromorphone est supérieure d’un point de vue clinique. Notre objectif principal était de déterminer s’il existait une différence dans les scores de douleur postopératoire entre des patients adultes ayant reçu de l’hydromorphone intraveineuse comparativement à de la morphine intraveineuse lors de leur congé de la salle de réveil. MéTHODE: Pour cette étude de cohorte historique, un échantillonnage de commodité a été utilisé pour identifier les premiers 605 patients ≥ 18 ans subissant une chirurgie non cardiaque non urgente. Les patients ont été catégorisés en fonction du traitement reçu à la salle de réveil, soit hydromorphone (n = 326) ou morphine (n = 279). Les scores de douleur (échelle de 0-10), les nausées et vomissements (échelle de 0-3), le prurit (échelle de 0-3) et la sédation (échelle de 0-4), ainsi que la dose totale d’opioïdes administrés entre l’arrivée en salle de réveil et le moment de recevoir le congé ont été évalués. RéSULTATS: En ce qui touche à notre critère d’évaluation principal de douleur rapportée au moment du congé de la salle de réveil, aucune différence significative n’a été observée entre le score moyen (écart type) de l’hydromorphone sur l’échelle d’évaluation numérique (EEN) [2,8 (1,6)] et celui de la morphine [2,5 (1,5)] après avoir ajusté les valeurs pour tenir compte des facteurs de confusion potentiels (différence moyenne ajustée, 0,10; intervalle de confiance 95 %, -0,21 à 0,42; P = 0,53). De la même manière, aucune différence intergroupe significative n’a été observée en matière de durée de séjour à la salle de réveil, d’analgésie satisfaisante, de nausées et vomissements, et de sédation. CONCLUSION: Cette étude sert à guider le processus de prise de décision lors du choix de la morphine ou de l’hydromorphone pour l’analgésie postopératoire aiguë. Globalement, nous n’avons observé aucune différence significative dans l’analgésie procurée ou les effets secondaires néfastes liés aux opioïdes entre ces deux molécules en période postopératoire au moment du congé de la salle de réveil. En outre, selon ces données, le ratio d’efficacité équivalente de l’hydromorphone par rapport à la morphine est plus proche de 1:6,5 que du ratio fréquemment utilisé de 1:5.

Purpose: Immunotherapy has been demonstrably effective against multiple cancers, yet tumor escape is common. It remains unclear how brain tumors escape immunotherapy and how to overcome this immune escape. Experimental Design: We studied KR158B-luc glioma-bearing mice during treatment with adoptive cellular therapy (ACT) with polyclonal tumor-specific T cells. We tested the immunogenicity of primary and escaped tumors using T-cell restimulation assays. We used flow cytometry and RNA profiling of whole tumors to further define escape mechanisms. To treat immune-escaped tumors, we generated escape variant-specific T cells through the use of escape variant total tumor RNA and administered these cells as ACT. In addition, programmed cell death protein-1 (PD-1) checkpoint blockade was studied in combination with ACT. Results: Escape mechanisms included a shift in immunogenic tumor antigens, downregulation of MHC class I, and upregulation of checkpoint molecules. Polyclonal T cells specific for escape variants displayed greater recognition of escaped tumors than primary tumors. When administered as ACT, these T cells prolonged median survival of escape variant-bearing mice by 60%. The rational combination of ACT with PD-1 blockade prolonged median survival of escape variant glioma-bearing mice by 110% and was dependent upon natural killer cells and T cells. Conclusions: These findings suggest that the immune landscape of brain tumors are markedly different postimmunotherapy yet can still be targeted with immunotherapy.

Laser interstitial thermal therapy (LITT) remains a promising advance in the treatment of primary central nervous system malignancies. As indications for its use continue to expand, there has been growing interest in its ability to induce prolonged blood brain barrier (BBB) permeability through hyperthermia, potentially increasing the effectiveness of current therapeutics including BBB-impermeant agents and immunotherapy platforms. In this review, we highlight the mechanism of hyperthermic BBB disruption and LITT-induced immunogenic cell death in preclinical models and humans. Additionally, we summarize ongoing clinical trials evaluating a combination approach of LITT and immunotherapy, which will likely serve as the basis for future neuro-oncologic treatment paradigms. There is evidence to suggest a highly immunogenic response to laser interstitial thermal therapy through activation of both the innate and adaptive immune response. These mechanisms have been shown to potentiate standard methods of oncologic care. There are only a limited number of clinical trials are ongoing to evaluate the utility of LITT in combination with immunotherapy. LITT continues to be studied as a possible technique to bridge the gap between exciting preclinical results and the limited successes seen in the field of neuro-oncology. Preliminary data suggests a substantial benefit for use of LITT as a combination therapy in several clinical trials. Further investigation is required to determine whether or not this treatment paradigm can translate into long-term durable results for primary intracranial malignancies.

Patient safety indicators (PSIs) and hospital-acquired conditions (HACs) are reported quality measures. We compared their prevalence in patients with secretory and nonsecretory pituitary adenoma using the National (Nationwide) Inpatient Sample (NIS), Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality.The NIS was queried for hospitalizations 2002-2014 involving pituitary adenomas. Prevalence of PSI, HAC, and 9 pituitary-related complications was determined using International Classification of Diseases, Ninth Revision codes. Patient risk factors were evaluated through multivariate analysis.A total of 20,743 patients with nonsecretory tumor and 3385 patients with secretory tumor were identified. Among patients with nonsecretory tumor, 3.79% experienced any PSI or HAC. Of patients with secretory tumor, 2.54% had any PSI or HAC. Before adjusting for covariation, secretory patients were less likely to have any PSI or HAC (odds ratio [OR], 0.652; P = 0.0002), experience any pituitary-related complication (OR, 0.804; P0.0001), have a poor outcome (hazard ratio [HR], 0.435; P0.0001), and die during hospitalization (HR, 0.293; P = 0.0015). Secretory patients had significantly shorter mean hospital length of stay (secretory/nonsecretory percent difference, -11.95%; P0.0001). However, inverse propensity score-weighted ORs comparing the groups' outcomes showed that there was no significant difference in the prevalence of any PSIs and HACs (OR, 0.963; P = 0.8570), pituitary-related complications (OR, 0.894; P = 0.1321), poor outcomes (HR, 0.990; P = 0.9287), in-hospital death (HR, 0.663; P = 0.2967), and length of stay (percent difference, -2.31%; P = 0.2967) between groups.Lack of significant difference in outcome measures after controlling for covariation is consistent with our finding that patients with nonsecretory tumor have more comorbidities on presentation for treatment. PSIs and HACs have limited ability to measure complications specific to pituitary tumors.

Microglia are resident macrophages in the brain that emerge in early development and respond to the local environment by altering their molecular and phenotypic states. Fundamental questions about microglia diversity and function during development remain unanswered because we lack experimental strategies to interrogate their interactions with other cell types and responses to perturbations exvivo. We compared human microglia states across culture models, including cultured primary and pluripotent stem cell-derived microglia. We developed a "report card" of gene expression signatures across these distinct models to facilitate characterization of their responses across experimental models, perturbations, and disease conditions. Xenotransplantation of human microglia into cerebral organoids allowed us to characterize key transcriptional programs of developing microglia invitro and reveal that microglia induce transcriptional changes in neural stem cells and decrease interferon signaling response genes. Microglia additionally accelerate the emergence of synchronized oscillatory network activity in brain organoids by modulating synaptic density.

Introduction: A comprehensive comparison of the performance of different femoral stem geometries in total hip arthroplasty (THA) is yet to be described. The primary aim of this study was to evaluate objective and subjective outcome measures in primary THA with different femoral implant styles. Methods: Stems were classified into the following five classes: cemented, conical, fit and fill, modular, and wedge. The objective outcomes of interest were the length of inpatient hospital stay (LOS), 90-day readmission rate, one-year revision rate, and two-year mortality rate. Preoperative and postoperative patient-reported outcome measures (PROMs), including hip disability and osteoarthritis outcome score (HOOS) - physical function shortform (HOOS-PS), patient-reported outcomes measurement information system physical function short form 10a (PROMIS PF-10a), and patient-reported outcomes measurement information system - short form - mental 10a (PROMIS M-10a) were recorded and compared between different classes. Results: Patients with a wedge stem had a significantly lower LOS versus every other stem group, while patients with a cemented stem had the highest LOS, approximately twofold that of the wedge stem group. Accounting for potential confounders, the conical and fit and fill groups had a significantly higher two-year mortality rate than the wedge stem group. Fit and fill stems conferred a slight risk of revision THA at one-year compared to wedge stems. There was no significant difference in the rates of failure to achieve the minimal clinically important difference (MCID) for the PROMs. Conclusion: Placement of wedge stems resulted in a significantly lower LOS compared to every other stem class and a lower mortality rate than the conical, fit and fill, and modular stems. As for the 90-day readmission, one-year revision, and the rates of failure to achieve the MCID for general or hip-specific PROMs, stem design had no meaningful effect.

INTRODUCTION Bone marrow-derived hematopoietic stem and progenitor cells (HSPCs) give rise to the cellular components of the immune system. Unfortunately, immune reconstitution from HSPCs are negatively impacted by solid cancers, including high-grade gliomas. For example, an expansion of myeloid progenitor cells has been previously described across several cancers that originate outside the CNS. A similar expansion of MDSCs coupled with diminished T cell function has also been described in the peripheral blood of patients with newly-diagnosed GBM. Alterations in both lymphoid and myeloid compartments due to CNS malignancy led us to determine how intracranial gliomas impact HSPCs in both their capacity to reconstitute the immune compartment and in their cell fate determination. This is important to better understand the impact of gliomas on immunity and how we can leverage these findings to better develop cellular immunotherapeutics. METHODS HSPCs were isolated from bone marrow of C57BL/6 mice with orthotopic KR158B glioma, or age-matched naïve mice. Experiments were conducted to compare relative changes in: gene expression (RNA-sequencing), precursor frequencies, cell fate determination, and cellular function of cells derived from HSPCs of glioma-bearing mice. RESULTS RNA-sequencing revealed 700+ genes whose expression was significantly up- or downregulated in HSPCs from glioma-bearing mice, particularly those involved with stemness and metabolic activity. Importantly, HSPCs from glioma-bearing mice expressed upregulation of genes involved in myelopoiesis relative to naïve mice. This was coupled with an expansion of granulocyte macrophage precursors (GMPs), the progenitors to gMDSCs. Next, differentiation assays revealed that HSPCs from glioma-bearing mice had higher propensity of differentiating into MDSC under homeostatic conditions relative to controls both in vitro and in vivo. Furthermore, mice bearing intracranial gliomas possess an expansion of MDSCs which are more suppressive on T cell proliferation and hinders T cell-mediated tumor cell killing relative to MDSCs derived from naïve control mice.

Adeno-associated viruses (AAVs) hold tremendous promise as delivery vectors for clinical gene therapy, but they need improvement. AAVs with enhanced properties, such as more efficient and/or cell-type specific infection, can be engineered by creating a large, diverse starting library and screening for desired phenotypes, in some cases iteratively. Although this approach has succeeded in numerous specific cases, such as infecting cell types from the brain to the lung, the starting libraries often contain a high proportion of variants unable to assemble or package their genomes, a general prerequisite for engineering any gene delivery goal. Herein, we develop and showcase a machine learning (ML)-based method for systematically designing more effective starting libraries — ones that have broadly good packaging capabilities while being as diverse as possible. Such carefully designed but general libraries stand to significantly increase the chance of success in engineering any property of interest. Furthermore, we use this approach to design a clinically-relevant AAV peptide insertion library that achieves 5-fold higher packaging fitness than the state-of-the-art library, with negligible reduction in diversity. We demonstrate the general utility of this designed library on a downstream task to which our approach was agnostic: infection of primary human brain tissue. The ML-designed library had approximately 10-fold more successful variants than the current state-of-the-art library. Not only should our new library serve useful for any number of other engineering goals, but our library design approach itself can also be applied to other types of libraries for AAV and beyond.

Polygenicity and pleiotropy are key properties of the genomic architecture of psychiatric disorders. An optimistic interpretation of polygenicity is that genomic variants converge on a limited set of mechanisms at some level from genes to behavior. Alternatively, convergence may be minimal or absent.We took advantage of brain connectivity, measured by resting-state functional MRI (rs- fMRI), as well as rare and common genomic variants to understand the effects of polygenicity and pleiotropy on large-scale brain networks, a distal step from genes to behavior. We processed ten rs-fMRI datasets including 32,988 individuals, to examine connectome-wide effects of 16 copy number variants (CNVs), 10 polygenic scores, 6 cognitive and brain morphometry traits, and 4 idiopathic psychiatric conditions.Although effect sizes of CNVs on connectivity were correlated to cognition and number of genes, increasing polygenicity was associated with decreasing effect sizes on connectivity. Accordingly, the effect sizes of polygenic scores on connectivity were 6-fold lower compared to CNVs. Despite this heterogeneity of connectivity profiles, multivariate analysis identified convergence of genetic risks and psychiatric disorders on the thalamus and the somatomotor network. Based on spatial correlations with transcriptomic data, we hypothesize that excitatory thalamic neurons may be primary contributors to brain alteration profiles shared across genetic risks and conditions. Finally, pleiotropy measured by genetic and transcriptomic correlations between 38 pairs of conditions/traits showed significant concordance with connectomic correlations, suggesting a substantial causal genetic component for shared connectivity.Such findings open avenues to delineate general mechanisms - amenable to intervention - across conditions and genetic risks.One sentence summaryEffects of rare and common genomic variants on brain functional connectivity shed light on the impact of polygenicity and pleiotropy in psychiatry.

INTRODUCTION AND OBJECTIVE:Erectile dysfunction (ED) and urinary incontinence (UI) are important quality-of-life measures especially after prostate cancer treatment. When both conditions are presen...

INTRODUCTION AND OBJECTIVE:Urinary incontinence (UI) and erectile dysfunction (ED) are important quality-of-life measures especially after prostate cancer treatment. When both conditions are presen...

OPINION STATEMENT Laser interstitial thermal therapy (LITT) is a minimally invasive treatment option for brain tumors including glioblastoma, other primary central nervous system (CNS) neoplasms, metastases, and radiation necrosis. LITT employs a fiber optic coupled laser delivery probe stabilized via stereotaxis to deliver thermal energy that induces coagulative necrosis in tumors to achieve effective cytoreduction. LITT complements surgical resection, radiation treatment, tumor treating fields, and systemic therapy, especially in patients who are high risk for surgical resection due to tumor location in eloquent regions or poor functional status. These factors must be balanced with the increased rate of cerebral edema post LITT compared to surgical resection. LITT has also been shown to induce transient disruption of the blood-brain barrier (BBB), especially in the peritumoral region, which allows for enhanced CNS delivery of anti-neoplastic agents, thus greatly expanding the armamentarium against brain tumors to include highly effective anti-neoplastic agents that have poor BBB penetration. In addition, hyperthermia-induced immunogenic cell death is another secondary side effect of LITT that opens up immunotherapy as an attractive adjuvant treatment for brain tumors. Numerous large studies have demonstrated the safety and efficacy of LITT against various CNS tumors and as the literature continues to grow on this novel technique so will its indications.

Introduction For the estimated 15 million cancer survivors in the United States, access to accurate information regarding quality of life issues such as sexual health and fertility preservation is a very important part of cancer recovery. Aim Because National Cancer Institute (NCI)–designated cancer centers (CCs) are leaders of cancer care, we sought to determine the prevalence and quality of information relating to male and female sexual health and fertility on all NCI-designated CC websites. Methods A total of 70 NCI-designated CC websites listed on www.cancer.gov and divided by geographic regions were carefully analyzed for the presence and quality of male and female sexual health and fertility information. Fisher’s exact test was performed to assess for differences between websites. Main Outcome Measure We determined the number and percentage of NCI-designated CC websites with sexual health and/or fertility information, availability of information by region, and information available for each gender. Results Sexual health and/or fertility information was accessible on 43 of 63 (68.3%) CC websites and was more prevalent on comprehensive CC compared with non-comprehensive CC websites (37 of 49 [75.5%] vs 6 of 14 [42.9%] websites, respectively; P < .05). NCI-designated CC websites had less information on sexual health compared with that on fertility (24 of 63 [38.1%] vs 41 of 63 [65.1%] websites, respectively; P < .01). Access to data was less available for men compared with women (35 of 41 [85.4%] vs 41 of 41 [100%] websites, respectively; P < .05) on CC websites providing fertility preservation information. Fifteen CCs in the South Atlantic (11) and East South Central (4) regions did not offer sexual health information on their respective websites. Conclusion Information regarding sexual health and fertility preservation after cancer treatment is not common and less available for men compared with women on NCI-designated CC websites. The aforementioned data highlight the need to improve the quality and accessibility of sexual health and fertility preservation information for all NCI-designated CC websites.

BACKGROUND CONTEXT The increasing volume of free-text notes available in electronic health records has created an opportunity for natural language processing (NLP) algorithms to mine this unstructured data in order to detect and predict adverse outcomes. Given the volume and diversity of documentation available in spine surgery, it remains unclear which types of documentation offer the greatest value for prediction of adverse outcomes. STUDY DESIGN/SETTING Retrospective review of medical records at two academic and three community hospitals. PURPOSE The purpose of this study was to conduct an exploratory analysis in order to examine the utility of free-text notes generated during the index hospitalization for lumbar spine fusion for prediction of 90-day unplanned readmission. PATIENT SAMPLE Adult patients 18 years or older undergoing lumbar spine fusion for lumbar spondylolisthesis or lumbar spinal stenosis between January 1, 2016 and December 31, 2020. OUTCOME MEASURES The primary outcome was inpatient admission within 90-days of discharge from the index hospitalization. METHODS The predictive performance of NLP algorithms developed by using discharge summary notes, operative notes, nursing notes, physical therapy notes, case management notes, medical doctor (MD) (resident or attending), and allied practice professional (APP) (nurse practitioner or physician assistant) notes were assessed by discrimination, calibration, overall performance. RESULTS Overall, 708 patients were included in the study and 83 (11.7%) had 90-day inpatient readmission. In the independent testing set of patients (n=141) not used for model development, the area under the receiver operating curve of NLP algorithms for prediction of 90-day readmission using discharge summary notes, operative notes, nursing notes, physical therapy notes, case management notes, MD/APP notes was 0.70, 0.57, 0.57, 0.60, 0.60, and 0.49 respectively. CONCLUSION In this exploratory analysis, discharge summary, physical therapy, and case management notes had the most utility and daily MD/APP progress notes had the least utility for prediction of 90-day inpatient readmission in lumbar fusion patients among the free-text documentation generated during the index hospitalization.

Background Intrathecal analgesia (IA) has been recommended by the Enhanced Recovery After Surgery (ERAS) Society for laparoscopic colon resections; however, although IA is used in open liver resections, it has not been extensively studied in laparoscopic hepatobiliary surgery. This retrospective chart review was undertaken to explore postoperative pain within 48 hours among patients who underwent laparoscopic liver resections (LLR), receiving either IA with or without patient-controlled analgesia (IA±PCA) versus PCA alone. Methods After ethics approval, charts were reviewed for adult patients who underwent LLR between January 2016 and April 2019, and had IA±PCA or PCA alone. Patients with any contraindication to IA with morphine, obstructive sleep apnea, body mass index >40 kg/m2, history of chronic pain, and/or history of drug use were excluded. Descriptive statistics used to describe postoperative pain levels at 48 hours by treatment group for each pain outcome. Results Of 111 patients identified, 79 patients were finally included; 22 patients had IA±PCA and 57 patients had PCA only. There were no statistically significant differences in baseline characteristics, use of non-opioid pain control, and postoperative complications between the two groups. IA use was associated with reduced postoperative opioid consumption (measured in oral morphine equivalents) compared to PCA alone (mean difference [95% confidence interval] -45.92 [-83.10 to -8.75]; p=0.016). Conclusions IA has the potential to decrease postoperative opioid use for patients undergoing LLR, and appears to be safe and effective in the setting of LLR. These findings are consistent with the ERAS Society recommendations for laparoscopic colorectal surgery.

As post-secondary education migrates online, developing and evaluating new avenues for assessment in anatomy is paramount. Three-dimensional (3D) visualization technology is one area with the potential to augment or even replace resource-intensive cadaver use in anatomical education. This manuscript details the development of a smartphone application, entitled "Virtual Reality Bell-Ringer (VRBR)," capable of displaying monoscopic two-dimensional (2D) or stereoscopic 3D images with the use of an inexpensive cardboard headset for use in spot examinations. Cadaveric image use, creation, and pinning processes are explained, and the source code is provided. To validate this tool, this paper compares traditional laboratory-based spot examination assessment stations against those administered using the VRBR application to test anatomical knowledge. Participants (undergraduate, n = 38; graduate, n = 13) completed three spot examinations specific to their level of study, one in each of the modalities (2D, 3D, laboratory) as well as a mental rotation test (MRT), Stereo Fly stereotest, and cybersickness survey. Repeated measures ANCOVA suggested participants performed significantly better on laboratory and 3D stations compared to 2D stations. Moderate to severe cybersickness symptoms were reported by 63% of participants in at least one category while using the VRBR application. Highest reported symptoms included: eye strain, general discomfort, difficulty focusing, and difficulty concentrating. Overall, the VRBR application is a promising tool for its portability, affordability, and accessibility. Due to reported cybersickness and other technical limitations, the use of VRBR as an alternative to cadaveric specimens presents several challenges when testing anatomy knowledge that must be addressed before widespread adoption.

Despite therapeutic advances for other malignancies, gliomas remain challenging solid tumors to treat. Complete surgical resection is nearly impossible due to gliomas’ diffuse infiltrative nature, and treatment is hampered by restricted access to the tumors due to limited transport across the blood–brain barrier. Recent advances in genomic studies and next-generation sequencing techniques have led to a better understanding of gliomas and identification of potential aberrant signaling pathways. Targeting the specific genomic abnormalities via novel molecular therapies has opened a new avenue in the management of gliomas, with encouraging results in preclinical studies and early clinical trials. However, molecular characterization of gliomas revealed significant heterogeneity, which poses a challenge for targeted therapeutic approaches. In this context, leading neuro-oncology researchers and clinicians, industry innovators, and patient advocates convened at the inaugural annual Remission Summit held in Orlando, FL in February 2019 to discuss the latest advances in immunotherapy and precision medicine approaches for the treatment of adult and pediatric brain tumors and outline the unanswered questions, challenges, and opportunities that lay ahead for advancing the duration and quality of life for patients with brain tumors. Here, we provide historical context for precision medicine in other cancers, present emerging approaches for gliomas, discuss their limitations, and outline the steps necessary for future success. We focus on the advances in small molecule targeted therapy, as the use of immunotherapy as an emerging precision medicine modality for glioma treatment has recently been reviewed by our colleagues.

Background and purpose - Patient-acceptable symptom states (PASS) represent the level on a patient-reported outcome measure (PROM) at which patients are satisfied with postoperative outcomes. We defined the PASS for the Oxford Hip Score (OHS) and Forgotten Joint Score (FJS-12) at 3-month, 1-year, and 2-year intervals after primary total hip arthroplasty (THA).Patients and methods - Between July 2018 and April 2019, primary THA patients in an academic medical center's registry completed the OHS, FJS-12, and a satisfaction anchor question at 3-month (n = 230), 1-year (n = 180), or 2-year (n = 187) postoperative intervals. PASS thresholds were derived with receiver operating characteristic analysis using the 80% specificity method. 95% confidence intervals (CI) were calculated using 1,000 non-parametric bootstrap replications.Results - 74%, 85%, and 86% of patients reported having a satisfactory symptom state at 3 months, 1, and 2 years after surgery, respectively. At 3-month, 1-year, and 2-year intervals, PASS thresholds were 34 (CI 31-36), 40 (CI 36-44), and 39 (CI 35-42) points for the OHS and 59 (CI 54-64), 68 (CI 61-75), and 69 (CI 62-75) points for the FJS-12.Interpretation - PASS thresholds varied with time for both the OHS and the FJS-12, with lower 3-month compared with 1-year and 2-year thresholds. These PASS thresholds represent OHS and FJS-12 levels at which the average patient is satisfied with THA outcomes, helping to interpret PROMs and serving as clinically significant benchmarks and patient-centered outcomes for research.

Male infertility is a common disease. Male infertility is also a core competency of urology training and clinical practice. In this white paper from the Society for the Study of Male Reproduction and the Society for Male Reproduction and Urology, we identify and define different physician productivity plans. We then describe the advantages and disadvantages of various physician productivity measurement systems for male infertility practices. We close with recommendations for measuring productivity that we hope urologists and administrators can use when creating productivity plans for male infertility practices.

Opinion statement Malignant gliomas remain a challenging cancer to treat due to limitations in both therapeutic and efficacious options. Tumor treating fields (TTFields) have emerged as a novel, locoregional, antineoplastic treatment modality with favorable efficacy and safety being demonstrated in the most aggressive type of malignant gliomas, glioblastoma (GBM). In 2 large randomized, controlled phase 3 trials, the addition of TTFields was associated with increased overall survival when combined with adjuvant temozolomide (TMZ) chemotherapy in patients with newly diagnosed GBM (ndGBM) and comparable overall survival compared with standard chemotherapy in patients with recurrent GBM (rGBM). TTFields target cancer cells by several mechanisms of action (MoA) including suppression of proliferation, migration and invasion, disruption of DNA repair and angiogenesis, antimitotic effects, and induction of apoptosis and immunogenic cell death. Having several MoAs makes TTFields an attractive modality to combine with standard, salvage, and novel treatment regimens (e.g., radiotherapy, chemotherapy, and immunotherapy). Treatment within the field of malignant gliomas is evolving to emphasize combinatorial approaches that work synergistically to improve patient outcomes. Here, we review the current use of TTFields in GBM, discuss MOA and treatment delivery, and consider the potential for its wider adoption in other gliomas.

Highlights • Paraneoplastic syndromes are rarely associated with ovarian malignancies. • Paraneoplastic syndromes may be the presenting symptom of an underlying malignancy. • Rheumatologic disorders with unusual presentations may be malignancy related. • These rheumatologic disorders are often refractory to standard treatments.

Facile analysis of the architecture of the mammalian brain is key to understanding how brain function emerges during development and dysregulated in disorders including neurodegeneration. Immunolabeling of mammalian brain tissue, especially scarce human brain tissue, is time-consuming, can introduce sample-to-sample variation, and is not compatible with live imaging. We report joint optimization of polarization-resolved label-free imaging and deep learning to map brain architecture. We visualize diverse structures in human brain tissue by mapping optical properties of density, birefringence, orientation, and scattering. We design computationally efficient variants of U-Nets to predict tract distribution and cell types from intrinsic optical properties of the tissue.

Cortical organoids are self-organizing three-dimensional cultures that model features of the developing human cerebral cortex1,2. However, the fidelity of organoid models remains unclear3-5. Here we analyse the transcriptomes of individual primary human cortical cells from different developmental periods and cortical areas. We find that cortical development is characterized by progenitor maturation trajectories, the emergence of diverse cell subtypes and areal specification of newborn neurons. By contrast, organoids contain broad cell classes, but do not recapitulate distinct cellular subtype identities and appropriate progenitor maturation. Although the molecular signatures of cortical areas emerge in organoid neurons, they are not spatially segregated. Organoids also ectopically activate cellular stress pathways, which impairs cell-type specification. However, organoid stress and subtype defects are alleviated by transplantation into the mouse cortex. Together, these datasets and analytical tools provide a framework for evaluating and improving the accuracy of cortical organoids as models of human brain development.

The etiology of male infertility can often be identified as either genetic, endocrine, or anatomic, and appropriately targeted therapy or alternative conception treatment options can be provided. Idiopathic male infertility is the diagnosis given to patients when no identifiable male infertility factor is found but abnormalities are still present on semen analysis, and this condition is found in 30–40% of all infertile males.

SIGNIFICANCE New promising clinical trials for glioblastoma are evaluating the efficacy of neoadjuvant immunotherapy in the context of recurrent tumor surgery. OBJECTIVE We investigated the effects of neoadjuvant PD1 blockade on the glioma tumor microenvironment in a clinically relevant murine model of recurrent tumor. RESULTS Using an orthotopic mouse KR158 resection model of glioblastoma that we have established, we show that neoadjuvant anti-PD1 and surgery enhance animal survival and increase the recruitment of CD8+ and CD4+ T cells at recurrent tumor sites following bulk tumor resection compared to surgery followed by adjuvant immunotherapy. Transcriptome and spatial genomic analyses reveal alterations in immune exhaustion and activation pathway signaling after neoadjuvant anti-PD1treatment when compared with adjuvant anti-PD1-treatment or surgery alone. CONCLUSIONS These results provide insights into the effects of neoadjuvant PD1 blockade on the tumor microenvironment and uncover additional treatment targets.

Background: Inflammatory myofibroblastic tumor is a rare, poorly understood tumor that has been found to occur in almost every organ tissue. Its location within the central nervous system is uncommon, and patients tend to present with nonspecific symptoms. Case Description: A female in her eighth decade presented to neurosurgery clinic with complaints of headache and dizziness. Initial imaging was consistent with a low-grade, benign brain lesion in the region of the left choroidal fissure. She was recommended for observation but returned 1 month later with progressive symptoms and doubling of the lesion size. She underwent surgical resection and was found to have an IMT arising from the wall of the left anterior choroidal artery. Conclusion: Intracranial IMT remains a rare and poorly understood entity. The present case demonstrates a novel presentation of IMT in an adult patient and exemplifies the heterogeneity of the disease presentation.

Strategies for improving value-based healthcare in anterior cervical discectomy and fusion (ACDF) include a shift towards outpatient procedures. The primary outcomes was prolonged length of stay defined as length of stay greater than one day. Overall, 2917 patients underwent ACDF, of which 35.2% (n = 1027) had length of stay greater than one day. The variables used for prediction of prolonged LOS were age, sex, marital status, private insurance, myelopathy, patient-reported drug allergies, presence of at least one medical comorbidity, preoperative medications, and preoperative laboratory values. These models may be helpful for triaging the patients most likely to benefit from outpatient ACDF.

Deep learning is increasingly impactful for healthcare research and delivery. In orthopaedics, there has been a significant increase in the number of publications using deep learning for interpreting radiographs; however, there are only a few applications of deep learning specific to spine surgery. In this review, we discuss the potential of deep learning within spine surgery in four contexts: diagnosis (1), prognosis (2), patient management (3) and integration with virtual/augmented reality, robotic surgery and biomedical wearables (4). Additionally, we discuss current literature, future potentials and provide takeaways for clinicians who wish to apply deep learning in their research and practice.

INTRODUCTION AND OBJECTIVES:For the estimated 15 million cancer survivors in the United States, access to accurate information regarding quality of life issues such as fertility preservation and se...

Objective To characterize the referral patterns and characteristics of men presenting for infertility evaluation using data obtained from the Andrology Research Consortium. Design Standardized male infertility questionnaire. Setting Male infertility centers. Patient(s) Men presenting for fertility evaluation. Intervention(s) Not applicable. Main Outcome Measure(s) Demographic, infertility history, and referral data. Result(s) The questionnaires were completed by 4,287 men, with a mean male age of 40 years ± 7.4 years and female partners age of 37 years ± 4.9 years. Most were Caucasian (54%) with other races being less commonly represented (Asian 18.6%, and African American 5.5%). The majority (59.7%) were referred by a reproductive gynecologist, 19.4% were referred by their primary care physician, 4.2% were self-referred, and 621 (14.5%) were referred by “other.” Before the male infertility investigation, 12.1% of couples had undergone intrauterine insemination, and 4.9% of couples had undergone in vitro fertilization (up to six cycles). Among the male participants, 0.9% reported using finasteride (5α-reductase inhibitor) at a dose used for androgenic alopecia, and 1.6% reported exogenous testosterone use. Conclusion(s) This broad North American patient survey shows that reproductive gynecologists are the de facto gateway for most male infertility referrals, with most men being assessed in the male infertility service being referred by reproductive endocrinologists. Some of the couples with apparent male factor infertility are treated with assisted reproductive technologies before a male factor investigation. The survey also identified potentially reversible causes for the male infertility including lifestyle factors such as testosterone and 5α-reductase inhibitor use.

Deep brain stimulation surgery has become the treatment of choice for appropriately selected patients with Parkinson’s disease, essential tremor, and dystonia. Despite the significant risk associated with minimally invasive brain surgery, the risk-to-benefit ratio for DBS surgery is quite favorable, and the overwhelming majority of patients derive substantial improvement in their motor function and quality of life from well-executed DBS therapy. A nonnegligible number of movement disorders patients, however, report unsatisfactory outcomes after DBS surgery. If we define “DBS failure” as any case in which the patient and her/his caregivers are dissatisfied with the outcome of DBS surgery, then potential causes of DBS failure include failure to set appropriate expectations preoperatively, inappropriate patient selection, failures of postoperative device programming and medical management, in addition to various surgical and device-related complications including suboptimal lead placement, hardware failures, and rare instances of procedure-related brain injury resulting in permanent neurologic impairment. In this chapter, we focus on the various causes of DBS failure that are potentially correctable through surgical intervention. We review methods for evaluating patients presenting with DBS failure to identify appropriate candidates for various surgical salvage procedures, and we present successful decision-making strategies and surgical techniques for carrying out these operations.

Summary Gene Ontology analyses of autism spectrum disorders (ASD) risk genes have repeatedly highlighted synaptic function and transcriptional regulation as key points of convergence. However, these analyses rely on incomplete knowledge of gene function across brain development. Here we leverage Xenopus tropicalis to study in vivo ten genes with the strongest statistical evidence for association with ASD. All genes are expressed in developing telencephalon at time points mapping to human mid-prenatal development, and mutations lead to an increase in the ratio of neural progenitor cells to maturing neurons, supporting previous in silico systems biological findings implicating cortical neurons in ASD vulnerability, but expanding the range of convergent functions to include neurogenesis. Systematic chemical screening identifies that estrogen, via Sonic hedgehog signaling, rescues this convergent phenotype in Xenopus and human models of brain development, suggesting a resilience factor that may mitigate a range of ASD genetic risks.

X-linked dystonia-parkinsonism (XDP) is a hereditary neurodegenerative disorder involving a progressive loss of striatal medium spiny neurons. The mechanisms underlying neurodegeneration are not known, in part because there have been few cellular models available for studying the disease. The XDP haplotype consists of multiple sequence variations in a region of the X chromosome containing TAF1, a large gene with at least 38 exons, and a multiple transcript system (MTS) composed of five unconventional exons. A previous study identified an XDP-specific insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon in intron 32 of TAF1, as well as a neural-specific TAF1 isoform, N-TAF1, which showed decreased expression in post-mortem XDP brain compared with control tissue. Here, we generated XDP patient and control fibroblasts and induced pluripotent stem cells (iPSCs) in order to further probe cellular defects associated with this disease. As initial validation of the model, we compared expression of TAF1 and MTS transcripts in XDP versus control fibroblasts and iPSC-derived neural stem cells (NSCs). Compared with control cells, XDP fibroblasts exhibited decreased expression of TAF1 transcript fragments derived from exons 32-36, a region spanning the SVA insertion site. N-TAF1, which incorporates an alternative exon (exon 34′), was not expressed in fibroblasts, but was detectable in iPSC-differentiated NSCs at levels that were ∼threefold lower in XDP cells than in controls. These results support the previous findings that N-TAF1 expression is impaired in XDP, but additionally indicate that this aberrant transcription might occur in neural cells at relatively early stages of development that precede neurodegeneration., Summary: This study describes a new iPSC model of X-linked dystonia-parkinsonism (XDP), which was initially validated by demonstrating a similar transcriptional defect as has been previously reported in XDP brain tissue.