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Introduction: Diabetes belongs to the chronic disease group with an average high prevalence rate of 463 million worldwide. This research aims to investigate factors associated with self-care behavior among elderly patients with type 2 diabetes. Methods: The sample included 441 patients diagnosed with diabetes admitted to the Tambon Health Promoting Hospital in Nakhon Nayok Province. The sample size used in this study was calculated according to the sampling group of Yamane with a 95% confidence level. Data were analyzed by descriptive statistics, correlation coefficients, and multiple regression analysis at the statistical significance level of 0.05. Results: The results showed that the average value of knowledge was 9.17 (SD=2.38), and the average values of attitude and social support behavior towards diabetes were 2.72 (SD=0.64) and 1.83 (SD=0.27), respectively. The results indicated that knowledge, attitude, and social support towards diabetes showed an average of a medium level. Moreover, the average value of self-care behavior towards diabetes was 30.52 (SD= 7.19). The results indicated that the knowledge about diabetes, attitude towards diabetes, and social support towards diabetes positively affected self-care behavior towards diabetes with the statistical significance of 0.05. Conclusion: Health promotion programs for patients with diabetes should be organized to promote knowledge and awareness on proper health behavior. In order to take care of themselves, diabetic patients must first get awareness regarding diabetes and then build skills for self-care. The results obtained in the study can help diabetic patients stay healthier, reduce the manifestation of both acute and chronic complications, and improve the quality of life of the elderly with diabetes.

The neocortex is disproportionately expanded in human compared with mouse1,2, both in its total volume relative to subcortical structures and in the proportion occupied by supragranular layers composed of neurons that selectively make connections within the neocortex and with other telencephalic structures. Single-cell transcriptomic analyses of human and mouse neocortex show an increased diversity of glutamatergic neuron types in supragranular layers in human neocortex and pronounced gradients as a function of cortical depth3. Here, to probe the functional and anatomical correlates of this transcriptomic diversity, we developed a robust platform combining patch clamp recording, biocytin staining and single-cell RNA-sequencing (Patch-seq) to examine neurosurgically resected human tissues. We demonstrate a strong correspondence between morphological, physiological and transcriptomic phenotypes of five human glutamatergic supragranular neuron types. These were enriched in but not restricted to layers, with one type varying continuously in all phenotypes across layers 2 and 3. The deep portion of layer 3 contained highly distinctive cell types, two of which express a neurofilament protein that labels long-range projection neurons in primates that are selectively depleted in Alzheimer’s disease4,5. Together, these results demonstrate the explanatory power of transcriptomic cell-type classification, provide a structural underpinning for increased complexity of cortical function in humans, and implicate discrete transcriptomic neuron types as selectively vulnerable in disease., Combined patch clamp recording, biocytin staining and single-cell RNA-sequencing of human neurocortical neurons shows an expansion of glutamatergic neuron types relative to mouse that characterizes the greater complexity of the human neocortex.

Packed red blood cell (PRBC) transfusions are commonly administered in pediatric patients following the Norwood operation. This study was conducted to determine the effect of PRBC transfusions on hemodynamic parameters in pediatric patients with single-ventricle physiology and parallel circulation. A single-center, retrospective chart review was conducted. Pediatric patients admitted to the cardiac intensive care unit after Norwood operation between 2017 and 2018 were identified. Hemodynamic parameters were collected within a four-hour period before and after a PRBC transfusion. Univariate analyses using paired t tests were conducted to compare blood gas values before and after PRBC transfusion. Next, multivariate regression analyses were conducted to model the impact of transfusion volume, change in hemoglobin levels, and change in FiO2 on the change in PaO2 and PaCO2. These analyses included data from 33 eligible patients who received a PRBC transfusion following a Norwood operation. The hemoglobin levels (p

The amygdala is a medial temporal lobe structure known to be involved in processing emotional conflict. However, its role in processing non-emotional conflict is not well understood. Previous studies have utilized the Stroop Task to examine brain modulation of humans under the color-word conflict scenario, which is non-emotional conflict processing, and found hippocampal theta-band (4-7 Hz) modulation. This study aims to survey amygdaloid theta power changes during non-emotional conflict processing using intracranial depth electrodes in nine epileptic patients (3 female; age 20-62). All patients were asked to perform a modified Stroop task. During task performance, local field potential (LFP) data was recorded from macro contacts sampled at 2 K Hz and used for analysis. Mean theta power change from baseline was compared between the incongruent and congruent task condition groups using a paired sample t-test. Seven patients were available for analysis after artifact exclusion. In five out of seven patients, statistically significant increases in theta-band power from baseline were noted during the incongruent task condition (paired sample t-test p 0.001), including one patient exhibiting theta power increases in both task conditions. Average response time was 1.07 s (failure trials) and 1.04 s (success trials). No speed-accuracy tradeoff was noted in this analysis. These findings indicate that human amygdaloid theta-band modulation may play a role in processing non-emotional conflict. It builds directly upon work suggesting that the amygdala processes emotional conflict and provides a neurophysiological mechanism for non-emotional conflict processing as well.

Background: Aortic cusp extension is a technique for aortic valve (AV) repairs in pediatric patients. The choice of the material used in this procedure may influence the time before reoperation is required. We aimed to assess post-operative and long-term outcomes of patients receiving either pericardial or synthetic repairs. Methods: We conducted a single center, retrospective study of pediatric patients undergoing aortic cusp extension valvuloplasty (N=38) with either autologous pericardium (n=30) or CorMatrix (n=8) between April 2009 and July 2016. Short and long-term postoperative outcomes were compared between the two groups. Freedom from reoperation was compared using Kaplan Meier analysis. Degree of aortic stenosis (AS) and aortic regurgitation (AR) were recorded at baseline, post-operatively, and at outpatient follow-up. Results: At five years after repair, freedom from reoperation was significantly lower in the CorMatrix group (12.5%) compared to the pericardium group (62.5%) (P = 0.01). For the entire cohort, there was a statistically significant decrease in the peak trans-valvar gradient between pre- and post-operative assessments with no significant change at outpatient follow-up. In the pericardium group, 28 (93%) had moderate to severe AR at baseline which improved to 11 (37%) post-operatively and increased to 21 (70%) at time of follow-up. In the biomaterial group, 8 (100%) had moderate to severe AR which improved to 3 (38%) post-operatively and increased to 7 (88%) at time of follow-up. Conclusion: In terms of durability, the traditional autologous pericardium may outperform the new CorMatrix for AV repairs using the cusp extension method.

Objective: Coherence between the hippocampus and other brain structures has been shown with the theta frequency (3–8 Hz). Cortical decreases in theta coherence are believed to reflect response accuracy efficiency. However, the role of theta coherence during conflict resolution is poorly understood in noncortical areas. In this study, coherence between the hippocampus and orbitofrontal cortex (OFC) was measured during a conflict resolution task. Although both brain areas have been previously implicated in the Stroop task, their interactions are not well understood. Methods: Nine patients were implanted with stereotactic electroencephalography contacts in the hippocampus and OFC. Local field potential data were sampled throughout discrete phases of a Stroop task. Coherence was calculated for hippocampal and OFC contact pairs, and coherence spectrograms were constructed for congruent and incongruent conditions. Coherence changes during cue processing were identified using a nonparametric cluster-permutation t test. Group analysis was conducted to compare overall theta coherence changes among conditions. Results: In 6 of 9 patients, decreased theta coherence was observed only during the incongruent condition (P < 0.05). Congruent theta coherence did not change from baseline. Group analysis showed lower theta coherence for the incongruent condition compared with the congruent condition (P < 0.05). Conclusions: Theta coherence between the hippocampus and OFC decreased during conflict. This finding supports existing theories that theta coherence desynchronization contributes to improved response accuracy and processing efficiency during conflict resolution. The underlying theta coherence observed between the hippocampus and OFC during conflict may be distinct from its previously observed role in memory.

Introduction: Spleen angiosarcoma (SA) is a rare malignant neoplasm that arises from the splenic vascular endothelium, with only around 300 cases reported to date. Due to a limited number of reported cases, there is a paucity of data and a lack of understanding of its presentation, diagnosis, and management. In this study, we aim to provide a comprehensive review of SA. Areas covered: On 27 February 2021, a literature search was done in PubMed and Embase database. The search yielded 122 articles involving 205 patients. The focus was on patient demographics, risk factors, clinical presentations, investigation results, preliminary diagnoses, therapies provided, and patient outcomes. These factors were analyzed to identify possible risk factors, diagnostic modalities, and therapeutic principles that were not mentioned before. Expert opinion: The clinical presentation or investigation results of patients with SA are often nonspecific. Hence, they may not be sufficient to clinch the diagnosis of SA if used alone. The authors recommend a triple assessment of clinical examination, imaging findings, and pathology to diagnose SA with high accuracy. Splenectomy should be the mainstay of management, with chemotherapy and radiotherapy considered as adjuncts, especially in the presence of metastases.

Objective Textural differences between entheses reflect biomechanical activities of the musculoskeletal system. Methods used to measure these surfaces have limitations. Here, the surface metrology of roughness of articular and entheseal surfaces of the knee are investigated with an optical profiler. Methods Osteological specimens of six femora and seven tibiae were prepared from cadavers. Measurements were obtained to surrogate body mass. Specimens were molded with polyvinylsiloxane and casts prepared with resin, which were scanned using a white light optical profiler. Scans were processed by a computer program. Each scan produced 32 variables, categorized into 6 groups for each location. Results The distribution of data was mostly normal. ANOVA identified Ssk significant (p-value 0.002); post hoc Tukey testing indicated significance between femoral PCL and tibial ACL entheses groups (p-value 0.007), and between tibial ACL and tibial entheses groups (p-value 0.002) suggesting the ability to differentiate anterior and posterior cruciate ligament entheses. Sku was found significant with a T-test between articular and entheseal surfaces. Correlation coefficients were significant between surface metrology parameters and measurements related to body mass. Conclusions This study distinguished differences between entheses of the anterior and posterior cruciate ligaments, with the Ssk parameter most useful. Differences in articular and entheseal surfaces were found with the Sku parameter most useful. Correlations indicated a relationship between body mass and surface metrology parameters. Lastly, these findings suggest this method can be used for further investigation of spondyloarthropathies. This article is protected by copyright. All rights reserved.

SARS-CoV-2, the virus that causes COVID-19, is constantly mutating, leading to new variants (1). Variants have the potential to affect transmission, disease severity, diagnostics, therapeutics, and natural and vaccine-induced immunity. In November 2020, CDC established national surveillance for SARS-CoV-2 variants using genomic sequencing. As of May 6, 2021, sequences from 177,044 SARS-CoV-2-positive specimens collected during December 20, 2020-May 6, 2021, from 55 U.S. jurisdictions had been generated by or reported to CDC. These included 3,275 sequences for the 2-week period ending January 2, 2021, compared with 25,000 sequences for the 2-week period ending April 24, 2021 (0.1% and 3.1% of reported positive SARS-CoV-2 tests, respectively). Because sequences might be generated by multiple laboratories and sequence availability varies both geographically and over time, CDC developed statistical weighting and variance estimation methods to generate population-based estimates of the proportions of identified variants among SARS-CoV-2 infections circulating nationwide and in each of the 10 U.S. Department of Health and Human Services (HHS) geographic regions.* During the 2-week period ending April 24, 2021, the B.1.1.7 and P.1 variants represented an estimated 66.0% and 5.0% of U.S. SARS-CoV-2 infections, respectively, demonstrating the rise to predominance of the B.1.1.7 variant of concern† (VOC) and emergence of the P.1 VOC in the United States. Using SARS-CoV-2 genomic surveillance methods to analyze surveillance data produces timely population-based estimates of the proportions of variants circulating nationally and regionally. Surveillance findings demonstrate the potential for new variants to emerge and become predominant, and the importance of robust genomic surveillance. Along with efforts to characterize the clinical and public health impact of SARS-CoV-2 variants, surveillance can help guide interventions to control the COVID-19 pandemic in the United States.

BACKGROUND & AIMS Bariatric surgery is common, but alcohol misuse has been reported following these procedures. We aimed to determine if bariatric surgery is associated with increased risk of alcohol-related cirrhosis (AC) and alcohol misuse. METHODS Retrospective observational analysis of obese adults with employer-sponsored insurance administrative claims from 2008 to 2016. Subjects with diagnosis codes for bariatric surgery were included. Primary outcome was risk of AC. Secondary outcome was risk of alcohol misuse. Bariatric surgery was divided into before 2008 and after 2008 to account for patients who had a procedure during the study period. Cox proportional hazard regression models using age as the time variable were used with interaction analyses for bariatric surgery and gender. RESULTS A total of 194 130 had surgery from 2008 to 2016 while 209 090 patients had bariatric surgery prior to 2008. Age was 44.1 years, 61% women and enrolment was 3.7 years. A total of 4774 (0.07%) had AC. Overall risk of AC was lower for those who received sleeve gastrectomy and laparoscopic banding during the study period (HR 0.4, P

BACKGROUND Our study examined some of the social and medical factors associated with receiving pain palliation alone over more aggressive cytoreductive palliative measures, such as surgery, chemotherapy, or radiation among patients with head and neck cancer. METHODS This retrospective study used the National Cancer Database 2016 for data analysis. Patient and tumor characteristics were examined using bivariate analysis and logistic regression to identify their association with receiving pain palliation alone versus cytoreductive palliation treatment. RESULTS Using multivariate logistic regression analysis, insurance status (odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.15-0.50, p

Intracortical microstimulation in human primary somatosensory cortex has been used to successfully evoke naturalistic sensations. However, the neurophysiological mechanisms underlying the evoked sensations remain unknown. To understand how specific stimulation parameters elicit certain sensations we must first understand the representation of those sensations in the brain. In this study we record from intracortical microelectrode arrays implanted in primary somatosensory cortex, pre-motor cortex and posterior parietal cortex of a male human participant performing a somatosensory imagery task. The sensations imagined were those previously elicited by intracortical microstimulation of primary somatosensory cortex, in the same array of the same participant. In both spike and local field potential recordings, features of the neural signal can be used to classify different imagined sensations. These features are shown to be stable over time. The sensorimotor cortices only encode the imagined sensation during the imagery task, while posterior parietal cortex encodes the sensations starting with cue presentation. These findings demonstrate that different aspects of the sensory experience can be individually decoded from intracortically recorded human neural signals across the cortical sensory network. Activity underlying these unique sensory representations may inform the stimulation parameters for precisely eliciting specific sensations via intracortical microstimulation in future work. SIGNIFICANCE STATEMENT Electrical stimulation of human cortex is increasingly more common for providing feedback in neural devices. Understanding the relationship between naturally evoked and artificially evoked neurophysiology for the same sensations will be important in advancing such devices. Here we investigate the neural activity in human primary somatosensory, pre-motor, and parietal cortices during somatosensory imagery. The sensations imagined were those previously elicited during intracortical microstimulation of the same somatosensory electrode array. We elucidate the neural features during somatosensory imagery that significantly encode different aspects of individual sensations and demonstrate feature stability over almost a year. The correspondence between neurophysiology elicited with or without stimulation for the same sensations will inform methods to deliver more precise feedback through stimulation in the future.

INTRODUCTION Young adults with alcohol-associated liver disease (ALD) are the fastest increasing demographic contributing to liver-related deaths; their outcomes after liver transplantation (LT) are understudied. METHODS Using the United Network for Organ Sharing registry, we performed sex-specific analyses because of a significant interaction between sex and the explanatory variable, age. Cox regression was used with overall post-LT death as the primary outcome, adjusted for survival characteristics and center clustering. We calculated the absolute difference in adjusted 5-year post-LT survival between patient groups. Causes of death were supplemented by manual review of free-text entries. RESULTS Among 42,014 LT recipients, 16,190 women (2,782 with ALD and 13,408 without ALD) and 25,824 men (9,502 with ALD and 16,322 without ALD), age of 40-50 years had the lowest risk of death. Women with ALD younger than 40 years had incrementally lower adjusted 5-year survival (95% confidence interval): 74% (63%-88%) for those aged 18-29 years, 82% (78%-87%) for those aged 30-39 years, and 90% (88%-92%) for those aged 40-49 years. Among women without ALD, men with ALD, and men without ALD, adjusted 5-year survival for ages 18-29, 30-39, and 40-49 years was similar. Among women, not men, there were significant interactions between younger age and ALD. Adjusted hazard for mortality for women with ALD vs without ALD was greater for those who aged 18-29 years (2.82 vs 1.09, P = 0.002) and 30-39 years (1.83 vs 1.09, P = 0.007 [reference age 40-49 years]). Among women with ALD, those aged 18-29 and 30-39 years had an absolute 17.7% and 9.5% excess in adjusted 5-year mortality vs similarly aged women without ALD. DISCUSSION Young women (age < 40) with ALD have excess mortality beyond one-year post-LT. Recurrent disease or explicit mention of alcohol was the most common identified cause of death in this demographic.

Expression of Concern: Medical Acupuncture issues an Expression of Concern pertaining to a published article in the October 2021 issue of the journal entitled, “Self-Administration of Auricular Acu...

Background Acromioclavicular (AC) separations are commonly seen shoulder injuries. Numerous surgical reconstruction techniques have been described. In this study, we present a series of patients who underwent an anatomic reconstruction using a synthetic ligament and allograft construct. Methods We performed a retrospective review of patients with type IV or V AC separations who underwent primary or revision AC reconstruction with a luggage-tag synthetic ligament and a semitendinosus allograft placed through the anatomic insertion sites of the coracoclavicular ligaments. Patient-reported outcomes, as well as complication rates, were recorded at a minimum 2-year follow-up. Results Ten patients with a mean age of 44.2 ± 14.9 years were included in the study. The mean Disabilities of the Arm, Shoulder and Hand score was 15.5 ± 15.4; mean Single Assessment Numeric Evaluation score, 81.8 ± 12.1; mean Simple Shoulder Test score, 11.4 ± 1.1; mean American Shoulder and Elbow Surgeons score, 84.6 ± 15.7; mean Constant score, 82.5 ± 11.6; and mean visual analog scale score, 2 ± 2.6. Conclusion The technique using a luggage-tag synthetic ligament along with an anatomic allograft coracoclavicular ligament reconstruction is a safe, effective alternative to other techniques described in the literature.

Background This study evaluated the presence of the rotator cable intraoperatively and compared its prevalence according to both patient age and rotator cuff integrity. The study hypothesis was that the cable would be more prevalent in older patients and patients with partial-thickness tears. Methods Patients who were undergoing shoulder arthroscopy and were aged at least 16 years were included in this study, whereas those who had a cuff tear of more than 1 tendon or who had a video with poor visualization of the rotator cuff insertion were excluded. Intraoperative videos were collected, deidentified, and distributed to 7 orthopedic surgeons to define rotator cable and cuff tear characteristics. Results A total of 58 arthroscopic videos (average patient age, 46 years; range, 16-75 years) were evaluated. The observers were in the most agreement on identifying the presence of a cable, with a κ coefficient of 0.276. Patients with the rotator cable were significantly older than those without it (mean age, 52.1 years vs. 42.5 years; P = .008), and a positive and significant correlation was found between rotator cable presence and increasing patient age (r = 0.27, P = .04). A significant association was noted between tear degree and cable presence (P = .002). There was no significant association with cable presence in patients with a full-thickness tear. Conclusions In this study, an intraoperative analysis was performed to define the presence of the rotator cable and correlate this with both patient age and rotator cuff integrity. The hypothesis was confirmed in that patients older than 40 years had a significantly higher rotator cable prevalence.

Introduction The passage of Senate Bill 493 (SB 493) granted California pharmacists the ability to order and interpret lab tests without physician approval. Despite this legislation, not all pharmacists are aware of, or exercise, this authority. The goals of this study are to describe 1) pharmacists' willingness, 2) perceived factors influencing pharmacist preparedness, and 3) challenges and barriers to ordering laboratory tests in the community setting. Methods This is a prospective, descriptive survey study that was performed using online survey software from August 31, 2017, to October 4, 2017. An anonymous link was distributed to California pharmacists via California Society of Health-System Pharmacists (CSHP) and California Pharmacists Association (CPhA) email newsletters. Additionally, targeted interviews of pharmacists were conducted by phone to qualitatively assess barriers as well as successful practices. Institutional Review Board (IRB) approval was obtained prior to initiating the study. Results Sixty-six pharmacist respondents completed the online survey. The reported two biggest barriers to ordering lab tests identified by community pharmacists were 1) lack of available time and 2) compensation structure. Despite these barriers, most pharmacists were willing to order and interpret laboratory tests and accept the liability, regardless of a reimbursement guarantee. Conclusions Community pharmacists self-report preparedness to order and interpret laboratory tests. Barriers in carrying out this task include lack of staff, resources, compensation, and reimbursement structure.

Background and aimsIn some states, liver transplantation (LT) for alcohol-associated liver disease (ALD) is covered by Medicaid only with documentation of abstinence and/or alcohol rehabilitation. Different Medicaid policies may affect the distribution of LT for ALD, particularly post-2011, as centers have adopted early (i.e., specific abstinence period not required) LT practices.Approach and resultsWe surveyed Medicaid policies in all states actively performing LT and linked state policies to prospectively collected national registry data on LT recipients from 2002 to 2017 with ALD as the primary listing diagnosis. We categorized Medicaid policies for states as "restrictive" (requiring documentation of a specific abstinence period and/or rehabilitation) versus "unrestrictive" (deferring to center eligibility policies). Difference-of-differences analysis, comparing 2002-2011 versus 2012-2017, evaluated whether restrictive policies were associated with decreased proportion of LTs paid by Medicaid among patients with ALD post-2011. We performed sensitivity analyses to account for any differences by diagnosis of hepatocellular carcinoma, hepatitis C virus, nonalcoholic steatohepatitis, or Medicare insurance. We also performed a sensitivity analysis to account for any difference by prevalence of ALD among restrictive versus unrestrictive states. Of 10,836 LT recipients in 2002-2017, 7,091 were from 24 states in the restrictive group and 3,745 from 14 states in the unrestrictive group. The adjusted proportion (95% confidence interval) of LTs paid by Medicaid among restrictive versus unrestrictive states between 2002 and 2011 was 17.6% (15.4%-19.8%) versus 18.9% (15.4%-22.3%) (P=0.54) and between 2012 and 2017, 17.2% (14.7%-19.7%) versus 23.2% (19.8%-26.6%) (P=0.005). In difference-of-differences analysis, restrictive (versus unrestrictive) policies were associated with a 4.7% (0.8%-8.6%) (P=0.02) absolute lower adjusted proportion of LTs for ALD paid by Medicaid post-2011.ConclusionsRestrictive Medicaid policies are present in most states with active LT centers and are associated with lower proportions of LTs for ALD paid by Medicaid post-2011 compared to states with unrestrictive Medicaid policies. Reevaluation of Medicaid alcohol use policies may be warranted, to align more closely with contemporary center-level practices.

Background Clinicians cannot reliably predict complications of acute hematogenous osteomyelitis (AHO). Methods Consecutive cases of AHO from 2 pediatric centers in the United States were analyzed retrospectively to develop clinical tools from data obtained within 96 hours of hospitalization to predict acute and chronic complications of AHO. Two novel composite prediction scores derived from multivariable logistic regression modeling were compared with a previously published severity of illness (SOI) score, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) using area under the receiver operating characteristic curve analyses. Results The causative organisms were identified in 73% of 261 cases. Bacteremia (45%), abscesses (38%), and associated suppurative arthritis (23%) were relatively common. Acute or chronic complications occurred in 24% and 11% of patients, respectively. Multivariable logistic regression identified bone abscess (odds ratio [OR], 2.3 [95% confidence interval {CI}, 1.0–5.2]), fever > 48 hours (OR, 2.7 [95% CI, 1.2–6.0]), suppurative arthritis (OR, 3.2 [95% CI, 1.3–7.5]), disseminated disease (OR, 4.6 [95% CI, 1.5–14.3]), and delayed source control (OR, 5.1 [95% CI, 1.4–19.0]) as strong predictors of acute complications. In a separate model, CRP ≥ 100 mg/L at 2–4 days after antibiotics (OR, 2.7 [95% CI, 1.0–7.3]), disseminated disease (OR, 3.3 [95% CI, 1.1–10.0]), and requirement for bone debridement (OR, 6.7 [95% CI, 2.1–21.0]) strongly predicted chronic morbidity. These variables were combined to create weighted composite prediction scores for acute (A-SCORE) and chronic (C-SCORE) osteomyelitis, which were superior to SOI, CRP, and ESR and had negative predictive values > 90%. Conclusions Two novel composite clinical scores were superior to existing tools to predict complications of pediatric AHO.

Viruses have long been implicated as potential triggers of autoimmune disease. In the case of pemphigus vulgaris, members of the herpesviridae family are often associated with its development. There have also been reports of pemphigus being triggered by the influenza vaccine. We report a case of a 17-year-old male who developed mucous membrane-predominant pemphigus vulgaris after testing positive for the influenza virus and discuss proposed hypotheses for the association between viral infections and autoimmunity, such as molecular mimicry and epitope spreading.

Interstitial brachytherapy (IBT) is often utilized to treat women with bulky endometrial or cervical cancers not amendable to intracavitary treatments. A modern trend in IBT is the utilization of magnetic resonance imaging (MRI) with a high dose rate (HDR) afterloader for conformal 3D image‐based treatments. The challenging part of this procedure is to properly complete many sequenced and co‐related physics preparations. We presented the physics preparations and clinical workflow required for implementing MRI‐based HDR IBT (MRI‐HDR‐IBT) of gynecologic cancer patients in a high‐volume brachytherapy center. The present document is designed to focus on the clinical steps required from a physicist’s standpoint. Those steps include: (a) testing IBT equipment with MRI scanner, (b) preparation of templates and catheters, (c) preparation of MRI line markers, (d) acquisition, importation and registration of MRI images, (e) development of treatment plans and (f) treatment evaluation and documentation. The checklists of imaging acquisition, registration and plan development are also presented. Based on the TG‐100 recommendations, a workflow chart, a fault tree analysis and an error‐solution table listing the speculated errors and solutions of each step are provided. Our workflow and practice indicated the MRI‐HDR‐IBT is achievable in most radiation oncology clinics if the following equipment is available: MRI scanner, CT (computed tomography) scanner, MRI/CT compatible templates and applicators, MRI line markers, HDR afterloader and a brachytherapy treatment planning system capable of utilizing MRI images. The OR/procedure room availability and anesthesiology support are also important. The techniques and approaches adopted from the GEC‐ESTRO (Groupe Européen de Curiethérapie ‐ European Society for Therapeutic Radiology and Oncology) recommendations and other publications are proven to be feasible. The MRI‐HDR‐IBT program can be developed over time and progressively validated through clinical experience, this document is expected to serve as a reference workflow guideline for implementing and performing the procedure.

Implantable neurostimulation devices provide a direct therapeutic link to the nervous system and can be considered brain-computer interfaces (BCI). Under this definition, BCI are not simply science fiction, they are part of existing neurosurgical practice. Clinical BCI are standard of care for historically difficult to treat neurological disorders. These systems target the central and peripheral nervous system and include Vagus Nerve Stimulation, Responsive Neurostimulation, and Deep Brain Stimulation. Recent advances in clinical BCI have focused on creating "closed-loop" systems. These systems rely on biomarker feedback and promise individualized therapy with optimal stimulation delivery and minimal side effects. Success of clinical BCI has paralleled research efforts to create BCI that restore upper extremity motor and sensory function to patients. Efforts to develop closed loop motor/sensory BCI is linked to the successes of today's clinical BCI.

Summary Background The expansion of the Medicaid public health insurance programme has varied by state in the USA. Longer-term mortality and factors associated with variability in outcomes after Medicaid expansion are under-studied. We aimed to investigate the association of state Medicaid expansion with all-cause mortality. Methods This was a population-based, national, observational cohort study capturing all reported deaths among adults aged 25–64 years via death certificate data in the Centers for Disease Control and Prevention's Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) database in the USA from Jan 1, 2010, to Dec 31, 2018. We obtained national demographic and mortality data for adults aged 25–64 years, and state-level demographics and 2010–18 mortality estimates for the overall population by linking federally maintained registries (CDC WONDER, Behavioral Risk Factor Surveillance System, Health Resources and Services Administration, US Census Bureau, and Bureau of Labor Statistics). States were categorised as Medicaid expansion or non-expansion states as classified by the Kaiser Family Foundation. Multivariable difference-in-differences analysis assessed the absolute difference in the annual, state-level, all-cause mortality per 100 000 adults after Medicaid expansion. Findings Among 32 expansion states and 17 non-expansion states, Medicaid expansion was associated with reductions in all-cause mortality (−11·8 deaths per 100 000 adults [95% CI −21·3 to −2·2]). There was variability in changes in all-cause mortality associated with Medicaid expansion by state (ranging from −63·8 deaths per 100 000 adults [95% CI −134·1 to −42·9] in Delaware to 30·4 deaths per 100 000 adults [–39·8 to 51·4] in New Mexico). State-level proportions of women (−17·8 deaths per 100 000 adults [95% CI −26·7 to −8·8] for each percentage point increase in women residents) and non-Hispanic Black residents (−1·4 deaths per 100 000 adults [–2·4 to −0·3] for each percentage point increase in non-Hispanic Black residents) were associated with greater adjusted reductions in all-cause mortality among expansion states. Interpretation After 4 years of implementation, Medicaid expansion remains associated with significant reductions in all-cause mortality, but reductions are variable by state characteristics. These results could inform policy makers to provide broad-based equitable improvements in health outcomes. Funding University of Southern California Research Center for Liver Diseases.

mHealth apps for patient use are promising but continue to face a plateau in usage. Current apps work for a limited segment of the patient population, i.e., those who enjoy tracking for intrinsic rewards. There are many opportunities to support patient care in between health care provider visits that are not currently being met for many diseases and patient types (personas). This is an area of great potential growth for mHealth apps and could contribute greatly to patient health and wellness. In this chapter, we propose a framework for how to think about the between-visit needs of patients that would motivate continued use of mhealth apps. We view the app design process from the following perspectives: 1) disease-specific needs, 2) non-disease specific needs, 3) behavioral theoretical aspects of app usage and 4) app-intrinsic usage motivators. Myasthenia gravis serves as the use case for illustrating these perspectives and how to use them in designing a disease-specific mHealth app.

BACKGROUND The treatment of glioblastoma (GBM) poses many challenges. The use of immune checkpoint inhibition (ICI) has been disappointing as GBM is characterized by a low mutational burden and low infiltration by T cells. The combination of ICI with other treatment modalities may improve efficacy. METHODS Patients with recurrent GBM were treated with 800 mg avelumab, a human IgG1 antibody directed against PD-L1, either alone (in part A) or within a week after MRI-guided laser interstitial thermal therapy (LITT, in part B) and by-weekly thereafter (NCT03341806). To spare steroid use, bevacizumab was allowed to be combined with avelumab. The primary objective was to characterize the tolerability and safety of the regimen. The secondary objectives included overall survival, progression-free survival, and signature of plasma analytes. RESULTS A total of 12 patients (median age 64, range 37 - 73) enrolled from June 2018 to November 2019, 5 in part A and 7 in part B. Three serious adverse events (SAE) occurred in the same patient, not leading to death. There were 94 AEs reported, 5 grade 3, 28 grade 2, and 61 grade 1. The median PFS was 16.7 weeks (range 7.4-56.7) for patients in Part A and 30.9 weeks (range 8.5-77.7) for patients in Part B. The median survival for patients in part A was 11 months and 13.5 months for part B. The risk ratio of death by combining bevacizumab was 0.573 (p=0.258) with significantly decreased levels of peripheral blood plasma inflammatory markers such as EGF, CXCL5, VEGFA, LAP.TGβ1, ANGPT2 in women. CONCLUSIONS Avelumab was generally well-tolerated, and the combination with LITT had a manageable safety profile and increased survival in a subset of patients. The addition of bevacizumab may increase survival by lowering cytokine expression in a gender-dependent manner. These results warrant further investigation in the next phase study.

Tetraplegia from spinal cord injury leaves many patients paralyzed below the neck, leaving them unable to perform most activities of daily living. Brain-machine interfaces (BMIs) could give tetraplegic patients more independence by directly utilizing brain signals to control external devices such as robotic arms or hands. The cortical grasp network has been of particular interest because of its potential to facilitate the restoration of dexterous object manipulation. However, a network that involves such high-level cortical areas may also provide additional information, such as the encoding of speech. Towards understanding the role of different brain areas in the human cortical grasp network, neural activity related to motor intentions for grasping and performing speech was recorded in a tetraplegic patient in the supramarginal gyrus (SMG), the ventral premotor cortex (PMv), and the somatosensory cortex (S1). We found that in high-level brain areas SMG and PMv, grasps were well represented by firing rates of neuronal populations already at visual cue presentation. During motor imagery, grasps could be significantly decoded from all brain areas. At identical neuronal population sizes, SMG and PMv achieved similar highly-significant decoding abilities, demonstrating their potential for grasp BMIs. During speech, SMG encoded both spoken grasps and colors, in contrast to PMv and S1, which were not able to significantly decode speech.These findings suggest that grasp signals can robustly be decoded at a single unit level from the cortical grasping circuit in human. Data from PMv suggests a specialized role in grasping, while SMG’s role is broader and extends to speech. Together, these results indicate that brain signals from high-level areas of the human cortex can be exploited for a variety of different BMI applications.

The Patch-seq approach is a powerful variation of the patch-clamp technique that allows for the combined electrophysiological, morphological, and transcriptomic characterization of individual neurons. To generate Patch-seq datasets at scale, we identified and refined key factors that contribute to the efficient collection of high-quality data. We developed patch-clamp electrophysiology software with analysis functions specifically designed to automate acquisition with online quality control. We recognized the importance of extracting the nucleus for transcriptomic success and maximizing membrane integrity during nucleus extraction for morphology success. The protocol is generalizable to different species and brain regions, as demonstrated by capturing multimodal data from human and macaque brain slices. The protocol, analysis and acquisition software are compiled at https://githubcom/AllenInstitute/patchseqtools. This resource can be used by individual labs to generate data across diverse mammalian species and that is compatible with large publicly available Patch-seq datasets.

Objective. Intracortical microelectrode arrays (MEA) can be used as part of a brain–machine interface system to provide sensory feedback control of an artificial limb to assist persons with tetraplegia. Variability in functionality of electrodes has been reported but few studies in humans have examined the impact of chronic brain tissue responses revealed postmortem on electrode performance in vivo. Approach. In a tetraplegic man, recording MEAs were implanted into the anterior intraparietal area and Brodmann’s area 5 (BA5) of the posterior parietal cortex and a recording and stimulation array was implanted in BA1 of the primary somatosensory cortex (S1). The participant expired from unrelated causes seven months after MEA implantation. The underlying tissue of two of the three devices was processed for histology and electrophysiological recordings were assessed. Main results. Recordings of neuronal activity were obtained from all three MEAs despite meningeal encapsulation. However, the S1 array had a greater encapsulation, yielded lower signal quality than the other arrays and failed to elicit somatosensory percepts with electrical stimulation. Histological examination of tissues underlying S1 and BA5 implant sites revealed localized leptomeningeal proliferation and fibrosis, lymphocytic infiltrates, astrogliosis, and foreign body reaction around the electrodes. The BA5 recording site showed focal cerebral microhemorrhages and leptomeningeal vascular ectasia. The S1 site showed focal tissue damage including vascular recanalization, neuronal loss, and extensive subcortical white matter necrosis. The tissue response at the S1 site included hemorrhagic-induced injury suggesting a likely mechanism for reduced function of the S1 implant. Significance. Our findings are similar to those from animal studies with chronic intracortical implants and suggest that vascular disruption and microhemorrhage during device implantation are important contributors to overall array and individual electrode performance and should be a topic for future device development to mitigate tissue responses. Neurosurgical considerations are also discussed.

Increasing numbers of compatible pairs are choosing to enter paired exchange programs, but motivations, outcomes, and system-level effects of participation are not well described. Using a linkage of the Scientific Registry of Transplant Recipients and National Kidney Registry, we compared outcomes of traditional (originally incompatible) recipients to originally compatible recipients using the Kaplan–Meier method. We identified 154 compatible pairs. Most pairs sought to improve HLA matching. Compared to the original donor, actual donors were younger (39 vs. 50 years, p < .001), less often female (52% vs. 68%, p < .01), higher BMI (27 vs. 25 kg/m(2), p = .03), less frequently blood type O (36% vs. 80%, p < .001), and had higher eGFR (99 vs. 94 ml/min/1.73 m(2), p = .02), with a better LKDPI (median 7 vs. 22, p < .001). We observed no differences in graft failure or mortality. Compatible pairs made 280 additional transplants possible, many in highly sensitized recipients with long wait times. Compatible pair recipients derived several benefits from paired exchange, including better donor quality. Living donor pairs should receive counseling regarding all options available, including kidney paired donation. As more compatible pairs choose to enter exchange programs, consideration should be given to optimizing compatible pair and hard-to-transplant recipient outcomes.

A landmark 2002 study identified Black liver transplant (LT) recipients as having lower post-LT survival compared to other races. While persistent disparities exist, changes over time and mediating factors are understudied. Capturing LT recipients between 2002 and 2018 in UNOS, we used logistic regression and Cox proportional-hazard models to calculate differences in post-LT mortality among races. We examined interactions between transplant year and race. A mediation analysis assessed biologic and environmental factors potentially associated with race differences in post-LT survival. The cohort included 46,997 LT recipients (3898 Black;36,560 White;6539 Hispanic). In most years, Black (vs. White) LT recipients had a higher probability of age-adjusted mortality, not observed among Hispanics. In multivariable analysis, Blacks (vs. Whites) had higher (aHR = 1.15, 95% CI 1.07-1.24), whereas Hispanics had lower (aHR = 0.78, 95% CI 0.72-0.83) risk of mortality. Differences in post-LT mortality among Blacks (vs. Whites) narrowed between 2002 and 2009, were similar between 2010 and 2013, and may have worsened between 2014 and 2018. Race differences were larger for mortality beyond 1-year post-LT (vs. within 1-year), and among non-HCV (vs. HCV). Alcohol-associated liver disease (ALD) was the strongest mediator (13.9%, 95% CI 8.7-32.7%) of the Black-White disparity in 2010-2018. Our analyses suggest disparities may worsen with longer follow-up, as HCV recedes with elimination efforts, and with further increases in ALD.

Background Since their inception, human induced pluripotent stem cells (hiPSCs) have held much promise for pharmacological applications and cell-based therapies. However, their potential can only be realised if large numbers of cells can be produced reproducibly on-demand. While bioreactors are ideal systems for this task, due to providing agitation and control of the culture parameters, the common impeller geometries were not designed for the expansion of mammalian cells, potentially leading to sub-optimal results. Results This work reports for the first time the usage of the novel Vertical-Wheel single-use bioreactors for the expansion of hiPSCs as floating aggregates. Cultures were performed in the PBS MINI 0.1 bioreactor with 60 mL of working volume. Two different culture media were tested, mTeSR1 and mTeSR3D, in a repeated batch or fed-batch mode, respectively, as well as dextran sulfate (DS) supplementation. mTeSR3D was shown to sustain hiPSC expansion, although with lower maximum cell density than mTeSR1. Dextran sulfate supplementation led to an increase in 97 and 106% in maximum cell number when using mTeSR1 or mTeSR3D, respectively. For supplemented media, mTeSR1 + DS allowed for a higher cell density to be obtained with one less day of culture. A maximum cell density of (2.3 ± 0.2) × 106 cells∙mL− 1 and a volumetric productivity of (4.6 ± 0.3) × 105 cells∙mL− 1∙d− 1 were obtained after 5 days with mTeSR1 + DS, resulting in aggregates with an average diameter of 346 ± 11 μm. The generated hiPSCs were analysed by flow cytometry and qRT-PCR and their differentiation potential was assayed, revealing the maintenance of their pluripotency after expansion. Conclusions The results here described present the Vertical-Wheel bioreactor as a promising technology for hiPSC bioprocessing. The specific characteristics of this bioreactor, namely in terms of the innovative agitation mechanism, can make it an important system in the development of hiPSC-derived products under current Good Manufacturing Practices.

Understanding the diversity of cell types in the brain has been an enduring challenge and requires detailed characterization of individual neurons in multiple dimensions. To systematically profile morpho-electric properties of mammalian neurons, we established a single-cell characterization pipeline using standardized patch-clamp recordings in brain slices and biocytin-based neuronal reconstructions. We built a publicly accessible online database, the Allen Cell Types Database, to display these datasets. Intrinsic physiological properties were measured from 1,938 neurons from the adult laboratory mouse visual cortex, morphological properties were measured from 461 reconstructed neurons, and 452 neurons had both measurements available. Quantitative features were used to classify neurons into distinct types using unsupervised methods. We established a taxonomy of morphologically and electrophysiologically defined cell types for this region of the cortex, with 17 electrophysiological types, 38 morphological types and 46 morpho-electric types. There was good correspondence with previously defined transcriptomic cell types and subclasses using the same transgenic mouse lines.

Alcohol-associated liver disease (ALD) can be coded in United Network for Organ Sharing (UNOS) as either alcoholic cirrhosis or alcoholic hepatitis (AH), without having specific criteria to assign either diagnosis. In this multicenter American Consortium of Early Liver Transplantation for Alcoholic Hepatitis (ACCELERATE-AH) study, we sought to assess the concordance of the clinician diagnosis of AH at liver transplantation (LT) listing versus UNOS data entry of AH as listing diagnosis. In a prior study, consecutive early LT recipients transplanted for AH between 2012 and 2017 were identified by chart review at 10 ACCELERATE-AH sites. In this current study, these same LT recipients were identified in the UNOS database. The primary UNOS diagnostic code was evaluated for concordance with the chart-review assignment of AH. In cases where the primary listing diagnosis in UNOS was not AH, we determined the reason for alternate classification. Among 124 ACCELERATE-AH LT recipients with a chart-review diagnosis of AH, only 43/124 (35%) had AH as listing diagnosis in UNOS; 80 (64%) were listed as alcoholic cirrhosis, and 1 (1%) as fulminant hepatic necrosis. Of the 81 patients missing AH as a UNOS listing diagnosis code, the reasons for alternate classification were 44 (54%) due to a lack of awareness of a separate diagnosis code for AH; 13 (16%) due to concomitant clinical diagnosis of AH and alcoholic cirrhosis in the chart; 12 (15%) due to clinical uncertainty regarding the diagnosis of AH versus acute decompensated alcoholic cirrhosis; and 12 (15%) due to a data entry error. In conclusion, in a large cohort of LT recipients with AH, only 35% were documented as such in UNOS. Increased education and awareness for those performing UNOS data entry, the establishment of specific criteria to define AH in the UNOS database, and the ability to document dates of alcohol use would allow future research on ALD to be more informative.

Alveolar macrophages resident in the lung are prominent phagocytic effector cells of the pulmonary innate immune response, and paradoxically, are attractive harbors for pathogens. Consequently, facultative intracellular bacteria, such as Francisella tularensis, can cause severe systemic disease and sepsis, with high morbidity and mortality associated with pulmonary infection. Current clinical treatment, which involves exhaustive oral or intravenous antibiotic therapy, has limitations such as systemic toxicity and off-target effects. Pulmonary administration represents a promising alternative to systemic dosing for delivering antibiotics directly to the lung. Here, we present synthesized mannosylated ciprofloxacin polymeric prodrugs for efficient pulmonary delivery, targeting, and subsequent internalization by alveolar macrophages. We demonstrate significant improvement in efficacy against intracellular infections in an otherwise uniformly lethal airborne Francisella murine model (F. novicida). When administered to the lungs of mice in a prophylactic regimen, the mannosylated ciprofloxacin polymeric prodrugs led to 50% survival. In a treatment regimen that was concurrent with infection, the survival of mice increased to 87.5%. Free ciprofloxacin antibiotic was ineffective in both cases. This significant difference in antibacterial efficacy demonstrates the impact of this delivery platform based on improved physiochemical, pharmacokinetic, and pharmacodynamic properties of ciprofloxacin administered via our glycan polymeric prodrug. This modular platform provides a route for overcoming the limitations of free drug and increasing efficacy in treatment of intracellular infection.

Image-guided percutaneous nephrostomy is a relatively safe and successful procedure for access to the renal collecting system for multiple purposes including relief of urinary obstruction, urinary diversion, access for endourologic procedures, and diagnostic testing. Although placing a percutaneous nephrostomy catheter is most times straightforward, providing immediate benefit for the patient and satisfaction for the practitioner, there can be situations that make the procedure more difficult or risky. A thorough review of the patient's imaging and medical record will help to set a path for success. However, there may be innuendos and unforeseen circumstances that occur. Having knowledge of most of these "stumbling blocks" and how to deal with them will keep you on the path. This paper serves to fill some of that mental file with the aim to increase clinical success.

Alcohol‐associated liver disease (AALD) represents 40% to 50% of liver deaths in the United States. Since 2016, AALD has become the most common indication for LT in the United States.1 Although LT treats the hepatic complications of alcohol use disorder, it does not treat the addiction to alcohol, a chronic illness with relapsing and remitting periods of disease.2 This review discusses the patterns of alcohol use after LT, its negative consequences, and the tools available to transplant providers to monitor alcohol use.

Intracellular bacterial infections localized to the lung alveolar macrophage (AM) remain one of the most challenging settings for antimicrobial therapy. Current systemic antibiotic treatment fails to deliver sustained doses to intracellular bacterial reservoirs, which necessitates prolonged treatment regimens. Herein, we demonstrate a new intracellular enzyme-cleavable polymeric prodrug with tailored ciprofloxacin release profiles in the lungs and AM. The targeted polymeric prodrug, termed “drugamers”, incorporates (1) hydrophilic mannose residues to solubilize the antibiotic cargo and to target and enhance AM uptake and intracellular delivery, and (2) enzyme-cleavable linkage chemistry to provide high and sustained intracellular AM drug dosing. Prodrug monomers, derived from the antibiotic ciprofloxacin, were synthesized with either an intracellular protease cleavable dipeptide linker or a hydrolytic phenyl ester linker. RAFT polymerization was used to copolymerize the prodrug monomers and mannose monomer to synthesize well-defined drugamers without requiring a post-polymerization conjugation step. In addition to favorable in vivo safety profiles following intratracheal administration, a single dose of the drugamers sustained ciprofloxacin dosing in lungs and AMs above the minimum inhibitory concentration (MIC) over at least a 48 h period. The enzyme-cleavable therapeutic achieved a greater than 10-fold increase in sustained ciprofloxacin in AM, and maintained a significantly higher whole lung PK as well. Ciprofloxacin dosed in identical fashion displayed rapid clearance with a half-life of approximately 30 min. Notably, inhalation of the mannose-targeted ciprofloxacin drugamers achieved full survival (100%) in a highly lethal mouse model of pneumonic tularemia, contrasted with 0% survival using free ciprofloxacin. These findings demonstrate the versatility of the drugamer platform for engineering the intracellular pharmacokinetic profiles and its strong therapeutic activity in treating pulmonary intracellular infections.

This paper provides the first evidence of the causal effect of COVID-19 on metro use using real-time data from the Taipei Metro System in Taiwan. In contrast to other cities or countries, Taiwan did not enforce strict social lockdowns or mandatory stay-at-home orders to combat COVID-19. The major prevention strategies to the pandemic in Taiwan include promoting social distancing, mandating the wearing of face masks in public areas, and requiring all international arrivals to quarantine for 14 days. Using administrative data on confirmed cases of COVID-19 and ridership from metro stations with the difference-in-differences model, we find that an additional new confirmed case of COVID-19 reduces metro use by 1.43% after controlling for local socio-demographic variables associated with ridership and the number of international arrivals to Taiwan. This result implies that the reduction in metro trips is attributable to decreases in residents' use of public transportation due to perceived health risks. Furthermore, the effect of COVID-19 on metro use disproportionally impacts stations with different characteristics. The effect is more pronounced for metro stations connected to night markets, shopping centers, or colleges. Although decreases in metro ridership lower the revenue of the Taipei Metro System, our results indicate a tradeoff between increased financial burdens of public transportation systems and reducing medical expenses associated with COVID-19.

Surfactant has been routinely used in the neonatal population, particularly in the setting of prematurity and neonatal respiratory distress syndrome. Current evidence, however, does not delineate the effect of surfactant use in neonates and older children during cardiac surgery admissions. This study aimed to characterize the impact of surfactant on pediatric cardiac surgery admissions. Admissions of those under 18 years of age with cardiac surgery were identified from the Pediatric Health Information System (PHIS) database between 2004 and 2015, using ICD-9 procedure codes. Univariate analyses were conducted to compare admission characteristics between those that did and not utilize surfactant. Variables shown to be significant were then entered as independent variables into the regression analyses. Surfactant was entered into each model as an independent variable. A total of 81,313 admissions met the inclusion criteria. Of these, 109 (0.1%) had surfactant utilized. Univariate analyses identified several differences between admissions with and without surfactant use and demonstrated significantly increased mortality in the surfactant group (38.5% versus 4.6%, p < .01). Regression analyses demonstrated that surfactant was independently associated with increased mortality (odds ratio 6.0, 95% confidence interval 3.9–9.3, p < .01). Univariate analysis in only surfactant admissions demonstrated the following to be associated with inpatient mortality: younger age, prematurity, Ebstein anomaly, and hypoplastic left heart syndrome. Surfactant administration during pediatric cardiac surgery admissions is independently associated with a sixfold increase in inpatient mortality. It is likely that these findings are mediated by augmentation of the decrease in pulmonary vascular resistance and a subsequent decrease in systemic blood flow in the setting of parallel circulation. Surfactant should be administered with special consideration in neonates with cardiac disease and may be best avoided in those with parallel circulation.

© 2021 Wiley Periodicals LLC, Human-induced pluripotent stem cells (iPSCs) have great potential for disease modeling. However, generating iPSC-derived models to study brain diseases remains a challenge. In particular, the ability to recapitulate cerebellar development in vitro is still limited. We presented a reproducible and scalable production of cerebellar organoids by using the novel single-use Vertical-Wheel bioreactors, in which functional cerebellar neurons were obtained. Here, we evaluate the global gene expression profiles by RNA sequencing (RNA-seq) across cerebellar differentiation, demonstrating a faster cerebellar commitment in this novel dynamic differentiation protocol. Furthermore, transcriptomic profiles suggest a significant enrichment of extracellular matrix (ECM) in dynamic-derived cerebellar organoids, which can better mimic the neural microenvironment and support a consistent neuronal network. Thus, an efficient generation of organoids with cerebellar identity was achieved for the first time in a continuous process using a dynamic system without the need of organoids encapsulation in ECM-based hydrogels, allowing the possibility of large-scale production and application in high-throughput processes. The presence of factors that favors angiogenesis onset was also detected in dynamic conditions, which can enhance functional maturation of cerebellar organoids. We anticipate that large-scale production of cerebellar organoids may help developing models for drug screening, toxicological tests, and studying pathological pathways involved in cerebellar degeneration., This study was supported by Fundação para a Ciência e a Tecnologia (FCT), Portugal (UIDB/04565/2020 through Programa Operacional Regional de Lisboa 2020, Project no. 007317, PD/BD/105773/2014 to Teresa P. Silva and SFRH/BD/147906/2019 to Rui Sousa-Luís), projects co-funded by FEDER (POR Lisboa 2020—Programa Operacional Regional de Lisboa PORTUGAL 2020) and FCT through Grant PAC-PRECISE LISBOA-01-0145-FEDER-016394 and CEREBEX Generation of Cerebellar Organoids for Ataxia Research Grant LISBOA-01-0145-FEDER-029298.