Sex and disease severity-based analysis of steroid hormones in ME/CFS.

PURPOSE: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by persistent fatigue and decreased daily activity following physical and/or cognitive exertion. While ME/CFS affects both sexes, there is a higher prevalence in women. However, studies evaluating this sex-related bias are limited. METHODS: Circulating steroid hormones, including mineralocorticoids (aldosterone), glucocorticoids (cortisol, corticosterone, 11-deoxycortisol, cortisone), androgens (androstenedione, testosterone), and progestins (progesterone, 17α-hydroxyprogesterone), were measured in plasma samples using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Samples were obtained from mild/moderate (ME/CFSmm; females, n=20; males, n=8), severely affected patients (ME/CFSsa; females, n=24; males, n=6), and healthy controls (HC, females, n=12; males, n=17). RESULTS: After correction for multiple testing, we observed that circulating levels of 11-deoxycortisol, 17α-hydroxyprogesterone in females, and progesterone in males were significantly different between HC, ME/CFSmm, and ME/CFSsa. Comparing two independent groups, we found that female ME/CFSsa had higher levels of 11-deoxycortisol (vs. HC and ME/CFSmm) and 17α-hydroxyprogesterone (vs. HC). In addition, female ME/CFSmm showed a significant increase in progesterone levels compared to HC. In contrast, our study found that male ME/CFSmm had lower circulating levels of cortisol and corticosterone, while progesterone levels were elevated compared to HC. In addition to these univariate analyses, our correlational and multivariate approaches identified differential associations between our study groups. Also, using two-component partial least squares discriminant analysis (PLS-DA), we were able to discriminate ME/CFS from HC with an accuracy of 0.712 and 0.846 for females and males, respectively. CONCLUSION: Our findings suggest the potential value of including steroid hormones in future studies aimed at improving stratification in ME/CFS. Additionally, our results provide new perspectives to explore the clinical relevance of these differences within specific patient subgroups.

Purkinje cell dysfunction causes disrupted sleep in ataxic mice.

Purkinje cell dysfunction disrupts movement and causes disorders such as ataxia. Recent evidence suggests that Purkinje cell dysfunction may also alter sleep regulation. Here, we used an ataxic mouse model generated by silencing Purkinje cell neurotransmission (L7Cre;Vgatfx/fx) to better understand how cerebellar dysfunction impacts sleep physiology. We focused our analysis on sleep architecture and electrocorticography (ECoG) patterns based on their relevance to extracting physiological measurements during sleep. We found that circadian activity was unaltered in the mutant mice, although their sleep parameters and ECoG patterns were modified. The L7Cre;Vgatfx/fx mutant mice had decreased wakefulness and rapid eye movement (REM) sleep, whereas non-REM sleep was increased. The mutants had an extended latency to REM sleep, which is also observed in human patients with ataxia. Spectral analysis of ECoG signals revealed alterations in the power distribution across different frequency bands defining sleep. Therefore, Purkinje cell dysfunction may influence wakefulness and equilibrium of distinct sleep stages in ataxia. Our findings posit a connection between cerebellar dysfunction and disrupted sleep and underscore the importance of examining cerebellar circuit function in sleep disorders.

Liposomal bupivacaine intercostal block placed under direct vision reduces morphine use in thoracic surgery.

Background: Thoracic epidural analgesia (TEA) and liposomal bupivacaine (LB) are two methods used for postoperative pain control after thoracic surgery. Some studies have compared LB to standard bupivacaine. However, data comparing the outcomes of LB to TEA after minimally invasive lung resection is limited. Therefore, the objective of our study was to compare postoperative pain, opioid usage, and outcomes between patients who received TEA vs. LB. Methods: We conducted a retrospective chart review of patients who underwent minimally invasive lung resections over an 8-month period. Intraoperatively, patients received either LB under direct vision or a TEA. Pain scores were obtained in the post-anesthesia care unit (PACU) and at 12, 24, and 48 hours postoperatively. Morphine milligram equivalents (MMEs) were calculated at 24 and 48 hours postoperatively. Postoperative outcomes were then compared between groups. Results: In total, 391 patients underwent minimally invasive lung resection: 236 (60%) wedge resections, 51 (13%) segmentectomies, and 104 (27%) lobectomies. Of these, 326 (83%) received LB intraoperatively. Fewer patients in the LB group experienced postoperative complications (18% vs. 34%, P=0.004). LB patients also had lower median pain scores at 24 (P=0.03) and 48 hours (P=0.001) postoperatively. There was no difference in MMEs at 24 hours (P=0.49). However, at 48 hours, patients who received LB required less narcotics (P=0.02). Median hospital length of stay (LOS) was significantly shorter in patients who received LB (2 vs. 4 days, P<0.001). On multivariable analysis, increasing age, postoperative complications, and use of TEA were independently associated with a longer hospital LOS. Conclusions: Compared to TEA, LB intercostal block placed under direct vision reduced morphine use 48 hours after thoracic surgery. It was also associated with fewer postoperative complications and shorter median hospital LOS. LB is a good alternative to TEA for pain management after minimally invasive lung resection.

The circadian molecular clock in the suprachiasmatic nucleus is necessary but not sufficient for fear entrainment.

We show that nocturnal aversive stimuli presented to mice while they are eating and drinking outside of their safe nest can entrain circadian behaviors, leading to a shift toward daytime activity. We also show that the canonical molecular circadian clock is necessary for fear entrainment and that an intact molecular clockwork in the suprachiasmatic nucleus, the site of the central circadian pacemaker, is necessary but not sufficient to sustain fear entrainment of circadian rhythms. Our results demonstrate that entrainment of a circadian clock by cyclic fearful stimuli can lead to severely mistimed circadian behavior that persists even after the aversive stimulus is removed. Together, our findings support the interpretation that circadian and sleep symptoms associated with fear and anxiety disorders are, in part, the output of a fear-entrained clock, and provide a mechanistic insight into this clock.

Cerebellar deep brain stimulation as a dual-function therapeutic for restoring movement and sleep in dystonic mice.

Dystonia arises with cerebellar dysfunction, which plays a key role in the emergence of multiple pathophysiological deficits that range from abnormal movements and postures to disrupted sleep. Current therapeutic interventions typically do not simultaneously address both the motor and non-motor (sleep-related) symptoms of dystonia, underscoring the necessity for a multi-functional therapeutic strategy. Deep brain stimulation (DBS) is effectively used to reduce motor symptoms in dystonia, with existing parallel evidence arguing for its potential to correct sleep disturbances. However, the simultaneous efficacy of DBS for improving sleep and motor dysfunction, specifically by targeting the cerebellum, remains underexplored. Here, we test the effect of cerebellar DBS in two genetic mouse models with dystonia that exhibit sleep defects- Ptf1a Cre ;Vglut2 fx/fx and Pdx1 Cre ;Vglut2 fx/fx -which have overlapping cerebellar circuit miswiring defects but differing severity in motor phenotypes. By targeting DBS to the cerebellar fastigial and interposed nuclei, we modulated sleep dysfunction by enhancing sleep quality and timing in both models. This DBS paradigm improved wakefulness (decreased) and rapid eye movement (REM) sleep (increased) in both mutants. Additionally, the latency to reach REM sleep, a deficit observed in human dystonia patients, was reduced in both models. Cerebellar DBS also induced alterations in the electrocorticogram (ECoG) patterns that define sleep states. As expected, DBS reduced the severe dystonic twisting motor symptoms that are observed in the Ptf1a Cre ;Vglut2 fx/fx mutant mice. These findings highlight the potential for using cerebellar DBS to improve sleep and reduce motor dysfunction in dystonia and uncover its potential as a dual-effect in vivo therapeutic strategy.

The circadian molecular clock in the suprachiasmatic nucleus is necessary but not sufficient for fear entrainment in the mouse.

Nocturnal aversive stimuli presented to mice during eating and drinking outside of their safe nest can entrain circadian behaviors, leading to a shift toward daytime activity. We show that the canonical molecular circadian clock is necessary for fear entrainment and that an intact molecular clockwork in the suprachiasmatic nucleus (SCN), the site of the central circadian pacemaker, is necessary but not sufficient to sustain fear entrainment of circadian rhythms. Our results demonstrate that entrainment of a circadian clock by cyclic fearful stimuli can lead to severely mistimed circadian behavior that persists even after the aversive stimulus is removed. Together, our results support the interpretation that circadian and sleep symptoms associated with fear and anxiety disorders may represent the output of a fear-entrained clock. One-Sentence Summary: Cyclic fearful stimuli can entrain circadian rhythms in mice, and the molecular clock within the central circadian pacemaker is necessary but not sufficient for fear-entrainment.

Purkinje cell dysfunction causes disrupted sleep in ataxic mice.

Purkinje cell dysfunction causes movement disorders such as ataxia, however, recent evidence suggests that Purkinje cell dysfunction may also alter sleep regulation. Here, we used an ataxia mouse model generated by silencing Purkinje cell neurotransmission ( L7 Cre ;Vgat fx/fx ) to better understand how cerebellar dysfunction impacts sleep physiology. We focused our analysis on sleep architecture and electrocorticography (ECoG) patterns based on their relevance to extracting physiological measurements during sleep. We found that circadian activity is unaltered in the mutant mice, although their sleep parameters and ECoG patterns are modified. The L7 Cre ;Vgat fx/fx mutant mice have decreased wakefulness and rapid eye movement (REM) sleep, while non-rapid eye movement (NREM) sleep is increased. The mutant mice have an extended latency to REM sleep, which is also observed in human ataxia patients. Spectral analysis of ECoG signals revealed alterations in the power distribution across different frequency bands defining sleep. Therefore, Purkinje cell dysfunction may influence wakefulness and equilibrium of distinct sleep stages in ataxia. Our findings posit a connection between cerebellar dysfunction and disrupted sleep and underscore the importance of examining cerebellar circuit function in sleep disorders. Summary Statement: Utilizing a precise genetic mouse model of ataxia, we provide insights into the cerebellum's role in sleep regulation, highlighting its potential as a therapeutic target for motor disorders-related sleep disruptions.

The cerebellum contributes to generalized seizures by altering activity in the ventral posteromedial nucleus.

Thalamo-cortical networks are central to seizures, yet it is unclear how these circuits initiate seizures. We test whether a facial region of the thalamus, the ventral posteromedial nucleus (VPM), is a source of generalized, convulsive motor seizures and if convergent VPM input drives the behavior. To address this question, we devise an in vivo optogenetic mouse model to elicit convulsive motor seizures by driving these inputs and perform single-unit recordings during awake, convulsive seizures to define the local activity of thalamic neurons before, during, and after seizure onset. We find dynamic activity with biphasic properties, raising the possibility that heterogenous activity promotes seizures. Virus tracing identifies cerebellar and cerebral cortical afferents as robust contributors to the seizures. Of these inputs, only microinfusion of lidocaine into the cerebellar nuclei blocks seizure initiation. Our data reveal the VPM as a source of generalized convulsive seizures, with cerebellar input providing critical signals.

Electromyography as a Method for Distinguishing Dystonia in Mice.

Electromyography (EMG) methods allow quantitative analyses of motor function. The techniques include intramuscular recordings that are performed in vivo. However, recording muscle activity in freely moving mice, particularly in models of motor disease, often creates challenges that prevent the acquisition of clean signals. Recording preparations must be stable enough for the experimenter to collect an adequate number of signals for statistical analyses. Instability results in a low signal-to-noise ratio that prohibits proper isolation of EMG signals from the target muscle during the behavior of interest. Such insufficient isolation prevents the analysis of full electrical potential waveforms. In this case, resolving the shape of a waveform to differentiate individual spikes and bursts of muscle activity can be difficult. A common source of instability is an inadequate surgery. Poor surgical techniques cause blood loss, tissue damage, poor healing, encumbered movement, and unstable implantation of the electrodes. Here, we describe an optimized surgical procedure that ensures electrode stability for in vivo muscle recordings. We implement our technique to obtain recordings from agonist and antagonist muscle pairs in the hindlimbs of freely moving adult mice. We validate the stability of our method by holding EMG recordings during dystonic behavior. Our approach is ideal for studying normal and abnormal motor function in actively behaving mice and valuable for recording intramuscular activity when considerable motion is expected.

Disrupted sleep in dystonia depends on cerebellar function but not motor symptoms in mice.

Although dystonia is the third most common movement disorder, patients often also experience debilitating nonmotor defects including impaired sleep. The cerebellum is a central component of a "dystonia network" that plays various roles in sleep regulation. Importantly, the primary driver of sleep impairments in dystonia remains poorly understood. The cerebellum, along with other nodes in the motor circuit, could disrupt sleep. However, it is unclear how the cerebellum might alter sleep and mobility. To disentangle the impact of cerebellar dysfunction on motion and sleep, we generated two mouse genetic models of dystonia that have overlapping cerebellar circuit miswiring but show differing motor phenotype severity: Ptf1a Cre ;Vglut2 fx/fx and Pdx1 Cre ;Vglut2 fx/fx mice. In both models, excitatory climbing fiber to Purkinje cell neurotransmission is blocked, but only the Ptf1a Cre ;Vglut2 fx/fx mice have severe twisting. Using in vivo ECoG and EMG recordings we found that both mutants spend greater time awake and in NREM sleep at the expense of REM sleep. The increase in awake time is driven by longer awake bouts rather than an increase in bout number. We also found a longer latency to reach REM in both mutants, which is similar to what is reported in human dystonia. We uncovered independent but parallel roles for cerebellar circuit dysfunction and motor defects in promoting sleep quality versus posture impairments in dystonia.

Perioperative Esophagectomy Outcomes in Older Esophageal Cancer Patients in Two Different Time Eras.

To investigate perioperative outcomes of esophagectomies by age groups. Retrospective analysis of esophageal cancer patients undergoing esophagectomy from 2005 to 2020 at a single academic institution. Baseline characteristics and outcomes were analyzed by 3 age groups: <70, 70-79, and ≥80 years-old. Sub-analysis was done for 2 time periods: 2005-2012 and 2013-2020. Of 1135 patients, 789 patients were <70, 294 were 70-79, and 52 were ≥80 years-old. Tumor characteristics, and operative technique were similar, except positive longitudinal margins rates (all <3%) (P = 0.008). Older adults experienced increased complications (53.6% vs 69.7% vs 65.4% respectively; P < 0.001) attributable to grade II complications (41.4% vs 62.2% vs 63.5% respectively; P < 0.001). Hospital length of stay (LOS) and rehabilitation requirements were higher in older adults (both P < 0.05). 30-day readmissions, reoperation, and 30-day mortality rates (all <2%) showed no association with age group. Overall complications, LOS, discharge disposition and re-operative rates improved from 2005 to 2012 to 2013-2020 for all (P < 0.05). Increasing age was an independent risk factor for cardiovascular complications (OR 1.7, 95% CI 1.23-2.46 for ages 70-79 and OR 2.7, 95% CI 1.37-5.10 for ages ≥80 ), inpatient rehabilitation (OR 3.3, 95% CI 2.26-5.05 for ages 70-79 and OR 12.1 95% CI 5.83-25.04 for ages ≥80), and prolonged LOS (OR 1.64 95% CI 1.16-2.31 for ages 70-79 and OR 3.6 95% CI 1.71-7.67 for ≥80. After adjusting for time period, older age remained associated with complications (P < 0.05). Highly selected older adults at a large volume esophagectomy center can undergoesophagectomy with increased minor complication and rehabilitation needs.

Propranolol Modulates Cerebellar Circuit Activity and Reduces Tremor.

Tremor is the most common movement disorder. Several drugs reduce tremor severity, but no cures are available. Propranolol, a ß-adrenergic receptor blocker, is the leading treatment for tremor. However, the in vivo circuit mechanisms by which propranolol decreases tremor remain unclear. Here, we test whether propranolol modulates activity in the cerebellum, a key node in the tremor network. We investigated the effects of propranolol in healthy control mice and Car8wdl/wdl mice, which exhibit pathophysiological tremor and ataxia due to cerebellar dysfunction. Propranolol reduced physiological tremor in control mice and reduced pathophysiological tremor in Car8wdl/wdl mice to control levels. Open field and footprinting assays showed that propranolol did not correct ataxia in Car8wdl/wdl mice. In vivo recordings in awake mice revealed that propranolol modulates the spiking activity of control and Car8wdl/wdl Purkinje cells. Recordings in cerebellar nuclei neurons, the targets of Purkinje cells, also revealed altered activity in propranolol-treated control and Car8wdl/wdl mice. Next, we tested whether propranolol reduces tremor through ß1 and ß2 adrenergic receptors. Propranolol did not change tremor amplitude or cerebellar nuclei activity in ß1 and ß2 null mice or Car8wdl/wdl mice lacking ß1 and ß2 receptor function. These data show that propranolol can modulate cerebellar circuit activity through ß-adrenergic receptors and may contribute to tremor therapeutics.

Report on lung cancer surgery during COVID-19 pandemic at a high volume US institution.

Background: The impact of COVID-19 has been felt in every field of medicine. We sought to understand how lung cancer surgery was affected at a high volume institution. We hypothesized that patients would wait longer for surgery, have more advanced tumors, and experience more complications during the COVID-19 crisis. Methods: A retrospective review was conducted, comparing pathologically confirmed non-small cell lung cancer (NSCLC) surgical cases performed in 2019 to cases performed from March to May 2020, during the height of the COVID-19 crisis. Clinical and pathologic stage, tumor size, time to surgery, follow up time, and complications were evaluated. Results: A total of 375 cases were performed in 2019 vs. 58 cases in March to May 2020. Overall, there were no differences in the distribution of clinical stages or in the distribution of median wait times to surgery between groups (COVID-19 16.5 days vs. pre-COVID-19 17 days, P=0.54), nor were there differences when subdivided into Stage I-II and Stage III-IV. Case volume was lowest in April 2020 with 6 cases vs. 37 in April 2019, P<0.01. Tumor size was clinically larger in the COVID-19 group (median 2.1 vs. 1.9 cm, P=0.05) but not at final pathology. No differences in complications were observed between groups (COVID-19 31.0% vs. pre-COVID-19 30.9%, P=1.00). No patients from the COVID-19 group tested positive for the disease during their hospital stay or by the median 15 days to first follow-up. Conclusions: Surgical wait time, pathologic tumor size, and complications were not different among patients undergoing surgery before vs. during the pandemic. Importantly, no patients became infected as a result of their hospital stay. The significant decrease in surgical cases is concerning for untreated cancers that may progress without proper treatment.

Salvage surgery for local recurrence after sublobar surgery in Stages I and II non-small cell lung cancer.

BACKGROUND AND OBJECTIVES: To examine if patients undergoing salvage surgery for local recurrence following sublobar resection (SLR) have similar perioperative complications and overall survival (OS) compared to lobectomy patients for early stage non-small cell lung cancer (NSCLC). METHODS: Patients undergoing lobectomy and SLR (segmentectomy or wedge resection) for Stages I and II NSCLC from 2010 to 2016 were reviewed. Lobectomy patients and those who underwent salvage surgery for local recurrence after SLR were compared. Salvage surgeries were curative-intent resections for recurrence. RESULTS: Cases included 634 lobectomies and 986 SLR. Fifty-nine SLR patients (6.0%) recurred at a local site compared to 11 lobectomy patients (1.7%; p < 0.001). Twenty-three locally recurrent SLR patients (39.0%) went on to salvage surgery. Peri-operative complications after salvage surgeries were similar to lobectomies (34.8% 8/23 vs. 34.7% 220/634, p = 1.00). OS at 5 years for salvage surgery patients was similar to lobectomy patients (79.6% 13/23 vs. 70.6% 227/634, p = 0.23). OS for patients who underwent salvage surgery was significantly better than those who did not have salvage surgery for recurrence (79.6% vs. 53.0%, p = 0.02). CONCLUSIONS: Patients who undergo salvage surgery for local recurrence after SLR had similar perioperative complications and OS compared to lobectomy patients but less than half underwent salvage surgery.

Long-term Outcomes Following Esophagectomy in Older and Younger Adults with Esophageal Cancer.

BACKGROUND: Patterns of overall and disease-free survival after esophagectomy for esophageal cancer in older adults have not been carefully studied. METHODS: Retrospective analysis of all patients with esophageal cancer undergoing esophagectomy from 2005 to 2020 at our institution was performed. Differences in outcomes were stratified by age groups, < 75 and ≥ 75 years old, and two time periods, 2005-2012 and 2013-2020. RESULTS: A total of 1135 patients were included: 979 (86.3%) patients were < 75 (86.3%), and 156 (13.7%) were ≥ 75 years old. Younger patients had fewer comorbidities, better nutritional status, and were more likely to receive neoadjuvant and adjuvant therapy (all p < 0.05). However, tumor stage and operative approach were similar, except for increased performance of the McKeown technique in younger patients (p = 0.02). Perioperatively, younger patients experienced fewer overall and grade II complications (both p < 0.05). They had better overall survival (log-rank p-value < 0.001) and median survival, 62.2 vs. 21.5 months (p < 0.05). When stratified by pathologic stage, survival was similar for yp0 and pathologic stage II disease (both log-rank p-value > 0.05). Multivariable Cox models showed older age (≥ 75 years old) had increased hazard for reduced overall survival (HR 2.04 95% CI 1.5-2.8; p < 0.001) but not disease-free survival (HR 1.1 95% CI 0.78-1.6; p = 0.54). Over time, baseline characteristics remained largely similar, while stage became more advanced with a rise in neoadjuvant use and increased performance of minimally invasive esophagectomy (all p < 0.05). While overall complication rates improved (p < 0.05), overall and recurrence-free survival did not. Overall survival was better in younger patients during both time periods (both log-rank p < 0.05). CONCLUSIONS: Despite similar disease-free survival rates, long-term survival was decreased in older adults as compared to younger patients. This may be related to unmeasured factors including frailty, long-term complications after surgery, and competing causes of death. However, our results suggest that survival is similar in those with complete pathologic responses.

Geographic differences in therapy for stage I non-small-cell lung cancer in older adults.

BACKGROUND: Geographic and socioeconomic factors impact patient treatment choices for certain cancers. Whether they impact treatment in older adults with lung cancer is unknown. We investigated geographic differences in treatment for stage I non-small-cell lung cancer (NSCLC) in older adults in the United States. METHODS: Using the Surveillance, Epidemiology and End Results Database 18th submission, a cohort of stage I NSCLC patients ≥60-years-old was created. Treatment differences (surgery or radiation alone) by geographic location and socioeconomic factors were analyzed. RESULTS: Forty-three thousand three hundred and eighty-seven stage I NSCLC patients were analyzed. Demographics and socioeconomic factors varied across all 13 states (p < 0.001). Surgery was the most common treatment in all states (range 58.6% in AK to 86.5% in CT) (all p < 0.001). Our multivariable analysis found older individuals had higher odds of getting radiation as compared to surgery (odds ratio [OR]: 1.22 for 65-69 years-old to OR: 8.95 for 85+ years-old; p < 0.001). Multiple states (LA, HI, IA, MI, WA, NM) were associated with increased odds of radiation use (vs. surgery alone) (all p < 0.05). People with lower education level (OR: 0.98) and median income (OR: 0.99) and non-Black race (OR: 0.52 for "other" to OR: 0.68 for "White" race with respect to Black race) were associated with lower odds of radiation (p < 0.05). CONCLUSIONS: Our study identified treatment differences for stage I NSCLC patients in the United States related to demographics, socioeconomic factors, and geographic location.

Quantification of Behavioral Deficits in Developing Mice With Dystonic Behaviors.

Converging evidence from structural imaging studies in patients, the function of dystonia-causing genes, and the comorbidity of neuronal and behavioral defects all suggest that pediatric-onset dystonia is a neurodevelopmental disorder. However, to fully appreciate the contribution of altered development to dystonia, a mechanistic understanding of how networks become dysfunctional is required for early-onset dystonia. One current hurdle is that many dystonia animal models are ideally suited for studying adult phenotypes, as the neurodevelopmental features can be subtle or are complicated by broad developmental deficits. Furthermore, most assays that are used to measure dystonia are not suited for developing postnatal mice. Here, we characterize the early-onset dystonia in Ptf1a Cre ;Vglut2 fl/fl mice, which is caused by the absence of neurotransmission from inferior olive neurons onto cerebellar Purkinje cells. We investigate motor control with two paradigms that examine how altered neural function impacts key neurodevelopmental milestones seen in postnatal pups (postnatal day 7-11). We find that Ptf1a Cre ;Vglut2 fl/fl mice have poor performance on the negative geotaxis assay and the surface righting reflex. Interestingly, we also find that Ptf1a Cre ;Vglut2 fl/fl mice make fewer ultrasonic calls when socially isolated from their nests. Ultrasonic calls are often impaired in rodent models of autism spectrum disorders, a condition that can be comorbid with dystonia. Together, we show that these assays can serve as useful quantitative tools for investigating how neural dysfunction during development influences neonatal behaviors in a dystonia mouse model. Our data implicate a shared cerebellar circuit mechanism underlying dystonia-related motor signs and social impairments in mice.

Risk of chyle leak after robotic versus video-assisted thoracoscopic esophagectomy.

BACKGROUND: We investigate the incidence and risk factors for post-operative outcomes including chyle leak following minimally invasive esophagectomy (MIE). METHODS: Patients undergoing MIE from May 2016 until August 2020 were prospectively followed. Outcomes of robotic and video-assisted thoracoscopic surgery (VATS) esophagectomy were analyzed. RESULTS: 347 esophagectomies were performed: 70 cases were done robotically by 2 surgeons and 277 by VATS by 14 surgeons. Patients had similar demographics, surgical technique, length of stay (LOS), and re-operation rates. Overall complication rates between robotic and VATS MIE were statistically similar (61% vs. 50%; p = 0.082). The majority of complications for either VATS (41.5%) or robotic-assisted minimally invasive esophagectomy (RAMIE) (51.4%) were grade II. Nineteen patients developed a chyle leak. Patients with a chyle leak were similar in age, gender, and hospital LOS (all p > 0.05), but were more likely to undergo a three-hole or robotic esophagectomy (both p < 0.05) as well as have higher rehabilitation requirements on discharge (26% vs. 10%; p = 0.05). Among the two surgeons who each performed > 20 robotic esophagectomies (n = 70), nine chyle leaks occurred. Rates varied by surgeon (7 vs. 2; p = 0.003). Lower leak rates occurred in the surgeon with more robotic esophagectomy experience (n = 47 vs. 23). Patients were similar in age, and gender (p > 0.05), but those with a chyle leak were more likely to undergo three-hole esophagectomies, prophylactic thoracic duction ligations, undergo the abdominal portion via laparotomy, and not have a prophylactic omental flap (all p < 0.05). CONCLUSION: Robotic and VATS esophagectomy have similar rates of re-operation, length of stay, discharge needs and complications. Differences in outcomes between VATS and Robotic esophagectomy appears to be related to surgeon experience with the robot but may also be associated with techniques such as anastomotic height, omental flap utilization and performance of laparoscopy.

Antimicrobial stewardship programs in adult intensive care units in Latin America: Implementation, assessments, and impact on outcomes.

OBJECTIVE: To assess the impact of antimicrobial stewardship programs (ASPs) in adult medical-surgical intensive care units (MS-ICUs) in Latin America. DESIGN: Quasi-experimental prospective with continuous time series. SETTING: The study included 77 MS-ICUs in 9 Latin American countries. PATIENTS: Adult patients admitted to an MS-ICU for at least 24 hours were included in the study. METHODS: This multicenter study was conducted over 12 months. To evaluate the ASPs, representatives from all MS-ICUs performed a self-assessment survey (0-100 scale) at the beginning and end of the study. The impact of each ASP was evaluated monthly using the following measures: antimicrobial consumption, appropriateness of antimicrobial treatments, crude mortality, and multidrug-resistant microorganisms in healthcare-associated infections (MDRO-HAIs). Using final stewardship program quality self-assessment scores, MS-ICUs were stratified and compared among 3 groups: ≤25th percentile, >25th to <75th percentile, and ≥75th percentile. RESULTS: In total, 77 MS-ICU from 9 Latin American countries completed the study. Twenty MS-ICUs reached at least the 75th percentile at the end of the study in comparison with the same number who remain within the 25th percentile (score, 76.1 ± 7.5 vs 28.0 ± 7.3; P < .0001). Several indicators performed better in the MS-ICUs in the 75th versus 25th percentiles: antimicrobial consumption (143.4 vs 159.4 DDD per 100 patient days; P < .0001), adherence to clinical guidelines (92.5% vs 59.3%; P < .0001), validation of prescription by pharmacist (72.0% vs 58.0%; P < .0001), crude mortality (15.9% vs 17.7%; P < .0001), and MDRO-HAIs (9.45 vs 10.96 cases per 1,000 patient days; P = .004). CONCLUSION: MS-ICUs with more comprehensive ASPs showed significant improvement in antimicrobial utilization.