Who Can Be Discharged Home after Adult Spinal Deformity Surgery?

Introduction: After adult spinal deformity (ASD) surgery, patients often require postoperative rehabilitation at an inpatient rehabilitation (IPR) center or a skilled nursing facility (SNF). However, home discharge is often preferred by patients and hsas been shown to decrease costs. In a cohort of patients undergoing ASD surgery, we sought to (1) report the incidence of discharge to home, (2) determine the factors significantly associated with discharge to home in the form of a simple scoring system, and (3) evaluate the impact of discharge disposition on patient-reported outcome measures (PROMs). Methods: A single-institution, retrospective cohort study was undertaken for patients undergoing ASD surgery from 2009 to 2021. Inclusion criteria were ≥ 5-level fusion, sagittal/coronal deformity, and at least 2-year follow-up. Exposure variables included preoperative, perioperative, and radiographic data. The primary outcome was discharge status (dichotomized as home vs. IPR/SNF). Secondary outcomes included PROMs, such as the numeric rating scales (NRSs) for back and leg pain, the Oswestry Disability Index (ODI), and EQ-5D. A subanalysis comparing IPR to SNF discharge was conducted. Univariate analysis was performed. Results: Of 221 patients undergoing ASD surgery with a mean age of 63.6 ± 17.6, 112 (50.6%) were discharged home, 71 (32.2%) were discharged to an IPR center, and 38 (17.2%) were discharged to an SNF. Patients discharged home were significantly younger (55.7 ± 20.1 vs. 71.8 ± 9.1, p < 0.001), had lower rate of 2+ comorbidities (38.4% vs. 45.0%, p = 0.001), and had less hypertension (57.1% vs. 75.2%, p = 0.005). Perioperatively, patients who were discharged home had significantly fewer levels instrumented (10.0 ± 3.0 vs. 11.0 ± 3.4 levels, p = 0.030), shorter operative times (381.4 ± 139.9 vs. 461.6 ± 149.8 mins, p < 0.001), less blood loss (1101.0 ± 977.8 vs. 1739.7 ± 1332.9 mL, p < 0.001), and shorter length of stay (5.4 ± 2.8 vs. 9.3 ± 13.9 days, p < 0.001). Radiographically, preoperative SVA (9.1 ± 6.5 vs. 5.2 ± 6.8 cm, p < 0.001), PT (27.5 ± 11.1° vs. 23.4 ± 10.8°, p = 0.031), and T1PA (28.9 ± 12.7° vs. 21.6 ± 13.6°, p < 0.001) were significantly higher in patients who were discharged to an IPR center/SNF. Additionally, the operating surgeon also significantly influenced the disposition status (p < 0.001). A scoring system of the listed factors was proposed and was validated using univariate logistic regression (OR = 1.55, 95%CI = 1.34-1.78, p < 0.001) and ROC analysis, which revealed a cutoff value of > 6 points as a predictor of non-home discharge (AUC = 0.75, 95%CI = 0.68-0.80, p < 0.001, sensitivity = 63.3%, specificity = 74.1%). The factors in the scoring system were age > 56, comorbidities ≥ 2, hypertension, TIL ≥ 10, operative time > 357 mins, EBL > 1200 mL, preop SVA > 6.6 cm, preop PT > 33.6°, and preop T1PA > 15°. When comparing IPR (n = 71) vs. SNF (n = 38), patients discharged to an SNF were significantly older (74.4 ± 8.6 vs. 70.4 ± 9.1, p = 0.029) and were more likely to be female (89.5% vs. 70.4%, p = 0.024). Conclusions: Approximately 50% of patients were discharged home after ASD surgery. A simple scoring system based on age > 56, comorbidities ≥ 2, hypertension, total instrumented levels ≥ 10, operative time > 357 mins, EBL > 1200 mL, preop SVA > 6.6 cm, preop PT > 33.6°, and preop T1PA > 15° was proposed to predict non-home discharge. These findings may help guide postoperative expectations and resource allocation after ASD surgery.

Combined Anterior-Posterior vs. Posterior-Only Approach in Adult Spinal Deformity Surgery: Which Strategy Is Superior?

Introduction: Whether a combined anterior-posterior (AP) approach offers additional benefits over the posterior-only (P) approach in adult spinal deformity (ASD) surgery remains unknown. In a cohort of patients undergoing ASD surgery, we compared the combined AP vs. the P-only approach in: (1) preoperative/perioperative variables, (2) radiographic measurements, and (3) postoperative outcomes. Methods: A single-institution, retrospective cohort study was performed for patients undergoing ASD surgery from 2009 to 2021. Inclusion criteria were ≥5-level fusion, sagittal/coronal deformity, and 2-year follow-up. The primary exposure was the operative approach: a combined AP approach or P alone. Postoperative outcomes included mechanical complications, reoperation, and minimal clinically important difference (MCID), defined as 30% of patient-reported outcome measures (PROMs). Multivariable linear regression was controlled for age, BMI, and previous fusion. Results: Among 238 patients undergoing ASD surgery, 34 (14.3%) patients underwent the AP approach and 204 (85.7%) underwent the P-only approach. The AP group consisted mostly of anterior lumbar interbody fusion (ALIF) at L5/S1 (73.5%) and/or L4/L5 (38.0%). Preoperatively, the AP group had more previous fusions (64.7% vs. 28.9%, p < 0.001), higher pelvic tilt (PT) (29.6 ± 11.6° vs. 24.6 ± 11.4°, p = 0.037), higher T1 pelvic angle (T1PA) (31.8 ± 12.7° vs. 24.0 ± 13.9°, p = 0.003), less L1-S1 lordosis (-14.7 ± 28.4° vs. -24.3 ± 33.4°, p < 0.039), less L4-S1 lordosis (-25.4 ± 14.7° vs. 31.6 ± 15.5°, p = 0.042), and higher sagittal vertical axis (SVA) (102.6 ± 51.9 vs. 66.4 ± 71.2 mm, p = 0.005). Perioperatively, the AP approach had longer operative time (553.9 ± 177.4 vs. 397.4 ± 129.0 min, p < 0.001), more interbodies placed (100% vs. 17.6%, p < 0.001), and longer length of stay (8.4 ± 10.7 vs. 7.0 ± 9.6 days, p = 0.026). Radiographically, the AP group had more improvement in T1PA (13.4 ± 8.7° vs. 9.5 ± 8.6°, p = 0.005), L1-S1 lordosis (-14.3 ± 25.6° vs. -3.2 ± 20.2°, p < 0.001), L4-S1 lordosis (-4.7 ± 16.4° vs. 3.2 ± 13.7°, p = 0.008), and SVA (65.3 ± 44.8 vs. 44.8 ± 47.7 mm, p = 0.007). These outcomes remained statistically significant in the multivariable analysis controlling for age, BMI, and previous fusion. Postoperatively, no significant differences were found in mechanical complications, reoperations, or MCID of PROMs. Conclusions: Preoperatively, patients undergoing the combined anterior-posterior approach had higher PT, T1PA, and SVA and lower L1-S1 and L4-S1 lordosis than the posterior-only approach. Despite increased operative time and length of stay, the anterior-posterior approach provided greater sagittal correction without any difference in mechanical complications or PROMs.

Indirect structural changes and reduced controllability after temporal lobe epilepsy resection.

OBJECTIVE: To understand the potential behavioral and cognitive effects of mesial temporal resection for temporal lobe epilepsy (TLE) a method is required to characterize network-wide functional alterations caused by a discrete structural disconnection. The objective of this study was to investigate network-wide alterations in brain dynamics of patients with TLE before and after surgical resection of the seizure focus using average regional controllability (ARC), a measure of the ability of a node to influence network dynamics. METHODS: Diffusion-weighted imaging (DWI) data were acquired in 27 patients with drug-resistant unilateral mesial TLE who underwent selective amygdalohippocampectomy. Imaging data were acquired before and after surgery and a presurgical and postsurgical structural connectome was generated from whole-brain tractography. Edge-wise strength, node strength, and node ARC were compared before and after surgery. Direct and indirect edge-wise strength changes were identified using patient-specific simulated resections. Direct edges were defined as primary edges disconnected by the resection zone itself. Indirect edges were secondary measured edge strength changes. Changes in node strength and ARC were then related to both direct and indirect edge changes. RESULTS: We found nodes with significant postsurgical changes in both node strength and ARC surrounding the resection zone (paired t tests, p < .05, Bonferroni corrected). ARC identified additional postsurgical changes in nodes outside of the resection zone within the ipsilateral occipital lobe, which were associated with indirect edge-wise strength changes of the postsurgical network (Fisher's exact test, p < .001). These indirect edge-wise changes were facilitated through the "hub" nodes including the thalamus, putamen, insula, and precuneus. SIGNIFICANCE: Discrete network disconnection from TLE resection results in widespread structural and functional changes not predicted by disconnection alone. These can be well characterized by dynamic controllability measures such as ARC and may be useful for investigating changes in brain function that may contribute to seizure recurrence and behavioral or cognitive changes after surgery.

Imaging and Stereotactic Electroencephalography Functional Networks to Guide Epilepsy Surgery.

Epilepsy surgery is a potentially curative treatment of drug-resistant epilepsy that has remained underutilized both due to inadequate referrals and incomplete localization hypotheses. The complexity of patients evaluated for epilepsy surgery has increased, thus new approaches are necessary to treat these patients. The paradigm of epilepsy surgery has evolved to match this challenge, now considering the entire seizure network with the goal of disrupting it through resection, ablation, neuromodulation, or a combination. The network paradigm has the potential to aid in identification of the seizure network as well as treatment selection.

Longer Screws Decrease the Risk of Radiographic Pseudarthrosis Following Elective Anterior Cervical Discectomy and Fusion.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: In patients undergoing elective anterior cervical discectomy and fusion (ACDF), we sought to determine the impact of screw length on: (1) radiographic pseudarthrosis, (2) pseudarthrosis requiring reoperation, and (3) patient-reported outcome measures (PROMs). METHODS: A single-institution, retrospective cohort study was undertaken from 2010-21. The primary independent variables were: screw length (mm), screw length divided by the anterior-posterior vertebral body diameter (VB%), and the presence of any screw with VB% < 75% vs all screws with VB% ≥ 75%. Multivariable logistic regression controlled for age, BMI, gender, smoking, American Society of Anesthesiology grade, number of levels fused, and whether a corpectomy was performed. RESULTS: Of 406 patients undergoing ACDF, levels fused were: 1-level (39.4%), 2-level (42.9%), 3-level (16.7%), and 4-level (1.0%). Mean screw length was 14.3 ± 2.3 mm, and mean VB% was 74.4 ± 11.2. A total of 293 (72.1%) had at least one screw with VB% < 75%, 113 (27.8%) had all screws with VB% ≥ 75%, and 141 (34.7%) patients had radiographic pseudarthrosis at 1-year. Patients who had any screw with VB% < 75% had a higher rate of radiographic pseudarthrosis compared to those had all screws with VB% ≥ 75% (39.6% vs 22.1%, P < .001). Multivariable logistic regression revealed that a higher VB% (OR = .97, 95%CI = .95-.99, P = .035) and having all screws with VB% ≥ 75% (OR = .51, 95%CI = .27-.95, P = .037) significantly decreased the odds of pseudarthrosis at 1-year, with no difference in reoperation or PROMs (all P > .05). CONCLUSION: Longer screws taking up ≥75% of the vertebral body protected against radiographic pseudarthrosis at 1-year. Maximizing screw length in ACDF is an easily modifiable factor directly under the surgeon's control that may mitigate the risk of pseudarthrosis.

Artificial Intelligence to Preoperatively Predict Proximal Junction Kyphosis Following Adult Spinal Deformity Surgery: Soft Tissue Imaging May Be Necessary for Accurate Models.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: In a cohort of patients undergoing adult spinal deformity (ASD) surgery, we used artificial intelligence to compare three models of preoperatively predicting radiographic proximal junction kyphosis (PJK) using: (1) traditional demographics and radiographic measurements, (2) raw preoperative scoliosis radiographs, and (3) raw preoperative thoracic magnetic resonance imaging (MRI). SUMMARY OF BACKGROUND DATA: Despite many proposed risk factors, PJK following ASD surgery remains difficult to predict. MATERIALS AND METHODS: A single-institution, retrospective cohort study was undertaken for patients undergoing ASD surgery from 2009 to 2021. PJK was defined as a sagittal Cobb angle of upper-instrumented vertebra (UIV) and UIV+2>10° and a postoperative change in UIV/UIV+2>10°. For model 1, a support vector machine was used to predict PJK within 2 years postoperatively using clinical and traditional sagittal/coronal radiographic variables and intended levels of instrumentation. Next, for model 2, a convolutional neural network (CNN) was trained on raw preoperative lateral and posterior-anterior scoliosis radiographs. Finally, for model 3, a CNN was trained on raw preoperative thoracic T1 MRIs. RESULTS: A total of 191 patients underwent ASD surgery with at least 2-year follow-up and 89 (46.6%) developed radiographic PJK within 2 years. Model 1: Using clinical variables and traditional radiographic measurements, the model achieved a sensitivity: 57.2% and a specificity: 56.3%. Model 2: a CNN with raw scoliosis x-rays predicted PJK with a sensitivity: 68.2% and specificity: 58.3%. Model 3: a CNN with raw thoracic MRIs predicted PJK with average sensitivity: 73.1% and specificity: 79.5%. Finally, an attention map outlined the imaging features used by model 3 elucidated that soft tissue features predominated all true positive PJK predictions. CONCLUSIONS: The use of raw MRIs in an artificial intelligence model improved the accuracy of PJK prediction compared with raw scoliosis radiographs and traditional clinical/radiographic measurements. The improved predictive accuracy using MRI may indicate that PJK is best predicted by soft tissue degeneration and muscle atrophy.

Corticostriatal beta oscillation changes associated with cognitive function in Parkinson's disease.

Cognitive impairment is the most frequent non-motor symptom in Parkinson's disease and is associated with deficits in a number of cognitive functions including working memory. However, the pathophysiology of Parkinson's disease cognitive impairment is poorly understood. Beta oscillations have previously been shown to play an important role in cognitive functions including working memory encoding. Decreased dopamine in motor cortico-striato-thalamo-cortical (CSTC) circuits increases the spectral power of beta oscillations and results in Parkinson's disease motor symptoms. Analogous changes in parallel cognitive CSTC circuits involving the caudate and dorsolateral prefrontal cortex (DLPFC) may contribute to Parkinson's disease cognitive impairment. The objective of our study is to evaluate whether changes in beta oscillations in the caudate and DLPFC contribute to cognitive impairment in Parkinson's disease patients. To investigate this, we used local field potential recordings during deep brain stimulation surgery in 15 patients with Parkinson's disease. Local field potentials were recorded from DLPFC and caudate at rest and during a working memory task. We examined changes in beta oscillatory power during the working memory task as well as the relationship of beta oscillatory activity to preoperative cognitive status, as determined from neuropsychological testing results. We additionally conducted exploratory analyses on the relationship between cognitive impairment and task-based changes in spectral power in additional frequency bands. Spectral power of beta oscillations decreased in both DLPFC and caudate during working memory encoding and increased in these structures during feedback. Subjects with cognitive impairment had smaller decreases in caudate and DLPFC beta oscillatory power during encoding. In our exploratory analysis, we found that similar differences occurred in alpha frequencies in caudate and theta and alpha in DLPFC. Our findings suggest that oscillatory power changes in cognitive CSTC circuits may contribute to cognitive symptoms in patients with Parkinson's disease. These findings may inform the future development of novel neuromodulatory treatments for cognitive impairment in Parkinson's disease.

Structural disconnection relates to functional changes after temporal lobe epilepsy surgery.

Epilepsy surgery consists of surgical resection of the epileptic focus and is recommended for patients with drug-resistant focal epilepsy. However, focal brain lesions can lead to effects in distant brain regions. Similarly, the focal resection in temporal lobe epilepsy surgery has been shown to lead to functional changes distant from the resection. Here we hypothesize that there are changes in brain function caused by temporal lobe epilepsy surgery in regions distant from the resection that are due to their structural disconnection from the resected epileptic focus. Therefore, the goal of this study was to localize changes in brain function caused by temporal lobe epilepsy surgery and relate them to the disconnection from the resected epileptic focus. This study takes advantage of the unique opportunity that epilepsy surgery provides to investigate the effects of focal disconnections on brain function in humans, which has implications in epilepsy and broader neuroscience. Changes in brain function from pre- to post-epilepsy surgery were quantified in a group of temporal lobe epilepsy patients (n = 36) using a measure of resting state functional MRI activity fluctuations. We identified regions with significant functional MRI changes that had high structural connectivity to the resected region in healthy controls (n = 96) and patients based on diffusion MRI. The structural disconnection from the resected epileptic focus was then estimated using presurgical diffusion MRI and related to the functional MRI changes from pre- to post-surgery in these regions. Functional MRI activity fluctuations increased from pre- to post-surgery in temporal lobe epilepsy in the two regions most highly structurally connected to the resected epileptic focus in healthy controls and patients-the thalamus and the fusiform gyrus ipsilateral to the side of surgery (PFWE < 0.05). Broader surgeries led to larger functional MRI changes in the thalamus than more selective surgeries (P < 0.05), but no other clinical variables were related to functional MRI changes in either the thalamus or fusiform. The magnitude of the functional MRI changes in both the thalamus and fusiform increased with a higher estimated structural disconnection from the resected epileptic focus when controlling for the type of surgery (P < 0.05). These results suggest that the structural disconnection from the resected epileptic focus may contribute to the functional changes seen after epilepsy surgery. Broadly, this study provides a novel link between focal disconnections in the structural brain network and downstream effects on function in distant brain regions.

Arousal and salience network connectivity alterations in surgical temporal lobe epilepsy.

OBJECTIVE: It is poorly understood why patients with mesial temporal lobe epilepsy (TLE) have cognitive deficits and brain network changes that extend beyond the temporal lobe, including altered extratemporal intrinsic connectivity networks (ICNs). However, subcortical arousal structures project broadly to the neocortex, are affected by TLE, and thus may contribute to these widespread network effects. The authors' objective was to examine functional connectivity (FC) patterns between subcortical arousal structures and neocortical ICNs, possible neurocognitive relationships, and FC changes after epilepsy surgery. METHODS: The authors obtained resting-state functional magnetic resonance imaging (fMRI) in 50 adults with TLE and 50 controls. They compared nondirected FC (correlation) and directed FC (Granger causality laterality index) within the salience network, default mode network, and central executive network, as well as between subcortical arousal structures; these 3 ICNs were also compared between patients and controls. They also used an fMRI-based vigilance index to relate alertness to arousal center FC. Finally, fMRI was repeated in 29 patients > 12 months after temporal lobe resection. RESULTS: Nondirected FC within the salience (p = 0.042) and default mode (p = 0.0008) networks, but not the central executive network (p = 0.79), was decreased in patients in comparison with controls (t-tests, corrected). Nondirected FC between the salience network and subcortical arousal structures (nucleus basalis of Meynert, thalamic centromedian nucleus, and brainstem pedunculopontine nucleus) was reduced in patients in comparison with controls (p = 0.0028-0.015, t-tests, corrected), and some of these connectivity abnormalities were associated with lower processing speed index, verbal comprehension, and full-scale IQ. Interestingly, directed connectivity measures suggested a loss of top-down influence from the salience network to the arousal nuclei in patients. After resection, certain FC patterns between the arousal nuclei and salience network moved toward control values in the patients, suggesting that some postoperative recovery may be possible. Although an fMRI-based vigilance measure suggested that patients exhibited reduced alertness over time, FC abnormalities between the salience network and arousal structures were not influenced by the alertness levels during the scans. CONCLUSIONS: FC abnormalities between subcortical arousal structures and ICNs, such as the salience network, may be related to certain neurocognitive deficits in TLE patients. Although TLE patients demonstrated vigilance abnormalities, baseline FC perturbations between the arousal and salience networks are unlikely to be driven solely by alertness level, and some may improve after surgery. Examination of the arousal network and ICN disturbances may improve our understanding of the downstream clinical effects of TLE.

The Effectiveness of Ultraviolet-C (UV-C) Irradiation on the Viability of Airborne Pseudomonas aeruginosa.

Pseudomonas aeruginosa (Pa) is the predominant bacterial pathogen in people with cystic fibrosis (CF) and can be transmitted by airborne droplet nuclei. Little is known about the ability of ultraviolet band C (UV-C) irradiation to inactivate Pa at doses and conditions relevant to implementation in indoor clinical settings. We assessed the effectiveness of UV-C (265 nm) at up to seven doses on the decay of nebulized Pa aerosols (clonal Pa strain) under a range of experimental conditions. Experiments were done in a 400 L rotating sampling drum. A six-stage Andersen cascade impactor was used to collect aerosols inside the drum and the particle size distribution was characterized by an optical particle counter. UV-C effectiveness was characterized relative to control tests (no UV-C) of the natural decay of Pa. We performed 112 tests in total across all experimental conditions. The addition of UV-C significantly increased the inactivation of Pa compared with natural decay alone at all but one of the UV-C doses assessed. UV-C doses from 246-1968 µW s/cm2 had an estimated effectiveness of approximately 50-90% for airborne Pa. The effectiveness of doses ≥984 µW s/cm2 were not significantly different from each other (p-values: 0.365 to ~1), consistent with a flattening of effectiveness at higher doses. Modelling showed that delivering the highest dose associated with significant improvement in effectiveness (984 µW s/cm2) to the upper air of three clinical rooms would lead to lower room doses from 37-49% of the 8 h occupational limit. Our results suggest that UV-C can expedite the inactivation of nebulized airborne Pa under controlled conditions, at levels that can be delivered safely in occupied settings. These findings need corroboration, but UV-C may have potential applications in locations where people with CF congregate, coupled with other indoor and administrative infection control measures.

Presurgical temporal lobe epilepsy connectome fingerprint for seizure outcome prediction.

Temporal lobe epilepsy presents a unique situation where confident clinical localization of the seizure focus does not always result in a seizure-free or favourable outcome after mesial temporal surgery. In this work, magnetic resonance imaging derived functional and structural whole-brain connectivity was used to compute a network fingerprint that captures the connectivity profile characteristics that are common across a group of nine of these patients with seizure-free outcome. The connectivity profile was then computed for 38 left-out patients with the hypothesis that similarity to the fingerprint indicates seizure-free surgical outcome. Patient profile distance to the fingerprint was compared with 1-year seizure outcome and standard clinical parameters. Distance to the fingerprint was higher for patients with Engel III-IV 1-year outcome compared with those with Engel Ia, Ib-d, and II outcome (Kruskal-Wallis, P < 0.01; Wilcoxon rank-sum p corr <0.05 Bonferroni-corrected). Receiver operator characteristic analysis revealed 100% sensitivity and 90% specificity in identifying patients with Engel III-IV outcome based on distance to the fingerprint in the left-out patients. Furthermore, distance to the fingerprint was not related to any individual clinical parameter including age at scan, duration of disease, total seizure frequency, presence of mesial temporal sclerosis, lateralizing ictal, interictal scalp electroencephalography, invasive stereo-encephalography, or positron emission tomography. And two published algorithms utilizing multiple clinical measures for predicting seizure outcome were not related to distance to the fingerprint, nor predictive of seizure outcome in this cohort. The functional and structural connectome fingerprint provides quantitative, clinically interpretable and significant information not captured by standard clinical assessments alone or in combinations. This automated and simple method may improve patient-specific prediction of seizure outcome in patients with a clinically identified focus in the mesial temporal lobe.

Temporal lobe epilepsy lateralisation and surgical outcome prediction using diffusion imaging.

OBJECTIVE: We sought to augment the presurgical workup of medically refractory temporal lobe epilepsy by creating a supervised machine learning technique that uses diffusion-weighted imaging to classify patient-specific seizure onset laterality and surgical outcome. METHODS: 151 subjects were included in this analysis: 62 patients (aged 18-68 years, 36 women) and 89 healthy controls (aged 18-71 years, 47 women). We created a supervised machine learning technique that uses diffusion-weighted metrics to classify subject groups. Specifically, we sought to classify patients versus healthy controls, unilateral versus bilateral temporal lobe epilepsy, left versus right temporal lobe epilepsy and seizure-free versus not seizure-free surgical outcome. We then reduced the dimensionality of derived features with community detection for ease of interpretation. RESULTS: We classified the subject groups in withheld testing data sets with a cross-fold average testing areas under the receiver operating characteristic curve of 0.745 for patients versus healthy controls, 1.000 for unilateral versus bilateral seizure onset, 0.662 for left versus right seizure onset, 0.800 for left-sided seizure-free vsersu not seizure-free surgical outcome and 0.775 for right-sided seizure-free versus not seizure-free surgical outcome. CONCLUSIONS: This technique classifies important clinical decisions in the presurgical workup of temporal lobe epilepsy by generating discerning white-matter features. We believe that this work augments existing network connectivity findings in the field by further elucidating important white-matter pathology in temporal lobe epilepsy. We hope that this work contributes to recent efforts aimed at using diffusion imaging as an augmentation to the presurgical workup of this devastating neurological disorder.

Network dysfunction in pre and postsurgical epilepsy: connectomics as a tool and not a destination.

PURPOSE OF REVIEW: Patients with focal drug-resistant epilepsy (DRE) sometimes continue to have seizures after surgery. Recently, there is increasing interest in using advanced network analyses (connectomics) to better understand this problem. Connectomics has changed the way researchers and clinicians view DRE, but it must be applied carefully in a hypothesis-driven manner to avoid spurious results. This review will focus on studies published in the last 18 months that have thoughtfully used connectomics to advance our fundamental understanding of network dysfunction in DRE - hopefully for the eventual direct benefit to patient care. RECENT FINDINGS: Impactful recent findings have centered on using patient-specific differences in network dysfunction to predict surgical outcome. These works span functional and structural connectivity and include the modalities of functional and diffusion magnetic resonance imaging (MRI) and electrophysiology. Using functional MRI, many groups have described an increased functional segregation outside of the surgical resection zone in patients who fail surgery. Using electrophysiology, groups have reported network characteristics of resected tissue that suggest whether a patient will respond favorably to surgery. SUMMARY: If we can develop accurate models to outline functional and structural network characteristics that predict failure of standard surgical approaches, then we can not only improve current clinical decision-making; we can also begin developing alternative treatments including network approaches to improve surgical success rates.

A deep learning approach to identify gene targets of a therapeutic for human splicing disorders.

Pre-mRNA splicing is a key controller of human gene expression. Disturbances in splicing due to mutation lead to dysregulated protein expression and contribute to a substantial fraction of human disease. Several classes of splicing modulator compounds (SMCs) have been recently identified and establish that pre-mRNA splicing represents a target for therapy. We describe herein the identification of BPN-15477, a SMC that restores correct splicing of ELP1 exon 20. Using transcriptome sequencing from treated fibroblast cells and a machine learning approach, we identify BPN-15477 responsive sequence signatures. We then leverage this model to discover 155 human disease genes harboring ClinVar mutations predicted to alter pre-mRNA splicing as targets for BPN-15477. Splicing assays confirm successful correction of splicing defects caused by mutations in CFTR, LIPA, MLH1 and MAPT. Subsequent validations in two disease-relevant cellular models demonstrate that BPN-15477 increases functional protein, confirming the clinical potential of our predictions.

Preclinical validation of a potent γ-secretase modulator for Alzheimer's disease prevention.

A potent γ-secretase modulator (GSM) has been developed to circumvent problems associated with γ-secretase inhibitors (GSIs) and to potentially enable use in primary prevention of early-onset familial Alzheimer's disease (EOFAD). Unlike GSIs, GSMs do not inhibit γ-secretase activity but rather allosterically modulate γ-secretase, reducing the net production of Aß42 and to a lesser extent Aß40, while concomitantly augmenting production of Aß38 and Aß37. This GSM demonstrated robust time- and dose-dependent efficacy in acute, subchronic, and chronic studies across multiple species, including primary and secondary prevention studies in a transgenic mouse model. The GSM displayed a >40-fold safety margin in rats based on a comparison of the systemic exposure (AUC) at the no observed adverse effect level (NOAEL) to the 50% effective AUC or AUCeffective, the systemic exposure required for reducing levels of Aß42 in rat brain by 50%.

People with mesial temporal lobe epilepsy have altered thalamo-occipital brain networks.

While temporal lobe epilepsy (TLE) is a focal epilepsy, previous work demonstrates that TLE causes widespread brain-network disruptions. Impaired visuospatial attention and learning in TLE may be related to thalamic arousal nuclei connectivity. Our prior preliminary work in a smaller patient cohort suggests that patients with TLE demonstrate abnormal functional connectivity between central lateral (CL) thalamic nucleus and medial occipital lobe. Others have shown pulvinar connectivity disturbances in TLE, but it is incompletely understood how TLE affects pulvinar subnuclei. Also, the effects of epilepsy surgery on thalamic functional connectivity remains poorly understood. In this study, we examine the effects of TLE on functional connectivity of two key thalamic arousal-nuclei: lateral pulvinar (PuL) and CL. We evaluate resting-state functional connectivity of the PuL and CL in 40 patients with TLE and 40 controls using fMRI. In 25 patients, postoperative images (>1 year) were also compared with preoperative images. Compared to controls, patients with TLE exhibit loss of normal positive connectivity between PuL and lateral occipital lobe (p < 0.05), and a loss of normal negative connectivity between CL and medial occipital lobe (p < 0.01, paired t-tests). FMRI amplitude of low-frequency fluctuation (ALFF) in TLE trended higher in ipsilateral PuL (p = 0.06), but was lower in the lateral occipital (p < 0.01) and medial occipital lobe in patients versus controls (p < 0.05, paired t-tests). More abnormal ALFF in the ipsilateral lateral occipital lobe is associated with worse preoperative performance on Rey Complex Figure Test Immediate (p < 0.05, r = 0.381) and Delayed scores (p < 0.05, r = 0.413, Pearson's Correlations). After surgery, connectivity between PuL and lateral occipital lobe remains abnormal in patients (p < 0.01), but connectivity between CL and medial occipital lobe improves and is no longer different from control values (p > 0.05, ANOVA, post hoc Fischer's LSD). In conclusion, thalamic arousal nuclei exhibit abnormal connectivity with occipital lobe in TLE, and some connections may improve after surgery. Studying thalamic arousal centers may help explain distal network disturbances in TLE.

Design and synthesis of novel methoxypyridine-derived gamma-secretase modulators.

The evolution of gamma-secretase modulators (GSMs) through the introduction of novel heterocycles with the goal of aligning activity for reducing the levels of Aß42 and properties consistent with a drug-like molecule are described. The insertion of a methoxypyridine motif within the tetracyclic scaffold provided compounds with improved activity for arresting Aß42 production as well as improved properties, including solubility. In vivo pharmacokinetic analysis demonstrated that several compounds within the novel series were capable of crossing the BBB and accessing the therapeutic target. Treatment with methoxypyridine-derived compound 64 reduced Aß42 levels in the plasma of J20 mice, in addition to reducing Aß42 levels in the plasma and brain of Tg2576 mice.

Transmission of bacteria in bronchiectasis and chronic obstructive pulmonary disease: Low burden of cough aerosols.

BACKGROUND AND OBJECTIVE: Aerosol transmission of Pseudomonas aeruginosa has been suggested as a possible mode of respiratory infection spread in patients with cystic fibrosis (CF); however, whether this occurs in other suppurative lung diseases is unknown. Therefore, we aimed to determine if (i) patients with bronchiectasis (unrelated to CF) or chronic obstructive pulmonary disease (COPD) can aerosolize P. aeruginosa during coughing and (ii) if genetically indistinguishable (shared) P. aeruginosa strains are present in these disease cohorts. METHODS: People with bronchiectasis or COPD and P. aeruginosa respiratory infection were recruited for two studies. Aerosol study: Participants (n = 20) underwent cough testing using validated cough rigs to determine the survival of P. aeruginosa aerosols in the air over distance and duration. Genotyping study: P. aeruginosa sputum isolates (n = 95) were genotyped using the iPLEX20SNP platform, with a subset subjected to the enterobacterial repetitive intergenic consensus polymerase chain reaction (ERIC-PCR) assay to ascertain their genetic relatedness. RESULTS: Aerosol study: Overall, 7 of 20 (35%) participants released P. aeruginosa cough aerosols during at least one of the cough aerosol tests. These cough aerosols remained viable for 4 m from the source and for 15 min after coughing. The mean total aerosol count of P. aeruginosa at 2 m was two colony-forming units. Typing study: No shared P. aeruginosa strains were identified. CONCLUSION: Low viable count of P. aeruginosa cough aerosols and a lack of shared P. aeruginosa strains observed suggest that aerosol transmission of P. aeruginosa is an unlikely mode of respiratory infection spread in patients with bronchiectasis and COPD.

Cystic fibrosis pathogens survive for extended periods within cough-generated droplet nuclei.

The airborne route is a potential pathway in the person-to-person transmission of bacterial strains among cystic fibrosis (CF) populations. In this cross-sectional study, we investigate the physical properties and survival of common non-Pseudomonas aeruginosa CF pathogens generated during coughing. We conclude that Gram-negative bacteria and Staphylococcus aureus are aerosolised during coughing, can travel up to 4 m and remain viable within droplet nuclei for up to 45 min. These results suggest that airborne person-to-person transmission is plausible for the CF pathogens we measured.

Exposure to ambient air pollution and risk of childhood cancers: A population-based study in Tehran, Iran.

The relationship between air pollution and childhood cancer is inconclusive. We investigated the associations between exposure to ambient air pollution and childhood cancers in Tehran, Iran. This project included children between 1 and 15 years-of-age with a cancer diagnosis by the Center for the Control of Non Communicable Disease (n = 161) during 2007 to 2009. Controls were selected randomly within the city using a Geographic Information System (GIS) (n = 761). The cases were geocoded based on exact home addresses. Air pollution exposure of cases and random controls were estimated by a previously developed Land Use Regression (LUR) model for the 2010 calendar year. The annual mean concentrations of Particulate Matter ≤ 10 µm (PM10), nitrogen dioxide (NO2) and sulfur dioxide (SO2) in the locations of cancer cases were 101.97 µg/m3, 49.42 ppb and 38.92 ppb respectively, while in the random control group, respective mean exposures were 98.63 µg/m3, 45.98 ppb and 38.95 ppb. A logistic regression model was used to find the probability of childhood cancer per unit increase in PM10, NO2 and SO2. We observed a positive association between exposures to PM10 with childhood cancers. We did, however, observe a positive, but not statistically significant association between NO2 exposure and childhood cancer. Our study is the first to highlight an association between air pollution exposure and childhood cancer risk in Iran, however these findings require replication through future studies.