Citations

AbstractBackground and PurposeSpinal cord stimulation (SCS) is approved by the Food and Drug Administration for treating chronic intractable pain in the back, trunk, or limbs through stimulation of the dorsal column. Numerous studies have used swine as an analog of the human spinal cord to better understand SCS and further improve its efficacy. We performed high‐resolution imaging of the porcine spinal cord with intact dura mater using micro‐computed tomography (μCT) to construct detailed 3‐dimensional (3D) visualizations of the spinal cord and characterize the morphology of the dorsal and ventral rootlets.MethodsWe obtained spinal cords from Yorkshire/Landrace crossbred swine (N = 7), stained samples with osmium tetroxide, and performed μCT imaging of the T12‐T15 levels at isotropic voxel resolutions ranging from 3.3 to 50 μm. We measured the anatomical morphology using the 3D volumes and compared our results to measurements previously collected from swine and human spinal cords via microdissection techniques in prior literature.ResultsWhile the porcine thoracic‐lumbar spinal cord is a popular model for SCS, we highlight multiple notable differences compared to previously published T8‐T12 human measurements including rootlet counts (porcine dorsal/ventral: 12.2 ± 2.6, 26.6 ± 3.4; human dorsal/ventral: 5.3 ± 1.3, 4.4 ± 2.4), rootlet angles (porcine ventral‐rostral: 161 ± 1°, ventral‐caudal: 155 ± 6°, dorsal‐rostral: 148 ± 9°, dorsal‐caudal: 142 ± 6°; human ventral‐rostral: 170 ± 3°, ventral‐caudal: 22 ± 10°, dorsal‐rostral: 171 ± 3°, dorsal‐caudal: 15 ± 7°), and the presence and count of dorsal rootlet bundles.ConclusionsDetailed measurements and highlighted differences between human and porcine spinal cords can inform variations in modeling and electrophysiological experiments between the two species. In contrast to other approaches for measuring the spinal cord and rootlet morphology, our method keeps the dura intact, reducing potential artifacts from dissection.

Abstract Purpose Many women are employed at the time of breast cancer (BC) diagnosis. Pre-diagnosis psychological distress is prevalent among early-stage BC patients. We prospectively evaluated return to work (RTW) in BC patients with and without reported pre-diagnosis psychological distress over a 15-month period to determine if such distress affects workforce participation and mental health status after curative treatment. Methods 188 patients with newly diagnosed stage 0-III BC and working 35-plus hours/week participated at Mayo Clinic in Minnesota and Florida. Patients received an email survey at diagnosis and 3 and 15 months later. Incidence of severe psychological distress (SPD) per the Kessler Psychological Distress Scale (K6, score ≥ 13) was assessed at each timepoint. Results 77/188 survey respondents (41%) reported pre-diagnosis psychological distress, with 23.5% noting job-related stress. 59/188 patients (31%) had SPD at diagnosis, with similar incidence in the group that had pre-diagnosis distress (+ stress) and the non-stressed group (no-stress). The sample was highly educated and well salaried. The + stress group worked more hours on average at diagnosis (41.3 vs. 39.3 hours, p = 0.034). At 3 months, 83/141 respondents (60.1%) reported taking time off work after diagnosis, with 46.6% returning within 2 weeks and 42.5% requiring > 4 weeks’ break. More + stress patients reported RTW to maintain health insurance (13/56 vs. 6/85, p = 0.006), although this difference resolved by 15 months. SPD rates decreased over time but affected 17/104 respondents (16.3%) at 15 months. Conclusion Job-related stress is a primary driver of pre-diagnosis psychological distress. Three months after BC diagnosis, many women with pre-diagnosis psychological distress were motivated to RTW to keep employer-linked health insurance. SPD is prominent in BC patients; while SPD declined over time, it did not resolve completely.

Background: Isavuconazole (ISA) has a favorable side effect profile that makes it attractive for treatment of invasive fungal infections (IFI). It carries FDA approval for invasive aspergillosis and mucormycosis, but there are fewer data for other organisms and non-pulmonary infections. We conducted this review to investigate how ISA performed at treating IFI, with an especial interest in these non-approved indications. Methods: We retrospectively identified and reviewed 131 patients who received ISA as treatment for IFI at our institution, some of whom received ISA as their first anti-fungal therapy and others who received ISA as either step-down therapy or salvage therapy. We identified the microbiologic cause of infection as well as the anatomic site involved for each patient. We then classified patients according to their response to ISA: namely cured, partially responded, or stabilized. Results: The majority of patients were immunocompromised (n = 76, 58%). ISA was used primarily as a secondary therapy (n = 116, 89%); either as a step-down/switching from other agents, or as salvage therapy. The most common reasons for switching to ISA were toxicities with prior agents followed by QT prolongation. Although pulmonary aspergillosis and mucormycosis were represented in more than half of the cohort, ISA was also used off-label for treatment of other organisms such as endemic fungi (n = 19, 15%) as well as central nervous system (CNS) infections (n = 15, 11%). We have described the detailed clinical characteristics of these CNS infections cases. The overall clinical response rate varied by type of infection and site involved (57–73% response rate). Conclusions: We demonstrated encouraging clinical responses, particularly outside the FDA-approved indications, as well as good tolerability. This report highlights the critical need for expanded scope of prospective studies to delineate the efficacy of this better-tolerated agent, especially in central nervous system infections.

Abstract Background The US Food and Drug Administration (FDA) released a draft guidance document detailing core patient-reported outcomes in cancer clinical trials, including physical function (PF). This study aimed to develop analytic methods and visualizations of patient-reported PF in patients with cancer. Methods We applied an estimand framework to a patient-reported tolerability endpoint to develop data summaries cross-sectionally and over time, along with visualizations. We accomplished this through iterative feedback with clinicians, statisticians, and FDA stakeholders using three clinical trial datasets in hematologic malignancies. Graphical approaches were applied to three datasets in hematologic malignancies: (1) patients with myeloproliferative neoplasms enrolled in MPN-RC 111/112 trials completed EORTC QLQ-C30 over 12 months; (2) patients with hematologic malignancies undergoing CAR-T cell therapy or autologous transplant who completed FACT questionnaires over 6 months; and (3) patients with multiple myeloma or amyloidosis who completed the PROMIS-29 questionnaire over 6 months. Zoom polls were administered to two stakeholder groups (clinicians/clinical investigators and patient advocates) to elicit feedback. Results Visualizations included stacked bar charts, line plots of arithmetic mean changes from baseline, pie charts, waffle plots, and waterfall plots of PF data. Graphics considered scaled scores and individual items and included delineation of PRO completion rate at each time point. Confidence intervals and reference lines were included as applicable, and colorblind accessible colors were implemented to ensure inclusivity of all visualizations. Data summaries over time reporting “worst” change were difficult to interpret. In terms of stakeholders’ preference, patients preferred stacked bar charts while clinicians equally favored stacked bar charts and line plots; both patients and clinicians preferred waterfall plots to pie charts. Patient feedback highlighted the need for various graphics to convey group level trends and granular individual-patient level information. Conclusion Patient-reported PF informs the evaluation of treatment tolerability in cancer trials. Data summaries and visualizations of physical function developed through an iterative process were reviewed favorably by patients, clinicians and FDA stakeholders in this study. Future work to systematically assess accuracy of interpretation of the various analytic and visualization methods is a necessary next step across clinical, regulatory, payer and patient stakeholders. Trial registration NCT01259817, NCT01259856

Germline mutations modulate the risk of developing schizophrenia (SCZ). Much less is known about the role of mosaic somatic mutations in the context of SCZ. Deep (239×) whole-genome sequencing (WGS) of brain neurons from 61 SCZ cases and 25 controls postmortem identified mutations occurring during prenatal neurogenesis. SCZ cases showed increased somatic variants in open chromatin, with increased mosaic CpG transversions (CpG>GpG) and T>G mutations at transcription factor binding sites (TFBSs) overlapping open chromatin, a result not seen in controls. Some of these variants alter gene expression, including SCZ risk genes and genes involved in neurodevelopment. Although these mutational processes can reflect a difference in factors indirectly involved in disease, increased somatic mutations at developmental TFBSs could also potentially contribute to SCZ.

AbstractObjectiveEpilepsy raises critical challenges to accurately localize the epileptogenic zone (EZ) to guide presurgical planning. Previous research has suggested that interictal spikes overlapping with high‐frequency oscillations, referred to here as pSpikes, serve as a reliable biomarker for EZ estimation, but there remains a question as to whether and to how pSpikes perform as compared to other types of epileptic spikes. This study aims to address this question by investigating the source imaging capabilities of pSpikes alongside other spike types.MethodsA total of 2819 interictal spikes from 76‐channel scalp electroencephalography (EEG) were analyzed in a cohort of 24 drug‐resistant focal epilepsy patients. All patients received surgical resection, and 16 were declared seizure‐free based on at least 1 year of postoperative follow‐up. A recently developed electrophysiological source imaging algorithm—fast spatiotemporal iteratively reweighted edge sparsity (FAST‐IRES)—was used for source imaging of the detected interictal spikes. The performance of 217 pSpikes was compared with 772 nSpikes (spikes with irregular high‐frequency activations), 1830 rSpikes (spikes with no high‐frequency activity), and all 2819 aSpikes (all interictal spikes).ResultsThe localization and extent estimation using pSpikes are concordant with the clinical ground truth; using pSpikes yields the best performance compared with nSpikes, rSpikes, and conventional spike imaging (aSpikes). For multiple spike type seizure‐free patients, the mean localization error for pSpike imaging was 6.8 mm, compared with 15.0 mm for aSpikes. The sensitivity, precision, and specificity were .41, .67, and .93 for pSpikes compared with .32, .48, and .93 for aSpikes.SignificanceThese results demonstrate the merits of noninvasive EEG source localization, and that (1) pSpike is a superior biomarker, outperforming conventional spike imaging for the localization of epileptic sources, and especially those with multiple irritative zones; and (2) FAST‐IRES provides accurate source estimation that is highly concordant with clinical ground truth, even in situations of single spike analysis with low signal‐to‐noise ratio.