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STUDY DESIGN: Retrospective cohort study. OBJECTIVES: Identify optimal lumbar lordosis in adult deformity correction to achieve age-adjusted targets and sustained alignment. METHODS: Surgical adult spinal deformity patients reaching an age-adjusted ideal alignment at one year were identified. Multilinear regression analysis was used to identify the relationship between regional curvatures (LL and TK) that enabled achievement of a given global alignment (T1 pelvic angle, TPA) based on pelvic incidence (PI). RESULTS: 347 patients out of 1048 available reached their age-adjusted TPA within 5° (60-year-old, 72% women, body mass index 29 ± 6.2). They had a significant improvement in all sagittal parameters (except PI) from pre-operative baseline to 1 year following surgery (P < .001). Multilinear regression predicting L1-S1 based on TK, TPA, and PI demonstrated excellent results (R2 = .85). Simplification of the coefficients of prediction combined with a conversion to an age-based formula led to the following: LL = PI - 0.3TK - 0.5Age + 10. Internal validation of the formula led to a mean error of -.4°, and an absolute error of 5.0°. Internal validation on patients with an age-adjusted alignment revealed similar accuracy across the entire age-adjusted TPA spectrum (ranges of LL errors: ME = .2° to 1.7°, AE = 4.0° to 5.3°). CONCLUSION: This study provides a simple guideline to identify the amount of LL needed to reach a given alignment (i.e., age-adjusted target) based on PI and associated TK. Implementation of this predictive formula during pre-operative surgical planning may help to reduce unexpected sub-optimal post-operative alignment outcomes.

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Cell divisions are accurately positioned to generate cells of the correct size and shape. In plant cells, the new cell wall is built in the middle of the cell by vesicles trafficked along an antiparallel microtubule and a microfilament array called the phragmoplast. The phragmoplast expands toward a specific location at the cell cortex called the division site, but how it accurately reaches the division site is unclear. We observed microtubule arrays that accumulate at the cell cortex during the telophase transition in maize (Zea mays) leaf epidermal cells. Before the phragmoplast reaches the cell cortex, these cortical-telophase microtubules transiently interact with the division site. Increased microtubule plus end capture and pausing occur when microtubules contact the division site-localized protein TANGLED1 or other closely associated proteins. Microtubule capture and pausing align the cortical microtubules perpendicular to the division site during telophase. Once the phragmoplast reaches the cell cortex, cortical-telophase microtubules are incorporated into the phragmoplast primarily by parallel bundling. The addition of microtubules into the phragmoplast promotes fine-tuning of the positioning at the division site. Our hypothesis is that division site-localized proteins such as TANGLED1 organize cortical microtubules during telophase to mediate phragmoplast positioning at the final division plane.

* Context.--Epithelioid angiomyolipomas (eAMLs) are rare tumors of the kidney that occur in patients with tuberous sclerosis complex or in a sporadic setting; a subset of these tumors exhibit metastatic behavior. Objective.--To analyze molecular profiling data to identify pathogenic alterations in rare cases of metastatic eAML, and to identify immunohistochemistry (IHC)-based surrogate markers. Design.--Molecular profiling data from the American Association for Cancer Research GENIE registry was accessed for 23 patients with angiomyolipomas, and 9 of 16 patients with eAMLs in our institutional registry were evaluated with next-generation sequencing. IHC was performed to screen for alterations of P53, RB, and ATRX for all 16 institutional cases. Results.--Combined alterations of 5 tumor-suppressor genes (TP53, ATRX, RB1, APC, and NF1) were identified using next-generation sequencing in 7 of 8 (88%) patients with metastatic disease compared to a single patient with nonmetastatic disease (RB1 variant of uncertain significance; 1 of 24, 4%). No cases with abnormal IHC results were identified in 11 patients with nonmetastatic disease compared to 3 of 5 patients with metastatic disease. Conclusions.--Our results show that the majority of metastatic eAMLs have mutations of 5 tumor-suppressor genes (TP53, ATRX, RB1, APC, and NF1), while these are rare in patients with nonmetastatic disease. Furthermore, IHC for P53, RB, and ATRX may serve as a screen for a subset of these alterations in resource-limited settings. These findings, if validated in larger data sets, have the potential to predict metastatic behavior in eAMLs. (Arch Pathol Lab Med. 2023;147:817-825; doi: 10.5858/ arpa.2022-0127-OA), Renal angiomyolipomas (AMLs) are mesenchymal neoplasms that are typically comprised of spindle cells arising from thick-walled vessels, intermixed with variable amounts of adipose tissue; they frequently express markers such as [...]

AimSymptoms of bipolar disorder (BD) include changes in mood, activity, energy, sleep, and appetite. Since many of these processes are regulated by circadian function, circadian rhythm disturbance has been examined as a biological feature underlying BD. The International Society for Bipolar Disorders Chronobiology Task Force (CTF) was commissioned to review evidence for neurobiological and behavioral mechanisms pertinent to BD.MethodDrawing upon expertise in animal models, biomarkers, physiology, and behavior, CTF analyzed the relevant cross-disciplinary literature to precisely frame the discussion around circadian rhythm disruption in BD, highlight key findings, and for the first time integrate findings across levels of analysis to develop an internally consistent, coherent theoretical framework.ResultsEvidence from multiple sources implicates the circadian system in mood regulation, with corresponding associations with BD diagnoses and mood-related traits reported across genetic, cellular, physiological, and behavioral domains. However, circadian disruption does not appear to be specific to BD and is present across a variety of high-risk, prodromal, and syndromic psychiatric disorders. Substantial variability and ambiguity among the definitions, concepts and assumptions underlying the research have limited replication and the emergence of consensus findings.ConclusionsFuture research in circadian rhythms and its role in BD is warranted. Well-powered studies that carefully define associations between BD-related and chronobiologically-related constructs, and integrate across levels of analysis will be most illuminating.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a common and disabling disorder primarily characterized by persistent fatigue and exercise intolerance, with associated sleep disturbances, autonomic dysfunction, and cognitive problems. The causes of ME/CFS are not well understood but may coincide with immune and inflammatory responses following viral infections. During the current SARS-CoV2 coronavirus pandemic, ME/CFS has been increasingly reported to overlap with persistent "long COVID" symptoms, also called the post-acute sequelae of COVID-19 (PASC). Given the prominence of activity and sleep problems in ME/CFS, circadian rhythm disruption has been examined as a contributing factor in ME/CFS. While these studies of circadian rhythms have been pursued for decades, evidence linking circadian rhythms to ME/CFS remains inconclusive. A major limitation of older chronobiology studies of ME/CFS was the unavailability of modern molecular methods to study circadian rhythms and incomplete understanding of circadian rhythms outside the brain in peripheral organ systems. Major methodological and conceptual advancements in chronobiology have since been made. Over the same time, biomarker research in ME/CFS has progressed. Together, these new developments may justify renewed interest in circadian rhythm research in ME/CFS. Presently, we review ME/CFS from the perspective of circadian rhythms, covering both older and newer studies that make use of modern molecular methods. We focus on transforming growth factor beta (TGFB), a cytokine that has been previously associated with ME/CFS and has an important role in circadian rhythms, especially in peripheral cells. We propose that disrupted TGFB signaling in ME/CFS may play a role in disrupting physiological rhythms in sleep, activity, and cognition, leading to the insomnia, energy disturbances, cognition problems, depression, and autonomic dysfunction associated with ME/CFS. Since SARS-like coronavirus infections cause persistent changes in TGFB and previous coronavirus outbreaks have caused ME/CFS-like syndromes, chronobiological considerations may have immediate implications for understanding ME/CFS in the context of the COVID-19 pandemic and possibly suggest new avenues for therapeutic interventions.

Antipsychotic drugs (AP) are highly efficacious treatments for psychiatric disorders but are associated with significant metabolic side-effects. The circadian clock maintains metabolic homeostasis by sustaining daily rhythms in feeding, fasting and hormone regulation but how circadian rhythms interact with AP and its associated metabolic side-effects is not well-known. We hypothesized that time of AP dosing impacts the development of metabolic side-effects. Weight gain and metabolic side-effects were compared in C57Bl/6 mice and humans dosed with APs in either the morning or evening. In mice, AP dosing at the start of the light cycle/rest period (AM) resulted in significant increase in food intake and weight gain compared with equivalent dose before the onset of darkness/active period (PM). Time of AP dosing also impacted circadian gene expression, metabolic hormones and inflammatory pathways and their diurnal expression patterns. We also conducted a retrospective examination of weight and metabolic outcomes in patients who received risperidone (RIS) for the treatment of serious mental illness and observed a significant association between time of dosing and severity of RIS-induced metabolic side-effects. Time restricted feeding (TRF) has been shown in both mouse and some human studies to be an effective therapeutic intervention against obesity and metabolic disease. We demonstrate, for the first time, that TRF is an effective intervention to reduce AP-induced metabolic side effects in mice. These studies identify highly effective and translatable interventions with potential to mitigate AP-induced metabolic side effects.

ObjectiveThe narrow therapeutic window of lithium medications necessitates frequent serum monitoring, which can be expensive and inconvenient for the patient. Compared to blood, saliva collection is easier, non-invasive, requires less processing, and can be done without the need for trained personnel. This study investigated the utility of longitudinal salivary lithium level monitoring.MethodsWe measured salivary lithium levels using ICP-OES in n = 169 passive drool samples, collected both as single observations and longitudinally for up to 18 months, from a multi-center cohort of n = 75 patients with bipolar disorder or other psychiatric conditions.ResultsSaliva and serum lithium levels were highly correlated. Adjustment for daily lithium dose, diabetes, and smoking improved this relationship (r = 0.77). Using the adjusted intersubject equation and a patient's salivary lithium value, we observed a strong correlation between the predicted vs. observed serum lithium levels (r = 0.70). Most patients had highly stable saliva/serum ratios across multiple visits, with longitudinal variability significantly greater with age. Use of the intrasubject saliva/serum ratio from a single prior observation had similar predictive power to the use of the adjusted intersubject equation. However, the use of the mean intrasubject ratio from three prior observations could robustly predict serum lithium levels (predicted vs. observed r = 0.90).ConclusionsThese findings strongly suggest that saliva could be used for lithium monitoring, and open the door for the development and implementation of a point-of-care salivary lithium device for use at home or the clinic. We propose that the use of saliva will dramatically improve treatment opportunities for patients with mood disorders.

Mountains are important suppliers of freshwater to downstream areas, affecting large populations in particular in High Mountain Asia (HMA). Yet, the propagation of water from HMA headwaters to downstream areas is not fully understood, as interactions in the mountain water cycle between the cryo-, hydro- and biosphere remain elusive. We review the definition of blue and green water fluxes as liquid water that contributes to runoff at the outlet of the selected domain (blue) and water lost to the atmosphere through vapor fluxes, that is evaporation from water, ground, and interception plus transpiration (green) and propose to add the term white water to account for the (often neglected) evaporation and sublimation from snow and ice. We provide an assessment of models that can simulate the cryo-hydro-biosphere continuum and the interactions between spheres in high mountain catchments, going beyond disciplinary separations. Land surface models are uniquely able to account for such complexity, since they solve the coupled fluxes of water, energy, and carbon between the land surface and atmosphere. Due to the mechanistic nature of such models, specific variables can be compared systematically to independent remote sensing observations – providing vital insights into model accuracy and enabling the understanding of the complex watersheds of HMA. We discuss recent developments in spaceborne earth observation products that have the potential to support catchment modeling in high mountain regions. We then present a pilot study application of the mechanistic land surface model Tethys & Chloris to a glacierized watershed in the Nepalese Himalayas and discuss the use of high-resolution earth observation data to constrain the meteorological forcing uncertainty and validate model results. We use these insights to highlight the remaining challenges and future opportunities that remote sensing data presents for land surface modeling in HMA. [ABSTRACT FROM AUTHOR]

Study Design: Survey Objective: In March of 2020, an original study by Louie et al investigated the impact of COVID-19 on 902 spine surgeons internationally. Since then, due to varying government responses and public health initiatives to the pandemic, individual countries and regions of the world have been affected differently. Therefore, this follow-up study aimed to assess how the COVID-19 impact on spine surgeons has changed 1 year later. Methods: A repeat, multi-dimensional, 90-item survey written in English was distributed to spine surgeons worldwide via email to the AO Spine membership who agreed to receive surveys. Questions were categorized into the following domains: demographics, COVID-19 observations, preparedness, personal impact, patient care, and future perceptions. Results: Basic respondent demographics, such as gender, age, home demographics, medical comorbidities, practice type, and years since training completion, were similar to those of the original 2020 survey. Significant differences between groups included reasons for COVID testing, opinions of media coverage, hospital unemployment, likelihood to be performing elective surgery, percentage of cases cancelled, percentage of personal income, sick leave, personal time allocation, stress coping mechanisms, and the belief that future guidelines were needed (P<.05). Conclusion: Compared to baseline results collected at the beginning of the COVID-19 pandemic in 2020, significant differences in various domains related to COVID-19 perceptions, hospital preparedness, practice impact, personal impact, and future perceptions have developed. Follow-up assessment of spine surgeons has further indicated that telemedicine and virtual education are mainstays. Such findings may help to inform and manage expectations and responses to any future outbreaks. [ABSTRACT FROM AUTHOR]

Study Design: Retrospective cohort study Objective: Given changes in bone density induced by degenerative disease, general measures of bone health (ie DEXA) are inadequate to evaluate bone density in surgical areas of interest. Regional differences in HU in the cervical spine may influence surgical strategies. The purposes of our study were to determine whether cervical Hounsfield units (HU) vary by level, examine their relationship with age, comorbidities, and alignment, and propose a technique to measure HU in the lateral masses. Methods: Two hundred twenty-four patients with degenerative spine pathology with a cervical computed tomography were included (2015-2019). Measurements were performed in each vertebral body (C2-T1; mid-axial, anterior-axial, posterior-axial, mid-coronal, and mid-sagittal) and 2 regions of the lateral masses (C3-C6; mid-cor, mid-sag). To evaluate reliability, 6 observers each measured 355 HU values, inter-relater reliability assessed with intraclass correlation coefficients Correlations of HU with age, BMI, comorbidities, and cervical alignment were evaluated. Results: Bone density differed by level, with the lowest HU scores in the lower cervical spine (C6-T1) (P <.001). No correlations were found between LM HU and age, BMI, CCI, or alignment (P >.05). Increased kyphosis was weakly correlated with VB HU, while age and CCI showed moderate correlations with VB HU at all levels (P<.001). ICC for HU measurements were good to excellent for the VBs, but poor to moderate for the LMs. Conclusion: Bone is least dense in the lower cervical spine. HU scoring is not reliable in the lateral masses. We recommend that a level-specific approach to bone density is considered in surgical planning. [ABSTRACT FROM AUTHOR]