Deep electrical imaging of the ultraslow-spreading Mohns Ridge.

More than a third of mid-ocean ridges have a spreading rate of less than 20 millimetres a year1. The lack of deep imaging data means that factors controlling melting and mantle upwelling2,3, the depth to the lithosphere-asthenosphere boundary (LAB)4,5, crustal thickness6-9 and hydrothermal venting are not well understood for ultraslow-spreading ridges10,11. Modern electromagnetic data have greatly improved our understanding of fast-spreading ridges12,13, but have not been available for the ultraslow-spreading ridges. Here we present a detailed 120-kilometre-deep electromagnetic joint inversion model for the ultraslow-spreading Mohns Ridge, combining controlled source electromagnetic and magnetotelluric data. Inversion images show mantle upwelling focused along a narrow, oblique and strongly asymmetric zone coinciding with asymmetric surface uplift. Although the upwelling pattern shows several of the characteristics of a dynamic system3,12-14, it probably reflects passive upwelling controlled by slow and asymmetric plate movements instead. Upwelling asthenosphere and melt can be traced to the inferred depth of the Mohorovicic discontinuity and are enveloped by the resistivity (100 ohm metres) contour denoted the electrical LAB (eLAB). The eLAB may represent a rheological boundary defined by a minimum melt content. We also find that neither the melt-suppression model7 nor the inhibited-migration model15, which explain the correlation between spreading rate and crustal thickness6,16-19, can explain the thin crust below the ridge. A model in which crustal thickness is directly controlled by the melt-producing rock volumes created by the separating plates is more likely. Active melt emplacement into oceanic crust about three kilometres thick culminates in an inferred crustal magma chamber draped by fluid convection cells emanating at the Loki's Castle hydrothermal black smoker field. Fluid convection extends for long lateral distances, exploiting high porosity at mid-crustal levels. The magnitude and long-lived nature of such plumbing systems could promote venting at ultraslow-spreading ridges.

Design, synthesis and validation of a new Crimped Head-Piece for DNA-Encoded libraries generation.

Codification of DNA Encoded Libraries (DELs) is critical for successful ligand identification of molecules that bind a protein of interest (POI). There are different encoding strategies that permit, for instance, the customization of a DEL for testing single or dual pharmacophores (single strand DNA) or for producing and screening large diversity libraries of small molecules (double strand DNA). Both approaches challenges, either from the synthetic and encoding point of view, or from the selection methodology to be utilized for the screening. The Head-Piece contains the DNA sequence that is attached to a chemical compound, allowing the encoding of each molecule with a unique DNA tag. Designing the Head-Piece for a DNA-encoded library involves careful consideration of several key aspects including DNA barcode identity, sequence length and attachment chemistry. Here we describe a double stranded DNA versatile Head-Piece that can be used for the generation of single or dual pharmacophore libraries, but also shows other advanced DEL functionalities, stability and enlarged encoding capacity.

Structural basis for dual-mode inhibition of the ABC transporter MsbA.

The movement of core-lipopolysaccharide across the inner membrane of Gram-negative bacteria is catalysed by an essential ATP-binding cassette transporter, MsbA. Recent structures of MsbA and related transporters have provided insights into the molecular basis of active lipid transport; however, structural information about their pharmacological modulation remains limited. Here we report the 2.9 Å resolution structure of MsbA in complex with G907, a selective small-molecule antagonist with bactericidal activity, revealing an unprecedented mechanism of ABC transporter inhibition. G907 traps MsbA in an inward-facing, lipopolysaccharide-bound conformation by wedging into an architecturally conserved transmembrane pocket. A second allosteric mechanism of antagonism occurs through structural and functional uncoupling of the nucleotide-binding domains. This study establishes a framework for the selective modulation of ABC transporters and provides rational avenues for the design of new antibiotics and other therapeutics targeting this protein family.

Direct coordination of pterin to FeII enables neurotransmitter biosynthesis in the pterin-dependent hydroxylases.

The pterin-dependent nonheme iron enzymes hydroxylate aromatic amino acids to perform the biosynthesis of neurotransmitters to maintain proper brain function. These enzymes activate oxygen using a pterin cofactor and an aromatic amino acid substrate bound to the FeII active site to form a highly reactive FeIV = O species that initiates substrate oxidation. In this study, using tryptophan hydroxylase, we have kinetically generated a pre-FeIV = O intermediate and characterized its structure as a FeII-peroxy-pterin species using absorption, Mössbauer, resonance Raman, and nuclear resonance vibrational spectroscopies. From parallel characterization of the pterin cofactor and tryptophan substrate-bound ternary FeII active site before the O2 reaction (including magnetic circular dichroism spectroscopy), these studies both experimentally define the mechanism of FeIV = O formation and demonstrate that the carbonyl functional group on the pterin is directly coordinated to the FeII site in both the ternary complex and the peroxo intermediate. Reaction coordinate calculations predict a 14 kcal/mol reduction in the oxygen activation barrier due to the direct binding of the pterin carbonyl to the FeII site, as this interaction provides an orbital pathway for efficient electron transfer from the pterin cofactor to the iron center. This direct coordination of the pterin cofactor enables the biological function of the pterin-dependent hydroxylases and demonstrates a unified mechanism for oxygen activation by the cofactor-dependent nonheme iron enzymes.

Subthalamic Nucleus Deep Brain Stimulation Restores Motor and Sensorimotor Cortical Neuronal Oscillatory Activity in the Free-Moving 6-Hydroxydopamine Lesion Rat Parkinson Model.

OBJECTIVES: Enhanced beta oscillations in cortical-basal ganglia (BG) thalamic circuitries have been linked to clinical symptoms of Parkinson's disease. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) reduces beta band activity in BG regions, whereas little is known about activity in cortical regions. In this study, we investigated the effect of STN DBS on the spectral power of oscillatory activity in the motor cortex (MCtx) and sensorimotor cortex (SMCtx) by recording via an electrocorticogram (ECoG) array in free-moving 6-hydroxydopamine (6-OHDA) lesioned rats and sham-lesioned controls. MATERIALS AND METHODS: Male Sprague-Dawley rats (250-350 g) were injected either with 6-OHDA or with saline in the right medial forebrain bundle, under general anesthesia. A stimulation electrode was then implanted in the ipsilateral STN, and an ECoG array was placed subdurally above the MCtx and SMCtx areas. Six days after the second surgery, the free-moving rats were individually recorded in three conditions: 1) basal activity, 2) during STN DBS, and 3) directly after STN DBS. RESULTS: In 6-OHDA-lesioned rats (N = 8), the relative power of theta band activity was reduced, whereas activity of broad-range beta band (12-30 Hz) along with two different subbeta bands, that is, low (12-30 Hz) and high (20-30 Hz) beta band and gamma band, was higher in MCtx and SMCtx than in sham-lesioned controls (N = 7). This was, to some extent, reverted toward control level by STN DBS during and after stimulation. No major differences were found between contacts of the electrode grid or between MCtx and SMCtx. CONCLUSION: Loss of nigrostriatal dopamine leads to abnormal oscillatory activity in both MCtx and SMCtx, which is compensated by STN stimulation, suggesting that parkinsonism-related oscillations in the cortex and BG are linked through their anatomic connections.

Does Temporary Externalization of Electrodes After Deep Brain Stimulation Surgery Result in a Higher Risk of Infection?

OBJECTIVES: Deep brain stimulation (DBS) is a well-established surgical therapy for movement disorders that comprises implantation of stimulation electrodes and a pacemaker. These procedures can be performed separately, leaving the possibility of externalizing the electrodes for local field potential recording or testing multiple targets for therapeutic efficacy. It is still debated whether the temporary externalization of DBS electrodes leads to an increased risk of infection. We therefore aimed to assess the risk of infection during and after lead externalization in DBS surgery. MATERIALS AND METHODS: In this retrospective study, we analyzed a consecutive series of 624 DBS surgeries, including 266 instances with temporary externalization of DBS electrodes for a mean of 6.1 days. Patients were available for follow-up of at least one year, except in 15 instances. In 14 patients with negative test stimulation, electrodes were removed. All kinds of infections related to implantation of the neurostimulation system were accounted for. RESULTS: Overall, infections occurred in 22 of 624 surgeries (3.5%). Without externalization of electrodes, infections were noted after 7 of 358 surgeries (2.0%), whereas with externalization, 15 of 252 infections were found (6.0%). This difference was significant (p = 0.01), but it did not reach statistical significance when comparing groups within different diagnoses. The rate of infection with externalized electrodes was highest in psychiatric disorders (9.1%), followed by Parkinson's disease (7.3%), pain (5.7%), and dystonia (5.5%). The duration of the externalization of the DBS electrodes was comparable in patients who developed an infection (6.1 ± 3.1 days) with duration in those who did not (6.0 ± 3.5 days). CONCLUSIONS: Although infection rates were relatively low in our study, there was a slightly higher infection rate when DBS electrodes were externalized. On the basis of our results, the indication for electrode externalization should be carefully considered, and patients should be informed about the possibility of a higher infection risk when externalization of DBS electrodes is planned.

Surgery with locking plate or hemiarthroplasty versus nonoperative treatment of 3-4-part proximal humerus fractures in older patients (NITEP): An open-label randomized trial.

BACKGROUND: Proximal humerus fractures (PHFs) are common fractures, especially in older female patients. These fractures are commonly treated surgically, but the consensus on the best treatment is still lacking. METHODS AND FINDINGS: The primary aim of this multicenter, randomized 3-arm superiority, open-label trial was to assess the results of nonoperative treatment and operative treatment either with locking plate (LP) or hemiarthroplasty (HA) of 3- and 4-part PHF with the primary outcome of Disabilities of the Arm, Shoulder, and Hand (DASH) at 2-year follow-up. Between February 2011 and December 2019, 160 patients 60 years and older with 3- and 4-part PHFs were randomly assigned in 1:1:1 fashion in block size of 10 to undergo nonoperative treatment (control) or operative intervention with LP or HA. In total, 54 patients were assigned to the nonoperative group, 52 to the LP group, and 54 to the HA group. Five patients assigned to the LP group were reassigned to the HA group perioperatively due to high comminution, and all of these patients had 4-part fractures. In the intention-to-treat analysis, there were 42 patients in the nonoperative group, 44 in the LP group, and 37 in the HA group. The outcome assessors were blinded to the study group. The mean DASH score at 2-year follow-up was 30.4 (standard error (SE) 3.25), 31.4 (SE 3.11), and 26.6 (SE 3.23) points for the nonoperative, LP, and HA groups, respectively. At 2 years, the between-group differences were 1.07 points (95% CI [-9.5,11.7]; p = 0.97) between nonoperative and LP, 3.78 points (95% CI [-7.0,14.6]; p = 0.69) between nonoperative and HA, and 4.84 points (95% CI [-5.7,15.4]; p = 0.53) between LP and HA. No significant differences in primary or secondary outcomes were seen in stratified age groups (60 to 70 years and 71 years and over). At 2 years, we found 30 complications (3/52, 5.8% in nonoperative; 22/49, 45% in LP; and 5/49, 10% in HA group, p = 0.0004) and 16 severe pain-related adverse events. There was a revision rate of 22% in the LP group. The limitation of the trial was that the recruitment period was longer than expected due to a high number of exclusions after the assessment of eligibility and a larger exclusion rate than anticipated toward the end of the trial. Therefore, the trial was ended prematurely. CONCLUSIONS: In this study, no benefit was observed between operative treatment with LP or HA and nonoperative treatment in displaced 3- and 4-part PHFs in patients aged 60 years and older. Further, we observed a high rate of complications related to operative treatments. TRIAL REGISTRATION: ClinicalTrials.gov NCT01246167.

Quantifying KRAS G12C Covalent Drug Inhibitor Activity in Mouse Tumors Using Mass Spectrometry.

The growing opportunities recognized for covalent drug inhibitors, like KRAS G12C inhibitors, are driving the need for mass spectrometry methods that can quickly and robustly measure therapeutic drug activity in vivo for drug discovery research and development. Effective front-end sample preparation is critical for proteins extracted from tumors but is generally labor intensive and impractical for large sample numbers typical in pharmacodynamic (PD) studies. Herein, we describe an automated and integrated sample preparation method for the measurement of activity levels of KRAS G12C drug inhibitor alkylation from complex tumor samples involving high throughput detergent removal and preconcentration followed by quantitation using mass spectrometry. We introduce a robust assay with an average intra-assay coefficient of variation (CV) of 4% and an interassay CV of 6% obtained from seven studies, enabling us to understand the relationship between KRAS G12C target occupancy and the therapeutic PD effect from mouse tumor samples. Further, the data demonstrated that the drug candidate GDC-6036, a KRAS G12C covalent inhibitor, shows dose-dependent target inhibition (KRAS G12C alkylation) and MAPK pathway inhibition, which correlate with high antitumor potency in the MIA PaCa-2 pancreatic xenograft model.

Reference genes for quantitative Arabidopsis single molecule RNA fluorescence in situ hybridization.

Subcellular mRNA quantities and spatial distributions are fundamental for driving gene regulatory programmes. Single molecule RNA fluorescence in situ hybridization (smFISH) uses fluorescent probes to label individual mRNA molecules, thereby facilitating both localization and quantitative studies. Validated reference mRNAs function as positive controls and are required for calibration. Here we present selection criteria for the first set of Arabidopsis smFISH reference genes. Following sequence and transcript data assessments, four mRNA probe sets were selected for imaging. Transcript counts per cell, correlations with cell size, and corrected fluorescence intensities were all calculated for comparison. In addition to validating reference probe sets, we present sample preparation steps that can retain green fluorescent protein fluorescence, thereby providing a method for simultaneous RNA and protein detection. In summary, our reference gene analyses, modified protocol, and simplified quantification method together provide a firm foundation for future quantitative single molecule RNA studies in Arabidopsis root apical meristem cells.

Mortality following proximal humerus fracture-a nationwide register study of 147,692 fracture patients in Sweden.

Little is known about survival after proximal humerus fracture. In this manuscript, we found the mortality to be high (almost four times higher than in age- and sex-matched controls). While frailty hip fracture has gained attention, we hope our manuscript will shed light on frailty proximal humerus fracture patients. INTRODUCTION: Proximal humerus fractures (PHF) are common and occur mostly after the 6th decade of life. While mortality following PHF has been reported previously, mortality data after longer follow-up on a national level is lacking. METHODS: We obtained data from the Swedish Hospital Discharge Register (SHDR), on all adult patients (≥ 18 years) with a diagnosis of PHF (S42.2, S42.20, or S42.21) for the period between 2001 and 2016. We used the Swedish Cause of Death Register (SCDR) to investigate mortality in the fracture cohort. We compared the mortality of fracture patients with age- and sex-matched population-based mortality data obtained from Statistics Sweden. RESULTS: A total of 147 692 PHF patients were identified, with a male to female ratio of 1:3. The mean age was 69 years (range, 18 to 111). Most patients were treated non-surgically (n = 126,487, 86%). The crude mortality rate was 2.2% at 1 month, 4.1% at 3 months, 8.5% at 12 months, and 24% at 48 months after sustaining a PHF. Mortality increased with age; however, the standardized mortality rate (SMR) was highest among young patients. SMR was 5.4 in the 18- to 39-year age group, 3.9 in the 40- to 64-year age group, 1.8 in the 65-79-year age group, and 1.2 in the ≥ 80-year-old population. The age-adjusted SMR was 3.9 in the whole adult PHF population. CONCLUSION: The mortality rate and SMR suggest that PHF patients are heterogeneous. Some older PHF patients may benefit from specialized care (e.g., orthogeriatric), and this should be evaluated in future studies.

Connectivity concepts in neuronal network modeling.

Sustainable research on computational models of neuronal networks requires published models to be understandable, reproducible, and extendable. Missing details or ambiguities about mathematical concepts and assumptions, algorithmic implementations, or parameterizations hinder progress. Such flaws are unfortunately frequent and one reason is a lack of readily applicable standards and tools for model description. Our work aims to advance complete and concise descriptions of network connectivity but also to guide the implementation of connection routines in simulation software and neuromorphic hardware systems. We first review models made available by the computational neuroscience community in the repositories ModelDB and Open Source Brain, and investigate the corresponding connectivity structures and their descriptions in both manuscript and code. The review comprises the connectivity of networks with diverse levels of neuroanatomical detail and exposes how connectivity is abstracted in existing description languages and simulator interfaces. We find that a substantial proportion of the published descriptions of connectivity is ambiguous. Based on this review, we derive a set of connectivity concepts for deterministically and probabilistically connected networks and also address networks embedded in metric space. Beside these mathematical and textual guidelines, we propose a unified graphical notation for network diagrams to facilitate an intuitive understanding of network properties. Examples of representative network models demonstrate the practical use of the ideas. We hope that the proposed standardizations will contribute to unambiguous descriptions and reproducible implementations of neuronal network connectivity in computational neuroscience.

Long non-coding RNA APDC plays important regulatory roles in metabolism of bone and adipose tissues.

The long noncoding RNA (lncR) ANRIL in the human genome is an established genetic risk factor for atherosclerosis, periodontitis, diabetes, and cancer. However, the regulatory role of lncR-ANRIL in bone and adipose tissue metabolism remains unclear. To elucidate the function of lncRNA ANRIL in a mouse model, we investigated its ortholog, AK148321 (referred to as lncR-APDC), located on chr4 of the mouse genome, which is hypothesized to have similar biological functions to ANRIL. We initially revealed that lncR-APDC in mouse bone marrow cells (BMSCs) and lncR-ANRIL in human osteoblasts (hFOBs) are both increased during early osteogenesis. Subsequently, we examined the osteogenesis, adipogenesis, osteoclastogenesis function with lncR-APDC deletion/overexpression cell models. In vivo, we compared the phenotypic differences in bone and adipose tissue between APDC-KO and wild-type mice. Our findings demonstrated that lncR-APDC deficiency impaired osteogenesis while promoting adipogenesis and osteoclastogenesis. Conversely, the overexpression of lncR-APDC stimulated osteogenesis, but impaired adipogenesis and osteoclastogenesis. Furthermore, KDM6B was downregulated with lncR-APDC deficiency and upregulated with overexpression. Through binding-site analysis, we identified miR-99a as a potential target of lncR-APDC. The results suggest that lncR-APDC exerts its osteogenic function via miR-99a/KDM6B/Hox pathways. Additionally, osteoclasto-osteogenic imbalance was mediated by lncR-APDC through MAPK/p38 and TLR4/MyD88 activation. These findings highlight the pivotal role of lncR-APDC as a key regulator in bone and fat tissue metabolism. It shows potential therapeutic for addressing imbalances in osteogenesis, adipogenesis, and osteoclastogenesis.

Resection of posterior fossa tumors in the semi-sitting position in children younger than 4 years of age.

PURPOSE: The semi-sitting position for resection of posterior fossa tumors is a matter of ongoing debate. Here we report about our experience with this approach in children younger than 4 years of age. METHODS: We retrospectively analyzed data of children younger than 4 years of age operated on in our institution in the semi-sitting position over a 15-year period. Patients were intraoperatively monitored for venous air embolism (VAE) by transthoracic Doppler (TTD) or transesophageal echocardiography (TEE). The severity of VAE was classified according to the Tübingen grading scale. Intraoperative incidents of VAE were recorded and the patients' course was followed postoperatively with a special focus on possible complications. RESULTS: Twenty-four children (18 boys, 6 girls) were operated on in the semi-sitting position (26 operations). Mean age was 2.2 years (± 1.0), range between 0.4 and 3.9 years. External ventricular drains were inserted in 18 children with hydrocephalus preoperatively. VAE was detected in 6 instances during surgery (6/26 (23.1%)). In 3 patients with grade 1 VAE, no additional treatment was necessary. In one patient with grade 2 VAE, intracardiac air suction via the central venous catheter was performed, and in two patients with grade 4 VAE, additional cathecholamine-infusion was administered. No major intraoperative complications occurred. Postoperative CT images showed pneumocephalus in all children. In two children, small asymptomatic impression skull fractures at the site of the Mayfield pin occurred. Revision surgery was necessary in one child with a suboccipital CSF fistula. CONCLUSION: The semi-sitting position for resection of tumors in the posterior fossa in children younger than 4 years of age can be safely performed in experienced centers taking special caution to detect and treat potential complications in an interdisciplinary setting.

Evaluation of a concerted vs. sequential oxygen activation mechanism in α-ketoglutarate-dependent nonheme ferrous enzymes.

Determining the requirements for efficient oxygen (O2) activation is key to understanding how enzymes maintain efficacy and mitigate unproductive, often detrimental reactivity. For the α-ketoglutarate (αKG)-dependent nonheme iron enzymes, both a concerted mechanism (both cofactor and substrate binding prior to reaction with O2) and a sequential mechanism (cofactor binding and reaction with O2 precede substrate binding) have been proposed. Deacetoxycephalosporin C synthase (DAOCS) is an αKG-dependent nonheme iron enzyme for which both of these mechanisms have been invoked to generate an intermediate that catalyzes oxidative ring expansion of penicillin substrates in cephalosporin biosynthesis. Spectroscopy shows that, in contrast to other αKG-dependent enzymes (which are six coordinate when only αKG is bound to the FeII), αKG binding to FeII-DAOCS results in ∼45% five-coordinate sites that selectively react with O2 relative to the remaining six-coordinate sites. However, this reaction produces an FeIII species that does not catalyze productive ring expansion. Alternatively, simultaneous αKG and substrate binding to FeII-DAOCS produces five-coordinate sites that rapidly react with O2 to form an FeIV=O intermediate that then reacts with substrate to produce cephalosporin product. These results demonstrate that the concerted mechanism is operative in DAOCS and by extension, other nonheme iron enzymes.

Microsurgical posterior fossa re-exploration for recurrent trigeminal neuralgia after previous microvascular decompression: common grounds-scarring, deformation, and the "piston effect".

OBJECTIVE: Microvascular decompression (MVD) is a well-accepted treatment modality for trigeminal neuralgia (TN) with high initial success rates. The causes for recurrence of TN after previously successful MVD have not been fully clarified, and its treatment is still a matter of debate. Here, we present the surgical findings and the clinical outcome of patients with recurrent TN after MVD who underwent posterior fossa re-exploration. METHODS: Microsurgical posterior fossa re-exploration was performed in 26 patients with recurrent TN (mean age 59.1 years) who underwent MVD over a period of 10 years. The trigeminal nerve was exposed, and possible factors for recurrent TN were identified. Arachnoid scars and Teflon granulomas were dissected meticulously without manipulating the trigeminal nerve. Outcome of posterior fossa re-exploration was graded according to the Barrow Neurological Institute (BNI) pain intensity score. Follow-up was analyzed postoperatively at 3, 12, and 24 months and at the latest available time point for long-term outcome. RESULTS: The mean duration of recurrent TN after the first MVD was 20 months. Pain relief was achieved in all patients with recurrent TN on the first postoperative day. Intraoperative findings were as follows: arachnoid scar tissue in 22/26 (84.6%) patients, arterial compression in 1/26 (3.8%), venous contact in 8/26 (30.8%), Teflon granuloma in 14/26 (53.8%), compression by an electrode in Meckel's cave used for treatment of neuropathic pain in 1/26 (3.8%), evidence of pulsations transmitted to the trigeminal nerve through the Teflon inserted previously/scar tissue ("piston effect") in 15/26 (57.7%), and combination of findings in 18/26 (69.2%). At long-term follow-up (mean 79.5 months; range, 29-184 months), 21/26 (80.8%) patients had favorable outcome (BNI I-IIIa). New hypaesthesia secondary to microsurgical posterior fossa re-exploration occurred in 5/26 (19.2%) patients. CONCLUSIONS: Posterior fossa re-exploration avoiding manipulation to the trigeminal nerve, such as pinching or combing, may be a useful treatment option for recurrent TN after previously successful MVD providing pain relief in the majority of patients with a low rate of new hypaesthesia.

The semi-sitting position in patients with indwelling CSF shunts: perioperative management and avoidance of complications.

OBJECTIVE: Posterior fossa or midline tumors are often associated with hydrocephalus and primary tumor removal with or without perioperative placement of an external ventricular drain (EVD) is commonly accepted as first-line treatment. Shunting prior to posterior fossa surgery (PFS) is mostly reserved for symptomatic cases or special circumstances. There are limited data regarding the anticipated risk for symptomatic pneumocephalus and the perioperative management using the semi-sitting position (SSP) in such a scenario. Here, we therefore assessed the safety of performing PFS in a consecutive series of patients over a period of 15 years to allow the elaboration of recommendations for perioperative management. METHODS: According to specific inclusion and exclusion criteria a total of 13 patients who underwent 17 operations was identified. Supratentorial pneumocephalus was evaluated with semiautomatic-volumetric segmentation. The volume of pneumocephalus was evaluated according to age and ventricular size. RESULTS: Ten of the 13 patients had a programmable valve (preoperative valve setting range 6-14 cmH20; mean 7.5 cmH20) while 3 patients had non programmable valves. A variable amount of supratentorial air collection was evident in all patients postoperatively (range 3.2-331 ml; mean 122.32 ml). Positive predictors for the volume of postoperative pneumocephalus were higher age and a preoperative Evans ratio > 0.3. In our series, we encountered no cases of tension pneumocephalus necessitating an air replacement procedure as well as no obstruction, disconnection, infection or hardware malfunction of the shunt system. CONCLUSIONS: Our findings indicate that a CSF shunt in situ is not a contraindication for performing PFS in the semi-sitting position and it does not increase the pre-existing risk for postoperative tension pneumocephalus. In cases of primary shunting for hydrocephalus associated with posterior fossa tumors a programmable valve set at a medium opening pressure with a gravitational device is a valid option when PFS in the semi-sitting position is opted. In patients with an indwelling shunt diversion system special caution is indicated in order to prevent and detect overdrainage especially in not adjustable valves or shunts without antisiphon devices.

Inflammation and Fibrosis in Orbital Inflammatory Disease: A Histopathologic Analysis.

PURPOSE: The purpose of this study was to compare the histopathologic inflammation and fibrosis of orbital adipose tissue in orbital inflammatory disease (OID) specimens. METHODS: In this retrospective cohort study, inflammation, and fibrosis in orbital adipose tissue from patients with thyroid-associated orbitopathy (TAO), granulomatosis with polyangiitis (GPA), sarcoidosis, nonspecific orbital inflammation (NSOI), and healthy controls were scored by 2 masked ocular pathologists. Both categories were scored on a scale of 0 to 3 with scoring criteria based on the percentage of specimens containing inflammation or fibrosis, respectively. Tissue specimens were collected from oculoplastic surgeons at 8 international centers representing 4 countries. Seventy-four specimens were included: 25 with TAO, 6 with orbital GPA, 7 with orbital sarcoidosis, 24 with NSOI, and 12 healthy controls. RESULTS: The mean inflammation and fibrosis scores for healthy controls were 0.0 and 1.1, respectively. Orbital inflammatory disease groups' inflammation (I) and fibrosis (F) scores, formatted [I, F] with respective p -values when compared to controls, were: TAO [0.2, 1.4] ( p = 1, 1), GPA [1.9, 2.6] ( p = 0.003, 0.009), sarcoidosis [2.4, 1.9] ( p = 0.001, 0.023), and NSOI [1.3, 1.8] ( p ≤ 0.001, 0.018). Sarcoidosis had the highest mean inflammation score. The pairwise analysis demonstrated that sarcoidosis had a significantly higher mean inflammation score than NSOI ( p = 0.036) and TAO ( p < 0.0001), but no difference when compared to GPA. GPA had the highest mean fibrosis score, with pairwise analysis demonstrating a significantly higher mean fibrosis score than TAO ( p = 0.048). CONCLUSIONS: Mean inflammation and fibrosis scores in TAO orbital adipose tissue samples did not differ from healthy controls. In contrast, the more "intense" inflammatory diseases such as GPA, sarcoidosis, and NSOI did demonstrate higher histopathologic inflammation and fibrosis. This has implications in prognosis, therapeutic selection, and response monitoring in orbital inflammatory disease.

Lumbar Loads and Muscle Activity During Flywheel and Barbell Leg Exercises.

ABSTRACT: Sjöberg, M, Eiken, O, Norrbrand, L, Berg, HE, and Gutierrez-Farewik, EM. Lumbar loads and muscle activity during flywheel and barbell leg exercises. J Strength Cond Res 37(1): 27-34, 2023-It is anticipated that flywheel-based leg resistance exercise will be implemented in future long-duration space missions, to counter deconditioning of weight-bearing bones and postural muscles. The aim was to examine low back loads and muscle engagements during flywheel leg press (FWLP) and flywheel squat (FWS) and, for comparisons, free-weight barbell back squat (BBS). Eight resistance-trained subjects performed 8 repetition maximums of FWLP, FWS, and BBS. Motion analysis and inverse dynamics-based musculoskeletal modeling were used to compute joint loads and muscle forces. Muscle activities were measured with electromyography (EMG). At the L4-L5 level, peak vertebral compression force was similarly high in all exercise modes, whereas peak vertebral posteroanterior shear force was greater ( p < 0.05) in FWLP and BBS than in FWS. Among the back-extensor muscles, the erector spinae longissimus exerted the greatest peak force, with no difference between exercises. Peak force in the lumbar multifidus was lower ( p < 0.05) during FWLP than during FWS and BBS. Peak EMG activity in the lumbar extensor muscles ranged between 31 and 122% of maximal voluntary isometric contraction across muscles and exercise modes, with the greatest levels in the lumbar multifidus. The vertebral compression forces and muscle activations during the flywheel exercises were sufficiently high to presume that when implementing such exercise in space countermeasure regimens, they may be capable of preventing muscle atrophy and vertebral demineralization in the lumbar region.

Musculoskeletal injuries in trauma patients: a Swedish nationwide register study including 37,266 patients.

BACKGROUND AND PURPOSE: Trauma causes over 4 million annual deaths globally and accounts for over 10% of the global burden of disease. Trauma patients often sustain multiple injuries in multiple organ systems. We aimed to investigate the proportion and distribution of musculoskeletal injuries in adult trauma patients. PATIENTS AND METHODS: This is a register-based study using data from the national Swedish trauma register (SweTrau) collected in 2015-2019. By categorizing Abbreviated Injury Scale (AIS) codes into different injury types, we provide a detailed description of the types of musculoskeletal injuries that occurred in trauma patients. RESULTS: 51,335 cases were identified in the register. After exclusion of 7,696 cases that did not have any trauma diagnosis (AIS codes) registered from the trauma and 6,373 patients aged < 18, a total of 37,266 patients were included in the study. 15,246 (41%) had sustained musculoskeletal injury. Of the patients with musculoskeletal injuries, 7,733 (51%) had more than 1 such injury. Spine injuries were the most common injury location (n = 7,083 patients, 19%) followed by lower extremity injuries (n = 5,943 patients, 16%) and upper extremity injuries (n = 6,273 patients, 17%). Fractures were the dominating injury type with 30,755 (87%) of injuries being a fracture. CONCLUSION: 41% of the trauma patients had at least 1 musculoskeletal injury. A spine injury was the most common injury location. Fractures was the dominating injury type constituting 87% of all injuries. We also found that half the patients (51%) with spine or extremity injuries had ≥ 2 such injuries.

Complications after surgical treatment of acetabular fractures: a 5-year follow-up of 229 patients.

PURPOSE: Acetabular fractures are injuries often surgically treated, but the surgical intervention is associated with a high risk of subsequent complications. The primary aim of this study was to explore the rate of reoperations and to identify potential risk factors for reoperation. Secondary aims were other adverse events and mortality. METHODS: Patients ≥ 18 years with a surgically treated acetabular fracture at a single trauma center in Sweden between 2010 and 2019 were retrospectively included. Data were collected through review of medical records and radiographs. Logistic regression analysis was performed to investigate factors associated with reoperations and other adverse events. RESULTS: A total of 229 patients with a surgically treated acetabular fracture were included, mean age (± SD, range) 60 (19, 19-94) years. The majority of the patients were males (n = 180, 79%), and the median (IQR) follow-up time was 1779 (1906) days (4.9 years). 47 patients (21%) underwent a reoperation. THA as surgical method was associated with a lower reoperation rate compared to ORIF (OR 0.3, 95% CI 0.1-0.8, p < 0.01). 72 patients (31%) sustained an adverse event not requiring reoperation, and admittance to ICU was associated with an increased risk (OR 2.6, 95% CI 1.2-5.7, p = 0.02). 30-day mortality was 3.1% and 1-year mortality 5.7%. CONCLUSION: The complication rate after acetabular fracture surgery was high, and surgical treatment with primary THA was associated with a reduced risk for reoperation.