Laser-guided lightning.

Lightning discharges between charged clouds and the Earth's surface are responsible for considerable damages and casualties. It is therefore important to develop better protection methods in addition to the traditional Franklin rod. Here we present the first demonstration that laser-induced filaments-formed in the sky by short and intense laser pulses-can guide lightning discharges over considerable distances. We believe that this experimental breakthrough will lead to progress in lightning protection and lightning physics. An experimental campaign was conducted on the Säntis mountain in north-eastern Switzerland during the summer of 2021 with a high-repetition-rate terawatt laser. The guiding of an upward negative lightning leader over a distance of 50 m was recorded by two separate high-speed cameras. The guiding of negative lightning leaders by laser filaments was corroborated in three other instances by very-high-frequency interferometric measurements, and the number of X-ray bursts detected during guided lightning events greatly increased. Although this research field has been very active for more than 20 years, this is the first field-result that experimentally demonstrates lightning guided by lasers. This work paves the way for new atmospheric applications of ultrashort lasers and represents an important step forward in the development of a laser based lightning protection for airports, launchpads or large infrastructures.

Fast negative breakdown in thunderstorms.

Thunderstorms are natural laboratories for studying electrical discharges in air, where the vast temporal, spatial, and energy scales available can spawn surprising phenomena that reveal deficiencies in our understanding of dielectric breakdown. Recent discoveries, such as sprites, jets, terrestrial gamma ray flashes, and fast positive breakdown, highlight the diversity of complex phenomena that thunderstorms can produce, and point to the possibility for electrical breakdown/discharge mechanisms beyond dielectric breakdown theory based mainly on laboratory experiments. Here we present one such confounding discovery, termed fast negative breakdown, that does not fit with our current understanding of dielectric breakdown. Our adaptation of radio astronomy imaging techniques to study extremely transient lightning-associated events confirms that electrical breakdown in thunderstorms can begin with oppositely-directed fast breakdown of negative polarity, similar and in addition to fast positive breakdown expected from conventional dielectric theory and recent observations. The discovery of fast negative breakdown calls for an addendum to the physical description of electrical discharges in air.

Observations of narrow bipolar events reveal how lightning is initiated in thunderstorms.

A long-standing but fundamental question in lightning studies concerns how lightning is initiated inside storms, given the absence of physical conductors. The issue has revolved around the question of whether the discharges are initiated solely by conventional dielectric breakdown or involve relativistic runaway electron processes. Here we report observations of a relatively unknown type of discharge, called fast positive breakdown, that is the cause of high-power discharges known as narrow bipolar events. The breakdown is found to have a wide range of strengths and is the initiating event of numerous lightning discharges. It appears to be purely dielectric in nature and to consist of a system of positive streamers in a locally intense electric field region. It initiates negative breakdown at the starting location of the streamers, which leads to the ensuing flash. The observations show that many or possibly all lightning flashes are initiated by fast positive breakdown.

Three-dimensional computed tomography for determination of femoral anteversion in a cerebral palsy model.

BACKGROUND: Previous investigation has proven 3-dimensional (3D) computed tomography (CT) to be a poor method of assessing femoral anteversion in patients with cerebral palsy. However, new advancements in CT software yield the potential to improve upon those dated results. METHODS: CT was performed on 9 femoral models with varying amounts of anteversion (20 to 60 degrees) and varying neck-shaft angles (120 to 160 degrees). Each model was scanned in 2 holding devices. One holder placed the femur in an ideal position relative to the gantry. The other placed the femur in flexion, adduction, and internal rotation simulating a common lower extremity posture in cerebral palsy. Femoral anteversion was measured on 3D reconstructions by 4 observers on 2 separate occasions. Interobserver and intraobserver reliability, accuracy, and the effect of increasing neck-shaft angle of the measurements were examined and compared with previously published data using the same models. RESULTS: Pearson correlation coefficients between first and second measurements by the same examiner were all above 0.96 regardless of positioning of the femur in the gantry. The correlation coefficients among all examiners were 0.97 regardless of positioning of the femur in the gantry. Accuracy in measurements was comparable using 3D CT techniques with mean differences between the normal and cerebral palsy-positioned models of <3.6 degrees (SD, 3.1 to 3.3 degrees). Accuracy of the study's 3D CT technique in measuring femoral anteversion in cerebral palsy-positioned femurs was significantly more accurate than that of 2D CT (P<0.0001). CONCLUSIONS: Recent improvements in processing software and 3D reconstruction have made assessment of femoral anteversion with 3D CT accurate through the studied range of anteversion and neck-shaft angles. Using this technique, high intraobserver and interobserver reliability in the determination of femoral anteversion can be expected regardless of neck-shaft angle or postural deformity. LEVEL OF EVIDENCE: Level II.

Fragment-based identification and optimization of a class of potent pyrrolo[2,1-f][1,2,4]triazine MAP4K4 inhibitors.

MAP4K4 has been shown to regulate key cellular processes that are tied to disease pathogenesis. In an effort to generate small molecule MAP4K4 inhibitors, a fragment-based screen was carried out and a pyrrolotriazine fragment with excellent ligand efficiency was identified. Further modification of this fragment guided by X-ray crystal structures and molecular modeling led to the discovery of a series of promising compounds with good structural diversity and physicochemical properties. These compounds exhibited single digit nanomolar potency and compounds 35 and 44 achieved good in vivo exposure.

Glenoid bone loss in the setting of an anterior labroligamentous periosteal sleeve avulsion tear.

BACKGROUND: Glenoid bone loss is a factor that has been inversely associated with the success of shoulder instability repair. Recently, patients with an anterior labroligamentous periosteal sleeve avulsion (ALPSA) lesion have also been identified as having a higher failure rate after surgical repair. PURPOSE: To determine differences in the amount of glenoid bone loss and to compare demographic factors of instability in patients with and without ALPSA tears. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Over a 3-year period, all patients (N = 83) who were treated for anterior shoulder instability at a single institution were reviewed retrospectively. A total of 39 (47%) were identified as having an ALPSA lesion and 44 (53%) as having no ALPSA tear. Glenoid bone loss was determined in 2 ways: (1) radiographically by 3-dimensional computed tomography (3D CT) (humeral head digitally subtracted by 3 blinded observers) and (2) with arthroscopic techniques at the time of surgery. Demographic data such as the time from the initial instability event to advanced imaging and surgery were noted. These data were then analyzed with the Student t test to determine any significant differences between the 2 groups. RESULTS: The patients with an ALPSA lesion had more preoperative instability events than those without (8.2 vs 3.6, respectively; P = .04). The mean glenoid bone loss measured by 3D CT was 12.7% (range, 0%-22.3%) for those with ALPSA tears versus 6.25% (range, 0%-23.1%) for those without (P = .002). The mean duration of total instability for those with ALPSA tears was 42.9 months versus 46.3 months for those without (P = .95). Lastly, the mean bone loss based on arthroscopic measures was 11.4% for patients with ALPSA tears and 4.3% for those without ALPSA tears (P = .017). From the existing magnetic resonance imaging/arthrography scans reviewed, 82% of patients could be correctly identified as having an ALPSA lesion. CONCLUSION: Patients with anterior shoulder instability who have an ALPSA lesion have nearly twice the amount of glenoid bone loss as those with a standard Bankart tear (no ALPSA lesion). Patients with ALPSA lesions had statistically more instability events, and this may be an additional factor in either developing an ALPSA lesion or glenoid bone loss or both.

Discovery of selective 4-Amino-pyridopyrimidine inhibitors of MAP4K4 using fragment-based lead identification and optimization.

Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is a serine/threonine kinase implicated in the regulation of many biological processes. A fragment-based lead discovery approach was used to generate potent and selective MAP4K4 inhibitors. The fragment hit pursued in this article had excellent ligand efficiency (LE), an important attribute for subsequent successful optimization into drug-like lead compounds. The optimization efforts eventually led us to focus on the pyridopyrimidine series, from which 6-(2-fluoropyridin-4-yl)pyrido[3,2-d]pyrimidin-4-amine (29) was identified. This compound had low nanomolar potency, excellent kinase selectivity, and good in vivo exposure, and demonstrated in vivo pharmacodynamic effects in a human tumor xenograft model.

Lead identification of novel and selective TYK2 inhibitors.

A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as psoriasis and inflammatory bowel diseases (IBD), by selective targeting of TYK2. Hit triage, following a high-throughput screen for TYK2 inhibitors, revealed pyridine 1 as a promising starting point for lead identification. Initial expansion of 3 separate regions of the molecule led to eventual identification of cyclopropyl amide 46, a potent lead analog with good kinase selectivity, physicochemical properties, and pharmacokinetic profile. Analysis of the binding modes of the series in TYK2 and JAK2 crystal structures revealed key interactions leading to good TYK2 potency and design options for future optimization of selectivity.

The crystal structure of the catalytic domain of the NF-κB inducing kinase reveals a narrow but flexible active site.

The NF-κB inducing kinase (NIK) regulates the non-canonical NF-κB pathway downstream of important clinical targets including BAFF, RANKL, and LTß. Despite numerous genetic studies associating dysregulation of this pathway with autoimmune diseases and hematological cancers, detailed molecular characterization of this central signaling node has been lacking. We undertook a systematic cloning and expression effort to generate soluble, well-behaved proteins encompassing the kinase domains of human and murine NIK. Structures of the apo NIK kinase domain from both species reveal an active-like conformation in the absence of phosphorylation. ATP consumption and peptide phosphorylation assays confirm that phosphorylation of NIK does not increase enzymatic activity. Structures of murine NIK bound to inhibitors possessing two different chemotypes reveal conformational flexibility in the gatekeeper residue controlling access to a hydrophobic pocket. Finally, a single amino acid difference affects the ability of some inhibitors to bind murine and human NIK with the same affinity.

Screening for syphilis with the treponemal immunoassay: analysis of discordant serology results and implications for clinical management.

BACKGROUND: Screening for syphilis with treponemal chemiluminescence immunoassays (CIA) identifies patients with discordant serology who are not identified with traditional screening methods (eg, CIA-positive, rapid plasma regain (RPR)-negative). We sought to describe the clinical characteristics and management of patients with discordant syphilis serology. METHODS: From August 2007-October 2007, patients with CIA-positive, RPR-negative serology were tested with the Treponema pallidum particle agglutination assay (TP-PA) at Kaiser Permanente Northern California. Clinical and demographic characteristics, prior syphilis history and CIA index values were compared for CIA-positive, RPR-negative patients according to TP-PA status. RESULTS: Of 21,623 assays, 439 (2%) were CIA-positive and 255/439 (58%) were RPR-negative; subsequently, 184 (72%) were TP-PA-positive and 71 (28%) were TP-PA--negative. TP-PA--positive patients were more likely to be male, HIV-positive, homosexual, previously treated for syphilis (57% versus 9%), with higher median CIA index values (9.8 versus 1.6) (all P < .0001). After repeat testing, 7/31 (23%) CIA-positive, RPR-negative, TP-PA--negative patients seroreverted to CIA-negative. CONCLUSIONS: TP-PA results in conjunction with clinical/behavioral assessment helped guide the management of patients with CIA-positive, RPR-negative serology. TP-PA-positive patients were both highly likely to have prior syphilis and major epidemiologic risk factors for syphilis. CIA-positive, RPR-negative, TP-PA-negative serology may represent a false-positive CIA in low-prevalence populations.

A new regulatory switch in a JAK protein kinase.

Members of the JAK family of protein kinases mediate signal transduction from cytokine receptors to transcription factor activation. Over-stimulation of these pathways is causative in immune disorders like rheumatoid arthritis, psoriasis, lupus, and Crohn's disease. A search for selective inhibitors of a JAK kinase has led to our characterization of a previously unknown kinase conformation arising from presentation of Tyr962 of TYK2 to an inhibitory small molecule via an H-bonding interaction. A small minority of protein kinase domains has a Tyrosine residue in this position within the αC-ß4 loop, and it is the only amino acid commonly seen here with H-bonding potential. These discoveries will aid design of inhibitors that discriminate among the JAK family and more widely among protein kinases.

GDC-0449-a potent inhibitor of the hedgehog pathway.

SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC.

Risser sign inter-rater and intra-rater agreement: is the Risser sign reliable?

BACKGROUND: Studies directly evaluating the reliability of the Risser sign are few in number, possess small sample sizes, and offer conflicting results. This study establishes the reliability of the Risser sign on a large sample size in an effort to provide clarification on the subject. METHODS: Two years' worth of AP pelvis radiographs from patients age 8-20 were downloaded from our institution's digital imaging system. One hundred of these images were selected for inclusion by an independent reviewer whose goal was to capture a spread of radiographs that included all Risser stages. Risser grading occurred in two rounds. In each round, three examiners randomly reviewed the 100 radiographs on three different occasions. The full AP pelvis radiograph was graded in Round 1 while only the iliac apophysis was visible in Round 2. Kappa coefficients and their confidence bounds are reported to indicate intra- and inter-observer reliability. The contrast between the rates of agreement about Risser stages in Rounds 1 versus 2 was assessed by McNemar's test. The signed-rank test was used to evaluate differences in intra-observer values between rounds. RESULTS: Round 1 inter-observer kappa was 0.76. Round 2 inter-observer kappa was 0.51. In Round 1, 63 radiographs showed perfect agreement within the same Risser stage for all observations compared to 44 radiographs with perfect agreement within the same Risser stage in Round 2 (p = 0.004). Round 1 intra-observer kappa values were 0.92, 0.86, and 0.88. Round 2 intra-observer kappa values were 0.91, 0.77, and 0.88. Intra-observer value differences between rounds were not significant for two observers (p = 0.074, 0.061) but was significant for the third observer (p = 0.002). CONCLUSION: The reliability of the Risser sign is acceptable and can be further improved when other markers of skeletal maturity on the pelvis radiograph are used to assist in grading.

An analysis of the rotator interval in patients with anterior, posterior, and multidirectional shoulder instability.

PURPOSE: To describe anatomic measurements of the rotator interval (RI) on magnetic resonance arthrogram (MRA) images and to assess the relationship between increased dimensions of the RI and instability conditions of the shoulder. METHODS: Three groups of patients with clinical instability were treated arthroscopically (anterior [A = 19 patients], posterior [P = 14 patients], and multidirectional [M = 13 patients]), and a group of 10 control patients without clinical instability were also identified. The MRAs of all groups were randomized, and 5 blinded reviewers recorded RI anatomic measurements of: (1) sagittal measures of the distance between the subscapularis (SSc) and supraspinatus (SS) tendons at 3 anatomic landmarks across the RI, and (2) the sagittal position of the long head of the biceps (LHB) relative to the most anterior aspect of the SS. RESULTS: The rotator interval distance between the SS and SSc tendons was nearly identical for all groups of instability, and was also not different from control groups. On the sagittal oblique sequences, the distance from the LHB tendon to the anterior edge of the SS tendon was significantly increased in posterior (7.4 mm) instability versus both the control group (2.4 mm; P = .025) and those with anterior instability (4.5 mm; P = .041), with the LHB in a consistent anterior position. The remainder of the measures was not statistically different between the groups. CONCLUSIONS: The distance between the SS and SSc and the overall size of the RI was well preserved in all instability patterns and control conditions. The LHB tendon assumes a more anterior position relative to the supraspinatus tendon in patients with posterior instability versus those patients with anterior instability or those without clinical instability. Additional work is necessary to further define objective radiographic evidence of RI insufficiency in patients with shoulder instability. LEVEL OF EVIDENCE: Level III, prognostic case-control study.

Evaluation of Versant hepatitis C virus genotype assay (LiPA) 2.0.

Hepatitis C virus (HCV) genotyping is a tool used to optimize antiviral treatment regimens. The newly developed Versant HCV genotype assay (LiPA) 2.0 uses sequence information from both the 5' untranslated region and the core region, allowing distinction between HCV genotype 1 and subtypes c to l of genotype 6 and between subtypes a and b of genotype 1. HCV-positive samples were genotyped manually using the Versant HCV genotype assay (LiPA) 2.0 system according to the manufacturer's instructions. For the comparison study, Versant HCV genotype assay (LiPA) 1.0 was used. In this study, 99.7% of the samples could be amplified, the genotype of 96.0% of samples could be determined, and the agreement with the reference method was 99.4% when a genotype was determined. The reproducibility study showed no significant differences in performance across sites (P = 0.43) or across lots (P = 0.88). In the comparison study, 13 samples that were uninterpretable or incorrectly genotyped with Versant HCV genotype assay (LiPA) 1.0 were correctly genotyped by Versant HCV genotype assay (LiPA) 2.0. Versant HCV genotype assay (LiPA) 2.0 is a sensitive, accurate, and reliable assay for HCV genotyping. The inclusion of the core region probes in Versant HCV genotype assay (LiPA) 2.0 results in a genotyping success rate higher than that of the current Versant HCV genotype assay (LiPA) 1.0.

An analysis of capsular area in patients with anterior, posterior, and multidirectional shoulder instability.

BACKGROUND: Although increased capsular volume has been implicated in shoulder instability, there is a paucity of clinical evidence to quantify the size of the capsule with specific instability conditions of the shoulder. HYPOTHESIS: Shoulder capsular area, as measured by magnetic resonance arthrography, is increased with specific patterns of shoulder instability. STUDY DESIGN: Cross-sectional study; Level of evidence, 4. METHODS: During an 8-month period, all patients with a diagnosis of anterior (n = 19), posterior (n = 14), or multidirectional (n = 13) instability of the shoulder and who were assessed with a magnetic resonance arthrogram were reviewed. A group of 10 control patients without clinical instability were also identified. The magnetic resonance arthrograms of all groups were randomly mixed, and 5 reviewers recorded measures of capsular length and area and determined labral abnormalities. The magnetic resonance arthrogram measurements were compared between groups, and interobserver agreement was determined. RESULTS: The cross-sectional area of the capsule was increased in patients with posterior (P = .017) or multidirectional instability (P = .021) versus controls, but not in patients with anterior instability. Additionally, the posteroinferior cross-sectional area was increased in patients with posterior (P = .001), multidirectional (P = .003), and anterior (P = .008) instability. In patients with a posterior labral tear, the mean axial (P = .043) and mean posteroinferior sagittal cross-sectional area (P = .011) was increased, but there were no differences in cross-sectional area for those with an anterior labral tear. The overall interobserver reliability was very good (correlation coefficient range, 0.68-0.94). CONCLUSION: Our results reinforce the concept that capsular elongation and laxity, either preexisting or acquired, play a role in certain instability conditions of the shoulder. Additional work is needed to determine how to correlate surgical decision making with the cross-sectional area measurements demonstrated in this study.

Persistent synchondrosis of a primary sacral ossification center in an adult with low back pain.

BACKGROUND CONTEXT: Persistence of a primary sacral ossification center resulting in synchondrosis in adulthood is rare and can confound diagnostic decision making during patient management. PURPOSE: To present a synchondrosis between the sacral ala and sacral body in a healthy 23-year-old US Marine who had low back pain. STUDY DESIGN/SETTING: Case report. OUTCOME MEASURES: Self-report measures included a numerical pain scale and Roland Morris Disability questionnaire; physiological measures included plain film radiography, computed tomography scans, magnetic resonance imaging, and physical examination procedures; and functional measures included the patient's ability to run and sit without pain and to maintain US Marine Corps fitness standards. METHODS: The initial management of his low back pain included a course of nonsteroidal anti-inflammatory medication, chiropractic manipulation of the sacroiliac joints and adjacent tissues, and therapeutic exercise. When the patient's condition did not improve as quickly as anticipated, plain X-ray films were ordered; this revealed a vertical cleft in the sacrum at the site of the patient's pain. Further imaging showed the anomalous cleft to be a synchondrosis between the costal element and the centrum of the sacrum. Manual manipulation, physical training, and ergonomic advice were continued. RESULTS: Pain severity decreased from 7 to 0, and the Roland Morris score decreased from 14 to 1. He could sit for prolonged periods of time and exercise to Marine Corps standards. CONCLUSIONS: It is unlikely that the synchondrosis was the structure responsible for generating the patient's low back pain. However, such an anomaly is clinically relevant because it may mimic a fracture.

The usefulness of magnetic resonance imaging in the diagnosis of anterolateral impingement of the ankle.

The purpose of this study is to assess the sensitivity and specificity of magnetic resonance imaging (MRI) in the diagnosis of anterolateral impingement of the ankle and to assess the most helpful sequence in making the diagnosis. Twenty-four patients who had undergone ankle arthroscopy were chosen. Twelve patients had arthroscopically documented anterolateral impingement, and 12 patients with no impingement on arthroscopy served as controls. Two musculoskeletal radiologists and an orthopedic surgeon, blinded to the operative diagnosis, retrospectively reviewed selective MRI images in the sagittal, axial, and coronal planes. The sensitivities and specificities were calculated for all 3 reviewers. The Kendall coefficient of concordance was calculated for overall agreement among reviewers. Sensitivities varied from 0.75 to 0.83, whereas specificities varied from 0.75 to 1.00. Using the Fisher exact test of contingency, the sensitivities and specificities showed that all reviewers' interpretations were statistically significant with P = .039, .001, and .012, respectively. The axial images were felt to be most helpful in making the diagnosis. The physicians felt that the sagittal images were helpful in 67%, 83%, and 100%, respectively. MRI is a useful tool that can aid the clinician in the diagnosis of anterolateral impingement of the ankle. T1 sagittal images demonstrating displacement of the normal fat signal anterior to the fibula by scar can be useful and help to confirm the diagnosis.