Free bone fragments are associated with the development of heterotopic ossification after hemiarthroplasty for femoral neck fracture: a retrospective observational study.

PURPOSE: Heterotopic ossification (HO) can occur after hemiarthroplasty (HA) for femoral neck fractures (FNF). This study aimed to investigate the frequency and factors contributing to the development of HO after HA. METHODS: The study included data from 92 of 183 patients (26 male and 66 female) who sustained FNF and underwent HA between April 2019 and January 2022. HO was identified on postoperative radiographic images. Patient background, operative duration, blood loss, and presence of free bone fragments immediately after surgery were compared between the HO and non-HO groups. Statistical analyses included the independent-sample t-test for continuous variables and the chi-squared test for categorical variables. A multivariate logistic regression analysis was performed using HO as an objective variable. RESULTS: HO occurred in 50 of the 92 (54%) patients. There were no statistically significant differences in patient backgrounds. Univariate analysis revealed significantly longer mean operative duration and greater blood loss in the HO group. Free bone fragments in the immediate postoperative period were observed in 29 of 50 (58%) patients in the HO group and in 3 of 42 (7.1%) patients in the non-HO group, a statistically significant difference. Logistic regression analysis revealed that the presence of free bone fragments was an independent explanatory factor for HO development. CONCLUSION: The presence of free bone fragments immediately after surgery may be significantly associated with the development of HO. Therefore, it is necessary to sufficiently remove such fragments during surgery because they may trigger HO.

Is preoperative glenoid defect size a reliable indicator of postoperative recurrence after arthroscopic Bankart repair in teenage competitive athletes?

BACKGROUND: Being younger than 20 years of age at the time of arthroscopic Bankart repair (ABR) is known to be one of the most important risk factors for postoperative recurrence of instability. When deciding on the appropriate surgical approach, surgeons generally consider only the size of a critical glenoid defect, and most of them do not take into account factors such as the size of bone fragments and possible bone union after arthroscopic bony Bankart repair (ABBR). Therefore, this retrospective study aimed to clarify the risk factors for postoperative recurrence after ABR in teenage competitive athletes by focusing on glenoid rim morphologies and bone union. METHODS: Participants were 115 teenage competitive athletes without a capsular injury who underwent primary ABR for chronic traumatic anterior instability and were followed up for a minimum of 2 years. Possible risk factors for postoperative recurrence were investigated by univariate and multivariate analysis. In shoulders with a glenoid defect and bone fragment, the influence of glenoid defect size and bone fragment size on bone union after ABBR was also investigated. RESULTS: Postoperative recurrence was seen in 16 patients (13.9%). Regarding glenoid defect size, recurrence was seen in 1 (3.2%) of 31 shoulders with a glenoid defect smaller than 5% (including those with a normal glenoid), 15 (22.1%) of 68 shoulders with a glenoid defect of 5%-20%, and 0 (0%) of 16 shoulders with a glenoid defect of 20% or larger (P = .009). Regarding bone union, recurrence was seen in 4 (6.9%) of 58 shoulders with complete or partial bone union after ABBR and 8 (40%) of 20 shoulders with nonunion or disappearance of the bone fragment (P = .001). Regarding bone fragment size, recurrence was seen in 12 (20.7%) of 58 shoulders with a small or no bone fragment (<7.5%) and in 3 (8.6%) of 35 shoulders with a large bone fragment (≥7.5%; P = .154). Multivariate analysis identified non-union or disappearance of the bone fragment after ABBR as a significant risk factor for recurrence. Complete or partial bone union was seen in 25 (58.1%) of 43 shoulders with a small bone fragment (<7.5%) and 33 (94.3%) of 35 shoulders with a large bone fragment (≥7.5%; P < .001). CONCLUSIONS: In teenage competitive athletes, bone union after ABBR affects postoperative recurrence after ABR, regardless of the preoperative glenoid defect size, and bone union rate after ABBR is significantly influenced by bone fragment size.

New bone formation after arthroscopic Bankart repair for unstable shoulders with an erosion-type glenoid defect.

BACKGROUND: The purpose of the present study was to retrospectively evaluate new bone formation after arthroscopic Bankart repair (ABR) and the influence of new bone formation on recurrence in shoulders with an erosion-type glenoid defect. METHODS: We analyzed data on shoulders with an erosion-type glenoid defect. Participants were patients who underwent computed tomography to evaluate new bone formation after ABR performed from 2004 to 2021 and were followed for a minimum of 2 years. We investigated the factors influencing new bone formation, in particular the presence of an intraoperative bone fragment, and the influence of new bone formation and its size on postoperative recurrence. RESULTS: A total of 100 shoulders were included. The mean glenoid defect size was 10.1% ± 6.3% (range, 1.2%-31.5%). New bone formed postoperatively in 15 shoulders (15.0%) and was seen in significantly more shoulders with an intraoperative bone fragment (11 of 18, 61.1%) than in those without a fragment (4 of 82, 4.9%; P < .001). Recurrence occurred in 22 shoulders (22.0%), and the rate of recurrence was not different between shoulders with new bone formation (3 of 15, 20.0%) and without new bone formation (19 of 85, 22.4%; P = .999). Among the 15 shoulders with new bone formation, the size of the new bone fragments relative to glenoid width was <5% in 2 shoulders, 5%-<7.5% in 8 shoulders, 7.5%-<10% in 3 shoulders, and ≥10% in 2 shoulders; in all 3 shoulders with postoperative recurrence, the relative size was <7.5%. CONCLUSIONS: Even in shoulders with an erosion-type glenoid defect, new bone may form after ABR, especially in shoulders with an intraoperative bone fragment. However, new bone formation does not decrease the rate of postoperative recurrence.

Infusion of Variable Chemical Structure to Tune Stacking among Metal-Organic Layers in 2D Nano MOF.

Thickness of two-dimensional (2D) metal-organic frameworks (MOFs) govern their intriguing functionalities. Primarily this thickness is controlled by the stacking between the metal-organic layers (MOL). It is observed that until now such modulating factors for stacking efficiency of MOL are not well studied. Here, we report a fundamental hypothesis to comprehend regulation of stacking efficiency among MOLs as a function of chemical structure of organic ligands (dicarboxylic acids and pillar linkers). This basically involves a series of isostructural three-dimensional (3D) MOFs which contain linkers of variable chemical nature that could be depillared to generate 2D stacked MOFs of different thickness. Depending on the linkers, we encountered the formation of single MOL to stacked multiple MOLs as evidenced from atomic force microscopic and other experimental analysis. The present study gives a concrete correlation between the stacking within 2D MOFs (from monolayer to multilayers), and their 3D counter parts, which may provide a thickness tuning pathway for 2D MOFs.

Infusion of Variable Chemical Structure to Tune Stacking among Metal-Organic Layers in 2D Nano MOFs.

Invited for the cover of this issue is the group of Biplab Manna at the University of Kumamoto. The image depicts various kinds of stacking between the metal-organic layers of MOFs. Read the full text of the article at 10.1002/chem.202201665.

On-the-Edge Anchor Placement May Be Protective Against Glenoid Rim Erosion After Arthroscopic Bankart Repair Compared to On-the-Face Anchor Placement.

PURPOSE: This retrospective study aimed to compare the effects of 2 different anchoring placements on glenoid rim erosion after arthroscopic Bankart repair (ABR). METHODS: Shoulders that underwent ABR from January 2013 to July 2020 were divided into 2 groups according to anchor placement (on-the-face, group F; on-the-edge, group E). We retrospectively calculated the percent change of glenoid width (Δ) on the first postoperative computed tomography scan (CT; performed within 6 months) and second postoperative CT (performed at 6 to 12 months) relative to the width on the preoperative CT and compared percent changes between the 2 groups. Also, we investigated the influence of preoperative glenoid structures (normal, erosion, bony Bankart) and the postoperative recurrence rate. RESULTS: We examined 225 shoulders in 214 patients (group F, n = 151; group E, n = 74). At first CT, anchoring placement was significantly associated with postoperative decrease of glenoid width (group F, -7.6% ± 7.9%; group E, -0.1% ± 9.7%; P < .0001). The difference between groups F and E was significant in shoulders with a preoperative glenoid defect (bony Bankart, -6.6% ± 8.8% vs 2.5% ± 11.2%, respectively; P < .0001; erosion, -6.6% ± 6.2% vs -2.6% ± 5.3%, respectively; P = .03). In 112 shoulders, CT was performed twice; Δ was -6.9% ± 7.3% in group F (n = 64) and -1.7% ± 10.1% in group E (n = 48; P = .005) at the first CT and -3.2% ± 10.0% and 1.0% ± 10.6% (P = .10), respectively, at the second CT, indicating recovery of glenoid width in both groups. The postoperative recurrence rate in patients with at least 2 years' follow-up was 14.7% in group F and 14.6% in group E. CONCLUSIONS: In the early stage after ABR, on-the-edge glenoid anchor placement was associated with less glenoid rim erosion than on-the-face anchor placement. LEVEL OF EVIDENCE: Level III, retrospective comparative trial.

A Glenoid Defect of 13.5% or Larger Is Not Always Critical in Male Competitive Rugby and American Football Players Undergoing Arthroscopic Bony Bankart Repair: Contribution of Resultant Large Bone Fragment.

PURPOSE: To investigate bone union and postoperative recurrence after arthroscopic bony Bankart repair (ABBR) in male competitive rugby and American football players with a subcritical glenoid defect of ≥13.5% and to compare findings with those in players with a glenoid defect of <13.5%. METHODS: Participants were male competitive rugby or American football players with a glenoid defect and bone fragment who underwent ABBR from July 2011 to December 2018 and were followed for a minimum of 2 years. We investigated the influence of glenoid defect and bone fragment size on bone union and postoperative recurrence after ABBR. RESULTS: We included 45 rugby players and 35 American football players. A total of 38 shoulders were assigned to the small defect group (<13.5%) and 42 to the large defect group (≥13.5%). The complete bone union rate was 47.4% in the small defect group and 71.4% in the large defect group (P = .040), and postoperative recurrence was seen in 13 (34.2%) and 5 shoulders (11.9%), respectively (P = .030). In the small defect group, the bone fragment size was <7.5% in 30 shoulders and ≥7.5% in 8 shoulders; in comparison, the respective numbers were 12 and 30 shoulders in the large defect group, and large fragments (>7.5%) were significantly more common in this group (P < .001). The complete union rate was significantly higher in shoulders with a large fragment (≥7.5%) than in those with a small fragment (<7.5%; 78.9% versus 42.9%, respectively; P = .001). The recurrence rate was 33.3% in shoulders with a small fragment (<7.5%) and 10.5% in shoulders with a large fragment (≥7.5%; P = .017) and was significantly lower in shoulders with a complete union than in those without a complete union (6.3% versus 46.9%, respectively; P < .001). CONCLUSION: The postoperative recurrence rate after ABBR was lower in male competitive rugby and American football players with a large glenoid defect (≥13.5%) than in those with a small glenoid defect (<13.5%) and might be associated with a higher rate of complete bone union of the resultant large bone fragment (≥7.5%). LEVEL OF EVIDENCE: III, case-control study.

Unrecognized glenoid fracture in opposite shoulders with symptomatic anterior instability.

BACKGROUND: The purpose of the present study was to investigate the characteristics of unrecognized glenoid fracture in opposite shoulders with symptomatic anterior instability. METHODS: Participants were 38 patients, who had complaints of instability on only one side (symptomatic shoulder) and had no complaints despite of a glenoid fracture on the other shoulder (asymptomatic shoulder) from 2011 to 2020. Factors that could influence the onset of symptoms including glenoid rim morphology were retrospectively investigated. RESULTS: Among the asymptomatic shoulders, 16 had a single traumatic event and 22 had no history of trauma. The glenoid morphology was normal in 6, erosion in 12 and bony Bankart in 20 on the symptomatic side, whereas the respective shoulders were 0, 16 and 22 on the asymptomatic side. Bone union of bony Bankart was complete in 9, partial in 3 and non-union in 8 on the symptomatic side, whereas the respective shoulders were 18, 3 and 1 on the asymptomatic side. The mean glenoid defect size was 10.4% and 7.8%, and the mean bone fragment size was 5.0% and 4.5%, respectively. The mean medial displacement of bone fragments was 2.6 mm and 1.0 mm, respectively (p < 0.001). A larger glenoid defect (≥10%) was recognized in 19 symptomatic shoulders and 10 asymptomatic shoulders. Among them, erosion was solely recognized in 5 symptomatic shoulders. In shoulders with bony Bankart, all 10 asymptomatic shoulders had a completely or partially united fragment with less than 2 mm displacement. On the other hand, among 14 symptomatic shoulders, united fragment was solely recognized in 8 shoulders, in which medial displacement was less than 2 mm in 3 shoulders. CONCLUSIONS: Even if a glenoid fracture occurred, symptom such as instability or pain was not always recognized by all patients. Regardless of glenoid defect size, shoulders with a completely or partially united bone fragment and with less than 2 mm displacement were found to be asymptomatic.

Knot location in arthroscopic inside-out meniscal repair: Cadaveric evaluation.

BACKGROUND: The inside-out repair technique is the gold standard for treatment of meniscal tears, while some soft tissues can be hung as the sutures are tied outside the capsule. The purpose was to clarify the association between the suture site and knot location in the arthroscopic inside-out technique. METHODS: Inside-out meniscal suture was arthroscopically performed on medial and lateral menisci in twenty-three cadaveric knees, on the assumption that longitudinal tear existed. A retractor was inserted above the semi-membranous tendon and anterior to the gastrocnemius for the medial side, while the retractor was placed in the anterior space of the gastrocnemius for the lateral side. After identifying three segments (anterior, middle and posterior segments), eight sutures were inserted into the following eight areas in each knee: anterior (M1, L1) and posterior (M2, L2) areas of the middle segment, and anterior (M3, L3) and posterior (M4, L4) areas of the posterior segment. Twelve knees underwent meniscal repair on femoral side and eleven passed sutures on the tibial side, while knots were tied outside of the joint. Attentive dissection was performed to assess the relation between knot locations and the principal structures around the knee joint. RESULTS: In medial meniscal suture, most sutures for the middle portion (M1, 2) bound medial collateral ligament (MCL), while a few cases included the semi-membranous tendon for the M4 area. In lateral meniscal suture, sutures for the L1 area tied some fibers of lateral collateral ligament (LCL) in high frequency, while popliteal muscles/tendons were tied over at the L3 area. CONCLUSIONS: Most suture knots were located on MCL or capsule in medial meniscus suture, while more than half sutures passed through LCL or popliteal tendon/muscle in lateral meniscus suture. An assistant should retract LCL under direct observation and the surgeon must confirm the direction of needle for lateral meniscal repair.

The process of bone union after arthroscopic bony Bankart repair in younger athletes with a subcritical glenoid defect: An advantage of remained large bone fragment.

BACKGROUND: The purpose of the present study was to investigate the bone union process after arthroscopic bony Bankart repair (ABBR) in shoulders with a subcritical glenoid defect of 13.5% or larger. METHODS: Bone union process after ABBR performed from 2011 to 2018 were retrospectively investigated in 47 athletes younger than 30 years with a subcritical glenoid defect, who underwent CT at least twice postoperatively. The change of bone union between first CT within 6 months and final CT later than 6 months was investigated, especially noticing bone fragment size (≥7.5% versus <7.5%). RESULTS: The mean period at first CT and at final CT was 4.1 ± 0.6 months (3-6 months) and 16.8 ± 11.6 months (7-71 months), respectively. From the first to final CT, among 15 shoulders with a small bone fragment (<7.5%), complete union increased from 4 shoulders (26.7%) to 8 shoulders (53.3%), while among 32 shoulders with a large bone fragment (≥7.5%), complete union increased from 15 shoulders (46.9%) to 25 shoulders (78.1%). On the other hand, while non-union or disappeared bone fragment was recognized in 8 shoulders (53.3%) with a small fragment and in 2 shoulders (6.3%) with a large fragment at first CT, it was solely recognized in 4 shoulders (26.7%) with a small fragment and in no shoulders with a large fragment at final CT. While postoperative glenoid fracture at the site of bone union was recognized in 7 shoulders, complete union was finally obtained after conservative treatment in 5 shoulders. So, final complete union was obtained in 9 (60%) of 15 shoulders with a small fragment and in 29 (90.6%) of 32 shoulders with a large fragment (p = 0.021). CONCLUSIONS: In shoulders with a subcritical glenoid defect, when a large bone fragment (≥7.5%) was repaired, complete union rate was higher and complete union could be obtained earlier.

Anatomical Triple Bundle Anterior Cruciate Ligament Reconstructions With Hamstring Tendon Autografts: Tunnel Locations and 2-Year Clinical Outcomes.

PURPOSE: To anatomically clarify the location of the tunnel apertures created using the bony landmark strategy and to elucidate clinical outcomes after anatomic triple-bundle (ATB) anterior cruciate ligament (ACL) reconstruction. METHODS: Thirty-two patients with unilateral ACL injury who had consented to undergo computed tomography (CT) at 3 weeks, as well as 2-year follow-up evaluation, were enrolled. At the time of surgery, remnant tissues were thoroughly cleared to create 2 femoral and 3 tibial tunnels inside the ACL attachment areas bordered by the bony landmarks. Two double-looped semitendinosus tendon autografts were prepared and fixed on the femur with two EndoButton-CLs and secured to the tibia with pullout sutures and plates with 10-20N of tension. The location of the tunnel aperture areas was assessed using 3-dimensional CT images, and 2-year postoperative clinical outcomes were evaluated. RESULTS: The CT evaluation showed 100% of the femoral tunnel aperture area and at least 79% of the tibial tunnel aperture area were located inside the anatomic attachment areas. Thirty patients were available for clinical evaluation. The International Knee Documentation Committee subjective assessment showed all of the patients were classified as "normal" or "nearly normal." Lachman and pivot-shift tests were negative in 100% and 93%, respectively. The mean side-to-side difference of anterior laxity at the maximum manual force with a KT-1000 Knee Arthrometer was 0.7 ± 0.7 mm, ranging from 0 to 2 mm. CONCLUSION: In ATB ACL reconstructions with hamstring tendon grafts, the tunnels can be created in proper locations using the arthroscopically-identifiable bony landmarks. Moreover, ATB ACL reconstruction with hamstring tendon grafts via the proper tunnels result in consistently satisfactory clinical outcomes. LEVEL OF EVIDENCE: Level IV, case series.

Surgical technique in tension band wiring method for selected comminuted olecranon fractures.

BACKGROUND: The use of tension band wiring (TBW) for comminuted olecranon fractures is less recommendable these days. However, some experts preferentially apply TBW to comminuted fractures resulting in favorable outcomes. We here present the surgical technique using TBW with eyelet and absorbable pins for selected comminuted olecranon fractures and review the clinical and radiographic outcomes. METHODS: Twenty-four surgically treated patients with Colton Group 2C or 2D olecranon fractures in focus on the intermediate fragment (IMF) were enrolled. IMFs were primarily fixed with buried bioabsorbable poly-L-lactic acid pins followed by definitive fixation of the olecranon process with TBW with eyelet. The adequacy of the reconstructed notch was especially estimated by parameters on radiographs using digital imaging software. RESULTS: The average follow-up was 30 months (10 to 86 months). All 24 fractures achieved union, and the maintenance of the articular curvature was confirmed according to statistical analysis on radiographs. The average elbow flexion was 135.1° (range 100° to 145°), and the average elbow extension was - 4.8° (range - 20° to 10°). The mean Mayo Elbow Performance score was 97.3 points (range 80 to 100 points). No cases of pin migration, infection, nerve problem, heterotrophic ossification, or secondary osteoarthritis were observed. CONCLUSIONS: For selected comminuted olecranon fractures, TBW with the eyelet pins and biodegradable pins could yield satisfactory clinical and radiographic outcomes.

Development of a detection method for antisense oligonucleotides in mouse kidneys by matrix-assisted laser desorption/ionization imaging mass spectrometry.

RATIONALE: Oligonucleotide therapeutics have recently gained much attention, but its pharmacokinetic evaluation methods are still not sufficient, and, in particular, more tools are needed to evaluate their tissue distribution and metabolites. We developed a matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS)-based method to evaluate the tissue distribution of oligonucleotide therapeutics. METHODS: We used an antisense oligonucleotide containing locked nucleic acids (LNA-A). Various washing protocols were examined using mouse kidney homogenate sections. Next, we applied a two-step matrix preparation strategy. As a first step, 3-hydroxypicolinic acid (3-HPA) matrix containing citrate and amines was sprayed using an airbrush and subsequently 3-HPA matrix containing citrate only was sprayed using the ImagePrep. Finally, kidney sections prepared from LNA-A-dosed mice were treated with our optimized method and analyzed with MALDI-IMS. RESULTS: The selected washing method made it possible to detect LNA-A with MALDI-IMS and, furthermore, our developed matrix pretreatment method enhanced signal intensity approximately two-fold. MALDI-IMS revealed that LNA-A localized in a portion presumed to be the renal cortex. We also obtained information on LNA-A metabolites, which showed the same distribution profile as LNA-A in kidneys. CONCLUSIONS: This study shows that MALDI-IMS can be applied to evaluate the tissue distribution of oligonucleotide therapeutics. Our method can evaluate the tissue distribution along with metabolites and has the potential to help the development of novel oligonucleotide therapeutics.

Vibration acceleration enhances proliferation, migration, and maturation of C2C12 cells and promotes regeneration of muscle injury in male rats.

Vibration acceleration (VA) using a whole-body vibration device is beneficial for skeletal muscles. However, its effect at the cellular level remains unclear. We aimed to investigate the effects of VA on muscles in vitro and in vivo using the C2C12 mouse myoblast cell line and cardiotoxin-induced injury in male rat soleus muscles. Cell proliferation was evaluated using the WST/CCK-8 assay and proportion of Ki-67 positive cells. Cell migration was assessed using wound-healing assay. Cell differentiation was examined by the maturation index in immunostained cultured myotubes and real-time polymerase chain reaction. Regeneration of soleus muscle in rats was assessed by recruitment of satellite cells, cross-sectional area of regenerated muscle fibers, number of centrally nucleated fibers, and conversion of regenerated muscle from fast- to slow-twitch. VA at 30 Hz with low amplitude for 10 min promoted C2C12 cell proliferation, migration, and myotube maturation, without promoting expression of genes related to differentiation. VA significantly increased Pax7-stained satellite cells and centrally nucleated fibers in injured soleus muscles on Day 7 and promoted conversion of fast- to slow-twitch muscle fibers with an increase in the mean cross-sectional area of regenerated muscle fibers on Day 14. VA enhanced the proliferation, migration, and maturation of C2C12 myoblasts and regeneration of injured rat muscles.

Anti-SARS-CoV-2 gapmer antisense oligonucleotides targeting the main protease region of viral RNA.

Given the worldwide risk for the outbreak of emerging/re-emerging respiratory viruses, establishment of new antiviral strategies is greatly demanded. In this study, we present a scheme to identify gapmer antisense oligonucleotides (ASOs) targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA that efficiently inhibit viral replication. We synthesized approximately 300 gapmer ASOs designed to target various SARS-CoV-2 RNA regions and evaluated their activity in cell-based assays. Through a multistep screening in cell culture systems, we identified that ASO#41, targeting the coding region for viral main protease, reduced SARS-CoV-2 RNA levels in infected cells and inhibited virus-induced cytopathic effects. Antiviral effect of ASO#41 was also observed in iPS cell-derived human lung organoids. ASO#41 depleted intracellular viral RNAs during genome replication in an endogenous RNaseH-dependent manner. ASO#41 showed a wide range of antiviral activity against SARS-CoV-2 variants of concern including Alpha, Delta, and Omicron. Intranasal administration to mice exhibited intracellular accumulation of ASO#41 in the lung and significantly reduced the viral infectious titer, with milder body weight loss due to SARS-CoV-2 infection. Further chemical modification with phosphoryl guanidine-containing backbone linkages provided an elevation of anti-SARS-CoV-2 activity, with 23.4 nM of 50% antiviral inhibitory concentration, one of the strongest anti-SARS-CoV-2 ASOs reported so far. Our study presents an approach to identify active ASOs against SARS-CoV-2, which is potentially useful for establishing an antiviral strategy by targeting genome RNA of respiratory viruses.

CD8+ Regulatory T Cells Induced by Lipopolysaccharide Improve Mouse Endotoxin Shock.

Sepsis is a systemic inflammatory disease caused by a bacterial infection that leads to severe mortality, especially in elderly patients, because of an excessive immune response and impaired regulatory functions. Antibiotic treatment is widely accepted as the first-line therapy for sepsis; however, its excessive use has led to the emergence of multidrug-resistant bacteria in patients with sepsis. Therefore, immunotherapy may be effective in treating sepsis. Although CD8+ regulatory T cells (Tregs) are known to have immunomodulatory effects in various inflammatory diseases, their role during sepsis remains unclear. In this study, we investigated the role of CD8+ Tregs in an LPS-induced endotoxic shock model in young (8-12 wk old) and aged (18-20 mo old) mice. The adoptive transfer of CD8+ Tregs into LPS-treated young mice improved the survival rate of LPS-induced endotoxic shock. Moreover, the number of CD8+ Tregs in LPS-treated young mice increased through the induction of IL-15 produced by CD11c+ cells. In contrast, LPS-treated aged mice showed a reduced induction of CD8+ Tregs owing to the limited production of IL-15. Furthermore, CD8+ Tregs induced by treatment with the rIL-15/IL-15Rα complex prevented LPS-induced body wight loss and tissue injury in aged mice. In this study, to our knowledge, the induction of CD8+ Tregs as novel immunotherapy or adjuvant therapy for endotoxic shock might reduce the uncontrolled immune response and ultimately improve the outcomes of endotoxic shock.

Preclinical safety profile of a liver-localized mitochondrial uncoupler: OPC-163493.

Mitochondrial uncouplers (mUncouplers) are known to exhibit a variety of toxic effects in animals. Here we report a safety profile of an mUncoupler, OPC-163493, recently synthesized at Otsuka Pharmaceutical Co, Ltd, and its development as a therapeutic agent for treating diabetes. To understand the acute and subchronic toxicity of OPC-163493, single and repeated oral dose studies in rats, dogs, and monkeys were performed. In the rat studies, rigor mortis and increased body temperatures were observed in the high dose group. Focal necrosis, fatty change, and granular eosinophilic cytoplasm of the hepatocytes were also observed in the high dose group. In the dog studies, gastrointestinal manifestations were observed with decreased body weight and decreased food consumption in the high dose group. Necrotizing arteritis was observed in multiple organs as well as meningitis with hemorrhage in the brain. In the monkey studies, vomiting, decreased food consumption, and decreased locomotor activity were observed in the high dose group. Degeneration of the proximal convoluted tubules and the straight tubular epithelium, regeneration of the proximal tubular epithelium, and degeneration of the collecting tubular epithelium were observed. The target organs of OPC-163493 were liver, blood vessels, and kidney in rats, dogs, and monkeys, respectively. In rats, dogs, and monkeys, safety ratios were 100:1, 13:1, and 20:1, respectively, in terms of total exposure (AUC24h). These safety ratios showed clear separation between exposure to OPC-163493 in animals at NOAEL and the exposure at the effective dose in ZDF rats. This information should contribute to the drug development of new and effective mUncoupler candidates.

Imaging Mass Spectrometry (IMS) for drug discovery and development survey: Results on methods, applications and regulatory compliance.

Imaging mass spectrometry (IMS) is increasingly used for drug discovery and development to understand target enagement, tissue distribution, drug toxicity, and disease mechanisms, etc. However, this is still a relatively new technique that requires further development validation before it will be an acceptable technique to support regulated development of new drugs. Thus, best practices will need to be established to build more confidence and gain wider acceptance by the scientific community, pharmaceutical industry, and regulatory authorities. The Imaging Mass Spectrometry Society (IMSS) and the Japan Association for Imaging Mass Spectrometry (JAIMS) have conducted a thorough survey to gather information on the current state of IMS and to identify key issues. The survey was sent to researchers or managers in the position who are currently using IMS techniques in support of their drug discovery and development efforts and/or who plan to use such tools as best practices are established. The survey probes questions related to details regarding technical aspects of IMS, which includes data acquisition, data analysis and quantitation, data integrity, reporting, applications, and regulatory concerns. This international survey was conducted online through the Survey Monkey (https://www.surveymonkey.com) in both English and Japanese from September 14 through September 30, 2020.

Performance evaluation of the new rapid fertility assays in whole blood and plasma on PATHFAST.

BACKGROUND: The purpose of this study was to evaluate the validity of the PATHFAST fertility marker assays for the rapid measurement of female hormones including: LH, FSH, Estradiol (E2), Progesterone (P4), Prolactin (PRL), and HCG. As for the PATHFAST fertility marker assays, female hormones can be measured by whole blood, plasma, and serum. METHODS: The correlation of the heparin whole blood and the plasma samples in the PATHFAST was examined. The method comparison study of PATHFAST fertility marker assays was performed with the Elecsys 2010, AIA-360, IMMULITE 2000, miniVIDAS, and ARCHITECT i2000. Determination of the reference range values of the PATHFAST fertility marker assays was performed with serum samples which were obtained during the follicular phase, mid-cycle, luteal phase, and postmenopausal phase. RESULTS: The results of plasma samples of female hormones measured by the PATHFAST correlated highly with those of whole blood samples (r > 0.9). The results of LH, FSH, E2, P4, PRL, and HCG as measured by the PATHFAST correlated well with other commercial fertility assays (r > 0.9). Reference values of PATHFAST fertility marker assays were equivalent to those of other commercial methods. CONCLUSIONS: The PATHFAST system is an accurate diagnostic tool for the rapid assay of female hormones. The PATHFAST fertility marker assays can be useful in a physician's office laboratory (POL) as well as various clinical sites during infertility treatment.

Comparison of accuracy of cup position using portable navigation versus alignment guide in total hip arthroplasty in supine position.

BACKGROUND: Accelerometer-based portable navigation systems in supine total hip arthroplasty (THA) have been developed, but there are no reports on the accuracy of cup placement. We aimed to investigate and compare the accuracy of the accelerometer-based portable navigation system versus the acetabular alignment guide placed on the pelvis in THA using the direct anterior approach (DAA). Both devices tracked changes in the pelvic position. METHODS: In this single-centre, retrospective study, we reviewed 115 hips in 113 patients who underwent primary THA via the DAA using an accelerometer-based portable navigation system in the supine position (portable navigation group) and 106 hips in 101 patients who underwent THA using an acetabular alignment guide (alignment guide group) as controls. Hips were evaluated postoperatively using computed tomography to measure cup orientation. The accuracy of cup orientation was compared between the 2 groups. RESULTS: Absolute values of inclination error were 3.1° ± 2.2° and 2.9° ± 2.3° (p = 0.708) in the portable navigation and alignment guide groups and those of anteversion error were 2.8° ± 2.3° and 3.7° ± 2.7°, respectively (p = 0.005). The number of cups placed within 10° of error was 98.3% and 96.2% in the portable navigation and alignment guide groups, respectively (p = 0.304). The portable navigation group had significantly more hips (72.2%) placed within a 5° margin of error than did the alignment guide group (56.6%) (p = 0.016). CONCLUSION: High accuracy in cup placement was achieved using accelerometer-based portable navigation in supine THA. Using a navigation system may contribute to improved long-term outcomes.