Human early-onset dementia caused by DAP12 deficiency reveals a unique signature of dysregulated microglia.

The TREM2-DAP12 receptor complex sustains microglia functions. Heterozygous hypofunctional TREM2 variants impair microglia, accelerating late-onset Alzheimer's disease. Homozygous inactivating variants of TREM2 or TYROBP-encoding DAP12 cause Nasu-Hakola disease (NHD), an early-onset dementia characterized by cerebral atrophy, myelin loss and gliosis. Mechanisms underpinning NHD are unknown. Here, single-nucleus RNA-sequencing analysis of brain specimens from DAP12-deficient NHD individuals revealed a unique microglia signature indicating heightened RUNX1, STAT3 and transforming growth factor-ß signaling pathways that mediate repair responses to injuries. This profile correlated with a wound healing signature in astrocytes and impaired myelination in oligodendrocytes, while pericyte profiles indicated vascular abnormalities. Conversely, single-nuclei signatures in mice lacking DAP12 signaling reflected very mild microglial defects that did not recapitulate NHD. We envision that DAP12 signaling in microglia attenuates wound healing pathways that, if left unchecked, interfere with microglial physiological functions, causing pathology in human. The identification of a dysregulated NHD microglia signature sparks potential therapeutic strategies aimed at resetting microglia signaling pathways.

Direct activation of microglia by ß-glucosylceramide causes phagocytosis of neurons that exacerbates Gaucher disease.

Gaucher disease (GD) is the most common lysosomal storage disease caused by recessive mutations in the degrading enzyme of ß-glucosylceramide (ß-GlcCer). However, it remains unclear how ß-GlcCer causes severe neuronopathic symptoms, which are not fully treated by current therapies. We herein found that ß-GlcCer accumulating in GD activated microglia through macrophage-inducible C-type lectin (Mincle) to induce phagocytosis of living neurons, which exacerbated Gaucher symptoms. This process was augmented by tumor necrosis factor (TNF) secreted from activated microglia that sensitized neurons for phagocytosis. This characteristic pathology was also observed in human neuronopathic GD. Blockade of these pathways in mice with a combination of FDA-approved drugs, minocycline (microglia activation inhibitor) and etanercept (TNF blocker), effectively protected neurons and ameliorated neuronopathic symptoms. In this study, we propose that limiting unrestrained microglia activation using drug repurposing provides a quickly applicable therapeutic option for fatal neuronopathic GD.

Age-dependent formation of TMEM106B amyloid filaments in human brains.

Many age-dependent neurodegenerative diseases, such as Alzheimer's and Parkinson's, are characterized by abundant inclusions of amyloid filaments. Filamentous inclusions of the proteins tau, amyloid-ß, α-synuclein and transactive response DNA-binding protein (TARDBP; also known as TDP-43) are the most common1,2. Here we used structure determination by cryogenic electron microscopy to show that residues 120-254 of the lysosomal type II transmembrane protein 106B (TMEM106B) also form amyloid filaments in human brains. We determined the structures of TMEM106B filaments from a number of brain regions of 22 individuals with abundant amyloid deposits, including those resulting from sporadic and inherited tauopathies, amyloid-ß amyloidoses, synucleinopathies and TDP-43 proteinopathies, as well as from the frontal cortex of 3 individuals with normal neurology and no or only a few amyloid deposits. We observed three TMEM106B folds, with no clear relationships between folds and diseases. TMEM106B filaments correlated with the presence of a 29-kDa sarkosyl-insoluble fragment and globular cytoplasmic inclusions, as detected by an antibody specific to the carboxy-terminal region of TMEM106B. The identification of TMEM106B filaments in the brains of older, but not younger, individuals with normal neurology indicates that they form in an age-dependent manner.

Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes.

Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson's disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.

Efficacy of the traction method for gastric endoscopic submucosal dissection: a randomized controlled trial (with videos).

BACKGROUND AND AIMS: To overcome the technical difficulties associated with gastric endoscopic submucosal dissection (ESD), a novel traction device that can alter the direction of traction was developed. This study compared the efficacy and safety of conventional ESD versus those of traction-assisted gastric ESD. METHODS: Patients with a single gastric epithelial neoplasm were randomized to receive conventional (n = 75) or traction-assisted (n = 73) gastric ESD. The primary outcome was ESD procedure time. RESULTS: There were no differences between the conventional and traction-assisted groups with respect to treatment results or adverse events. The mean procedure time was similar for both groups (78.9 vs 88.3 minutes, respectively; P = .3); however, times for the traction device tended to be shorter for lesions in the lesser curvature of the upper or middle stomach (84.6 vs 123.2 minutes; P = .057). CONCLUSIONS: Traction-assisted ESD for lesions in the lesser curvature of the upper or middle stomach were shorter, thereby reducing the procedure time of conventional ESD. (Clinical trial registration: University Hospital Medial Information Network Clinical Trials Registry, identifier 000044450.).

Conventional magnetic resonance imaging key features for distinguishing pathologically confirmed corticobasal degeneration from its mimics: a retrospective analysis of the J-VAC study.

PURPOSE: Due to the indistinguishable clinical features of corticobasal syndrome (CBS), the antemortem differentiation between corticobasal degeneration (CBD) and its mimics remains challenging. However, the utility of conventional magnetic resonance imaging (MRI) for the diagnosis of CBD has not been sufficiently evaluated. This study aimed to investigate the diagnostic performance of conventional MRI findings in differentiating pathologically confirmed CBD from its mimics. METHODS: Semiquantitative visual rating scales were employed to assess the degree and distribution of atrophy and asymmetry on conventional T1-weighted and T2-weighted images. Additionally, subcortical white matter hyperintensity (SWMH) on fluid-attenuated inversion recovery images were visually evaluated. RESULTS: In addition to 19 patients with CBD, 16 with CBD mimics (progressive supranuclear palsy (PSP): 9, Alzheimer's disease (AD): 4, dementia with Lewy bodies (DLB): 1, frontotemporal lobar degeneration with TAR DNA-binding protein of 43 kDa(FTLD-TDP): 1, and globular glial tauopathy (GGT): 1) were investigated. Compared with the CBD group, the PSP-CBS subgroup showed severe midbrain atrophy without SWMH. The non-PSP-CBS subgroup, comprising patients with AD, DLB, FTLD-TDP, and GGT, showed severe temporal atrophy with widespread asymmetry, especially in the temporal lobes. In addition to over half of the patients with CBD, two with FTLD-TDP and GGT showed SWMH, respectively. CONCLUSION: This study elucidates the distinct structural changes between the CBD and its mimics based on visual rating scales. The evaluation of atrophic distribution and SWMH may serve as imaging biomarkers of conventional MRI for detecting background pathologies.

Psychological distress mediates the association between COVID-19-related discrimination and subsequent PTSD symptom severity in healthcare workers: a two-year follow-up study.

BACKGROUND: Past research has suggested a cross-sectional association between COVID-19-related discrimination and PTSD symptom severity. However, no cohort study has examined the longitudinal association that better supports causal interpretation. Also, even if such an association genuinely exists, the specific pathway remains unclear. METHODS: We conducted a two-year follow-up study, obtaining data from healthcare workers in a hospital setting. We first evaluated how COVID-19-related discrimination in 2021 was associated with subsequent PTSD symptom severity in 2023. Thereafter, we conducted causal mediation analysis to examine how this association was mediated by psychological distress in 2022, accounting for exposure-mediator interaction. Missing data were handled using random forest imputation. RESULTS: A total of 660 hospital staff were included. The fully adjusted model showed greater PTSD symptom severity in individuals who experienced any COVID-19-related discrimination compared with those without such experiences (ß, 0.44; 95% CI, 0.04-0.90). Regarding each type of discrimination, perceived discrimination was associated with greater PTSD symptom severity (ß, 0.52; 95% CI, 0.08-0.96), whereas verbal discrimination did not reach statistical significance. Psychological distress mediated 28.1%-38.8% of the observed associations. CONCLUSIONS: COVID-19-related discrimination is associated with subsequent PTSD symptom severity in healthcare workers. Psychological distress may serve as an important mediator, underscoring the potential need for interventions targeting this factor.

Changes in the anteroposterior position of the femur relative to the tibia impact patient satisfaction in total knee arthroplasty.

BACKGROUND: In this study, we aimed to investigate the preoperative and postoperative anteroposterior position (AP) of the femur relative to the tibia in total knee arthroplasty (TKA) and assess the influence of change in the AP position on clinical outcomes. METHODS: We evaluated 49 knees that underwent bi-cruciate-substituted TKA using a navigation system. The preoperative and postoperative AP position of the femur relative to the tibia at maximum extension, 15°, 30°, 45°, 60°, 90°, 105°, and 120° and maximum flexion angles were calculated. The 2011 Knee Society Score was evaluated preoperatively and 1 year postoperatively. The Wilcoxon signed rank and Spearman's rank correlation tests were performed, with statistical significance set at P < 0.05. RESULTS: The postoperative AP position was significantly correlated with the preoperative AP position at each measured angle. The postoperative AP positions were statistically more anterior than those preoperatively. Furthermore, the changes in the AP position after TKA negatively correlated with the symptom (P = 0.027 at 30°, P = 0.0018 at 45°, P = 0.0003 at 60°, P = 0.01 at 90°, and P = 0.028 at 105°) and patient satisfaction (P = 0.018 at 60° and P = 0.009 at 90°) scores at 1 year postoperatively. CONCLUSION: The postoperative AP position of the femur relative to the tibia was strongly influenced by the preoperative those in TKA. Postoperative anterior deviation of the femur relative to the tibia from mid-flexion to deep flexion could worsen clinical outcomes.

New SNCA mutation and structures of α-synuclein filaments from juvenile-onset synucleinopathy.

A 21-nucleotide duplication in one allele of SNCA was identified in a previously described disease with abundant α-synuclein inclusions that we now call juvenile-onset synucleinopathy (JOS). This mutation translates into the insertion of MAAAEKT after residue 22 of α-synuclein, resulting in a protein of 147 amino acids. Both wild-type and mutant proteins were present in sarkosyl-insoluble material that was extracted from frontal cortex of the individual with JOS and examined by electron cryo-microscopy. The structures of JOS filaments, comprising either a single protofilament, or a pair of protofilaments, revealed a new α-synuclein fold that differs from the folds of Lewy body diseases and multiple system atrophy (MSA). The JOS fold consists of a compact core, the sequence of which (residues 36-100 of wild-type α-synuclein) is unaffected by the mutation, and two disconnected density islands (A and B) of mixed sequences. There is a non-proteinaceous cofactor bound between the core and island A. The JOS fold resembles the common substructure of MSA Type I and Type II dimeric filaments, with its core segment approximating the C-terminal body of MSA protofilaments B and its islands mimicking the N-terminal arm of MSA protofilaments A. The partial similarity of JOS and MSA folds extends to the locations of their cofactor-binding sites. In vitro assembly of recombinant wild-type α-synuclein, its insertion mutant and their mixture yielded structures that were distinct from those of JOS filaments. Our findings provide insight into a possible mechanism of JOS fibrillation in which mutant α-synuclein of 147 amino acids forms a nucleus with the JOS fold, around which wild-type and mutant proteins assemble during elongation.

Distinctive chaperonopathy in skeletal muscle associated with the dominant variant in DNAJB4.

DnaJ homolog, subfamily B, member 4, a member of the heat shock protein 40 chaperones encoded by DNAJB4, is highly expressed in myofibers. We identified a heterozygous c.270 T > A (p.F90L) variant in DNAJB4 in a family with a dominantly inherited distal myopathy, in which affected members have specific features on muscle pathology represented by the presence of cytoplasmic inclusions and the accumulation of desmin, p62, HSP70, and DNAJB4 predominantly in type 1 fibers. Both Dnajb4F90L knockin and knockout mice developed muscle weakness and recapitulated the patient muscle pathology in the soleus muscle, where DNAJB4 has the highest expression. These data indicate that the identified variant is causative, resulting in defective chaperone function and selective muscle degeneration in specific muscle fibers. This study demonstrates the importance of DNAJB4 in skeletal muscle proteostasis by identifying the associated chaperonopathy.

Endoscopic N-butyl-2-cyanoacrylate and ethanolamine oleate injection is equivalent to balloon-occluded retrograde transvenous obliteration for preventing gastric variceal bleeding.

OBJECTIVES: Endoscopic injection sclerotherapy (EIS) is effective for temporary hemostasis, but EIS and balloon-occluded retrograde transvenous obliteration (BRTO) have been reported as effective for secondary prophylaxis of gastric varices (GV) bleeding. This study retrospectively compared EIS and BRTO in patients with GV in terms of the efficacy for secondary prevention of GV bleeding and effects on liver function. METHODS: From our database of patients with GV who underwent EIS or BRTO between February 2011 and April 2020, a total of 42 patients with GV were retrospectively enrolled. The primary endpoint was the bleeding rate from GV, which was compared between EIS and BRTO groups. Secondary endpoints were liver function after treatment and rebleeding rate from EV, compared between EIS and BRTO groups. Rebleeding rates from GV and EV and liver function after treatment were also compared between EIS-ethanolamine oleate (EO)/histoacryl (HA) and EIS-HA groups. RESULTS: Technical success was achieved for all EIS cases, but two cases were unsuccessful in the BRTO group and underwent additional EIS. No significant differences in bleeding rates or endoscopic findings for GV improvement were seen between EIS and BRTO groups. Liver function also showed no significant difference in the amount of change after treatment between groups. CONCLUSION: EIS therapy appears effective for GV in terms of preventing GV rebleeding and effects on liver function after treatment. EIS appears to represent an effective treatment for GV.

Feasibility of Bone Mineral Density and Bone Microarchitecture Assessment Using Deep Learning With a Convolutional Neural Network.

OBJECTIVES: We evaluated the feasibility of using deep learning with a convolutional neural network for predicting bone mineral density (BMD) and bone microarchitecture from conventional computed tomography (CT) images acquired by multivendor scanners. METHODS: We enrolled 402 patients who underwent noncontrast CT examinations, including L1-L4 vertebrae, and dual-energy x-ray absorptiometry (DXA) examination. Among these, 280 patients (3360 sagittal vertebral images), 70 patients (280 sagittal vertebral images), and 52 patients (208 sagittal vertebral images) were assigned to the training data set for deep learning model development, the validation, and the test data set, respectively. Bone mineral density and the trabecular bone score (TBS), an index of bone microarchitecture, were assessed by DXA. BMDDL and TBSDL were predicted by deep learning with a convolutional neural network (ResNet50). Pearson correlation tests assessed the correlation between BMDDL and BMD, and TBSDL and TBS. The diagnostic performance of BMDDL for osteopenia/osteoporosis and that of TBSDL for bone microarchitecture impairment were evaluated using receiver operating characteristic curve analysis. RESULTS: BMDDL and BMD correlated strongly (r = 0.81, P < 0.01), whereas TBSDL and TBS correlated moderately (r = 0.54, P < 0.01). The sensitivity and specificity of BMDDL for identifying osteopenia or osteoporosis were 93% and 90%, and 100% and 94%, respectively. The sensitivity and specificity of TBSDL for identifying patients with bone microarchitecture impairment were 73% for all values. CONCLUSIONS: The BMDDL and TBSDL derived from conventional CT images could identify patients who should undergo DXA, which could be a gatekeeper tool for detecting latent osteoporosis/osteopenia or bone microarchitecture impairment.

An autopsy case of progressive multifocal leukoencephalopathy with massive iron deposition in juxtacortical lesions.

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease caused by JC virus infection of oligodendrocytes. Little has been reported on iron deposits in patients with PML. Herein, we report a case of PML with massive iron deposition in the juxtacortical regions attaching white matter lesions in a 71-year-old woman who developed bilateral visual disturbance and progressive aphasia after 16 months of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone treatment for follicular lymphoma. Magnetic resonance imaging revealed white matter lesions in the left parietal and other lobes with massive iron deposition in the juxtacortical lesions. A PCR test for JC virus was positive, confirming the diagnosis of PML. Despite treatment with mefloquine and mirtazapine, the patient died six months later. At autopsy, demyelination was found dominantly in the left parietal lobe. Moreover, hemosiderin-laden macrophages and reactive astrocytes containing ferritin were abundant in the juxtacortical regions adjacent to the white matter lesions. This is a previously unreported case of PML after lymphoma, in which iron deposition was confirmed both radiologically and pathologically.

Anti-N-methyl-D-aspartate receptor encephalitis with concurrent human herpes virus-6A deoxyribonucleic acid detection: An autopsy case.

We report an autopsy case of anti-N-methyl-D-aspartate (NMDA) receptor (NMDAR) encephalitis with concurrent human herpes virus-6 (HHV-6) A deoxyribonucleic acid (DNA) detection in cerebrospinal fluid (CSF). A 38-year-old previously healthy Japanese man presented with a generalized seizure. Brain magnetic resonance imaging (MRI) findings were unremarkable, but CSF revealed pleocytosis. On Day 11, HHV-6 DNA was detected in CSF, and IgG antibodies against the NR1 subunit of the NMDAR (GluN1) were subsequently detected. Since HHV-6 encephalitis was initially suspected, the patient was treated with foscarnet and ganciclovir, but the HHV-6A copy number increased from 200 (Day 22) to 2000 copies/mL (Day 47), and the therapy was ineffective. As typical symptoms of anti-NMDAR encephalitis developed, we changed the patient's treatment to combat anti-NMDAR encephalitis. He was repeatedly treated with first-line immunotherapy, and GluN1 antibody titer decreased. He was not treated with second-line immunotherapy because of recurrent infections; he died on Day 310. Postmortem examinations did not show systemic tumors. Microscopic examination of the brain revealed only severe neuronal rarefaction in the hippocampal cornu ammonis (CA) 3-4 areas with gliosis. Early initiation of aggressive immunotherapy may be required in a refractory case of anti-NMDAR encephalitis, even with HHV-6A DNA detection, because the significance of this concurrent detection in autoimmune encephalitis remains unclear.

Is There an Association Between Femoral Head Collapse and Acetabular Coverage in Patients With Osteonecrosis?

BACKGROUND: Osteonecrosis of the femoral head (ONFH) classification systems are based on the size, volume, and location of necrotic lesions. Often-but not always-ONFH results in femoral head collapse. Because acetabular coverage is associated with mechanical stress on the femoral head, it might also be associated with femoral head collapse in patients with ONFH. However, the association between acetabular coverage and femoral head collapse in these patients has not been established. QUESTIONS/PURPOSES: (1) Is femoral head collapse associated with acetabular coverage or pelvic incidence (PI) in patients with ONFH? (2) Are established predictors of femoral head collapse in ONFH classification systems associated with acetabular coverage? METHODS: Between 2008 and 2018, we evaluated 343 hips in 218 patients with ONFH. We considered all patients with ONFH except for those with a traumatic etiology, a history of surgical treatment before collapse, or those with collapse at initial presentation as potentially eligible for this study. Of those, 101 hips with ONFH (50% [50] were in males with a mean age of 44 ± 15 years) met our inclusion criteria. These patients were subsequently divided into two groups: those with femoral head collapse within 12 months (collapse group, 35 hips) and those without femoral head collapse (noncollapse group, 66 hips). No differences in patient demographics were observed between the two groups. CT images were used to measure the PI and acetabular coverage in three planes: the lateral center-edge angle (LCEA) in the coronal plane, the anterior and posterior center-edge angle in the sagittal plane, and the anterior and posterior acetabular sector angle in the axial plane; in addition, the difference between these parameters was investigated between the groups. The thresholds for femoral head collapse in the parameters that showed differences were investigated. Necrotic location and size were evaluated using the Japanese Investigation Committee (JIC) classification and the Steinberg grade classification, respectively. We examined the relationship between these parameters and classifications. RESULTS: The mean LCEA was slightly greater in the noncollapse group than in the collapse group (32° ± 6° versus 28° ± 7°; mean difference 4° [95% CI 1.15° to 6.46°]; p = 0.005); the clinical importance of this small difference is uncertain. There were no differences in PI between the two groups. After accounting for sex, age, BMI, and etiology as confounding factors, as well as acetabular coverage parameters and PI, we found a lower LCEA to be independently associated with increased odds of collapse, although the effect size is small and of questionable importance (OR 1.18 [95% CI 1.06 to 1.33]; p = 0.001). The threshold of LCEA for femoral head collapse was 28° (sensitivity = 0.79, specificity = 0.60, area under the curve = 0.73). The percentage of patients with an LCEA less than 28° was larger in JIC Type C1 (OR 6.52 [95% CI 1.64 to 43.83]; p = 0.006) and C2 (OR 9.84 [95% CI 2.34 to 68.38]; p = 0.001) than in patients with both Type A and Type B. The acetabular coverage data for the excluded patients did not differ from those of the patients included in the analysis. CONCLUSION: Our findings suggest that acetabular coverage appears to have little, if any, association with the likelihood of collapse in patients with ONFH. We found a small association between a lower LCEA and a higher odds of collapse, but the effect size may not be clinically important. Factors other than acetabular coverage need to be considered, and if our findings are verified by other investigators, osteotomy is unlikely to have a protective role. As the patients in our study were fairly homogeneous in terms of ethnicity and BMI, these factors need to be further investigated to determine whether they are associated with femoral head collapse in ONFH. LEVEL OF EVIDENCE: Level III, prognostic study.

What Changes in Pelvic Sagittal Tilt Occur 20 Years After THA?

BACKGROUND: Cup orientation in THA in the supine, standing, and sitting positions is affected by pelvic sagittal tilt (PT). Patterns of PT shift between these positions may increase the risk of dislocation and edge loading. The PT has also been reported to change during the aging process; however, there is limited research regarding long-term changes in PT and PT shifts after THA. QUESTIONS/PURPOSES: (1) What changes occur in PT in the supine, standing, and sitting positions during 20 years of follow-up after THA in patients who have not had revision or dislocation? (2) What factors are associated with the differences between preoperative supine PT and postoperative sitting or standing PT (Δ sitting and Δ standing, respectively) 20 years postoperatively? METHODS: Between January 1998 and December 1999, 101 consecutive patients underwent THA for appropriate indications. AP radiographs of the pelvis in the supine, standing, and sitting positions preoperatively and at 1, 10, and 20 years after THA were longitudinally performed to evaluate changes in PT. Fifty-nine percent (60 of 101) of patients were lost before 20 years of follow-up or had incomplete sets of imaging tests, leaving 41% (41 of 101) eligible for analysis here. There were no patients who had recurrent dislocation or underwent revision arthroplasty in the cohort; therefore, this analysis regarding postoperative changes in PT indicates the natural course of the change in PT during follow-up of THA. PT was measured based on the anterior pelvic plane. PT shifts with positional changes, Δ standing, and Δ sitting during the follow-up period were calculated. Posterior changes and shifts are represented by negative values. To analyze the factors associated with Δ standing and Δ sitting after 20 years, the correlations between these parameters and preoperative factors (including sex, age, pelvic incidence [PI], lumbar lordosis [LL], preoperative PT, and preoperative PT shift) and postoperative factors (including the occurrence of new lumbar vertebral fractures, lumbar spondylolisthesis, contralateral THA performed during follow-up, and PI-LL 20 years after THA) were determined. RESULTS: Median (IQR) supine and standing PTs changed (moved posteriorly) by -5° (-11° to -2°; p < 0.01) and -10° (-15° to -7°; p < 0.01), respectively. Sitting PT did not change during the 20-year follow-up period. Median (IQR) PT shift from standing to sitting changed from -34° preoperatively (-40° to -28°) to -23° after 20 years (-28° to -20°). There were posterior changes in median (range) Δ standing (median -12° at 20 years [-19° to -7°]); Δ sitting did not change during the follow-up period (median -36° at 20 years [-40° to -29°]). Patients with a large preoperative posterior PT shift from supine to standing demonstrated larger posterior tilt of Δ standing at 20 years. Patients with lumbar vertebral fractures during follow-up demonstrated larger posterior tilt of Δ standing at 20 years. CONCLUSION: Patients who demonstrate a large preoperative posterior shift from supine to standing deserve special consideration when undergoing THA. In such circumstances, we recommend that the anteversion of the cup not be excessive, given that there is a relatively high risk of further posterior tilt in PT, which may lead to anterior dislocation and edge loading. Further longitudinal study in a larger cohort of patients with complications including postoperative dislocation and revision, as well as older patients, is needed to verify these assumptions on the potential risk for dislocation and edge loading after THA. LEVEL OF EVIDENCE: Level III, therapeutic study.

Osteocompatibility of Si3N4-coated carbon fiber-reinforced polyetheretherketone (CFRP) and hydroxyapatite-coated CFRP with antibiotics and antithrombotic drugs.

This study used a rabbit model to investigate the osteocompatibility of Si3N4-coated carbon fiber-reinforced polyetheretherketone (CFRP) and hydroxyapatite (HA)-coated CFRP with antibiotics (vancomycin [VCM]) and antithrombotic drugs (polyvinylpyrrolidone [PVP]). HA-coated cylindrical CFRP implants were used as the controls (HA), and HA-coated implants treated with VCM and PVP were prepared (HA-VP) as the test groups; a cylindrical CFRP coated with Si3N4 was also prepared (SiN). Ten implants from each group were randomly inserted into the femoral diaphysis of rabbits. The pull-out test, radiological analysis using micro-computed tomography (µ-CT), and histological analysis were performed. The pull-out strength of the SiN group was lower than that of the HA group. µ-CT analysis revealed that the amount of bone formation around the implant in the SiN group was inferior to that in the HA group. Conversely, the HA-VP group had equivalent pull-out strength and bone formation as analyzed by µ-CT compared to the HA group. In conclusion, the additional surface treatment of the HA-coated CFRP with VCM and PVP provided sufficient bone fixation and formation.

Neurological post-acute sequelae of SARS-CoV-2 infection.

The novel coronavirus disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can have two phases: acute (generally 4 weeks after onset) and chronic (>4 weeks after onset). Both phases include a wide variety of signs and symptoms including neurological and psychiatric symptoms. The signs and symptoms that are considered sequelae of COVID-19 are termed post-COVID condition, long COVID-19, and post-acute sequelae of SARS-CoV-2 infection (PASC). PASC symptoms include fatigue, dyspnea, palpitation, dysosmia, subfever, hypertension, alopecia, sleep problems, loss of concentration, amnesia, numbness, pain, gastrointestinal symptoms, depression, and anxiety. Because the specific pathophysiology of PASC has not yet been clarified, there are no definite criteria of the condition, hence the World Health Organization's definition is quite broad. Consequently, it is difficult to correctly diagnose PASC. Approximately 50% of patients may show at least one PASC symptom up to 12 months after COVID-19 infection; however, the exact prevalence of PASC has not been determined. Despite extensive research in progress worldwide, there are currently no clear diagnostic methodologies or treatments for PASC. In this review, we discuss the currently available information on PASC and highlight the neurological sequelae of COVID-19 infection. Furthermore, we provide clinical suggestions for diagnosing and caring for patients with PASC based on our outpatient clinic experience.

Progression of varus deformity in osteoarthritic knees induces anterior paradoxical motion of the femur during early knee flexion.

PURPOSE: The purpose of this study was to investigate the position of the femur relative to the tibia throughout range of motion in the osteoarthritic knee to evaluate knee kinematics and assess its relationship with the degree of varus deformity. METHODS: In this study, 116 preoperative knees with varus deformity were evaluated using a navigation system. The internal-external, anteroposterior, and mediolateral positions of the femur relative to the tibia were measured at maximum extension, 15°, 30°, 45°, 60°, 90°, 105°, and 120°, and maximum flexion angles. From these parameters, two-dimensional translation of the surgical epicondylar axis was projected onto the tibial axial plane, and the femoral movement was evaluated relative to the tibia. In addition, the knees were retrospectively classified into three groups according to their degrees of preoperative hip-knee-ankle angle: mild (< 10°), moderate (10°-20°), and severe (> 20°). Then, the differences in each parameter between these groups were investigated. The Steel-Dwass test was performed to identify the difference among three groups. Statistical significance was set at p values < 0.05. RESULTS: There was a significant difference in the anteroposterior position of the femur relative to the tibia among the three groups, especially from extension to early flexion (p < 0.05). The anteroposterior position at knee extension deviated posteriorly according to the progression of varus deformity. Rotational and mediolateral translation were not significantly different among the groups. Normal knee kinematics were diminished in almost all cases in each group. In addition, anterior paradoxical motion of the femur during early knee flexion was observed in 45.6% (n = 26), 57.1% (n = 28), and 80.0% (n = 8) of cases in the mild, moderate, and severe groups, respectively. The anteroposterior position of the femur relative to the tibia at knee extension was significantly more posterior in patients with than in those without anterior paradoxical motion (p < 0.0001). CONCLUSION: The anteroposterior position of the femur relative to the tibia changed according to the progression of varus deformity in osteoarthritic knees, especially from knee extension to early flexion. Posterior deviation of the femur at knee extension induced its anteroposterior movement relative to the tibia, resulting in anterior paradoxical motion. LEVEL OF EVIDENCE: III.