A clinicopathological study of low back pain due to middle cluneal nerve entrapment: case series.

PURPOSE: The middle cluneal nerve (MCN) is a pure sensory nerve around the middle buttock. Its entrapment between the iliac crest and the long posterior sacroiliac ligament elicits low back pain (LBP) that can be treated by MCN neurolysis or neurectomy. Because few studies examined the pathology of MCN entrapment (MCN-E) we subjected 7 neurectomized specimens from 6 LBP patients to pathologic study. METHODS: We present 6 consecutive patients (7 sides) with intractable LBP who underwent successful MCN neurectomy. Their symptom duration ranged from 6 to 96 months (average 47.3 months); the follow-up period ranged from 6 to 17 months (average 11.7 months). The surgical outcomes were evaluated using the numerical rating scale (NRS) for LBP and the Roland-Morris Disability Questionnaire (RDQ) score. The resected MCNs underwent neuropathological analysis. RESULTS: Postoperatively, all 6 patients reported immediate LBP amelioration; their NRS and RDQ scores were improved significantly. Pathological study of the 7 resected nerves showed that the myelinated fiber density was decreased in 6 nerves; we observed marked enlargement (n = 5), perineurial thickening and disruption (n = 6), intrafascicular fibrous changes (n = 5), myelinated fibers separated by fibrous cells under the perineurium (n = 4), and Renaut bodies (n = 3). The 7th nerve appeared normal with respect to the density and size of the myelinated fibers, however, the perineurium was slightly thickened. CONCLUSION: We present pathological evidence at the MCN compression site of 7 nerves from 6 patients whose LBP was alleviated by MCN neurectomy, indicating that MCN entrapment can elicit LBP.

Long-term survival from progressive multifocal leukoencephalopathy in living-donor liver transplant recipient with preformed donor-specific antibody.

Intensive immunosuppression has enabled liver transplantation even in recipients with preformed donor-specific antibodies (DSA), an independent risk factor for graft rejection. However, these recipients may also be at high risk of progressive multifocal encephalopathy (PML) due to the comorbid immunosuppressed status. A 58-year-old woman presented with self-limited focal-to-bilateral tonic-clonic seizures 9 months after liver transplantation. She was desensitized using rituximab and plasma exchange before transplantation and was subsequently treated with steroids, tacrolimus, and everolimus after transplantation for her preformed DSA. Neurological examination revealed mild acalculia and agraphia. Cranial MRI showed asymmetric, cortex-sparing white matter lesions that increased over a week in the left frontal, left parietal, and right parieto-occipital lobes. Polymerase chain reaction (PCR) of the cerebrospinal fluid for the JC supported the diagnosis of PML. Immune reconstitution by reducing the immunosuppressant dose stopped lesion expansion, and PCR of the cerebrospinal fluid for the JC virus became negative. Graft rejection occurred 2 months after immune reconstitution, requiring readjustment of immunosuppressants. Forty-eight months after PML onset, the patient lived at home without disabling deficits. Intensive immunosuppression may predispose recipients to PML after liver transplantation with preformed DSA. Early immune reconstitution and careful monitoring of graft rejection may help improve outcomes.

Expanded clinical spectrum of oculopharyngodistal myopathy type 1.

INTRODUCTION/AIMS: Heterozygous CGG repeat expansions in low-density lipoprotein receptor-related protein 12 (LRP12) have recently been identified as a cause of oculopharyngodistal myopathy (OPDM), and the disease is designated as OPDM type 1 (OPDM1). In contrast to broadening of our knowledge on the genetic background of OPDM, what we know of the clinical phenotype of genetically confirmed OPDM1 remains limited. METHODS: This investigation was a single-center case series study of OPDM consisting of ten patients from seven families. Repeat-primed polymerase chain reaction and Southern blot analyses were performed to confirm the CGG repeat expansions in LRP12. Clinical findings were retrospectively reviewed. RESULTS: Seven patients from five families were identified as having CGG repeat expansions in LRP12. We found a high prevalence of axial muscle involvement, such as neck muscle weakness (6/7) and fatty infiltration in the rectus abdominis muscle, as revealed by computed tomography (5/5). We identified patients with very subtle oculopharyngeal symptoms, mimicking isolated distal myopathy. Muscle specimens were collected from the biceps brachii and tibialis anterior muscles of three patients. Myopathic changes were more severe with more atrophic fibers forming clusters in the tibialis anterior than the biceps brachii muscles of these three patients. No rimmed vacuoles were observed in the biceps brachii muscles in two of the three patients. DISCUSSION: This study shows the expanded clinical spectrum of OPDM1, highlighting the importance of axial muscle evaluation in OPDM1. Considering patients with very subtle oculopharyngeal symptoms, genetic analysis of LRP12 should be considered in patients with isolated distal myopathy.

Cardiomyopathy and altered integrin-actin signaling in Fhl1 mutant female mice.

X-linked scapuloperoneal myopathy (X-SM), one of Four-and-a-half LIM 1 (FHL1) related diseases, is an adult-onset slowly progressive myopathy, often associated with cardiomyopathy. We previously generated a knock-in mouse model that has the same mutation (c.365 G > C, p.W122S) as human X-SM patients. The mutant male mouse developed late-onset slowly progressive myopathy without cardiomyopathy. In this study, we observed that heterozygous (Het) and homozygous (Homo) female mice did not show alterations of skeletal muscle function or histology. In contrast, 20-month-old mutant female mice showed signs of cardiomyopathy on echocardiograms with increased systolic diameter [wild-type (WT): 2.74 ± 0.22 mm, mean ± standard deviation (SD); Het: 3.13 ± 0.11 mm, P < 0.01; Homo: 3.08 ± 0.37 mm, P < 0.05) and lower fractional shortening (WT: 31.1 ± 4.4%, mean ± SD; Het: 22.7 ± 2.5%, P < 0.01; Homo: 22.4 ± 6.9%, P < 0.01]. Histological analysis of cardiac muscle revealed frequent extraordinarily large rectangular nuclei in mutant female mice that were also observed in human cardiac muscle from X-SM patients. Western blot demonstrated decreased Fhl1 protein levels in cardiac muscle, but not in skeletal muscle, of Homo mutant female mice. Proteomic analysis of cardiac muscle from 20-month-old Homo mutant female mice indicated abnormalities of the integrin signaling pathway (ISP) in association with cardiac dysfunction. The ISP dysregulation was further supported by altered levels of a subunit of the ISP downstream effectors Arpc1a in Fhl1 mutant mice and ARPC1A in X-SM patient muscles. This study reveals the first mouse model of FHL1-related cardiomyopathy and implicates ISP dysregulation in the pathogenesis of FHL1 myopathy.

Fhl1 W122S causes loss of protein function and late-onset mild myopathy.

A member of the four-and-a-half-LIM (FHL) domain protein family, FHL1, is highly expressed in human adult skeletal and cardiac muscle. Mutations in FHL1 have been associated with diverse X-linked muscle diseases: scapuloperoneal (SP) myopathy, reducing body myopathy, X-linked myopathy with postural muscle atrophy, rigid spine syndrome (RSS) and Emery-Dreifuss muscular dystrophy. In 2008, we identified a missense mutation in the second LIM domain of FHL1 (c.365 G>C, p.W122S) in a family with SP myopathy. We generated a knock-in mouse model harboring the c.365 G>C Fhl1 mutation and investigated the effects of this mutation at three time points (3-5 months, 7-10 months and 18-20 months) in hemizygous male and heterozygous female mice. Survival was comparable in mutant and wild-type animals. We observed decreased forelimb strength and exercise capacity in adult hemizygous male mice starting from 7 to 10 months of age. Western blot analysis showed absence of Fhl1 in muscle at later stages. Thus, adult hemizygous male, but not heterozygous female, mice showed a slowly progressive phenotype similar to human patients with late-onset muscle weakness. In contrast to SP myopathy patients with the FHL1 W122S mutation, mutant mice did not manifest cytoplasmic inclusions (reducing bodies) in muscle. Because muscle weakness was evident prior to loss of Fhl1 protein and without reducing bodies, our findings indicate that loss of function is responsible for the myopathy in the Fhl1 W122S knock-in mice.

Limb-girdle muscular dystrophy 1F is caused by a microdeletion in the transportin 3 gene.

In 2001, we reported linkage of an autosomal dominant form of limb-girdle muscular dystrophy, limb-girdle muscular dystrophy 1F, to chromosome 7q32.1-32.2, but the identity of the mutant gene was elusive. Here, using a whole genome sequencing strategy, we identified the causative mutation of limb-girdle muscular dystrophy 1F, a heterozygous single nucleotide deletion (c.2771del) in the termination codon of transportin 3 (TNPO3). This gene is situated within the chromosomal region linked to the disease and encodes a nuclear membrane protein belonging to the importin beta family. TNPO3 transports serine/arginine-rich proteins into the nucleus, and has been identified as a key factor in the HIV-import process into the nucleus. The mutation is predicted to generate a 15-amino acid extension of the C-terminus of the protein, segregates with the clinical phenotype, and is absent in genomic sequence databases and a set of >200 control alleles. In skeletal muscle of affected individuals, expression of the mutant messenger RNA and histological abnormalities of nuclei and TNPO3 indicate altered TNPO3 function. Our results demonstrate that the TNPO3 mutation is the cause of limb-girdle muscular dystrophy 1F, expand our knowledge of the molecular basis of muscular dystrophies and bolster the importance of defects of nuclear envelope proteins as causes of inherited myopathies.

Severe finger necrosis in antisynthetase syndrome with positive anti-OJ antibodies.

Key Clinical Message: In a patient with anti-aminoacyl tRNA synthetase antibody and anti-OJ antibody syndrome, interventions likes warming, prostaglandins, and antiplatelets failed. However, prednisolone pulse treatment rapidly halted disease progression. Patients with mild interstitial pneumonia, myositis, and extremity necrosis should be promptly considered for anti-synthetase syndrome and receive immunosuppression after ruling out other causes. Abstract: Anti-aminoacyl tRNA synthetase (ARS) autoantibodies are myositis-specific, and patients who test positive for ARS and have common clinical features are usually diagnosed with antisynthetase antibody syndrome (antisynthetase syndrome). Anti-ARS antibodies include histidyl-tRNA synthetase-1 (Jo-1), anti-threonyl (PL-7), anti-alanyl (PL-12), anti-glycyl (EJ), anti-asparaginyl (KS), anti-tyrosyl (Ha), and anti-phenylalanyl (Zo) tRNA synthetases. Among these, anti-isoleucyl tRNA synthetase (OJ) autoantibodies are extremely rare, and patients with these are frequently complicated by interstitial pneumonia. We report the case of an older man with ARS antibody syndrome who tested positive for anti-OJ and anti-Sjögren's-syndrome-related antigen A (Ro-52) antibodies. He had muscle weakness due to myositis and unparalleled rapid and severe finger necrosis. Pulsed prednisolone effectively treated the myositis symptoms and terminated the progression of finger necrosis.

A Case of a Patient with Calpainopathy Carrying Compound Heterozygous Mutations of a de novo Pathogenic Variant of c.1333G>A and a Novel Variant of c.1331C>T in CAPN3.

Calpainopathy is primarily an autosomal recessive inherited myopathy; however, dominantly inherited cases with a pathogenic variant of c.1333G>A have been reported. A 13-year-old Japanese girl presented with toe walking and elevated serum creatine kinase levels. Genetic panel testing revealed compound heterozygosity for c.1333G>A and a novel variant of c.1331C>T in CAPN3, leading to a diagnosis of calpainopathy. A genetic analysis of her parents revealed the possibility that c.1333G>A was de novo. In this patient, the onset age was earlier than that of the reported autosomal dominant cases, suggesting the influence of the novel variant in the contralateral allele.

Age-associated CD4+ T cells with B cell-promoting functions are regulated by ZEB2 in autoimmunity.

Aging is a significant risk factor for autoimmunity, and many autoimmune diseases tend to onset during adulthood. We conducted an extensive analysis of CD4+ T cell subsets from 354 patients with autoimmune disease and healthy controls via flow cytometry and bulk RNA sequencing. As a result, we identified a distinct CXCR3midCD4+ effector memory T cell subset that expands with age, which we designated "age-associated T helper (THA) cells." THA cells exhibited both a cytotoxic phenotype and B cell helper functions, and these features were regulated by the transcription factor ZEB2. Consistent with the highly skewed T cell receptor usage of THA cells, gene expression in THA cells from patients with systemic lupus erythematosus reflected disease activity and was affected by treatment with a calcineurin inhibitor. Moreover, analysis of single-cell RNA sequencing data revealed that THA cells infiltrate damaged organs in patients with autoimmune diseases. Together, our characterization of THA cells may facilitate improved understanding of the relationship between aging and autoimmune diseases.

Development of Polyneuropathy, Organomegaly, Endocrinopathy, M Protein, and Skin Changes Syndrome after Conversion from Plasmacytoma of Bone to Multiple Myeloma.

A 36-year-old man developed polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome after conversion from solitary plasmacytoma of bone to multiple myeloma. Twenty-four days following the neurological onset, he lost his independent walking ability. The level of serum vascular endothelial growth factor (VEGF) at diagnosis was 5,250 pg/mL. Three months after initiating treatment, he regained his independent walking ability in line with a reduction in the elevated serum VEGF level. Due to their genomic instability gained during conversion, myeloma cells may overproduce humoral factors and cytokines, possibly contributing to the development of neuropathy as well as the production of VEGF.

Clinical and electrophysiological findings of facial palsy in a case of hereditary gelsolin amyloidosis.

Hereditary gelsolin amyloidosis (HGA) is an autosomal dominant systemic amyloidosis, characterized by cranial and sensory peripheral neuropathy, corneal lattice dystrophy, and cutis laxa. We report a case of HGA presenting with bilateral facial palsy. A 70-year-old Japanese man presented with slowly progressive bilateral facial palsy and facial twitching, which had started in his 40s. His mother also had the same symptoms due to an unknown cause but rest of the family did not. He showed incomplete facial palsy with no frontal muscle movement and partial movement of the orbicularis oris and orbicularis oculi muscles. The patient showed no synkinesis. Electroneurography revealed symmetric low compound motor action potential amplitude of the orbicularis oris muscle, and a nerve excitability test showed a symmetric increase in the response threshold. Despite the partial voluntary movement of the orbicularis oculi muscle, bilateral blink reflexes were absent. He also showed facial spasms after contraction of the orbicularis oris muscle. Genetic testing revealed a heterozygous c.640G>A mutation (p. Asp214Asn); therefore, the patient was diagnosed with HGA. HGA related facial palsy showed moderate bilateral, upper blanch-dominant axonal degeneration of the facial nerve without reinnervation, and trigeminal nerve neuropathy.

Anti-nuclear matrix protein 2 antibody-positive dermatomyositis with gastrointestinal ulcers: A case report.

Gastrointestinal manifestations are a very rare complication of dermatomyositis (DM) and are much less frequent in adult cases than in juvenile cases. Only a few previous papers have reported adult patients who had DM with anti-nuclear matrix protein 2 (anti-NXP2) antibodies and who developed gastrointestinal ulcers. Herein, we report a similar case of a 50-year-old man who had DM with anti-NXP2 antibodies followed by relapsing multiple gastrointestinal ulcers. Even after the administration of prednisolone, his muscle weakness and myalgia deteriorated and gastrointestinal ulcers relapsed. In contrast, intravenous immunoglobulin and azathioprine improved his muscle weakness and gastrointestinal ulcers. Based on the parallel disease activity of the muscular and gastrointestinal symptoms, we considered that his gastrointestinal ulcers were a complication of DM with anti-NXP2 antibodies. We also propose that early intensive immunosuppressive therapy would be required for the muscular and gastrointestinal symptoms in DM with anti-NXP2 antibodies.

Anti-Ku antibody-positive myositis presenting as a wide range of axial myopathies and myocarditis: A case report and review of the literature.

Idiopathic inflammatory myopathies (IIMs) are autoimmune diseases predominantly affecting proximal muscles; paraspinal muscle involvement is relatively rare. Because paraspinal myopathies do not always cause clinically evident symptoms, the diagnosis of IIMs with axial myopathies can be challenging. Anti-Ku autoantibodies, initially reported in polymyositis/systemic sclerosis overlap syndrome, are myositis-associated antibodies observed in patients with a wide variety of connective tissue diseases. Few reports have been published demonstrating predominant axial myopathy in IIM patients with anti-Ku antibodies. Herein, we investigated a previously healthy Japanese woman in her early 70s who presented with Raynaud's phenomenon, back pain, and exertional dyspnoea. The creatine kinase was elevated and antinuclear antibody staining was positive, but myositis-specific antibodies were negative. Magnetic resonance imaging revealed myocarditis and a wide range of axial muscle inflammation, including bilateral thoracolumbar paraspinal, infraspinatus, and trapezius muscles. The muscle biopsy was consistent with IIM. In addition, anti-Ku antibody was positive. The administration of prednisolone and tacrolimus quickly alleviated the symptoms, and the creatine kinase level returned to normal. The diagnosis of IIM was arduous in this case because she did not present with camptocormia, muscle weakness involving the proximal limbs was not apparent, and myositis-specific antibodies were negative. Whether axial myopathy and myocarditis are more prevalent in IIM patients with than without anti-Ku antibodies is uncertain. Clinicians should suspect axial myopathy and myositis-associated antibodies, such as anti-Ku antibodies, especially in patients in whom muscle weakness of the proximal limbs is not noticeable.

Diagnostic Values of Venous Peak Lactate, Lactate-to-pyruvate Ratio, and Fold Increase in Lactate from Baseline in Aerobic Exercise Tests in Patients with Mitochondrial Diseases.

Objective Although aerobic exercise tests on cycle ergometry have long been used for initial assessments of cases of suspected mitochondrial disease, the test parameters in patients with final diagnoses of other diseases via the widely used 15 W for 15 minutes exercise protocol have not been fully characterized. Methods We retrospectively reviewed all patients who underwent the test at our institution. We classified the patients with genetic diagnoses or those who met previously reported clinical criteria as having mitochondrial diseases and those with a final diagnosis of another disease as having other diseases. Results were available from 6 patients with mitochondrial disease and 15 with other diseases. Results During the test, elevated venous peak lactate above the upper normal limit of healthy controls at rest [19.2 mg/dL (2.13 mM)] was observed in 3 patients with mitochondrial diseases (50.0%) and 5 with other diseases (33.3%). In the group of patients with elevated venous peak lactate, a lactate-to-pyruvate ratio of >20 was observed in all 3 patients with mitochondrial disease but in only 1 of the 5 with other diseases. More than a 2-fold increase in venous lactate from baseline was observed in 4 patients with mitochondrial disease (66.7%) and 1 with another disease (6.7%). Conclusion Elevated venous peak lactate levels were observed in patients with final diagnoses of other diseases, even under a low 15-minute workload at 15 W. The lactate-to-pyruvate ratio and increase in lactate level from baseline may add diagnostic value to venous peak lactate levels alone.

Alanine transaminase is predominantly increased in the active phase of anti-HMGCR myopathy.

Autoantibodies against 3­hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and the signal recognition particle (SRP) are representative antibodies causing immune-mediated necrotizing myopathies (IMNM), called as anti-HMGCR and anti-SRP myopathies, respectively. Here, we analyzed the differences in routine blood test results between 56 anti-HMGCR and 77 anti-SRP myopathy patients. A higher alanine transaminase (ALT) level and a lower aspartate transaminase (AST)/ALT ratio were observed in anti-HMGCR myopathy patients [ALT, 265.7 ±â€¯213.3 U/L (mean ± standard deviation); AST/ALT ratio, 0.88 ±â€¯0.32] than in anti-SRP-myopathy patients (ALT, 179.3 ±â€¯111.2 U/L, p < 0.05; AST/ALT ratio, 1.28 ±â€¯0.40, p < 0.01). In the active phase, anti-HMGCR myopathy often showed ALT predominance, whereas anti-SRP myopathy often showed AST predominance. In addition, there were differences in erythrocyte sedimentation rate (ESR), total cholesterol (TChol) level, and high-density lipoprotein (HDL) level between anti-HMGCR and anti-SRP myopathies (ESR: HMGCR, 24.4 ±â€¯20.8 mm/1 h; SRP, 35.7 ±â€¯26.7 mm/1 h, p = 0.0334; TChol: HMGCR, 226.7 ±â€¯36.6 mg/dL; SRP, 207.6 ±â€¯40.8 mg/dL, p = 0.0163; HDL: HMGCR, 58.4 ±â€¯13.9 mg/dL; SRP, 46.2 ±â€¯17.3 mg/dL, p < 0.01). Additional studies on the differences in routine blood test results may further reveal the pathomechanisms of IMNM.

DMD exon 2 duplication due to a complex genomic rearrangement is associated with a somatic mosaicism.

We report the case of a patient with dystrophinopathy caused by DMD exon 2 duplication, showing marked asymmetric muscle atrophy. Immunostaining of the biopsied muscle tissue showed a mosaic staining, suggesting a somatic mosaicism. Polymerase chain reaction (PCR) analysis showed only one breakpoint, and long-read whole-genome sequencing revealed the entire structure of the rearranged sequence. The complex rearrangement was composed of two tandem duplications: one showed a microhomology near the breakpoint, suggesting a microhomology-mediated mechanism, whereas the other was associated with flanking short tandem repeats. The long-read sequencing also suggested the presence of a wild-type nonduplicated sequence, supporting somatic mosaicism. Whereas complementary DNA and western blot analyses were not useful, droplet digital PCR (ddPCR) analysis showed an average copy number of 1.61, enabling accurate estimation of the proportion of cells containing the duplication. Long-read sequencing and ddPCR analysis were useful for revealing the rearrangements and the precise copy number.

Cranial Nerve Involvement and Dysautonomia in Post-COVID-19 Guillain-Barré Syndrome.

The clinical characteristics of Guillain-Barré syndrome (GBS) after coronavirus disease 2019 (COVID-19) remain unclear due to the small number of cases. We herein report a case of a Japanese patient with post-COVID-19 GBS who presented with facial and limb muscle weakness, sensory deficits, and autonomic dysfunction. Nerve conduction studies revealed demyelination. Head magnetic resonance imaging showed contrast enhancement in the bilateral facial nerves. Systemic management, including intubation, intravenous immunoglobulin therapy, and rehabilitation, improved the patient's condition. This was the first Japanese case of acute inflammatory demyelinating polyneuropathy after COVID-19 and was characterized by autonomic dysfunction and facial nerve enhancement.

Pembrolizumab on pre-existing inclusion body myositis: a case report.

BACKGROUND: Cases of exacerbation of pre-existing neuromuscular diseases induced by immune checkpoint inhibitors (ICIs) have rarely been reported because patients with autoimmune diseases have generally been excluded from ICI therapy due to the increased risk of exacerbation. We describe the first case of an elderly patient who experienced exacerbation of a previously undiagnosed sporadic inclusion body myositis (sIBM), the most common myopathy in the geriatric population, which was triggered by anti-programmed cell death-1 therapy. CASE PRESENTATION: A 75-year-old man who was receiving pembrolizumab presented with limb weakness. Three years prior, he had noticed slowly progressive limb weakness, but he received no diagnosis. After the first infusion of pembrolizumab, his creatine kinase (CK) levels had increased. The neurological examination and muscle biopsy findings confirmed the diagnosis of sIBM and suggested exacerbation of sIBM induced by pembrolizumab. After the patient's CK levels decreased, pembrolizumab was restarted. The tumor progressed after its treatment with pembrolizumab. The patient died after 15 months of follow-up. CONCLUSIONS: In patients with slowly progressive limb weakness, sIBM should be explored before ICI therapy. In addition, if patients show high CK levels after ICI introduction, it is necessary to confirm whether they have sIBM in order to avoid unnecessary immunosuppressive therapies and assess whether they can tolerate ICI reintroduction.

A novel ferritin light chain gene mutation in a Japanese family with neuroferritinopathy: description of clinical features and implications for genotype-phenotype correlations.

Neuroferritinopathy is a hereditary neurodegenerative disorder caused by mutations in the ferritin light chain gene (FTL1). The cardinal features are progressive movement disturbance, hypoferritinemia, and iron deposition in the brain. To date, five mutations have been described in Caucasian and Japanese families, but the genotype-phenotype correlations remain to be established. We identified a novel FTL1 mutation (exon 4, c.641/642, 4-nucletotide duplication) in a Japanese family and compared the clinical traits with those previously reported. All mutations but one are insertions in exon 4, resulting in frameshifts. Clinical features are similar among patients with the same mutations. Middle-age onset chorea is common in patients with insertions in the 5' portion of exon 4 including our cases, whereas patients with insertions in the 3' portion of exon 4 develop early-onset tremor, suggesting genotype-phenotype correlations. In this family, male predominance and normal serum ferritin levels are characteristic.