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Alexander’s law states that spontaneous nystagmus increases when looking in the direction of fast-phase and decreases during gaze in slow-phase direction. Disobedience to Alexander’s law is occasionally observed in central nystagmus, but the underlying neural circuit mechanisms are poorly understood. In a retrospective analysis of 2,652 patients with posterior circulations stroke, we found a violation of Alexander’s law in one or both directions of lateral gaze in 17 patients with lesions of unilateral lateral medulla affecting the vestibular nucleus. Patients with vestibular neuritis served as a control. When Alexander’s law is violated, the time constant (Tc) was larger than that in the controls (median [interquartile range, IQR]: 14.4s [6.4–38.9] vs 9.0s [IQR 5.5–12.6], p = 0.036) while the Tc did not differ between the groups when Alexander’ law is obeyed (9.6s [3.6–16.1] vs 9.0s [5.5–12.6], p = 0.924). To test the study hypothesis that an unstable neural integrator may generate nystagmus violating Alexander’s law, we utilized the gaze-holding neural integrator model incorporating brainstem leaky neural integrator and negative velocity feedback loop via the cerebellum. The lesion-induced changes included false rotational cue, primarily attributed to central vestibular imbalance, and unstable neural integrator, examined in two ways: hyperexcitable brainstem neural integrator and paradoxical excitatory effect of Purkinje cells. With normal integrator function, the false rotational cue generated nystagmus consistent with Alexander’s law. However, both types of unstable neural integrators tested produced nystagmus that violated Alexander’s law. We propose that when the neural integrator is unstable with lesions in the brainstem neural integrator itself or the neural synapse between Purkinje cells and the brainstem vestibular nucleus, nystagmus violates Alexander’s law. The spontaneous nystagmus violating Alexander’s law may be the useful clue for identifying central vestibular syndrome. [ABSTRACT FROM AUTHOR]

Two vestibular signals, rotational and inertial cues, converge for the perception of complex motion. However, how vestibular perception is built on neuronal behaviors and decision-making processes, especially during the simultaneous presentation of rotational and inertial cues, has yet to be elucidated in humans. In this study, we analyzed the perceptual responses of 20 participants after pairwise rotational experiments, comprised of four control and four test sessions. In both control and test sessions, participants underwent clockwise and counterclockwise rotations in head-down and head-up positions. The difference between the control and test sessions was the head re-orientation relative to gravity after rotations, thereby providing only rotational cues in the control sessions and both rotational and inertial cues in the test sessions. The accuracy of perceptual responses was calculated by comparing the direction of rotational and inertial cues acquired from participants with that predicted by the velocity-storage model. The results showed that the accuracy of rotational perception ranged from 80 to 95% in the four control sessions but significantly decreased to 35 to 75% in the four test sessions. The accuracy of inertial perception in the test sessions ranged from 50 to 70%. The accuracy of rotational perception improved with repetitive exposure to the simultaneous presentation of both rotational and inertial cues, while the accuracy of inertial perception remained steady. The results suggested a significant interaction between rotational and inertial perception and implied that vestibular perception acquired in patients with vestibular disorders are potentially inaccurate. [ABSTRACT FROM AUTHOR]

Paroxysmal positional nystagmus frequently occurs in lesions involving the cerebellum, and has been ascribed to disinhibition and enhanced canal signals during positioning due to cerebellar dysfunction. This study aims to elucidate the mechanism of central positional nystagmus (CPN) by determining the effects of baclofen on the intensity of paroxysmal positional downbeat nystagmus due to central lesions. Fifteen patients with paroxysmal downbeat CPN were subjected to manual straight head-hanging before administration of baclofen, while taking baclofen 30 mg per day for at least one week, and two weeks after discontinuation of baclofen. The maximum slow phase velocity (SPV) and time constant (TC) of the induced paroxysmal downbeat CPN were analyzed. The positional vertigo was evaluated using an 11-point numerical rating scale (0 to 10) in 9 patients. After treatment with baclofen, the median of the maximum SPV of paroxysmal downbeat CPN decreased from 30.1°/s [interquartile range (IQR) = 19.6—39.0°/s] to 15.2°/s (IQR = 11.2—22.0°/s, Wilcoxon signed rank test, p < 0.001) with the median decrement ratio at 40.2% (IQR = 28.2—50.6%). After discontinuation of baclofen, the maximum SPV re-increased to 24.6°/s (IQR = 13.1—34.4°/s, Wilcoxon signed rank test, p = 0.001) with the median increment ratio at 23.5% (IQR = 5.2—87.9%). In contrast, the TCs of paroxysmal downbeat CPN remained unchanged at approximately 3.0 s throughout the evaluation. The positional vertigo also decreased with the medication (Wilcoxon signed rank test, p = 0.020), and remained unchanged even after discontinuation of medication (Wilcoxon signed rank test, p = 0.737). The results of this study support the prior presumption that paroxysmal CPN is caused by enhanced responses of the semicircular canals during positioning due to cerebellar disinhibition. Baclofen may be tried in symptomatic patients with paroxysmal CPN. [ABSTRACT FROM AUTHOR]

Trastuzumab emtansine (T-DM1) is widely utilized as a second-line and subsequent treatment for metastatic HER2+ breast cancer and has shown promise in early breast cancer treatment, particularly in adjuvant settings for residual disease after neoadjuvant chemotherapy. However, concerns have arisen regarding long-term hepatic adverse drug reactions (ADRs) not identified in clinical trials. We investigated potential safety signals of T-DM1 in hepatobiliary disorders and the time-to-onset of ADRs using the FDA Adverse Event Reporting System (FAERS) database. Suspected ADRs were extracted and divided into two groups: T-DM1 (N = 3387) and other drugs (N = 11,833,701). Potential signal for T-DM1 in hepatobiliary disorder were identified (reporting odds ratio [ROR] = 5.66, 95% confidence interval [CI] = 5.11–6.27; information component [IC] = 2.35, 95% Credibility Interval [Crl] = 2.18–2.51). A breast cancer indicated subgroup analysis (2519 T-DM1; 172,329 other drugs) also identified a potential safety signal (ROR = 3.28, 95% CI = 2.92–3.68; IC = 1.53, 95%CrI = 1.35–1.71). The median time-to-onset for T-DM1-associated hepatobiliary disorders was 41 days. For prolonged and chronic hepatobiliary disorders, median times were 322.5 and 301.5 days, respectively. These findings highlight the need for further research to inform clinical decisions on optimal T-DM1 treatment duration, balancing benefits with potential adverse reactions. [ABSTRACT FROM AUTHOR]

This letter, published in the Journal of Neurology, presents a case report and literature review on central paroxysmal positional nystagmus (CPN) mimicking posterior canal benign paroxysmal positional vertigo (BPPV) in pontine infarction. The report describes a 67-year-old man who presented with acute vertigo and nystagmus, initially diagnosed as right acute unilateral peripheral vestibulopathy with posterior canal BPPV. However, further examination revealed features of central vestibulopathy, and brain MRI confirmed an acute infarction in the lateral pontine tegmentum. The patient's symptoms resolved after two days, and follow-up showed no positional nystagmus. The authors discuss the characteristics of CPN and differentiate it from BPPV based on nystagmus patterns and response to treatment. [Extracted from the article]

Background: In recognition of the distinct clinical challenges and research gaps in young breast cancer (YBC) patients, we established the Comprehensive Young Age Breast Cancer (CHARM) registry to collect prospective data. Methods: This prospective cohort included patients who were newly diagnosed with histologically confirmed breast cancer without prior treatment at the Samsung Medical Center (SMC) in April 2013. We included patients who were either 40 years old or younger at the time of diagnosis, pregnant at breast cancer diagnosis or diagnosed with breast cancer within 1 year of delivery. All data were collected using Medidata's Rave Electronic Data. Clinical data were obtained from electronic medical records. Two experienced pathologists reviewed the pathologic data. Bone mineral densitometry tests have been conducted annually. To obtain multi-omics data, tumor tissues and blood samples were prospectively collected from consenting patients in the registry during surgery. The fertility-related factor also collected collaborated with the Department of Obstetrics and Gynecology. Anti-Müllerian hormone, estradiol, follicle-stimulating hormone, and luteinizing hormone levels were measured using an additional blood sample from baseline to last follow-up. Patient-reported outcomes were assessed using mobile questionnaires. Results: A total of 1868 participants were included in the SMC YBC study. The average (standard deviation) age was 35.57 (3.79) and 99.8% of the participants were premenopausal. Among them, 1062 participants completed the PRO questionnaires. Conclusions: The SMC YBC cohort serves as a comprehensive registry for YBC to optimize care and improve knowledge regarding the management of YBC. [ABSTRACT FROM AUTHOR]

This letter, published in the Journal of Neurology, discusses a case of torsional saccadic palsy in a patient with episodic ataxia type 2 (EA2). EA2 is a genetic disorder characterized by recurrent episodes of dizziness and ataxia. The patient in this case experienced intermittent dizziness and ataxia since the age of 10, with episodes occurring every 1 or 2 weeks and lasting for about 2-3 hours. The authors observed a loss of torsional quick eye movements during head oscillation in the roll plane, which is a characteristic finding of midbrain lesions. This report expands the clinical spectrum of EA2 and suggests involvement of the brainstem in this disorder. [Extracted from the article]

The original article can be found online at https://doi.org/10.1007/s00415-024-12346-9.Correction to: Journal of Neurologyhttps://doi.org/10.1007/s00415-024-12346-9In the original version of this article, few parts of Table 1 were duplicated. The correct Table 1 should have beenGraphBy Eunjin Kwon; Hye Seon Jeong; Seong-Hae Jeong; Hyo-Jung Kim and Ji-Soo KimReported by Author; Author; Author; Author; Author [Extracted from the article]

Opsoclonus refers to saccadic oscillations without an intersaccadic interval occurring in multiple planes. Opsoclonus mostly indicates dysfunction of the brainstem or cerebellum. We report opsoclonus induced by horizontal head-shaking without other signs of brainstem or cerebellar dysfunction in two patients with vestibular migraine (VM). The development of opsoclonus after horizontal head-shaking indicates unstable or hyperactive neural circuits between the excitatory and inhibitory saccadic premotor burst neurons in these patients with VM. [ABSTRACT FROM AUTHOR]

Isozymes are enzymes that catalyze identical biological reactions, yet exhibit slight variations in structures and catalytic efficiency, which enables the precise adjustment of metabolism to fulfill the specific requirements of a particular tissue or stage of development. Methionine aminopeptidase (MetAP) isozymes function a critical role in cleaving N-terminal methionine from nascent proteins to generate functional proteins. In humans, two distinct MetAP types I and II have been identified, with type I further categorized into cytosolic (MetAP1) and mitochondrial (MetAP1D) variants. However, despite extensive structural studies on both bacterial and human cytosolic MetAPs, the structural information remains unavailable for human mitochondrial MetAP. This study was aimed to elucidate the high-resolution structures of human mitochondrial MetAP1D in its apo-, cobalt-, and methionine-bound states. Through a comprehensive analysis of the determined structures and a docking simulation model with mitochondrial substrate peptides, we present mechanistic insights into the cleavage process of the initiator methionine from mitochondrial proteins. Notably, despite the shared features at the active site between the cytosolic and mitochondrial MetAP type I isozymes, we identified distinct structural disparities within the active-site pocket primarily contributed by two specific loops that could play a role in accommodating specific substrates. These structural insights offer a basis for the further exploration of MetAP isozymes as critical players in cellular processes and potential therapeutic applications. [ABSTRACT FROM AUTHOR]

Gemcitabine is considered a standard treatment for pancreatic cancer, but developing drug resistance greatly limits the effectiveness of chemotherapy and increases the rate of recurrence. Lysyl oxide-like 2 (LOXL2) is highly expressed in pancreatic cancer and is involved in carcinogenesis and EMT regulation. However, studies on the role of LOXL2 in drug resistance are limited. Here, we investigated the mechanism of LOXL2 induction and the effect of LOXL2 on EMT and CSC in gemcitabine-resistant pancreatic cancer. Glucose metabolism was activated in gemcitabine-resistant pancreatic cancer cells, and NF-κB signaling was regulated accordingly. Activated NF-κB directly induces transcription by binding to the promoters of LOXL2 and ZEB1. The EMT process was significantly inhibited by the coregulation of ZEB1 and LOXL2. In addition, LOXL2 inhibition reduced the expression of cancer stemness markers and stemness by regulating MAPK signaling activity. LOXL2 inhibits tumor growth of gemcitabine-resistant pancreatic cancer cells and increases the sensitivity to gemcitabine in mouse models. Key messages: We identified a specific mechanism for inducing LOXL2 overexpression in gemcitabine-resistant pancreatic cancer. Taken together, our results suggest LOXL2 has an important regulatory role in maintaining gemcitabine resistance and may be an effective therapeutic target to treat pancreatic cancer. [ABSTRACT FROM AUTHOR]

Introduction: With the availability of retrospective pharmacovigilance data, the common data model (CDM) has been identified as an efficient approach towards anonymized multicenter analysis; however, the establishment of a suitable model for individual medical systems and applications supporting their analysis is a challenge. Objective: The aim of this study was to construct a specialized Korean CDM (K-CDM) for pharmacovigilance systems based on a clinical scenario to detect adverse drug reactions (ADRs). Methods: De-identified patient records (n = 5,402,129) from 13 institutions were converted to the K-CDM. From 2005 to 2017, 37,698,535 visits, 39,910,849 conditions, 259,594,727 drug exposures, and 30,176,929 procedures were recorded. The K-CDM, which comprises three layers, is compatible with existing models and is potentially adaptable to extended clinical research. Local codes for electronic medical records (EMRs), including diagnosis, drug prescriptions, and procedures, were mapped using standard vocabulary. Distributed queries based on clinical scenarios were developed and applied to K-CDM through decentralized or distributed networks. Results: Meta-analysis of drug relative risk ratios from ten institutions revealed that non-steroidal anti-inflammatory drugs (NSAIDs) increased the risk of gastrointestinal hemorrhage by twofold compared with aspirin, and non-vitamin K anticoagulants decreased cerebrovascular bleeding risk by 0.18-fold compared with warfarin. Conclusion: These results are similar to those from previous studies and are conducive for new research, thereby demonstrating the feasibility of K-CDM for pharmacovigilance. However, the low quality of original EMR data, incomplete mapping, and heterogeneity between institutions reduced the validity of the analysis, thus necessitating continuous calibration among researchers, clinicians, and the government. [ABSTRACT FROM AUTHOR]

Background and objectives: Even though impaired horizontal and vertical saccades are well-known features of progressive supranuclear palsy (PSP), abnormalities of torsional quick phases of eye movements have not been defined in PSP and other Parkinsonian syndromes. This study aims to determine the diagnostic value of decreased torsional quick phases during head oscillations in the roll plane in patients with PSP. Methods: Using video-oculography, we recorded the head and eye motion during passive head oscillations in the roll plane and determined the decrease of torsional quick phases in patients with PSP (n = 13) in comparison to normal controls (n = 13) and those with multiple system atrophy (MSA, n = 17) or idiopathic Parkinson's disease (PD, n = 6). Results: Torsional quick phases were absent during the torsional vestibulo-ocular reflex (VOR) in 78.6% (11/13) of the patients with PSP, but only in 11.8% (2/17) of those with MSA and none with idiopathic PD or of normal controls (Chi-square tests, p < 0.001) while gains of the torsional VOR did not differ among the groups (Chi-square tests, p > 0.05). Furthermore, the torsional quick phases were smaller even when observed in patients with PSP. Conclusion: Loss of torsional quick phases is an early biological marker for diagnosis of PSP, and may be ascribed to degeneration of the rostral interstitial nucleus of the medial longitudinal fasciculus that contains the burst neurons for torsional as well as vertical saccades. [ABSTRACT FROM AUTHOR]

The incidence and characteristics of acute vestibular symptoms, responsible structures, and lateralization of the causative lesions in supratentorial stroke remain unknown. This study aimed to determine the incidence, clinical features, and anatomical correlation of acute vestibular symptoms in supratentorial stroke. We performed a prospective, multicenter, observational study that had recruited patients with supratentorial stroke from the neurology clinics of referral-based four university hospitals in Korea. All patients received a constructed neuro-otological evaluations, and neuroimaging. We analyzed the incidence of acute vestibular symptoms, abnormal ocular motor and vestibular function tests, and stroke lesions. Of 1301 patients with supratentorial stroke, 48 (3.7%) presented with acute vestibular symptoms, and 13 of them (1%) had the vestibular symptoms in isolation. In patients with acute vestibular symptoms, abnormal findings included spontaneous nystagmus (5%), impaired horizontal smooth pursuit (41%), and abnormal tilt of the subjective visual vertical (SVV) (20%). Video head impulse and caloric tests were normal in all the patients. There was no clear correlation between acute vestibular symptoms and involvement of specific vestibular cortex. In patients with unilateral stroke, there was also no lateralization of the causative lesions of acute vestibular symptoms (left vs. right; 52 vs. 48%), even in patients with vertigo (left vs. right; 58 vs. 42%). This study demonstrates that the incidence of acute vestibular symptoms in supratentorial stroke is 3.7%, with being isolated in 1%. The widespread lesions responsible for acute vestibular symptoms implicate diffuse multisensory cortical–subcortical networks in the cerebral hemispheres without a lateralization. [ABSTRACT FROM AUTHOR]

Background and objectives: The etiologic distribution and clinical features of diplopia may differ according to the specialties involved in the management. This study aimed to establish the clinical features and underlying etiologies of diplopia by recruiting patients from all departments. Methods: We reviewed the medical records of 4127 patients with diplopia as the chief complaint, who had been recruited from all departments at Seoul National University Bundang Hospital, Seongnam, Republic of Korea, from 2003 to 2020. Results: Diplopia was binocular in 3557 (94.2%) and monocular in 219 (5.8%) patients. The common causes of binocular diplopia included microvascular (n = 516, 14.5%), strokes (n = 412, 11.6%), neoplastic (n = 304, 8.5%), myasthenia gravis (n = 253, 7.1%), traumatic (n = 240, 6.7%), and decompensated phoria (n = 232, 6.5%), and comprised more than a half of the causes. Patients with binocular diplopia were usually managed by neurologists (2549/3557, 71.7%), followed by ophthalmologists (2247/3557, 63.2%), emergency physicians (1528/3557, 43.0%), neurosurgeons (361/3557, 10.1%), and others (271/3557, 7.6%). The etiologies of binocular diplopia differed markedly according to the patients' age and the specialties involved in the management (p < 0.001). Conclusions: Given the differences in the etiologic distribution of diplopia according to the patients' age and the specialties involved in the management, the results of previous reports on the characteristics and etiology of diplopia, primarily performed in a single specialty department, should be interpreted with a possible selection bias. [ABSTRACT FROM AUTHOR]

Differentiation of spinocerebellar ataxia type 17 (SCA17) from Huntington's disease (HD) is often challenging since they share the clinical features of chorea, parkinsonism, and dystonia. The ocular motor findings remain to be elucidated in SCA17, and may help differentiating SCA17 from HD. We retrospectively compared the ocular motor findings of 11 patients with SCA17 with those of 10 patients with HD. In SCA17, abnormal ocular motor findings included impaired smooth pursuit (9/11, 82%), dysmetric saccades (9/11, 82%), central positional nystagmus (CPN, 7/11, 64%), abnormal head-impulse tests (4/11, 36%), and horizontal gaze-evoked nystagmus (GEN, 3/11, 27%). Among these, CPN was more frequently observed in SCA17 than in HD (7/11 (64%) vs. 0/10 (0%), p = 0.004) while saccadic slowing was more frequently observed in HD than in SCA17 (8/10 (80%) vs. 2/11 (18%), p = 0.009). Of six patients with follow-up evaluation, five later developed bilateral saccadic hypermetria (n = 4), GEN (n = 1), CPN (n = 1), bilaterally abnormal smooth pursuit (n = 1), and hyperactive head-impulse responses (n = 1) along with a clinical decline. Ocular motor abnormalities can be utilized as a diagnostic marker for differentiation of SCA17 from HD as well as a surrogate marker for clinical decline in SCA17. [ABSTRACT FROM AUTHOR]

Background: Masticatory function is known to be related to cognitive ability; therefore, factors for improving masticatory function should be identified. Aims: This study aimed to identify factors influencing masticatory function associated with mild cognitive impairment (MCI) in elderly individuals. Methods: A total of 123 elderly participants [mean age: 76.5 ± 6.5 years; 82 females (66.7%), 41 males (33.3%)] were included. Cognitive function was evaluated by the Korean version of the Mini-Mental State Examination (KMMSE). Questionnaires for subjective evaluation were administered, and dynamic objective masticatory function evaluations, including chewing tests and bite force measurements, were performed. Intergroup differences were evaluated by the Wilcoxon rank-sum and chi-square test, and correlations between cognitive ability and masticatory function were evaluated by multilinear logistic regression. Results: The number of teeth, number of posterior teeth, bite force, masticatory ability index (MAI) and posterior support status showed significant differences between the normal (KMMSE > 23) and MCI (KMMSE ≤ 23) groups. However, only the MAI, representing dynamic masticatory performance, was significantly associated with MCI regardless of age, sex and removable prostheses. The number of teeth and posterior teeth, bite force, subjective masticatory ability and posterior occlusal support showed no significant association with MCI. Discussion: These results suggested the importance of chewing function for preventing the progression of cognitive impairment. Conclusions: Considering that only the MAI was significantly associated with MCI, it is more important to improve chewing efficiency by harmonizing therapeutic prosthetics with the surrounding masticatory system than simply increasing the number of teeth to prevent or delay cognitive impairment in elderly individuals. [ABSTRACT FROM AUTHOR]

Ophthalmoplegia is the diagnostic hallmark of anti-GQ1b antibody syndrome. This study aimed to define the patterns of acute comitant strabismus in patients with anti-GQ1b antibody syndromes. We retrospectively analyzed the ocular motor findings in 84 patients with anti-GQ1b antibody-associated ophthalmoplegia during the acute phases. Of the 84 patients, 11 (13%) showed acute comitant strabismus. Compared to those without, patients with acute comitant strabismus frequently showed abnormal ocular motor findings that included gaze-evoked (n = 8), spontaneous (n = 4) and positional nystagmus (n = 4), saccadic hypermetria (n = 3), head-shaking nystagmus (n = 2), pulse-step mismatch (n = 1), and impaired visual cancellation of the vestibulo-ocular reflex (n = 1, p < 0.001). On the contrary, iridoplegia (p = 0.029) and ptosis (p = 0.001) were more commonly observed in patients with paralytic (incomitant) strabismus than in those with acute comitant strabismus. Comitant strabismus can manifest during the acute phase of anti-GQ1b antibody syndromes in association with other central ocular motor abnormalities. These findings implicate that the cerebellum and/or brainstem can be the primary target of the anti-GQ1b antibodies. [ABSTRACT FROM AUTHOR]

The International Myeloma Working Group has recently revised the diagnostic criteria for primary plasma cell leukemia (PCL) to circulating plasma cells (CPCs) ≥ 5% in a peripheral blood smear. The present study validated new criteria in patients with multiple myeloma or PCL diagnosed using the previous diagnostic criteria, who were administered immunomodulatory drugs or proteasome inhibitors as induction therapy. We analyzed the medical records of 1357 patients from eight hospitals in South Korea. The median age of the all patients was 64 years, and 187 (13.8%) had CPCs at diagnosis. Only 79 (5.8%) of the patients had ≥ 5% CPCs. The median overall survival (OS) of patients with CPCs ≥ 5% and ≥ 20% was similar, but had significantly inferior median progression-free survival (PFS) and median OS than those with CPCs < 5% (13.1 vs. 21.5 months, P < 0.001, and 21.5 vs. 60.9 months, P < 0.001, respectively). Primary PCL diagnosed using the revised criteria presented with higher total calcium levels and serum creatinine levels, lower platelet counts and frequent organomegaly and plasmacytoma at diagnosis. Univariate and multivariate analyses demonstrated that the presence of plasmacytoma and elevated serum β2-microglobulin were significantly associated with OS in primary PCL. In conclusion, the revised criterion of CPCs ≥ 5% in a peripheral blood smear is appropriate for PCL diagnosis. [ABSTRACT FROM AUTHOR]

Posttranslational modifications (PTMs) are essential mechanisms that provide chemical diversity to proteins. The additional functional and structural elements can be introduced to exceed the primary amino acid composition. PTMs impact key biological and physiological processes including cell signaling, metabolism, protein degradation and influences interactions with other macromolecules. However, characterization of the structural and functional signatures of modified proteins has been historically limited. Since defects in PTMs are linked to numerous disorders and diseases, PTMs and their modifying enzymes are considered as potential drug targets. This has fueled new initiatives to determine how PTMs affect protein structure and function. In this review, I summarize some of the major, well-studied protein PTMs and related drug targets. Since PTMs are widely used for therapeutic targets or disease markers, highlighting structural changes after PTM provides new frontiers in understanding the detailed mechanism and related drug developments. [ABSTRACT FROM AUTHOR]

These corrective saccades were only noticeable during the bedside HITs and had been interpreted as back-up saccades. Herein, we describe overt back-up saccades during HITs due to hypermetric covert saccades in a patient with an acute circumscribed lesion involving the cerebellum, which were misinterpreted as reversed corrective saccades due to the hyperactive VOR during bedside examination. When these corrective saccades are hypermetric due to cerebellar dysfunction, the eyes would overshoot the target with corrective saccades in the opposite direction. (MP4 15487 KB) Graph: Supplementary file3 Video-head impulse tests show hypermetric covert corrective (red arrowhead) and overt back-up saccades (red arrow) during stimulation of the left horizontal semicircular canal and covert corrective saccades (blue arrowhead) during stimulation of the right horizontal canal. [Extracted from the article]

In central as well as peripheral vestibular lesions, right-beating horizontal nystagmus is almost always associated with clockwise (top poles of the eyes beating to the right ear) torsional nystagmus when observed and vice versa (concordant nystagmus). This study aimed to determine the etiologies and mechanisms of horizontal and torsional nystagmus beating in the opposite directions (discordant nystagmus). We reviewed the medical records of 16 consecutive patients with discordant horizontal–torsional nystagmus who had been evaluated at the dizziness clinics of Seoul National University Bundang Hospital (n = 11, from March 2003 to March 2021) and Korea University Medical Center (n = 5, from March 2019 to March 2021). The underlying etiologies included inferior vestibular neuritis (n = 7), Meniere's disease (n = 4), internuclear ophthalmoplegia (n = 3), medullary hemorrhage (n = 1), and normal pressure hydrocephalus (n = 1). The torsional nystagmus decreased during the gaze in the same direction (for instance, during rightward gaze in clockwise nystagmus) and increased during the gaze in the opposite direction. Head-impulse tests (HITs) were positive for the ipsilesional posterior canal (PC) in all 11 patients with unilateral peripheral vestibulopathy and two of the three patients with unilateral central vestibulopathy. Discordant horizontal–torsional nystagmus may be observed in peripheral as well as central lesions. Given the findings of HITs and modulation of spontaneous nystagmus during lateral gazes, discordant horizontal–torsional nystagmus may be ascribed to selective damage of the excitatory or inhibitory pathway from the PC that innervates the ipsilateral superior oblique and contralateral inferior rectus muscles. [ABSTRACT FROM AUTHOR]

We investigated the effects of the alkyl chain length of alkylamine ligands (AALs), known to modify metal halide perovskite crystallites, on the preferential alignment of the CsFAMA crystal domains using two-dimensional grazing incidence wide-angle X-ray scattering (2D GIWAXS) measurements at various incident angles. In the absence of AALs, most (100) perovskite crystals were tilted 45° from the surface normal; the ratio of the 45°-tilted to isotropically oriented (100) crystals was similar in both the surface and bulk regions. However, in the presence of AALs, the 45°-tilted (100) crystals decreased, while the isotropically oriented (100) crystals increased, in both regions. In addition, vertically oriented (100) crystals were formed in the presence of AALs, which were observed only in the surface region of AALs with short alkyl lengths. As the alkyl chain length increased, vertically oriented (100) crystals appeared in both the surface and bulk regions of the film, i.e., the whole region of the film. [ABSTRACT FROM AUTHOR]

These saccades were associated with alternating horizontal saccades, thus giving rise to a "saw-tooth" appearance, especially during downward saccades. According to a conductance-based model simulation, premature and poorly synchronized discharges from the degenerated IBNs cause breaks in the saccade trajectory and maladaptive superior colliculus activity, resulting in aberrant saccades that alter the intended trajectory of the ongoing saccades [[4]]. His fragmented vertical saccades were associated with alternating horizontal saccades, giving rise to a "saw-tooth" appearance, especially during downward saccades. The hypometric (stair-case pattern) vertical saccades were associated with alternating horizontal saccades, thus giving rise to a "saw-tooth" appearance, especially during downward saccades (Fig. [Extracted from the article]

Fixation nystagmus refers to the nystagmus that appears or markedly increases with fixation. While relatively common in infantile (congenital) nystagmus, acquired fixation nystagmus is unusual and has been ascribed to lesions involving the cerebellar nuclei or the fibers projecting from the cerebellum to the brainstem. We aimed to report the clinical features of patients with acquired fixation nystagmus and discuss possible mechanisms using a model simulation and diagnostic significance. We describe four patients with acquired fixation nystagmus that appears or markedly increases with visual fixation. All patients had lesions involving the cerebellum or dorsal medulla. All patients showed direction-changing gaze-evoked nystagmus, impaired smooth pursuit, and decreased vestibular responses on head-impulse tests. The clinical implication of fixation nystagmus is that it may occur in central lesions that impair both smooth pursuit and the vestibulo-ocular reflex (VOR) but without creating a spontaneous nystagmus in the dark. We develop a mathematical model that hypothesizes that fixation nystagmus reflects a central tone imbalance due to abnormal function in cerebellar circuits that normally optimize the interaction between visual following (pursuit) and VOR during attempted fixation. Patients with fixation nystagmus have central lesions involving the cerebellar circuits that are involved in visual–vestibular interactions and normally eliminate biases that cause a spontaneous nystagmus. [ABSTRACT FROM AUTHOR]

Due to several issues, standard treatments are not recommended for asymptomatic patients with moderate immune thrombocytopenia (ITP). Since platelet responses are reported in some patients with Helicobacter pylori (H. pylori)-positive ITP after eradication, we conducted a multicenter, phase 3 study to evaluate the safety and efficacy of recently established sequential eradication for these patients having moderate thrombocytopenia. Persistent or chronic ITP patients with platelet count (30 × 103 ~ 80 × 103/μL) and confirmed active H. pylori infection were randomly assigned to a treatment and a control group. The former received 10-day sequential treatment. Eradication was assessed by urea breath test at 3 months after treatment. Primary endpoint was the overall platelet response rate at 3 months in successfully eradicated treatment group and control group. Secondary endpoints were platelet response time, H. pylori eradication success rate, etc. The patient enrollment terminated early because of the change of national insurance and treatment guideline for H. pylori-positive patients in Korea during the study. Of the 28 H. pylori-positive ITP patients, 17 were randomized to the treatment group, and eradication was achieved for 15 (88.2%) at 3 months, and seven in control group after withdrawal. Statistically, significant difference in platelet response rates between the two groups were observed (p = 0.017). Our study verifies that H. pylori eradication was an effective ITP treatment for patients with H. pylori-associated moderate ITP. This sequential eradication regimen showed not only a high H. pylori eradication rate, but also a remarkable platelet response for ITP patients. Trial registration number and date of registration for these prospectively registered trials is ClinicalTrials.gov number, NCT03177629 and June 6, 2017. [ABSTRACT FROM AUTHOR]

A light-harvesting effect was successfully achieved in photovoltaic devices by the structuring of an active perovskite layer through nanoimprinting. This was done by transforming a commercial CD-R pattern into a polydimethylsiloxane (PDMS) film. The latter was then used for replicating the perovskite layers under increased pressures and temperatures. The Young's modulus of the PDMS film was regulated by the mixing ratio of the base and curing agents, and the average height of the pattern was reported for an optimal 5:1 base-to-curing agent ratio. Under these conditions, the replication efficiency reached 80% at a pressure of ~ 4.9 kPa. To investigate the manner in which the structuring of these patterned perovskite layers affects optoelectronic devices, we incorporated them into photovoltaic cells. This resulted in improved J–V characteristics, as observed from an increase in both fill factor (FF) and short circuit current density (Jsc), from 73.20 to 76.35% and from 12.853 to 15.532 mA cm−2, respectively. The increase in FF was attributed to a large contact area between the perovskite and electron transport layers, while the increase in Jsc was due to the enhanced light-trapping of the periodic grating patterns of the perovskite layer. [ABSTRACT FROM AUTHOR]

Nilotinib has also shown an efficacy for various cerebellar ataxias [[6]], Parkinson disease dementia (PDD), dementia with Lewy bodies (DLB) [[8]], and Alzheimer's disease (AD) [[12]]. Dear Sirs, Mutations of the cluster-Abelson (c-Abl) may lead to an enhanced protein kinase activity, increased cell proliferation, and chronic myeloid leukemia (CML). Left vertical axis indicates the scores of activity of daily living (ADL), dizziness handicap inventory (DHI), and the scale for the rating and assessment of ataxia (SARA). [Extracted from the article]

Episodic ataxia type 2 (EA2) can present diverse ocular motor abnormalities, but few studies have systematically evaluated vestibular function during the interictal periods. This study aimed to determine vestibular impairments in patients with EA2 during the interictal periods. We recruited 17 patients with genetically confirmed EA2 (10 men, age range = 16–85 years, median = 32 years). We systematically evaluated the vestibular function by measuring the semicircular canals (SCCs) function with bithermal caloric tests, rotatory chair test, and video head impulse test (vHIT), and the otolith function with subjective visual vertical (SVV) tilt and variability, and cervical and ocular vestibular-evoked myogenic potentials (VEMPs). Patients with EA2 commonly showed abnormal VOR responses at least for one SCC with high-acceleration, high-frequency head impulses (14/16, 88%), and impaired visual-vestibular interaction (7/12, 58%). In response to low acceleration and frequency stimuli, the VOR gains were generally normal. The majority of EA2 patients had impairments in at least one of the otolith function tests (13/16, 81%): SVV tilt or variability (7/14, 50%), oVEMP (8/15, 53%), and cVEMP (4/16, 25%). Vestibular impairments are common in EA2 even during the interictal periods. Selective decrease in the VOR responses during higher acceleration stimuli along with impaired visual-vestibular interaction and otolith function suggests degeneration of the vestibulocerebellum or vestibular nuclei. [ABSTRACT FROM AUTHOR]

Given that exyclodeviation and prominent adduction hypertropia, hyperdeviation may be ascribed to bilateral trochlear nerve palsy in association with combined skew deviation [as a constellation of ocular tilt reaction (OTR)] in our patient. Therefore, a combination of an OTR to the right with bilateral trochlear nerve palsy (more severely affected in the right eye) would explain the missing SVV tilt to the left on the left eye in association with the excyclotropia. As in our patient, patients often compound the problem of distinguishing bilateral trochlear nerve palsy from skew deviation. Keywords: Strabismus; Diplopia; Skew deviation; Trochlear nerve palsy EN Strabismus Diplopia Skew deviation Trochlear nerve palsy 1781 1783 3 03/01/23 20230301 NES 230301 Dear Sirs, Superior oblique palsy is a common cause of acquired hyperdeviation, mostly caused by traumatic injury of the trochlear nerve [[1]]. [Extracted from the article]

The mechanism of vestibular syncope, the syncope occurring during the vertigo attacks, remains uncertain. This study aims to clarify the mechanism of vestibular syncope by pursuing the function of vestibular system in cardiovascular autonomic control and by defining neuro-hemodynamic changes in vestibular syncope. By integrating the velocity-storage (VS) circuit in the brainstem and cerebellum, we propose that the vestibular syncope develops as a result of dyssynergia of the vestibulosympathetic and baroreflexes in which centrally estimated downward inertial acceleration during the vertigo attacks acts as a trigger. Recognition of the vestibular disorders as a possible cause of syncope would allow proper managements for prevention of further syncope and related complications in patients with vestibular disorders. [ABSTRACT FROM AUTHOR]

In multiple myeloma (MM), a high number of focal lesions (FL) detected using positron emission tomography/computed tomography (PET/CT) was found to be associated with adverse prognosis. To design a new risk stratification system that combines the Revised International Staging System (R-ISS) with FL, we analyzed the data of 380 patients with newly diagnosed MM (NDMM) who underwent 18F-fluorodeoxyglucose (18F-FDG) PET/CT upon diagnosis. The K-adaptive partitioning algorithm was adopted to define subgroups with homogeneous survival. The combined R-ISS with PET/CT classified NDMM patients into four groups: R-ISS/PET stage I (n = 31; R-ISS I with FL ≤ 3), stage II (n = 156; R-ISS I with FL > 3 and R-ISS II with FL ≤ 3), stage III (n = 162; R-ISS II with FL > 3 and R-ISS III with FL ≤ 3), and stage IV (n = 31; R-ISS III with FL > 3). The 2-year overall survival rates for stages I, II, III, and IV were 96.7%, 89.8%, 74.7%, and 50.3%. The 2-year progression-free survival rates were 84.1%, 64.7%, 40.8%, and 17.1%, respectively. The new R-ISS/PET was successfully validated in an external cohort. This new system had a remarkable prognostic power for estimating the survival outcomes of patients with NDMM. This system helps discriminate patients with a good prognosis from those with a poor prognosis more precisely. [ABSTRACT FROM AUTHOR]

Hyperventilation changes the extracellular pH modulating many central pathologies, such as tremor. The questions that remain unanswered are the following: (1) Hyperventilation modulates which aspects of the oscillations? (2) Whether the effects of hyperventilation are instantaneous and the recovery is rapid and complete? Here we study the effects of hyperventilation on eye oscillations in the syndrome of oculopalatal tremor (OPT), a disease model affecting the inferior olive and cerebellar system. These regions are commonly involved in the pathogenesis of many movement disorders. The focus on the ocular motor system also allows access to the well-known physiology and precise measurement techniques. We found that hyperventilation causes modest but insignificant changes in the intensity of oscillation displacement (i.e., how large the eye excursions are) and velocity (i.e., how fast do the eyes move during oscillations). We found the robust increase in the randomness of the oscillatory waveform during hyperventilation and it instantaneously reverts to the baseline after hyperventilation. The subsequent analysis classified the oscillations according to their waveform shape and randomness into different clusters. The hyperventilation substantially changed the cluster type in 60% of the subjects, but it reverted to the pre-hyperventilation cluster at the conclusion of the hyperventilation. In summary, hyperventilation instantaneously affects the randomness of the oscillatory waveforms but there are less substantial effects on the intensity. The deficits reverse immediately at the end of the hyperventilation. [ABSTRACT FROM AUTHOR]

We report atypical opsoclonus in a patient with multiple system atrophy and propose a mechanism based on the patterns of modulation by visual, vestibular, and saccadic and vergence stimulation. Firstly, the 6-Hz opsoclonus mostly in the vertical plane occurred only after the development of downbeat nystagmus in darkness without visual fixation. Even after a substantial build-up, visual suppression of the opsoclonus was immediate and complete. Furthermore, the latency for re-emergence of opsoclonus in darkness was greater when the duration of preceding visual fixation was longer. Secondly, the effect of preceding downbeat nystagmus on the development of opsoclonus was evaluated by changing the head position. The opsoclonus did not occur in the supine position when the downbeat nystagmus was absent. After horizontal head shaking, the opsoclonus in the vertical plane gradually evolved into horizontal plane and resumed its vertical direction again after vertical head shaking. Thirdly, any opsoclonus was not triggered by imaginary saccades in the supine position. Lastly, combined vergence and saccadic eye movements during the Müller paradigm did not induce opsoclonus. From these findings of modulation, we suggest that the opsoclonus observed in our patient was invoked by vestibular signals. When the function of the omnipause neurons and saccadic system was impaired, the centrally mediated vestibular eye velocity signals may activate the saccadic system to generate opsoclonus. These atypical patterns of opsoclonus, distinct from the classic opsoclonus frequently observed in para-neoplastic or para-infectious disorders, may be an unrevealing sign of degenerative brainstem or cerebellar disorders. [ABSTRACT FROM AUTHOR]

Caloric tests are useful for disease surveillance of Meniere's disease (MD), although the interpretation of caloric tests remains controversial during the attacks of MD. Therefore, we aimed to characterize the findings of caloric tests during the attacks of MD. We analyzed the results of bithermal caloric tests during and between the attacks in 43 patients with unilateral definite MD. Evaluation was performed during the irritative/recovery phase in 22 and during the paretic phase in 26 patients. During the irritative/recovery phase, less than half of patients (10/22, 45%) showed a caloric asymmetry of more than 25%, lesser responses in the affected ear in six and in the healthy ear in the other four. In contrast, patients usually showed a caloric asymmetry of more than 25% during the paretic phase (19/26, 73%) with a decreased response almost always in the affected ear (18/19, 95%). Between the attacks, caloric asymmetry was found in less than half of the patients (20/43, 47%) with a decreased response almost always in the affected ear (19/20, 95%) when observed. The caloric asymmetry was less during the irritative/recovery phases than between the attacks (p = 0.007). In contrast, the caloric asymmetry was larger during the paretic phase than between the attacks (p = 0.041). The caloric asymmetry decreased during the irritative/recovery phases with an estimated mean difference of 34% (adjusted 95% CI 16–53%, p < 0.001) and 23% (adjusted 95% CI 8–38%, p = 0.002) compared to the paretic and interictal phases. Caloric responses fluctuate during and between the attacks of MD depending on the electrophysiologic status of the vestibular afferents. The results of caloric tests in MD, thus should be interpreted with consideration of each phase when the evaluation was done. [ABSTRACT FROM AUTHOR]

We aimed to characterize the central positional nystagmus (CPN) observed in lesions involving the inferior cerebellar peduncle (ICP). We analyzed the clinical and neurotologic findings in six patients with an isolated unilateral ICP infarction that had been diagnosed at a university hospital in South Korea from 2003 to 2019. Patients usually presented with acute vestibular syndrome in isolation (4/6, 67%). Ipsilesional spontaneous nystagmus was observed in five while supine (5/6, 83%). Four (4/6, 67%) patients showed CPN which included apogeotropic (n = 3) or geotropic (n = 1) during head turning to either side while supine, and vertical nystagmus during straight-head hanging, Dix-Hallpike maneuvers, or up-righting (n = 3). Four patients showed contraversive ocular tilt reaction or tilt of the subjective visual vertical. Bedside and video head-impulse tests were normal in all patients. CPN is a usual finding in ICP lesions, and may be ascribed to damage of the fibers running from the nodulus/uvula onto the vestibular nucleus via the ICP. [ABSTRACT FROM AUTHOR]

We investigated the vestibular perception of position, velocity, and time (duration) in humans with rotational stimuli including low velocities and small amplitudes. The participants were categorized into young, middle, and old age groups, and each consisted of 10 subjects. Position perception was assessed after yaw rotations ranged from 30 to 180° in both clockwise and counterclockwise directions. For each position, the rotation was delivered at two or more different velocities ranging from 15 to 120°/s. Position perception tended to underestimate the actual position and was similar during the slow and fast rotations. However, the trends of underestimation disappeared in the old age group. Velocity perception was evaluated by forcing the selection of the faster direction in each pair of rotations toward two positions (30° and 60°) with velocity differences from 0 to 20°/s. Velocity discrimination was similar between the rotation amplitudes or among the age groups. For duration perception, participants chose the rotation of longer duration for three test paradigms with different amplitudes (small vs. large) and durations (short vs. long) of rotation. The accuracy of discriminating duration was similar across the test paradigms or age groups, but the precision was lower in the older group and altered significantly according to the test paradigm. In conclusion, vestibular perception can be assessed using rotations of low velocities and small amplitudes. The perception of position and duration is affected by aging. The precision of duration perception can be influenced by the interactions between the amplitude and duration of motion. [ABSTRACT FROM AUTHOR]

Given the characteristics of typewriter tinnitus, the paroxysmal nature with an excellent response to carbamazepine, the tinnitus may be ascribed to NVCC affecting the cochlear nerve [[2], [6]]. Dear Sirs, Vestibular paroxysmia (VP) is characterized by brief and recurrent vertigo that respond well to carbamazepine or oxcarbazepine [[1]]. Our patient presented with paroxysmal attacks of vertigo and typewriter tinnitus that resolved with carbamazepine. [Extracted from the article]

Benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo worldwide. This review considers recent advances in the diagnosis and management of BPPV including the use of web-based technology and artificial intelligence as well as the evidence supporting the use of vitamin D supplements for patients with BPPV and subnormal serum vitamin D. [ABSTRACT FROM AUTHOR]

Background: As general and oral health are closely interrelated, promoting oral health may extend a healthy life expectancy. Aims: To evaluate the long-term effects of simple oral exercise (SOE) and chewing gum exercise on mastication, salivation, and swallowing function in adults aged ≥ 65 years. Methods: Ninety-six participants were assigned to control, SOE, and GOE (chewing gum exercise with SOE) groups. The SOE comprised exercises to improve mastication, salivation, and swallowing function. Control group participants performed no exercises. The intervention period was 8 weeks, followed by a 3-week maintenance period. The Mixing Ability Index (MAI), occlusal force, unstimulated saliva, and repetitive saliva swallowing test were evaluated at baseline and 2, 5, 8, and 11 weeks later. Self-reported discomfort was re-evaluated after 8 weeks. Results: After 8 weeks, mean MAI differences from baseline significantly increased in both groups; the increase in the GOE group was largest and four times higher than in the control group. Mean differences of occlusal force from baseline increased by 56 N (SOE group) and 60 N (GOE group). The increase of salivation was greater in the SOE (3.6-fold) and GOE (2.2-fold) groups than in the control group. Furthermore, 27% and 18% of SOE and GOE group participants, respectively, were re-categorized as having good swallowing function. Participants reported less discomfort as oral functions improved. Discussion: These findings may facilitate the development of clinical practice guidelines for optimal oral care in older adults. Conclusion: While both SOE and GOE may improve oral function in older adults, GOE is recommended for those with impaired mastication. Trial registration: KCT0003305, retrospectively registered 31/10/2018. [ABSTRACT FROM AUTHOR]

This study aimed to determine the prevalence and mechanism of linear vertigo reported by the patients during the attacks of benign paroxysmal positional vertigo (BPPV). We prospectively evaluated the characteristics (rotational vs. linear) of positional vertigo in 70 patients with posterior and horizontal canal BPPV using a questionnaire allowing multiple choices. In patients with linear vertigo, we further assessed the directionality of linear vertigo. We adopted the velocity-storage model to explain the occurrence and direction of linear vertigo in these patients with BPPV. Patients reported only rotational vertigo in 46 (46/70, 65.7%), only linear vertigo in 10 (14.3%), and both rotational and linear vertigo in 14 (20%). The patients experienced fear from rotational vertigo in 54 (54/70, 77.1%) and from linear vertigo in 20 (20/70, 28.6%). The direction of linear vertigo was concordant with the direction of inertial acceleration predicted by the velocity-storage model. Patients with BPPV may experience linear as well as rotational vertigo during the attacks. This linear vertigo may be ascribed to centrally estimated inertial acceleration. [ABSTRACT FROM AUTHOR]

Telomerase reverse transcriptase gene promoter (TERTp) mutation is a potential candidate for pathogenesis and therapeutic target of tonsillar squamous cell carcinomas (TSCCs) in association with human papillomavirus (HPV). Their clinical relevance has not been validated under the new 8th American Joint Committee on Cancer (AJCC) staging system. We analyzed real-time peptide nucleic acid–mediated PCR and sequencing methods (TERTp mutation) and real-time PCR-based assay (HPV) in 80 surgically resected TSCCs. The 8th edition staging system improved the stratification of the early and advanced stages and between T or N categories for overall survival over the 7th edition. TERTp mutation was found in 7.5%, and HPV in 80.0% of the patients. The majority (83.3%) of TERTp mutation cases were HPV-positive TSCCs. Applying the 8th edition staging system, TERTp mutation was an independent factor of poor prognosis for disease-free survival (DFS) in TSCC patients, supporting the clinical significance of TERTp mutation in tonsil cancer. TERTp mutations were also negatively correlated with overall survival and DFS in HPV-negative TSCCs. Conclusively, TERTp mutation provides negative prognostic impact on survival of surgically managed tonsil cancers staged with the AJCC 8th edition. [ABSTRACT FROM AUTHOR]

The bilateral lateral medullary lesions disrupt both the inhibitory Purkinje outflow to bilateral vestibular nuclei and the climbing fibers participating in the cerebellar VOR adaptation, resulting in phenotypically identical HIS compared to the global cerebellar lesions. During vertical HITs for left or bilateral anterior canal semicircular canals, the VOR gain was slightly increased and small corrective saccades were followed in the anti-compensatory direction (Fig. Normally, vertical eye movements derived from each vertical canal are offset but not when the anterior canal gain is increased due to the vestibulocerebellar lesions [[9]]. [Extracted from the article]

We compared efficacy and safety, according to frailty, of elderly patients with relapsed and refractory multiple myeloma (RRMM) treated with lenalidomide and dexamethasone (Rd), for whom bortezomib treatment had failed. Patients, 164 (52.9%) and 146 (47.1%), were classified as non-frail and frail using a simplified frailty scale. The overall response rates (ORR) and survival outcomes were lower in frail than in non-frail patients (ORR: 56.2% vs. 67.7%, P = 0.069; median progression free survival: 13.17 vs. 17.80 months, P = 0.033; median overall survival: 23.00 vs. 36.27 months, P = 0.002, respectively). The number of treatment emergent adverse events in grade 3 or worse was higher in frail than in non-frail patients (41.8% vs. 24.4%, P = 0.002, respectively). In frail patients, independent poor prognostic factors for survival were two or more Charlson comorbidity index (CCI) score, prior to exposure to both bortezomib and thalidomide, and achieved less than partial response In conclusion, frailty could predict clinical outcomes of Rd treatment in elderly patients with RRMM who had failed prior bortezomib. In frail patients, lower CCI in addition to less previous treatment exposure and deep response were associated with better survival. [ABSTRACT FROM AUTHOR]

We suggest a combination of morphological control and the introduction of an additive as a strategy to completely convert thermally grown a PbI2 layer into the perovskite structure for inverted organic–inorganic hybrid perovskite solar cells (PSCs). For 2-step PSCs based on thermal evaporation, the complete conversion of PbI2 into the perovskite structure is a key parameter for device performance. To achieve complete conversion, we regulated the morphology of the PbI2 layer by controlling the growth rate. Compared to rapidly grown PbI2 layers, a PbI2 layer grown at a slow rate contained pinholes that enhanced the diffusion of methyl ammonium iodide (MAI) from the PbI2 surface. Despite the assistance of the pinholes, the conversion of the PbI2 was incomplete due to the limited interaction between the MAI and PbI2. Complete conversion of the pinhole-rich PbI2 occurred by introducing an additive into the MAI solution. The conversion of PbI2 was measured by grazing-incidence wide-angle X-ray scattering using synchrotron X-rays. By controlling the incidence angle of the X-rays, we quantitatively compared the amount of PbI2 as a function of the X-ray penetration depth. Using a completely converted 50 nm-thick PbI2 layer, we obtained a power conversion efficiency of 9.44%. Graphic Absract: [ABSTRACT FROM AUTHOR]

This study aimed to determine the etiologic distribution of dizziness and vertigo in a referral-based dizziness clinic in South Korea. We analyzed the diagnoses of 21,166 consecutive dizzy patients (12,691 women, mean age = 57.9 ± 15.7, age range = 3–97) seen from 2003 to 2019 using a registry and medical records. Overall, dizziness and vertigo were more common in women (60.0%, CI 0.59–0.61) than in men without a difference in age (57.7 ± 15.5 vs. 58.1 ± 16.1, p = 0.094). Benign paroxysmal positional vertigo (BPPV, 24.1%) was the most common cause of dizziness/vertigo, followed by psychiatric or persistent postural perceptual dizziness (20.8%), vascular disorders (12.9%), vestibular migraine (10.2%), Meniere's disease (7.2%), and vestibular neuritis (5.4%). These six disorders comprised more than 80% of all disorders. The etiology could not be determined in 5.0%, and more than one etiology was found in 14.1%. Vestibular migraine was the most common disorder in children and adolescents (< 19 years), psychiatric or persistent postural perceptual dizziness (26.3%) in the adults (19–64 years), and BPPV (28.2%) in the elderly (≥ 65 years). This etiologic distribution is similar to that reported in another country, and indicates no significant differences in the proportion of diseases causing dizziness and vertigo across different ethnic groups. This study provides valuable information to establish healthcare policy for dizziness and vertigo. [ABSTRACT FROM AUTHOR]

Background and Aims: Colitis-associated cancer (CAC) is one of the most serious complications in patients with inflammatory bowel disease. Sphingosine kinase 1 (Sphk1) is a key enzyme in the sphingolipid pathway and has oncogene potential for inducing both initiation and progression of tumors. The aim of this work is to characterize the role of epithelial Sphk1 in mouse colitis and CAC models.Methods: We investigated the roles of Sphk1 in CAC by conditional deletion of Sphk1 in intestinal epithelial cells (IECs).Results: CAC was induced in both Sphk1ΔIEC/ApcMin/+ and Sphk1IEC/ApcMin/+ mice by administration of 2% dextran sodium sulfate (DSS) for 7 days. Genetic deletion of Sphk1 significantly reduced the number and size of tumors in ApcMin/+ mice. Histologic grade was more severe in Sphk1ΔIEC/ApcMin/+ mice compared with Sphk1IEC/ApcMin/+ mice (invasive carcinoma, 71% versus 13%, p < 0.05). Deletion of Sphk1 decreased mucosal proliferation and inhibited STAT3 activation and genetic expression of cyclin D1 and cMyc in tumor cells. Conditional deletion of Sphk1 using CRISPR-Cas9 in HCT 116 cells inhibited interleukin (IL)-6-mediated STAT3 activation.Conclusions: Epithelial conditional deletion of Sphk1 inhibits CAC in ApcMin/+-DSS models in mice by inhibiting STAT3 activation and its target signaling pathways. [ABSTRACT FROM AUTHOR]