Comparison of baseline covariate adjustment methods for restricted mean survival time.

The restricted mean survival time provides a straightforward clinical measure that dispenses with the need for proportional hazards assumptions. We focus on two strategies to directly model the survival time and adjust covariates. Firstly, pseudo-survival time is calculated for each subject using a leave-one-out approach, followed by a model analysis that adjusts for covariates using all pseudo-values. This method is used to reflect information of censored subjects in the model analysis. The second approach adjusts for covariates for those subjects with observed time-to-event while incorporating censored subjects using inverse probability of censoring weighting (IPCW). This paper evaluates these methods' power to detect group differences through computer simulations. We find the interpretation of pseudo-values challenging with the pseudo-survival time method and confirm that pseudo-survival times deviate from actual data in a primary biliary cholangitis clinical trial, mainly due to extensive censoring. Simulations reveal that the IPCW method is more robust, unaffected by the balance of censors, whereas pseudo-survival time is influenced by this balance. The IPCW method retains a nominal significance level for the type-1 error rate, even amidst group differences concerning censor incidence rates and covariates. Our study concludes that IPCW and pseudo-survival time methods differ significantly in handling censored data, impacting parameter estimations. Our findings suggest that the IPCW method provides more robust results than pseudo-survival time and is recommended, even when censor probabilities vary between treatment groups. However, pseudo-survival time remains a suitable choice when censoring probabilities are balanced.

Attempt to Make the Upper-Limb Item of Objective Fugl-Meyer Assessment Using 9-Axis Motion Sensors.

The Fugl-Meyer Assessment (FMA) has been used as a functional assessment of upper-limb function in stroke patients. This study aimed to create a more objective and standardized evaluation based on an FMA of the upper-limb items. A total of 30 first-ever stroke patients (65.3 ± 10.3 years old) and 15 healthy participants (35.4 ± 13.4 years old) admitted to Itami Kousei Neurosurgical Hospital were included. A nine-axis motion sensor was attached to the participants, and the joint angles of 17 upper-limb items (excluding fingers) and 23 FMA upper-limb items (excluding reflexes and fingers) were measured. From the measurement results, we analyzed the time-series data of each movement and obtained the correlation between the joint angles of each part. Discriminant analysis showed that 17 and 6 items had a concordance rate of ≥80% (80.0~95.6%) and <80% (64.4~75.6%), respectively. In the multiple regression analysis of continuous variables of FMA, a good regression model was obtained to predict the FMA with three to five joint angles. The discriminant analysis for 17 evaluation items suggests the possibility of roughly calculating FMA scores from joint angles.

Dystonia-like Movement Disorders Ameliorated by Shear Force and Pressure Stimulation after Small Infarction in the Left Posterolateral Thalamus.

Focal dystonia (FD) can develop after thalamic lesions. Abnormal somatic sensations were argued to be responsible for FD. Our patient experienced FD-like movement disorders, agraphesthesia, and a reduced sense of shear force on the skin and pressure to deep tissues of the right upper limb following a small infarction in the left posterolateral thalamus. FD-like symptoms improved while the skin was being pulled or the deep tissue was being pushed in a manner proportional to the strength of muscle contractions. Therefore, the lack of these sensations was suggested to be related to FD-like symptoms.

Midlateral medullary infarction presenting with isolated thermoanaesthesia: a case report.

BACKGROUND: A small lateral medullary lesion could produce isolated impairment of temperature sensation without concomitant impaired pain sensation. However, only one such case has ever been reported, and there are no reports on subjective symptoms and detailed somatosensory testing. CASE PRESENTATION: Herein, we report the case of a 53-year-old female patient presenting with impaired temperature sensation on the left half of her body, from the neck down, following a small infarction of the right midlateral medulla. The chronological changes in the patient's introspection regarding impairment of thermoception and the results of detailed somatosensory tests, including thermal sense, are shown in this report. CONCLUSIONS: Thorough somatosensory tests, personal descriptions of symptoms, and electrophysiological quantification of similar cases are needed to improve our understanding of the neurological separation of the sensations of pain and temperature at the medullary level.

Factors associated with prognosis of upper limb function in branch atheromatous disease.

BACKGROUND: Branch atheromatous disease (BAD) is often associated with corticospinal tract injury, and some patients develop early neurological deterioration (END) in the acute phase. This study investigated the progress of upper limb prognosis after BAD in the acute phases and examined the factors related to the prognosis of upper limb function. PROCEDURES: 108 subjects diagnosed with BAD were included. Then subjects were classified into two groups: those with good recovery of upper limb function and those with poor recovery of upper limb function. Univariate and multivariate analyses were performed with the objective variable being good or poor upper limb function. The following factors were used as explanatory variables: age, the volume of infarction, initial Fugl-Meyer assessment (FMA) upper limb score, and presence of END. MAIN FINDINGS: The univariate analysis showed significant differences in age and volume of infarction (p < 0.05). Multivariate analysis showed the following finding: age;(OR 0.977,95%CI 0.917-0.997,p = 0.0061; volume of infarction;(OR 0.645,95%CI 0.461-0.902,p = 0.0104). A significant difference was found in the age and volume of the infarct. CONCLUSION: This study finding suggests that age and volume of infarction are associated with the prognosis of upper extremity paralysis in BAD.

A Patient with a Unilateral Insular Lesion Showing Bilaterally Reduced Perception of Noxious Stimulation.

No study has reported a unilateral localized cerebral lesion of the posterior insula bilaterally reducing noxious stimuli perception. A 57-year-old man with an infarct involving the right posterior insula presented with reduced somatosensory response in the upper and lower left extremities. Furthermore, there was a reduced response to noxious stimulation in the right upper and lower limbs. We noted reductions in pain, noxious heat and cold perceptions, and sensitivity to increasing temperature. Other somatic sensations, including non-noxious temperatures, remained intact in the right upper and lower extremities. These findings in our patient with a unilateral insular lesion indicated a bilaterally reduced perception of noxious stimulation.

Effects of mechanical thrombectomy for post-stroke patients with upper limb hemiparesis: Use of Propensity Score Matching.

BACKGROUND: Mechanical Thrombectomy (MT) is a recommended approach for post-cerebral ischemia in acute settings. Although a large amount of evidence suggests the use of MT, existing evidence has primarily focused on assessing lower limb performance or gait performance as an outcome measure. METHODS: This study was to investigate whether MT would be an effective approach for improving upper limb performance in post-stroke patients.This case control was divided into two groups: 154 patients as a control group only given conventional rehabilitation; and 25 patients as an intervention group given MT and conventional rehabilitation. Outcome variables were measured by calculating the change of Fugl-Meyer Assessment score at the last intervention compared with the beginning of the intervention. RESULT: By comparing the FMA scores after, the propensity matching compared between before receiving therapy intervention and after, the intervention group showed as follows: 30.4 ± 26.4-44.3 ± 25.4, p = 0.0019, r = 0.59. The control group showed as follows: 39.9 ± 24.1-49.1 ± 21.3, p = 0.002, r = 0.69. Lastly, a comparison of the intervention group with the control group about their FMA score change indicates as follows: intervention group: 13.9 ± 19.4, control group 9.2 ± 10.0, p = 0.2967, r = 0.15. CONCLUSION: This study indicated that there was no significant difference between MT and a conventional approach for improving UE function. However, this is the first study to investigate the course of recovery of UE function in the acute phase after MT, and this finding supports the need for further research.

Numbsense of shape, texture, and objects after left parietal infarction: A case report.

Numbsense is a phenomenon, wherein patients can correctly respond to somatosensory stimuli at a higher rate than expected by chance, but cannot perceive the same stimuli consciously. Previously, numbsense has been reported in tactile localization of stimuli on the patient's own body. Here, we describe a patient with numbsense that involved touched objects. The patient could not recognize the majority of somatosensory stimuli after left parietal infarction, but could correctly select shape, texture, and object stimuli more frequently than expected by chance.

Incidence and lesions causative of delusional misidentification syndrome after stroke.

OBJECTIVE: To better elucidate the symptomatology and pathophysiological mechanisms underlying delusional misidentification syndrome (DMS), we investigated the incidence rate and symptomatic features of DMS following stroke and relationships among DMS, other neuropsychological symptoms, and lesion locations. METHODS: The present study included 874 consecutive patients (371 women; mean age ± standard deviation = 72.2 ± 11.7 years) who were admitted to the rehabilitation wards at two hospitals within 2 months of their first stroke. We examined the clinical features and lesion sites of patients with DMS and compared them with those of a control group of patients with hemi-spatial neglect without DMS using voxel-based lesion-symptom mapping (VLSM). RESULTS: Among the 874 patients who experienced a stroke, we observed 10 cases of Fregoli syndrome. No other DMS subtypes were observed; however, eight patients exhibited somatoparaphrenia (five of them also had Fregoli syndrome) and one also exhibited reduplicative paramnesia. Right hemispheric lesions were found in all 10 cases. VLSM revealed statistically significant overlapping lesion sites specifically related to Fregoli syndrome when compared with the control group. The sites included the insula, inferior frontal lobe, anterior temporal lobe, and subcortical limbic system in the right hemisphere (i.e., areas connected by the uncinate fasciculus). CONCLUSION: The DMS incidence was 1.1% among patients after stroke. All patients had Fregoli syndrome and half had somatoparaphrenia, suggesting that the two syndromes share an underlying pathology. Lesions found with Fregoli syndrome were concentrated around the right uncinate fasciculus; this has not been reported in previous research.

Synthesis and evaluation of a potent, well-balanced EP2/EP3 dual agonist.

A highly potent and well-balanced dual agonist for the EP2 and EP3 receptors is described. Optimization of the lead compound was accomplished in consideration of the relative agonist activity against each EP subtype receptor and the pharmacokinetic profile. As the result, 2-[(2-{(1R,2R)-2-[(1E,4S)-5-cyclopentyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}eth-yl)thio]-1,3-thiazole-4-carboxylic acid (10) showed excellent potency (human EC50 EP2 = 1.1 nM, EP3 = 1.0 nM) with acceptable selectivity over the EP1 and EP4 subtypes (>2000-fold). Further fine-tuning of compound 10 led to identification of ONO-8055 as a clinical candidate. ONO-8055 was effective at an extremely low dose (0.01 mg/kg, po, bid) in rats, and dose-dependently improved voiding dysfunction in a monkey model of underactive bladder (UAB). ONO-8055 is expected to be a novel and highly promising drug for UAB.

Development of the Cognitive Test for Severe Dementia.

BACKGROUND/AIMS: Existing cognitive measures for moderate-to-severe dementia have shown floor effects and an inability to assess the remaining cognitive function, especially for profound dementia. METHODS: We constructed the Cognitive Test for Severe Dementia (CTSD), which consists of 13 items covering 7 cognitive domains, and examined its reliability and validity. RESULTS: Cronbach's α in severe dementia participants was 0.896. Interrater and test-retest reliability were 0.961 and 0.969, respectively. The CTSD showed a significant correlation with 3 other measures of cognitive function (Mini-Mental State Examination, Severe Cognitive Impairment Rating Scale, and Hasegawa Dementia Scale-Revised: r values = 0.870-0.922, p values <0.001). While the other measures showed floor effects, the CTSD did not. CONCLUSION: The CTSD was able to sensitively capture the remaining cognitive function in severe dementia patients when compared with other cognitive tests.

A one-year follow-up after modified constraint-induced movement therapy for chronic stroke patients with paretic arm: a prospective case series study.

BACKGROUND: Despite the confirmed short-term effects of constraint-induced movement therapy, the long-term effects have not been sufficiently verified in terms of functional improvement of the affected arm. OBJECTIVE: To evaluate the long-term effects and relationship between arm use in activities of daily living and arm improvement with modified constraint-induced movement therapy in chronic stroke patients. METHODS: At 1 year after completing modified constraint-induced movement therapy, arm function (Fugl-Meyer Assessment) and amount of daily arm use (motor activity log) were assessed. RESULTS: Fourteen post-stroke patients with mild to moderate impairment of arm function were analyzed. One year after completing modified constraint-induced movement therapy, participants consistently showed improvements in arm function and amount of daily arm use (analysis of variance: Fugl-Meyer Assessment, P < 0.001; Motor Activity Log, P < 0.001). For the Fugl-Meyer Assessment, post-hoc tests detected significant improvements (pre versus post, P = 0.009; pre versus 1 year, P < 0.0001; post versus 1 year, P < 0.036). For the Motor Activity Log, post-hoc tests also detected significant improvements (pre versus post, P = 0.0001; pre versus 1 year, P < 0.0001; post versus 1 year, P = 0.0014). The magnitude of the change in Fugl-Meyer Assessment score correlated significantly with the change in Motor Activity Log score (R = 0.778, P = 0.001). CONCLUSIONS: Among post-stroke patients with mild to moderate impairments of arm function, modified constraint-induced movement therapy without any other rehabilitation after intervention may improve arm function and increase arm use for 1 year. In addition, increasing arm use may represent an important factor in improving arm function, and vice versa.

Constraint-Induced Movement Therapy After Injection of Botulinum Toxin Type A for a Patient With Chronic Stroke: One-Year Follow-up Case Report.

BACKGROUND AND PURPOSE: Spasticity, an aspect of upper motor neuron syndrome, is a widespread problem in patients with stroke. To date, no study has reported the long-term (up to 1 year) outcomes of botulinum toxin (BTX) injection in combination with constraint-induced movement therapy in patients with chronic stroke. In this case report, the long-term (1 year) effects of the combination of BTX type A injection and constraint-induced movement therapy on spasticity and arm function in a patient with chronic stroke and arm paresis are described. CASE DESCRIPTION: The patient was a 66-year-old man who had had an infarction in the right posterior limb of the internal capsule 4 years before the intervention. At screening, the patient was not able to voluntarily extend his interphalangeal or metacarpophalangeal joints beyond the 10 degrees required for constraint-induced movement therapy. From 12 days after BTX type A injection, the patient received 5 hours of constraint-induced movement therapy for 10 weekdays. OUTCOMES: All outcome measures (Modified Ashworth Scale, Fugl-Meyer Assessment, Action Research Arm Test, and amount of use scale of the Motor Activity Log) improved substantially over the 1-year period (before intervention to 1 year after intervention). Repeat BTX type A injections were not necessary because muscle tone and arm function did not worsen during the observation period. DISCUSSION: The improved arm function may have reflected improvements in volitional movements and coordination or speed of movements in the paretic arm as a result of a reduction in spasticity, a reduction of learned nonuse behaviors, or use-dependent plasticity after the combination of BTX type A injection and constraint-induced movement therapy. In addition, the possibility of an influence of the passage of time or the Hawthorne effect cannot be ruled out. If this approach proves useful in future controlled studies, it may reduce the rising medical costs of the treatment of stroke.

Chiroptical molecular propellers based on hexakis(phenylethynyl)benzene through the complexation-induced intramolecular transmission of local point chirality.

We designed hexakis(phenylethynyl)benzene derivatives with a tertiary amide group on each blade to achieve a helically biased propeller arrangement through the complexation-induced intramolecular transmission of point chirality. A hydrogen-bonding ditopic guest was captured at two amide groups, and thus could pair two neighboring blades to form a supramolecular cyclic structure, in which an auxiliary chiral group associated with a blade acted as a chiral handle to control the helical bias, while the chiral auxiliary did not exert any helical influence on the dynamic helicity in the absence of a guest due to the high flexibility of each blade.

Therapeutic synergism in the treatment of post-stroke arm paresis utilizing botulinum toxin, robotic therapy, and constraint-induced movement therapy.

Botulinum toxin type A (BtxA) injection, constraint-induced movement therapy (CIMT), and robotic therapy (RT) each represent promising approaches to enhance arm motor recovery after stroke. To provide more effective treatment for a 50-year-old man with severe left spastic hemiparesis, we attempted to facilitate CIMT with adaptive approaches to extend the wrist and fingers using RT for 10 consecutive weeks after BtxA injection. This combined treatment resulted in substantial improvements in arm function and the amount of arm use in activities of daily living, and may be effective for stroke patients with severe arm paresis. However, we were unable to sufficiently prove the efficacy of combined treatment based only on a single case. To fully elucidate the efficacy of the combined approach for patients with severe hemiparesis after stroke, future studies of a larger number of patients are needed.

Diffusion tensor imaging predicts the outcome of constraint-induced movement therapy in chronic infarction patients with hemiplegia: A pilot study.

PURPOSE: To test whether diffusion tensor imaging could evaluate potential motor capability of patients with chronic cerebral infarction. METHODS: We used constraint-induced movement therapy (CIMT) as a rehabilitation, which reveals potential motor capability. We also investigated the relationship between the outcome of CIMT and the ratio between fractional anisotropy values (rFA) in affected and unaffected sites of the corticospinal tract before CIMT. Imaging was performed in cerebral infarction patients (n = 14) and the rFA of the posterior limb of internal capsule (PLIC) was measured before CIMT. Patients were evaluated before and after CIMT using the Fugl-Meyer (F-M) assessment, Wolf Motor Function Test, Action Research Arm Test, and Motor Activity Log and association between PLIC- rFA and these scores was determined. RESULTS: All patients showed an improvement in mobility following the 10-day CIMT session. Strong positive correlation was found only between F-M after CIMT and PLIC-rFA (r = 0.8098, p = 0.0004). A strong linear relationship was observed after CIMT. CONCLUSION: These data support PLIC-rFA as a new marker of the CIMT-induced improvement in motor function (F-M).

Effects of constraint-induced movement therapy on spasticity in patients with hemiparesis after stroke.

BACKGROUND: We sought to examine the effects of constraint-induced movement therapy on spasticity in patients with hemiparesis after stroke in 10 patients with chronic hemiparesis in their upper extremities. METHODS: Patients underwent a modified version of constraint-induced movement therapy (5 hours daily for 10 weekdays over 2 consecutive weeks). Motor function was assessed by the Fugl-Meyer Assessment, Wolf Motor Function Test, and the Motor Activity Log. Spasticity was assessed by the modified Ashworth scale and electromyography (F frequency, mean F/M ratio). These assessments were obtained immediately before and after the 2-week intervention. Wilcoxon rank sum tests were performed on these data (P < .05). RESULTS: Constraint-induced movement therapy significantly improved hand and arm function as indicated by the Fugl-Meyer Assessment, Wolf Motor Function Test, and the Motor Activity Log scores. Constraint-induced movement therapy also reduced spasticity as assessed by the modified Ashworth scale, F frequency, and mean F/M ratio. CONCLUSIONS: Comparable to motor function, constraint-induced movement therapy effectively reduces spasticity as confirmed by electromyography.

A 6-month follow-up after constraint-induced movement therapy with and without transfer package for patients with hemiparesis after stroke: a pilot quasi-randomized controlled trial.

OBJECTIVE: To investigate the long-term effects of the 'transfer package' in constraint-induced movement therapy, which is an optional protocol to facilitate actual use of the trained affected arm in activities of daily living. DESIGN: A pilot quasi-randomized controlled trial with a blinded single assessor with six-month follow-up. SETTING: Hospitalized care at university hospital. SUBJECTS: Twenty-one post-stroke patients were quasi-randomized to either a group with transfer package during constraint-induced movement therapy or a control group (without transfer package). INTERVENTIONS: The transfer package group received 4.5 hours of intensive task training and 0.5 hours of transfer package whereas the control group received 5.0 hours of intensive task training per day during 10 consecutive weekdays. MAIN MEASURES: Arm function was measured with Fugl-Meyer Assessment and Amount of Use score of Motor Activity Log. RESULTS: Twenty-three patients were quasi-randomized, but data from two patients were missing from the long-term follow-up. Both groups showed increase in arm function postintervention. However, at six months' follow-up only the transfer package group showed consistent increase in arm function (with transfer package group versus control group; Fugl-Meyer Assessment, mean (± SD) from 48.6 ± 7.8 (preintervention) to 55.7 ± 4.5 (postintervention) and 59.0 ± 3.6 (six months postintervention) versus from 49.1 ± 5.5 to 52.8 ± 6.0 and 53.3 ± 4.9, P= 0.003; Amount of Use scale of Motor Activity Log, mean from 1.3 ± 0.55 (preintervention) to 2.12 ± 0.55 (postintervention) and 2.79 ± 0.98 (six months postintervention) versus from 1.18 ± 0.70 to 1.61 ± 0.54 and 1.65 ± 0.68, P= 0.002). CONCLUSIONS: Our results confirmed the long-term effects of the transfer package in constraint-induced movement therapy.

A new route to (+)-estrone using a bicyclo[3.2.1]octane chiral building block.

A new route to (+)-estrone has been developed starting from the chiral building block having a bicyclo[3.2.1]octane framework based on the inherent stereochemical chemical nature of the chiral building block.