Clinical subtypes of older adults starting long-term care in Japan and their association with prognoses: a data-driven cluster analysis.

We aimed to identify the clinical subtypes in individuals starting long-term care in Japan and examined their association with prognoses. Using linked medical insurance claims data and survey data for care-need certification in a large city, we identified participants who started long-term care. Grouping them based on 22 diseases recorded in the past 6 months using fuzzy c-means clustering, we examined the longitudinal association between clusters and death or care-need level deterioration within 2 years. We analyzed 4,648 participants (median age 83 [interquartile range 78-88] years, female 60.4%) between October 2014 and March 2019 and categorized them into (i) musculoskeletal and sensory, (ii) cardiac, (iii) neurological, (iv) respiratory and cancer, (v) insulin-dependent diabetes, and (vi) unspecified subtypes. The results of clustering were replicated in another city. Compared with the musculoskeletal and sensory subtype, the adjusted hazard ratio (95% confidence interval) for death was 1.22 (1.05-1.42), 1.81 (1.54-2.13), and 1.21 (1.00-1.46) for the cardiac, respiratory and cancer, and insulin-dependent diabetes subtypes, respectively. The care-need levels more likely worsened in the cardiac, respiratory and cancer, and unspecified subtypes than in the musculoskeletal and sensory subtype. In conclusion, distinct clinical subtypes exist among individuals initiating long-term care.

The effect of lemborexant on insomnia in patients with psychiatric disorders: Detailed evaluation using the Athens Insomnia Scale.

Aim: Chronic insomnia disorder is common and associated with reduced quality of life. Benzodiazepine hypnotics are commonly prescribed for insomnia, but have potential side effects such as concentration impairment, somnolence, and dependence. Lemborexant (LEM) is an orexin receptor antagonist considered to have fewer side effects than benzodiazepine hypnotics. This study evaluated the effect of LEM on sleep in detail and examined whether benzodiazepine hypnotics can be gradually tapered by adding LEM. Methods: We retrospectively examined the effectiveness of LEM in 28 outpatients with insomnia. Insomnia symptoms were assessed using the Athens Insomnia Scale (AIS) before and after LEM administration. We also attempted to taper benzodiazepine hypnotics and assessed benzodiazepine dose using diazepam equivalents for some patients taking benzodiazepine hypnotics. Wilcoxon's signed-rank test was used for statistical analysis. Results: The mean AIS score was significantly improved after LEM treatment (8.7 ± 5.2 vs. 3.8 ± 3.3; P < 0.01). Among the AIS subitems, significant improvement was observed for six items: sleep induction, awakenings during the night, sleep quality, well-being, functioning capacity, and sleepiness during the day. The mean benzodiazepine dose was significantly lower after LEM treatment (4.6 ± 5.0 mg vs. 2.1 ± 3.3 mg; P < 0.01). Conclusions: This study indicated the potential of LEM for improving insomnia and reducing benzodiazepine dose.

Underlying Disorders in Children With Infection-Related Acute Encephalopathy.

BACKGROUND: Various factors contribute to the development of infection-related acute encephalopathy (AE) in children, such as infectious agents and chronic underlying disorders. We studied underlying disorders in children with AE to identify predisposing factors of AE. METHODS: We investigated underlying disorders or past histories in patients with two types of AE from the database in the Tokai area of Japan between 2009 and 2022: 204 patients with AE with reduced subcortical diffusion (AED) and 137 with clinically mild encephalopathy with a reversible splenial lesion (MERS). We compared them with 89 patients with acute disseminated encephalomyelitis (ADEM) to clarify the specific disorders in the two AE types. RESULTS: The prevalence of underlying disorders in AED (34%, 70 patients) was significantly higher than that in ADEM (12%, 11 patients) (P < 0.01). The prevalence of underlying disorders in MERS was 23% (32 patients). The underlying disorders included seizure disorders, premature birth, genetic/congenital disorders, and endocrine/renal diseases. In patients with seizure disorders in AED, five patients (18%) had Dravet syndrome and four (15%) had West syndrome, whereas none with MERS had these syndromes. Twenty-five (12%) of 204 patients with AED, three (2%) with MERS, and one (1%) with ADEM were preterm or low birth weight. CONCLUSIONS: The high prevalence of seizure disorders suggests that seizure susceptibility is an important predisposing factor in AED. Premature birth also has an impact on the development of AED. Caution is required regarding the development of AE in patients with chronic seizure disorders or premature birth.

Body composition and motor function in children born large for gestational age at term.

BACKGROUND: This cross-sectional study compared body composition and motor function between children who were born large for gestational age (LGA) and those born appropriate for gestational age (AGA) and to investigate the association between gait quality and other variables. METHODS: Body composition was determined using a bioelectrical impedance analyzer. Motor functions were assessed using one-leg standing time, timed up-and-go test, five times sit-to-stand test, and three-dimensional gait analysis. We compared the results between two groups. We performed multiple regression analysis to evaluate the association between gait deviation index and variables of LGA, fat mass index, and motor functions (adjusted for age and sex). RESULTS: Children aged 6-12 years who were born LGA at term (n = 23) and those who were born AGA at term (n = 147) were enrolled. The LGA group had a higher fat mass index (2.9 vs. 2.2, p = 0.006) and lower gait deviation index (91.4 vs. 95.4, p = 0.011) than the AGA group. On multiple regression analysis, gait deviation index was associated with being LGA and fat mass index. CONCLUSIONS: In school-aged children who were born LGA, monitoring increased fat mass index and decreased gait deviation index could lessen the risk of metabolic syndrome and reduced gait function. IMPACT: Children aged 6-12 years who were born large for gestational age (LGA) at term showed a higher fat mass index and lower gait deviation index than those who were born appropriate for gestational age at term. No significant differences in balance function or muscle strength were observed between groups. On multiple regression analysis, gait deviation index was associated with being LGA at birth and fat mass index. In school-aged children who were born LGA, monitoring increased fat mass index and decreased gait deviation index could lessen the risk of metabolic syndrome and reduced gait function.

Three-Dimensional Gait Analysis as a Biomarker for GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia.

BACKGROUND: GTP-cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD) typically presents in childhood with dystonic posture of the lower extremities, gait impairment, and a significant response to levodopa. We performed three-dimensional gait analysis (3DGA) to quantitatively assess the gait characteristics and changes associated with levodopa treatment in patients with GTPCH1-deficient DRD. METHODS: Three levodopa-treated patients with GTPCH1-deficient DRD underwent 3DGA twice, longitudinally. Changes were evaluated for cadence; gait speed; step length; gait deviation index; kinematic data of the pelvis, hip, knee, and ankle joints; and foot progression angle. RESULTS: Levodopa treatment increased the cadence and gait speed in one of three patients and increased the gait deviation index in two of three patients. The kinematic data for each joint exhibited different characteristics, with some improvement observed in each of the three patients. There was consistent marked improvement in the abnormal foot progression angle; one patient had excessive external rotation of one foot, another had excessive bilateral internal rotation, and the other had excessive internal rotation of one foot and excessive external rotation of the opposite foot, all of which improved. CONCLUSION: The 3DGA findings demonstrate that the gait pathology and recovery process in GTPCH1-deficient DRD vary from case to case. Changes in the foot progression angle and gait deviation index can enable the effects of treatment to be more easily evaluated.

Effect of levodopa on pathological gait in Dravet syndrome: A randomized crossover trial using three-dimensional gait analysis.

OBJECTIVE: Individuals with Dravet syndrome (DS) exhibit progressive gait disturbance. No quantitative studies have been conducted to evaluate the effectiveness of medication for gait disturbance. Therefore, the aim of this study was to evaluate the effectiveness of levodopa for pathological gait in people with DS using three-dimensional gait analysis (3DGA). METHODS: Nine individuals with DS, ages 6-20 years, participated in a crossover study of levodopa and were randomly assigned to the levodopa precedence or no levodopa precedence group. Levodopa/carbidopa hydrate was prescribed at a dose of 5 mg/kg/day (body weight <60 kg) or 300 mg/day (body weight ≥60 kg). The medication was taken for 4-6 weeks (4-week washout period). 3DGA was performed three times before the study, with and without levodopa. A mixed-effects model was used to evaluate the effectiveness of levodopa. The primary outcome was the change in the Gait Deviation Index (GDI). In addition, spatiotemporal gait parameters, 6-minute walking distance (6MD), and balance were evaluated. The correlation between the effectiveness of levodopa and age or gait performance before starting levodopa was analyzed. RESULTS: Levodopa improved the GDI by 4.2 points, (p = .029), 6MD by 52 m (p = .002), and balance test result by 4.1 mm (p = .011) in participants with DS. No severe adverse events were observed, with the exception of one participant, who exhibited fever and consequently stopped taking levodopa. Levodopa was more effective in younger participants with a higher baseline gait performance. SIGNIFICANCE: Our randomized crossover trial showed that levodopa has the potential to improve gait disturbance in people with DS.

Relationship between exercise habits and physical function in children aged 9-12 years.

Exercise improves physical health and positively impacts physical functions in children. Additionally, the habitual exercise established during childhood often continues into adulthood. Therefore, childhood is an important period for establishing healthy habits. Investigating the relationship between the presence or absence of daily exercise and physical functions may provide important information to confirm poor physical function in children with poor exercise habits. Therefore, this study examined the relationship between exercise habits as defined by the Japanese Ministry of Health, Labor, and Welfare and physical function in children aged 9-12 years. Approximately 239 children were included in this study. Participants answered a questionnaire about their exercise habits. We evaluated the skeletal muscle mass index, grip strength, standing broad jump, one-leg standing time, and gait deviation index. Logistic regression analyses were performed to assess exercise habit association with skeletal muscle mass index, physical function, and gait deviation index after adjusting for sex. Of the 239 children, 75.5% (n = 178) had exercise habits. A significant association was noted between exercise habits and skeletal muscle mass index and standing broad jump (skeletal muscle mass index: OR, 1.84; 95% CI, 1.01-3.36 and p<0.05; standing long jump: OR, 1.02; 95% CI, 1.00-1.04 and p<0.05). In conclusion, exercise regardless of exercise level for at least 30 min per day, 2 days per week, for at least 1 year is important for skeletal muscle mass and instantaneous lower limb muscular strength development in school-aged children.

Surgical antimicrobial prophylaxis in Japanese hospitals: Real status and challenges.

BACKGROUND: Information regarding the status of surgical antimicrobial prophylaxis (SAP) in Japanese hospitals is lacking. This study aimed to explore the status of SAP prescriptions for surgeries and adherence to Japanese SAP guidelines. METHODS: From February to July 2020, a 1-day multicentre point prevalent survey was conducted at 27 hospitals in Aichi Prefecture, Japan. Patients prescribed SAP were included in this study. The appropriateness of the SAP was evaluated based on the guidelines for selection of antimicrobials and their duration. Surgery was defined as appropriate when all the items were appropriate. RESULTS: A total of 728 patients (7.1 %; 728/10,199) received antimicrobials for SAP. Among them, 557 patients (76.5 %, 557/728) underwent the surgeries described in the guidelines. The overall appropriateness of all surgeries was 33.9 % (189/557). The appropriate selection of antimicrobial before/during and after surgery and their durations were 67.5 % (376/557), 67.5 % (376/557), and 43.3 % (241/557), respectively. The overall appropriateness ranged from 0 % (0/37, oral and maxillofacial surgery) to 58.7 % (88/150, orthopaedic surgery) and 27.7 % (36/130, community hospitals with 400-599 beds) to 47.2 % (17/36, specific hospitals). Cefazolin was the most prevalent antimicrobial prescribed before/during (55.5 %, 299/539), and after (45.1 %, 249/552) surgery. In total, 101 oral antimicrobials were prescribed postoperatively. CONCLUSIONS: SAP adherence by specific surgical fields and hospitals was shown in this study. Intensive intervention and repeated surveillance are necessary to improve SAP prescriptions in Japanese hospitals.

Relationship between low-back pain and flexibility in children: A cross-sectional study.

Low-back pain is common among school-aged children. Decreased trunk flexibility in childhood influences low-back pain in adulthood. Previous studies examining the association between low-back pain and trunk flexibility in children are insufficient. Examining this association among elementary school children may help to better understand trunk flexibility in children with low-back pain and to modify the management of inflexibility. Therefore, this study aimed to identify the prevalence of low-back pain and its relationship with physical function among elementary school students. School-aged children aged 6-12 years were recruited in Japan between May 2018 and March 2023. Fingertip-to-floor distance, back muscle strength, pelvic tilt angle during gait, and the visual analog scale for low-back pain were measured. In addition, factors independently related to low-back pain were determined through logistic regression analysis. Low-back pain was reported in 9.6% of the 394 participants (boys, 191; girls, 203). All children with low-back pain presented with back pain when they moved; however, the pain was non-specific. Logistic regression analysis showed that the fingertip-to-floor distance was an independent risk factor for low-back pain (odds ratio, 0.921; p = 0.007). The odds ratios calculated in the logistic regression analysis confirmed that low-back pain frequency increased as the fingertip-to-floor distance decreased. The risk of low-back pain was associated with inflexibility, regardless of sex and muscle strength. These findings suggest that children with low-back pain must increase their trunk and lower extremity flexibility.

Specific peptide conjugation to a therapeutic antibody leads to enhanced therapeutic potency and thermal stability by reduced Fc dynamics.

Antibody-drug conjugates are powerful tools for combatting a wide array of cancers. Drug conjugation to a therapeutic antibody often alters molecular characteristics, such as hydrophobicity and effector function, resulting in quality deterioration. To develop a drug conjugation methodology that maintains the molecular characteristics of the antibody, we engineered a specific peptide for conjugation to the Fc region. We used trastuzumab and the chelator (DOTA) as model antibody and payload, respectively. Interestingly, peptide/DOTA-conjugated trastuzumab exhibited enhanced antibody-dependent cellular cytotoxicity (ADCC) and increased thermal stability. Detailed structural and thermodynamic analysis clarified that the conjugated peptide blocks the Fc dynamics like a "wedge." We revealed that (1) decreased molecular entropy results in enhanced ADCC, and (2) blockade of Fc denaturation results in increased thermal stability. Thus, we believe that our methodology is superior not only for drug conjugation but also as for reinforcing therapeutic antibodies to enhance ADCC and thermal stability.

A Case of End-stage Renal Disease in Which Diazoxide was Effective in Treating Hypoglycemia Caused by Late Dumping Syndrome after Gastrectomy.

We herein report a case in which diazoxide was effective in treating reactive hypoglycemia caused by late dumping syndrome in a patient with ESRD. A 50-year-old man with end-stage renal disease (ESRD) and a history of gastrectomy underwent hemodialysis. Although he was administered voglibose to treat recurrent reactive hypoglycemia caused by late dumping syndrome, he had difficulty continuing treatment because of gastrointestinal side effects. When he began diazoxide treatment, the reactive hypoglycemia improved. The dose was gradually increased with no apparent side effects, and the hypoglycemic attacks disappeared one year after the start of treatment.

VNAR development through antigen immunization of Japanese topeshark (Hemitriakis japanica).

The VNAR (Variable New Antigen Receptor) is the smallest single-domain antibody derived from the variable domain of IgNAR of cartilaginous fishes. Despite its biomedical and diagnostic potential, research on VNAR has been limited due to the difficulties in obtaining and maintaining immune animals and the lack of research tools. In this study, we investigated the Japanese topeshark as a promising immune animal for the development of VNAR. This shark is an underutilized fishery resource readily available in East Asia coastal waters and can be safely handled without sharp teeth or venomous stingers. The administration of Venus fluorescent protein to Japanese topesharks markedly increased antigen-specific IgM and IgNAR antibodies in the blood. Both the phage-display library and the yeast-display library were constructed using RNA from immunized shark splenocytes. Each library was enriched by biopanning, and multiple antigen-specific VNARs were acquired. The obtained antibodies had affinities of 1 × 10-8 M order and showed high plasticity, retaining their binding activity even after high-temperature or reducing-agent treatment. The dissociation rate of a low-affinity VNAR was significantly improved via dimerization. These results demonstrate the potential utility of the Japanese topeshark for the development of VNAR. Furthermore, we conducted deep sequencing analysis to reveal the quantitative changes in the CDR3-coding sequences, revealing distinct enrichment bias between libraries. VNARs that were primarily enriched in the phage display had CDR3 coding sequences with fewer E. coli rare codons, suggesting translation machinery on the selection and enrichment process during biopanning.

Efficient detection of somatic UBA1 variants and clinical scoring system predicting patients with variants in VEXAS syndrome.

OBJECTIVES: To efficiently detect somatic UBA1 variants and establish a clinical scoring system predicting patients with pathogenic variants in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. METHODS: Eighty-nine Japanese patients with clinically suspected VEXAS syndrome were recruited [81 males and 8 females; median onset age (IQR) 69.3 years (62.1-77.6)]. Peptide nucleic acid-clamping PCR (PNA-PCR), regular PCR targeting exon 3 clustering UBA1 variants, and subsequent Sanger sequencing were conducted for variant screening. Partitioning digital PCR (pdPCR) or targeted amplicon deep sequencing (TAS) was also performed to evaluate the variant allele frequency (VAF). We developed our clinical scoring system to predict UBA1 variant-positive and ­negative patients and assessed the diagnostic value of our system using receiver operating characteristic (ROC) curve analysis. RESULTS: Forty patients with reported pathogenic UBA1 variants (40/89, 44.9%) were identified, including a case having a variant with VAF of 1.7%, using a highly sensitive method. Our clinical scoring system considering >50 years of age, cutaneous lesions, lung involvement, chondritis, and macrocytic anaemia efficiently predicted patients with UBA1 variants (the area under the curve for the scoring total was 0.908). CONCLUSIONS: Genetic screening with the combination of regular PCR and PNA-PCR detected somatic UBA1 variants with high sensitivity and specificity. Our scoring system could efficiently predict patients with UBA1 variants.

A Novel Strategy for Screening Tumor-Specific Variable Domain of Heavy-Chain Antibodies.

The properties of the variable domain of heavy-chain (VHH) antibodies are particularly relevant in cancer therapy. To isolate tumor cell-specific VHH antibodies, VHH phage libraries were constructed from multiple tumor cells. After enriching the libraries against particular tumor cell lines, a next-generation sequencer was used to screen the pooled phages of each library for potential antibody candidates. Based on high amplification folds, 50 sequences from each library were used to construct phylogenetic trees. Several clusters with identical CDR3 were observed. Groups X, Y, and Z were assigned as common sequences among the different trees. These identical groups over the trees were considered to be cross-reactive antibodies. To obtain monoclonal antibodies, we assembled 200 sequences (top 50 sequences from each library) and rebuilt a combined molecular phylogenetic tree. Groups were categorized as A-G. For each group, we constructed a phagemid and determined its binding specificity with tumor cells. The phage-binding results were consistent with the phylogenetic tree-generated groups, which indicated particular tumor-specific clusters; identical groups showed cross-reactivity. The strategy used in the current study is effective for screening and isolating monoclonal antibodies. Specific antibodies can be identified, even when the target markers of cancer cells are unknown.

A knowledge-based simple education program for patients with epilepsy in Japan: Effects sustained after the program implementation.

PURPOSE: To investigate the effects of an original education program on patients with epilepsy (PWE). The effects on knowledge about epilepsy, attitude to epilepsy, depression scales, and quality of life were investigated. METHOD: Thirty-five PWE participated in a lecture-style educational program using an original knowledge-oriented textbook. All patients were administered a total of four rating scales: the Knowledge about Epilepsy Scale (KES), the Attitude toward Epilepsy Scale (AES), and the Japanese version of the Quality of Life in Epilepsy Inventory (QOLIE-31-P), the Beck Depression Inventory (BDI). The KES and AES of patients (pKES and pAES) were compared to those of medical students (St) and residents (Rd). RESULTS: After education, pKES improved and showed significant differences among pre-and post-education and six months later. Before education, pKES was inferior to St and Rd. However, after education, pKES changed and became superior to St and Rd. Six months later, the advantage was lost, but not significantly. PAES also improved after education, with significant differences before, after, and six months later after education. PAES was statistically inferior to St and Rd before education, but the difference disappeared after education, and the effect persisted after six months. The non-depressed (BDI < 20) and depressed groups (BDI â‰§ 20) improved in the KES after education. About the AES, the non-depressive group has a statistical tendency, but not the depressive group. At six months, the depressed group's AES is significantly lower than the non-depressed group. CONCLUSION: While correct knowledge about epilepsy can improve attitudes and perceptions of epilepsy in PWE, special measures are needed for PWE with depression.

Stochastic Optimal Linear Control for Generalized Cost Functions With Time-Invariant Stochastic Parameters.

This study presents the design of feedback controllers for generalized cost functions to deal with stochastic optimal control problems. Target linear systems contain time-invariant stochastic parameters that describe system uncertainty. The cost functions involve nonlinear mappings and polynomial forms of the system states and inputs to express various performance metrics. Unfortunately, these properties cause difficulties in solving the problems. Conventional methods, such as the principle of optimality, are not employed to solve such problems owing to the time-invariant parameters. As opposed to the well-known quadratic functions, handling the generalized cost functions is a complicated task. This study overcomes these challenges by deriving an explicit relation between the cost function and the linear feedback gain of a controller. The derived relation enables the feedback gain to be optimized via a gradient method. A theoretical analysis ensures the convergence of the proposed gradient method. A suboptimal feedback controller is obtained to solve the problem, even for the generalized cost. Furthermore, the controller guarantees robust stability of the feedback system even with the stochastic parameters. It is demonstrated that the proposed cost function can express an expectation of a quadratic cost, risk-sensitive cost, polynomial cost, and input-to-state gain. A numerical simulation shows the effectiveness of the proposed method.

Characterization of human anti-EpCAM antibodies for developing an antibody-drug conjugate.

We previously generated fully human antibody-producing TC-mAb mice for obtaining potential therapeutic monoclonal antibodies (mAbs). In this study, we investigated 377 clones of fully human mAbs against a tumor antigen, epithelial cell adhesion molecule (EpCAM), to determine their antigen binding properties. We revealed that a wide variety of mAbs against EpCAM can be obtained from TC-mAb mice by the combination of epitope mapping analysis of mAbs to EpCAM and native conformational recognition analysis. Analysis of 72 mAbs reacting with the native form of EpCAM indicated that the EpCL region (amino acids 24-80) is more antigenic than the EpRE region (81-265), consistent with numerous previous studies. To evaluate the potential of mAbs against antibody-drug conjugates, mAbs were directly labeled with DM1, a maytansine derivative, using an affinity peptide-based chemical conjugation (CCAP) method. The cytotoxicity of the conjugates against a human colon cancer cell line could be clearly detected with high-affinity as well as low-affinity mAbs by the CCAP method, suggesting the advantage of this method. Thus, this study demonstrated that TC-mAb mice can provide a wide variety of antibodies and revealed an effective way of identifying candidates for fully human ADC therapeutics.

COVID-19 symptom-onset to diagnosis and diagnosis to treatment intervals are significant predictors of disease progression and hospitalization in high-risk patients: A real world analysis.

BACKGROUND: Coronavirus disease (COVID-19) is overwhelming healthcare systems worldwide. This study aimed to elucidate factors that influence disease progression to pneumonia and hospitalization before and after antiviral treatment for COVID-19 in an outpatient setting. METHODS: A total of 206 high-risk patients with COVID-19 were treated with sotrovimab, remdesivir, and molnupiravir at the Toshiwakai clinic between January 4 and April 30, 2022. Of these, 49 patients visited the Toshiwakai clinic directly and were treated immediately after diagnosis (Toshiwakai-clinic study group). The remaining patients were diagnosed elsewhere, and of these, 102 patients were quarantined at home (health-center study group) and 55 at designated facilities (quarantine-facility study group) before being referred to Toshiwakai clinic. Patients were categorized into those with mild and moderate COVID-19, based on the presence of pneumonia at the initial visit to Toshiwakai clinic. RESULTS: The symptom-onset-to-diagnosis and diagnosis-to-treatment intervals were significant predictors of moderate disease. Age, dyspnea, and diagnosis-to-treatment interval at the first visit to Toshiwakai clinic were significant predictors for hospitalization even after antiviral treatment. Although the symptom-onset-to-diagnosis interval did not differ among the three study groups, the diagnosis-to-treatment and symptom-onset-to-treatment intervals were significantly longer in the health-center and quarantine-facility study groups than in the Toshiwakai-clinic study group. CONCLUSION: The symptom-onset-to-diagnosis and diagnosis-to-treatment intervals reflect diagnostic and interventional delays, respectively, which are closely related to the current COVID-19 clinical management protocol. Easy access to the clinics and immediate antiviral treatment after diagnosis may be the best methods to prevent disease progression and hospitalization in high-risk patients.