Long-term Therapeutic Effects Research Articles

Non-gynaecological Applications of Menstrual-derived Stem Cells: A Systematic Review.

Menstrual-derived Stem Cells (MenSC) are a potential novel source of mesenchymal stem cells. There is an increased interest in investigating the therapeutic potential of MenSC due to the various advantages they exhibit, when compared to other types of stem cells. MenSC are obtained non-invasively from menstrual blood. Thus, collection of MenSC is simple, reproducible and can be carried out periodically, with minimal complications. MenSC are present in abundance, are highly proliferative, exhibit a low immunogenicity and lack ethical issues. MenSC have shown the ability to differentiate into several lineages. The therapeutic potential of MenSC in non-gynaecological applications has been investigated in wound healing, neurological, musculo-skeletal, cardiovascular, respiratory, and liver disorders, as well as in diabetes and cancer. Human clinical trials are limited. To date, therapeutic efficacy and safety have been reported in patients with Avian influenza A subtype H7N9, COVID-19, congestive heart failure, multiple sclerosis and Duchene muscular dystrophy. However, further clinical trials in humans should be conducted, to study the long-term therapeutic effects of these stem cells in various diseases and to further explore their mechanism of action. This systematic review focuses on the application of MenSC in non-gynaecological diseases.

Triple-combination therapy assisted with ultrasound-active gold nanoparticles and ultrasound therapy against 3D cisplatin-resistant ovarian cancer model

Cancer chemotherapy suffers from drug resistance and side effects of the drugs. Combination therapies have been attracted attention to overcome these limitations of traditional cancer treatments. Recently, increasing in intracellular chemotherapeutic concentration in the presence of ultrasonic waves (US) has been shown in the preclinical stage. In addition, some recent studies have shown that nanoparticles increase the effectiveness of ultrasound therapy. In this study, the US-active property of gold nanocones (AuNCs) was utilized for combinational US and cisplatin (Cis) to overcome drug resistance. The effect of the triple combination therapy US + AuNCs + Cis with low-dose Cis on 2/3D models of cisplatin-resistant ovarian cancer cell line (A2780cis) were investigated. In the 2D cell culture, 60% of the A2780cis cell population was suppressed with triple combination therapy; and the long-term therapeutic efficacy of the US + AuNCs + Cis with the low-dose drug was demonstrated by suppressing 83% of colony formation. According to the results in the 3D cell model, 60% of the spheroid formation was suppressed by the triple combination therapy with low-dose Cis. These results not only demonstrate the success of the US + AuNCs + Cis triple combination therapy for its long-term therapeutic effect on resistant cancer cells but also verified that it might enable effective cancer therapy in vivo and clinical stages based on the 3D tumor models. In addition, enhanced anti-cancer activity was demonstrated at the low-dose Cis on drug-resistant cancer cells indicating the triple-combination therapy successfully overcame drug resistance and this is a promising strategy to reduce the side effects of chemotherapy. This work exhibits a novel US and AuNCs-mediated combination cancer therapy, which demonstrates the role of ultrasound-active AuNCs to combat drug resistance with low-dose chemotherapy.

Advances in the Treatment of RET Fusion-positive Advanced Non-small Cell Lung Cancer

转染重排（rearranged during transfection, RET）融合阳性发生于0.7%-2%的非小细胞肺癌（non-small cell lung cancer, NSCLC）。RET基因与其他结构域之间的融合代表了NSCLC独特的生物学和临床病理学亚型。近些年以来，RET融合阳性晚期NSCLC治疗领域取得了重要进展。传统化疗能够带来一定的临床获益。在靶向药物临床应用之前或不适用的情况下，以铂类为基础的系统性化疗方案是患者初始治疗选择。免疫治疗在RET融合阳性人群中的报告数据较少且通常结果较差，不推荐免疫单药或免疫联合化疗方案作为这类患者的系统性治疗。多靶点激酶抑制剂在这类人群中的重新应用能够取得一定的治疗反应，目前仅卡博替尼和凡德他尼推荐在有限条件下作为初始或后续治疗。然而，依然存在不能满足的临床需求。普拉替尼（Pralsetinib）和塞尔帕替尼（Selpercatinib）作为RET选择性酪氨酸激酶抑制剂（tyrosine kinase inhibitor, TKI），显著改善了RET融合阳性NSCLC患者生存及预后。普拉替尼和塞尔帕替尼已确立成为这类患者一线或后续治疗的首选方案。与其他TKI治疗时观察到的类似，RET靶向抑制治疗也会导致耐药问题，而获得性耐药的出现将影响治疗的远期有效性，并限制后续的药物选择。因此，本文将围绕RET融合阳性晚期NSCLC治疗进展进行综述。

Citicoline in the Treatment of Mild Cognitive Impairment in Blood Relatives of Patients with Alzheimer’s Disease: Immediate and Long-Term Effects of Course Therapy

The aim was to study immediate and long-term (post-therapeutic) effects of a three-month course of therapy with citicoline in 1st-degree relatives of patients with Alzheimer’s disease (AD). All the included relatives of patients with AD revealed signs of minimal cognitive dysfunction (MCD) and mild cognitive decline syndrome (MCI — Mild Cognitive Impairment, ICD-10 code F06.7). Study participants: the study involved 90 first-degree relatives: 24 with MCI and 66 with MCD. Study design: an open-label comparative multidisciplinary study of the six-month dynamics of cognitive functioning of two groups of relatives who received a three-month course of citicoline therapy. The baseline indicators of the cognitive functioning of relatives with MCI syndrome and MKD were compared with the indicators at the end of the three-month course of therapy with citicoline at a daily dose of 1000 mg as well as 3 months after the end of the course of treatment. Methods: clinical, psychopathological, neuropsychological, psychometric, genetic, statistical ones. Results: а significant positive effect of the course therapy with citicoline on the cognitive impairment of 1st degree AD-patients’ relatives with minimal cognitive dysfunction and more pronounced cognitive impairments met the diagnostic criteria for MCI syndrome has been found. A significantly greater value of both immediate and long-term therapeutic effect of MKD compared with MCI in relatives was established by psychometric and neuropsychological indicators characterizing voluntary memorization of verbal and visual stimuli, optical and spatial activity, voluntary attention, and associative verbal thinking. Conclusion: the results of the study can be used as the basis for a model of prevention of the progression of cognitive deficit and the development of dementia in persons with a high risk of developing AD, i.e. in individuals with both genetic risk and signs of cognitive impairment.

Effects of Hydroxychloroquine on Proteinuria in IgA Nephropathy: A Systematic Review and Meta-Analysis.

Introduction The present meta-analysis was to explore the efficacy of hydroxychloroquine (HCQ) in IgA nephropathy patients in terms of proteinuria. Method We systematically searched PubMed and Embase for studies that compared HCQ and other treatments to reduce proteinuria in patients with IgA nephropathy up to June 2021. Mean ± SD of percentage change and level of proteinuria was calculated. Results A total of 5 studies with 587 participants were included. IgA nephropathy patients who received HCQ were at a lower level of mean proteinuria at 6 months. However, there was no statistical difference between HCQ and control group considering percentage reduction in proteinuria. The long-term therapeutic effect of HCQ might be inferior to HCQ and renin-angiotensin-aldosterone system inhibition. Conclusion HCQ might play a role in the reduction of proteinuria in IgA nephropathy patients. The addition of HCQ to other immunosuppressive agents should be clarified further.

Biologic Treatment for the Elbow Tendinopathy

Although elbow tendinopathy is the one of common diseases causing elbow pain, ideal nonoperative treatment to provide long-term satisfaction has not been introduced. Recently, there is significant interest in biological treatment to facilitate the healing environment and tissue proliferation in elbow tendinopathy. Biological agents such as platelet-rich plasma (PRP) or stem cells are likely to be established as one of the nonoperative treatment methods that can have long-term therapeutic effects in the future, given their theoretical basis. Despite many previous studies using biological agents such as PRP and stem cells in the elbow, its beneficial effect on elbow tendinopathy is controversial. Thus, the purpose of this review is to provide an evidence-based summary of the biologic agent for treating elbow tendinopathy and to identify areas where further research is warranted.

Immunomorphological features of women's skin with androgenetic alopecia in the treatment of plasma enriched with platelets in combination with topical minoxidil 2 % lotion

Introduction. The skin biopsies of 30 patients with androgenetic alopecia before and after treatment with platelet-rich plasma in combination with 2 % minoxidil were examined by immunohistochemistry. Goal. The study looked at immunohistochemical changes in the scalp biopsies of patients with stage I-II androgenetic alopecia according to the Ludwig scale and to identify possible changes after injection of platelet-rich plasma in combination with topical 2 % minoxidil lotion. Materials and methods. Skin biopsies of 30 patients with androgenetic alopecia were examined using an immunohistochemical study before and after treatment, which lasted 3 months and included 3 sessions of PRP (once per month) and topical application of minoxidil 2 % lotion twice a day. Results. It was found that androgenetic alorecia is accompanied by inflammatory perifollicular infiltration by T-lymphocytes CD3 +, CD4 + and CD8 +, macrophages (CD68 +); imbalance of germ polypeptides VEGF, TGF-β1, EGFR; accumulation of oxidative stress enzymes eNOS and iNOS; accumulation of pathological fraction of collagen IV. Injections of platelet-rich plasma in combination with topical administration of 2 % minoxidil as a treatment for androgenetic alopecia lead to normalization of immunohistochemical parameters of the skin, which indicates the possibility of using this combination for long-term therapeutic effect. Conclusions. This study complemented the understanding of the pathogenesis of AGA and serves as a basis for improving treatment regimens for this pathology. However, additional studies are needed to further study the pathomorphology of androgenetic alopecia and to standardize the technique of using platelet-rich plasma in patients with this disease.

A Brief, Individualized Exercise Program at Intensities Below the Ventilatory Threshold Exerts Therapeutic Effects for Depression: A Pilot Study.

Due to the fact that existing pharmacological treatments for depression are not ideal, effort has been devoted to the development of complementary, alternative therapies such as physical exercise. The antidepressant effect of exercise is well documented. However, current recommendations and prescriptions of exercise may be too demanding for depressed patients, as some complain about the design of exercise programs and depression is associated with reduced motivation and capacity to exercise. Therefore, appropriately designed, patient-friendly exercise programs may prove critical for the long-term maintenance and therapeutic effects of exercise. In this pilot study, we developed an exercise program based on patients’ individual level of ventilatory threshold (VT), a submaximal index of aerobic capacity measured by Cardiopulmonary Exercise Testing (CPX). Compared to traditional measures, CPX provides more trustable indices of aerobic capacity and more homogenous exercise prescriptions. The main episode of the program consisted of 15–25 min of cycling twice a week at an intensity that approached but never went higher than subjects’ VT (considered low to moderate in intensity). We found that in patients diagnosed with major depressive disorder or persistent depressive disorder (n = 8), the program resulted in a significant reduction in depressive symptoms at week 8, which was maintained at week 16. Meanwhile, patients’ social functioning, quality of life, and cognitive functions improved. Although we used a single arm, non-randomized design, our results suggest that even a brief, low to moderate intensity exercise program may exert therapeutic effects for depression and CPX may be a useful tool for exercise prescriptions.

Immunomorphological features of female patient’s skin with androgenetic alopecia in the treatment of platelet-rich plasma in combination with topical minoxidil 2 % lotion

The aim. The research was provided to obtain immunohistochemical changes in scalp biopsies of female patients with androgenetic alopecia (AGA) I-II stages according to the Ludwig scale and to detect possible changes after usage of platelet-rich plasma (PRP) injections in combination with topical minoxidil 2 % lotion.
 Materials and methods. Skin biopsies of 30 patients with AGA were examined by immunohistochemistry before and after treatment, which lasted for 3 months and included 3 PRP sessions (once per month) and topical application of minoxidil 2 % lotion twice daily.
 Results. It was found that AGA is accompanied by inflammatory perifollicular infiltration by T-lymphocytes CD3 +, CD4 + and CD8 +, macrophages (CD68 +); imbalance of growth polypeptides VEGF, TGF-β1, EGFR; accumulation of oxidative stress enzymes eNOS and iNOS; accumulation of pathological fraction of Collagen IV. The use of platelet-rich plasma in combination with topical 2 % minoxidil as AGA therapy leads to the normalization of immunohistochemical parameters of the skin, which indicates the possibility of its use for long-term therapeutic effect.
 Conclusions. This study supplemented the understanding of the pathogenesis of AGA and serves as the basis for improving treatment regimens for this pathology. But more research is required to further study the pathomorphology of androgenetic alopecia and to standardize the technique of using platelet-rich plasma in patients with this disease.

Exhausted local lactate accumulation via injectable nanozyme-functionalized hydrogel microsphere for inflammation relief and tissue regeneration

Local lactate accumulation greatly hinders tissue repair and regeneration under ischemic condition. Herein, an injectable microsphere (MS@MCL) for local lactate exhaustion was constructed by grafting manganese dioxide (MnO2) -lactate oxidase (LOX) composite nanozyme on microfluidic hyaluronic acid methacrylate (HAMA) microspheres via chemical bonds, achieving a long-term oxygen-promoted lactate exhaustion effect and a long half-life in vivo. The uniform and porous microspheres synthesized by microfluidic technology is beneficial to in situ injection therapy and improving encapsulation efficiency. Furthermore, chemical grafting into HAMA microspheres through amide reactions promoted local enzymatic concentration and activity enhancement. It was showed that the MS@MCL eliminated oxidative and inflammatory stress and promoted extracellular matrix metabolism and cell survival when co-cultured with nucleus pulposus cells (NPCs) in vitro. In the rat degenerative intervertebral disc model caused by lactate injection, MS@MCL showed a long-term therapeutic effect in reducing intervertebral height narrowing and preventing extracellular matrix (ECM) degradation as well as inflammatory damage in vivo. Altogether, this study confirms that this nanozyme-functionalized injectable MS@MCL effectively improves the regenerative and reparative effect in ischemic tissues by disposing of enriched lactate in local microenvironment.

P030 The effects of continuous positive airway pressure (CPAP) therapy in moderate to severe obstructive sleep apnea (OSA): A high-density electroencephalography (EEG) study

Abstract Introduction A previous high-density EEG investigation in OSA showed regional sleep EEG deficits particularly slow wave activity (SWA) in the parietal region. It is unclear whether CPAP treatment can reverse local sleep EEG abnormalities, and whether any recovery is related to improved cognitive function. Methods Fifteen males with moderate-severe OSA (age 50.4±6.5yrs, AHI 51.7±23.5/h) underwent polysomnography with 256-channel high-density EEG at baseline and following 3 months of CPAP. Tasks assessing cognitive performance and sleep-dependent memory were administered. Topographical spectral power maps were calculated for standard frequency ranges for sleep stages. Differences in normalized power between baseline and treatment were determined by statistical nonparametric mapping. Results In 11 CPAP compliant patients (data loss: intolerant of CPAP[n=3]/high-density EEG [n=1]), total sleep time did not change after CPAP but N1 (baseline vs. treatment: 66.9 vs. 39.5 mins, p=0.008) and N2 (195.0 vs. 150.6 mins, p=0.002) sleep was lower and N3 (89.8 vs. 128.7 mins, p=0.003) was higher. Topographic high-density EEG analysis revealed a regional increase in SWA (1–4.5Hz) during N3 sleep in a cluster of 22 electrodes overlying the parietal cortex (paired t-test, t(10)=-3.9, p=0.0029). The change in N3 SWA in the parietal cluster after CPAP was correlated with improved overnight procedural memory on the motor sequence task (rho=0.79, p=0.03) and better executive functioning (Stroop accuracy, rho=0.73, p=0.01). Conclusion CPAP treatment reduces localised deficits in sleep EEG, and specific regional recovery relates to short-term improvements in memory and executive function. These data also highlight the potential for long-term therapeutic effects on cognitive outcomes.

Bulking agents for minimally invasive correction of stress urinary incontinence in women

BACKGROUND:The study is relevant due to the widespread prevalence of stress urinary incontinence in women and the search for minimally invasive and safe treatment methods.
 AIM:The aim of this study was to present data based on modern evidence-based information on the effectiveness of urethral bulking agents and their safety in stress urinary incontinence treatment in women.
 MATERIALS AND METHODS:A review of the literature (original articles, systematic reviews) on the use of urethral bulking agents for stress urinary incontinence treatment in women was carried out.
 RESULTS:Urethral bulking agents for stress urinary incontinence treatment are effective due to the creation of additional bulk in the paraurethral area without fibrosis or because of inflammation followed by fibrous tissue formation. The efficacy and complications depend on the properties of the used urethral bulking agents. Since the performed studies are heterogeneous and the methods for evaluating the use of bulking fillers in stress urinary incontinence treatment vary, it is difficult to comparatively characterize urethral bulking agents to determine the most effective one. The search is being conducted for an ideal proper filler, which should be biocompatible and non-immunogenic and maintain a long-term therapeutic effect.
 CONCLUSIONS:Urethral bulking injections are an alternative therapy for women with stress urinary incontinence who are informed about its short-term effect and are expecting to avoid the risk of possible complications after surgery. Promising is to be regarded as the use of new urethral bulking agents based on hyaluronic acid with an optimal choice of concentration, degree of crosslinking and type of crosslinking agent to ensure maximum duration of action and minimum side effects.

Duloxetine ameliorates valproic acid-induced hyperactivity, anxiety-like behavior, and social interaction deficits in zebrafish.

Syndromic autism spectrum disorders (ASDs) are characterized by impaired social communication and repetitive/stereotyped behaviors. Currently available therapeutic agents against ASD have limited efficacy. Thus, searching for novel and effective drugs ameliorating core symptoms, in particular social deficits, is of utmost importance. Duloxetine (DLX), an antidepressant that has been identified as an agonist mimetic for the cell adhesion molecule L1, exhibits beneficial functions in vitro and in vivo. Therefore, in this study, we focused on the rapid and persistent neuroprotective function of DLX following valproic acid (VPA)-triggered hyperactivity, anxiety-like behavior and social deficits in zebrafish. Embryonic exposure to VPA reduced survival in a dose- and time-dependent manner, delayed hatching, and also resulted in a significant number of malformed larvae. After initial dose-response experiments in zebrafish larvae, 10μM VPA exposure between 0.33 and 4.5 days post fertilization (dpf) was identified as an effective concentration that led to an early and persistent ASD-like phenotype in zebrafish. ASD-like elevated acetylcholine esterase (AChE) activity and reduced Akt-mTOR signaling was observed in zebrafish whole brain. Acute administration of DLX (4.5-6 dpf) reduced the VPA-induced ASD-like phenotype in zebrafish larvae. Additionally, such early-life acute DLX treatment had long-term effects in ameliorating social impairments, hyperactivity, and anxiety-like behaviors through adulthood. This was accompanied by reduced AChE activity and by normalized Akt-mTOR signaling. Overall, DLX treatment showed a long-term therapeutic effect on autistic-like behaviors, and alteration of AChE activity and Akt-mTOR signaling were identified as crucial in the VPA-induced ASD zebrafish model.

Prophylactic hyperthermic intraperitoneal chemotherapy in gastric cancer management: short- and long-term outcomes of a prospective randomized study

Introduction. Assessment of toxicity and long-term results of hyperthermic intraperitoneal chemotherapy (HIPEC) treatment administered to patients with resectable serosa-invasive gastric cancers. Material and methods. The study was carried out in 2008–2016 and is based on the results of the treatment of 154 gastric cancer patients (stage IIB–IIIC, III–IV Borrmann type) who were randomly assigned to two groups. 76 patients underwent HIPEC combined with radical gastrectomy (HIPEC group) and 78 patients underwent radical gastrectomy without HIPEC (control group). HIPEC was administered after alimentary tract reconstruction and wound closure and comprised 5–6 L of Ringer’s solution (cisplatin 50 mg/m2 + doxorubicin 50 mg/m2) infused at an inflow temperature of 42°C for 1 hour. Results. Although the total number of complications was higher in the HIPEC group than in the control group the difference was statistically insignificant — 20 (26.3%) and 12 (15.3%), respectively (p = 0.141). Surgery-related complications in the HIPEC and control groups were observed in 9 and 5 cases, respectively (p = 0.372). Non-surgical complications were recorded in 11 and 7 cases, respectively (p = 0.435). Overall, the proposed HIPEC regimen administered in combination with radical surgery demonstrated satisfactory patient tolerability. The frequency of grade III toxic reactions according to CTCAE version 5.0 was 9.2%, no grade IV–V toxicities were registered at that. These satisfactory short-term results were followed up with fairly good long-term treatment outcomes. There was an increase in 5-year progression-free survival (42.1 ± 6.3% vs. 16.3 ± 5.5%, p < 0.001) and in dissemination-free survival (45.2 ± 6.3% vs. 19.4 ± 5.9%, p = 0.001) in the HIPEC group vs. the control group with a trend toward improving cancer-specific survival (CSS) in the HIPEC-treated patients [45.1.0 ± 6.4% vs. 27.0 ± 6.7% (p = 0.050)]. Conclusions. While substantially improving long-term GC therapeutic effect, the proposed HIPEC regimen using cisplatin 50 mg/m2 in combination with doxorubicin 50 mg/m2 made it possible to minimize complications (frequency of 26.3%) and toxic reactions [the frequency of grade III toxic reactions was 9.2% (CTCAE, version 5.0)].

Long-term therapeutic effects and liver fibrosis changes with direct-antiviral therapy in HIV/HCV co-infected patients

Objective: To investigate the long-term characteristic changes of virus, immune status, and liver fibrosis markers in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infected patients after receiving direct-antiviral agents (DAAs). Methods: HIV/HCV co-infected patients who visited the Guangzhou Eighth People's Hospital, Guangzhou Medical University from May 2014 to December 2019 were selected as the research subjects. The changes of virological response rate, peripheral blood CD4(+)T lymphocyte level and serological markers of liver fibrosis (APRI score and FIB-4 index) were observed during 144 weeks of follow-up course after the end of DAAs treatment. Kruskal-Wallis test was used for statistical approach. Results: A total of 103 cases were included in the study. There were 87 males (87.5%), with a median age of 44 years. Sustained virological response rate at 12 weeks (SVR12) after DAAs treatment was 97.6%, and the SVR during the entire follow-up period was at least 95.9%. Compared with baseline, CD4(+)T lymphocyte count were significantly increased equally at 12 weeks (Z = -2.283, P = 0.022), 24 weeks (Z = -3.538, P < 0.001), 48 weeks (Z = -3.297, P = 0.001), 96 weeks (Z = -3.562, P < 0.001), and 144 weeks (Z = -2.842, P = 0.004). APRI score (Z = -6.394, P < 0.001) and FIB-4 index (Z = -2.528, P = 0.011) were significantly lower than baseline at week 4 of DAAs treatment, and thereafter remained at a low level, without further declination. Conclusion: HIV/HCV co-infected patients can maintain high SVR for a long time, acquire good immune reconstitution, and significantly improve liver fibrosis after DAAs treatment.

Sub 5nm Gd3+ -Hemoporfin Framework Nanodots for Augmented Sonodynamic Theranostics and Fast Renal Clearance.

Metal-organic nanomaterials have emerged as promising therapeutic agents to produce reactive oxygen species (ROS) under ultrasound (US) or light irradiation for tumor treatments. However, their relatively large sizes (ranging from tens to hundreds of nanometers) usually lead to low ROS utilization and body metabolism, thus enlarging their long-term toxicity and low therapeutic effect. To solve these shortcomings, herein the ultrasmall Gd3+ -hemoporfin framework nanodots (GdHF-NDs， ≈5 nm) is reported as efficient nano-sonosensitizers. Compared with GdHF aggregation (GdHF-A, ≈400nm), the ultrasmall GdHF-NDs generate 2.3-fold toxic ROS amount under similar conditions, due to shorter diffusion path and larger relative specific surface area. When the GdHF-NDs dispersion is introvenously injected into tumor-bearing mouse, they are accumulated within tumors to provide high magnetic resonance imaging (MRI) contrast. Under US irradiation, the GdHF-NDs achieve a better sonodynamic therapeutic efficacy for tumors, compared with that from GdHF-A. More importantly, owing to ultrasmall size, most of GdHF-NDs can be rapidly cleared through the renal pathway. Therefore, GdHF-NDs can be used as a biosafety and high-performance sonodynamic agent for cancer theranostics.

Habituation After Deep Brain Stimulation in Tremor Syndromes: Prevalence, Risk Factors and Long-Term Outcomes.

Deep brain stimulation (DBS) of the thalamus is an effective treatment for medically refractory essential, dystonic and Parkinson's tremor. It may also provide benefit in less common tremor syndromes including, post-traumatic, cerebellar, Holmes, neuropathic and orthostatic tremor. The long-term benefit of DBS in essential and dystonic tremor (ET/DT) often wanes over time, a phenomena referred to as stimulation “tolerance” or “habituation”. While habituation is generally accepted to exist, it remains controversial. Attempts to quantify habituation have revealed conflicting reports. Placebo effects, loss of micro-lesional effect, disease related progression, suboptimal stimulation and stimulation related side-effects may all contribute to the loss of sustained long-term therapeutic effect. Habituation often presents as substantial loss of initial DBS benefit occurring as early as a few months after initial stimulation; a complex and feared issue when faced in the setting of optimal electrode placement. Simply increasing stimulation current tends only to propagate tremor severity and induce stimulation related side effects. The report by Paschen and colleagues of worsening tremor scores in the “On” vs. “Off” stimulation state over time, even after accounting for “rebound” tremor, supports the concept of habituation. However, these findings have not been consistent across all studies. Chronic high intensity stimulation has been hypothesized to induce detrimental plastic effects on tremor networks, with some lines of evidence that DT and ET may be more susceptible than Parkinson's tremor to habituation. However, Tsuboi and colleague's recent longitudinal follow-up in dystonic and “pure” essential tremor suggests otherwise. Alternatively, post-mortem findings support a biological adaption to stimulation. The prevalence and etiology of habituation is still not fully understood and management remains difficult. A recent study reported that alternating thalamic stimulation parameters at weekly intervals provided improved stability of tremor control consistent with reduced habituation. In this article the available evidence for habituation after DBS for tremor syndromes is reviewed; including its prevalence, time-course, possible mechanisms; along with expected long-term outcomes for tremor and factors that may assist in predicting, preventing and managing habituation.

Long-term outcome of stereotactic aspiration, endoscopic evacuation, and open craniotomy for the treatment of spontaneous basal ganglia hemorrhage: a propensity score study of 703 cases.

BackgroundTo compare the long-term therapeutic effects of stereotactic aspiration (SA), endoscopic evacuation (EE), and open craniotomy (OC) in the surgical treatment of spontaneous basal ganglia hemorrhage and explore the appropriate clinical indications for each technique.MethodsMultiple-treatment inverse probability of treatment weighting (IPTW)-adjusted logistic regression analysis was performed to evaluate the therapeutic effects of these techniques. The primary and secondary outcomes were 6-month modified Rankin Scale (mRS) and mortality rates, respectively.ResultsA total of 703 patients were ultimately enrolled. For the entire cohort, the 6-month mortality rate was significantly higher (OR 2.396, 95% CI: 1.865–3.080), and the 6-month functional outcome was significantly worse (OR 1.359, 95% CI: 1.091–1.692) for SA than that of EE. The 6-month mortality rate for OC was significantly higher (OR 1.395, 95% CI: 1.059–1.837) than that of EE. Further subgroup analysis was stratified by initial hematoma volume and Glasgow Coma Scale (GCS) score. The mortality rate for SA was significantly higher for patients with hematoma volume of 20–40 mL (OR 6.226, 95% CI: 3.848–10.075), 40–80 mL (OR 2.121, 95% CI: 1.492–3.016), and ≥80 mL (OR 5.544, 95% CI: 3.315–9.269) than in the same subgroups of EE. The functional outcomes for SA were significantly worse than that of EE for hematoma volume subgroups of 40–80 mL (OR 1.424, 95% CI: 1.039–1.951) and ≥80 mL (OR 4.224, 95% CI: 1.655–10.776). The mortality rate for SA was significantly higher than that of EE for the GCS score subgroups of 6–8 (OR 2.082, 95% CI: 1.410–3.076) and 3–5 (OR 2.985, 95% CI: 1.904–4.678). The mortality rate for OC was significantly higher for the GCS score of 3–5 subgroup (OR 1.718, 95% CI: 1.115–2.648), and a tendency for a higher mortality rate of 6–8 subgroup (OR 1.442, 95% CI: 0.965–2.156) than that of EE.ConclusionsEE can decrease the 6-month mortality rate and improve the 6-month functional outcomes of spontaneous basal ganglia hemorrhage in patients with a hematoma volume ≥40 mL. EE can decrease the 6-month mortality rate of spontaneous basal ganglia hemorrhage in patients with a GCS score of 3–8.

Cardiac Contractility Modulation in Patients with Ischemic versus Non-ischemic Cardiomyopathy: Results from the MAINTAINED Observational Study

BackgroundCardiac contractility modulation (CCM) is an FDA-approved device-based therapy for patients with systolic heart failure and normal QRS width who are symptomatic despite optimal drug therapy. The purpose of this study was to compare the long-term therapeutic effects of CCM therapy in patients with ischemic (ICM) versus non-ischemic cardiomyopathy (NICM). MethodsChanges in NYHA class, KDIGO CKD stage, left ventricular ejection fraction (LVEF), tricuspid annular plane systolic excursion (TAPSE), and NT-proBNP levels were compared as functional parameters. Moreover, observed mortality rates at 1 and 3 years were compared to those predicted by the MAGGIC heart failure risk score, and observed mortality rates were compared between groups for the entire follow-up period. ResultsOne hundred and seventy-four consecutive patients with chronic heart failure and CCM device implantation between 2002 and 2019 were included in this retrospective analysis. LVEF was significantly higher in NICM patients after 3 years of CCM therapy (35 ± 9 vs. 30 ± 9%; p = 0.0211), and after 5 years, also TAPSE of NICM patients was significantly higher (21 ± 5 vs. 18 ± 5%; p = 0.0437). There were no differences in other effectiveness parameters. Over the entire follow-up period, 35% of all patients died (p = 0.81); only in ICM patients, mortality was lower than predicted at 3 years (35 vs. 43%, p = 0.0395). ConclusionsRegarding improvement of biventricular systolic function, patients with NICM appear to benefit particularly from CCM therapy.

Некоторые аспекты движения жидкости внутри глазного яблока при математическом моделировании интравитреальной инъекции

Background. The avalanche-like growth of intravitreal injections in the world has significantly increased interest in the hemodynamics of the processes that occur in the eye when a drug is injected into the vitreous cavity. Every year, the number of intravitreally used drugs and promising areas in which they can be used is growing. This also applies to the creation of new combined medicines and the development of drugs with a long-term therapeutic effect. Aims. Create mathematical model of eyeball to evaluate the movement of the drug substance in it; to estimate the time of the drug's presence in the eye cavity before its complete removal, to characterize the ways of its removal from the eye cavity; to assess the significance of posterior vitreous detachment during the time when the drug is present in the eye cavity; to evaluate the effect on the hydrodynamics of the depth of drug administration. Results. When the drug is administered closer to the center of the eyeball, its residence time increases in comparison with the parietal administration. With a complete posterior detachment of the vitreous body, the time of finding the drug in the eye is prolonged compared to its absence. The obtained results of mathematical modeling of the movement of the drug administered intravitreally cannot be mechanically transferred to the human eye, due to the more complex structure of the latter. Key words: intravitreal injections, vitreous body, mathematic computing.