[Long-term consequences of COVID-19 in patients with functional bowel disorders, rehabilitation prospective of microbiocenosis-oriented therapy].

AIM: To analyze long-term consequences of the new coronavirus infection and rehabilitation prospective of microbiocenosis-oriented therapy in patients with functional bowel disorders. MATERIALS AND METHODS: The study enrolled 100 consecutive patients with various types of functional bowel disorders with recurrence of symptoms after the new coronavirus infection. The severity of abdominal pain was evaluated in points, and bowel movement disorders were assessed using the Bristol stool scale. A questionnaire was used as part of an in-depth clinical examination for COVID-19 survivors to identify the clinical symptoms typical for the post-COVID syndrome. The Hospital Anxiety and Depression Scale was used to identify and assess the severity of depression and anxiety, and the Asthenic State Scale was used to diagnose the asthenia. RESULTS: All patients in the study subjectively linked the recurrence of bowel disorders with the new coronavirus infection. The most common bowel disorder was irritable bowel syndrome with diarrhea. A distinctive feature of exacerbations of intestinal symptoms in the post-COVID period is their association with depression/anxiety and asthenic states. The addition of Zakofalk® metaprebiotic to the treatment regimen was associated with significant regression of abdominal pain and normalization of bowel movement, an improvement of asthenia, anxiety, and depression. CONCLUSION: The addition of Zakofalk® to treatment regimens for exacerbations of functional bowel disorders after the new coronavirus infection significantly improves the effectiveness of therapy.

Biocompatibility and Bioresorption of 3D-Printed Polylactide and Polyglycolide Tissue Membranes.

We studied biocompatibility and bioresorption of 3D-printed polylactide and polyglycolide tissue membranes. Ultrasound microscopy and histological examination showed that membranes fabricated of a copolymer of lactic and glycolic acids in a mass ratio of 1:9 are bioresorbed and have good biocompatibility with soft tissues (connective tissue, adipose tissue, and epithelium). An important feature of the copolymer membranes, which differs them from pure polylactide membranes, is the formation of a thin fibrous capsule that did not interfere its destruction by the mechanism of hydrolytic resorption.

[Clinical, morphological and microcirculatory criteria of local recurrence of the prostate cancer after HIFU therapy].

AIM: to study the clinical, morphological and microcirculatory criteria for treatment efficiency and prognosis of local recurrence after HIFU. MATERIALS AND METHODS: On the basis of the urological department of Clinical Hospital "Russian Railways - Medicine" in Barnaul (the clinical base of the Department of Urology and Andrology with a course of Specialized Surgery of FGBOU VO "Altai State Medical University") for the period 2011-2018, a comprehensive examination and treatment of 240 patients with prostate cancer (PCa) by means of HIFU using "Ablatherm" was performed following transurethral resection of the prostate (TURP). The indication for HIFU was morphologically-proven PCa (stage T2a-cN0M0) in patients with contraindications due to comorbidities or those who refused from radical prostatectomy. RESULTS: A decrease in PSA to 0.5 ng/ml or less was observed in 74% of patients. A stable PSA level for 3 years was observed in 76% of patients. PSA levels differed depending on the PCa risk group. In the low-risk PCa, negative biopsy was seen in 89.6% of cases, in comparison with 72.2% and 69.4% in intermediate and high-risk PCa, respectively. There was a significant decrease in the volume of the prostate in all patients with low-risk PCa. The largest decrease in prostate volume was observed 12 months after HIFU. Regarding recurrence-free survival after HIFU therapy, during follow-up of 3 years or more, 77% of patients didnt have any signs of recurrence. A 3-year overall survival after HIFU was 83%. In addition, an increase in postoperative PSA levels, change in parameters of Doppler study and laser Doppler flowmetry at the area of the prostate during the period of 6-36 months after HIFU was associated with a significant increase in the risk of recurrence of PCa at biopsy. CONCLUSION: HIFU therapy is an effective treatment method for inducing prostate necrosis with minimal collateral damage to the surrounding tissue. The best results were achieved in patients with low-risk PCa. There were minimal adverse events after HIFU. In addition, in case of relapse after HIFU therapy, there is an opportunity for an early assessment of the efficiency and prognosis.

[Possibilities of using sildenafil in patients with cardiovascular comorbidities who underwent transurethral resection of the prostate].

AIM: To study the efficacy and safety of using sildenafil in patients with erectile dysfunction (ED) and concomitant cardiovascular diseases (CVD) who underwent transurethral resection of the prostate (TURP). MATERIAL AND METHODS: A total of 59 patients (age from 50 to 75 years) with a diagnosis of benign prostatic hyperplasia (BPH), requiring surgical treatment due to inefficiency of drug therapy, I-PSS score more than 20 points), who were sexually active, but had erectile dysfunction (IIEF score < 21), coronary heart disease (NYHA class I) and stage 1-2 hypertension with stable blood pressure. All patients underwent bipolar TURP. From the first day after the TURP, therapy was prescribed as following: tamsulosin 0.4 mg once a day for 90 days, ciprofloxacin 500 mg twice a day for 10 days. In addition, the patients received treatment for comorbidities. In the main group (n=30), men additionally received sildenafil (EFFEX Sildenafil Evalar) 50 mg daily for 60 days, starting from the 30th day postoperatively. We have chosen this drug from an economic standpoint. RESULTS: At baseline, all patients in both groups had hemodynamic and microcirculatory disorders in the prostate, which got worse in the early postoperative period. During the long-term follow-up, hemodynamic and microcirculatory impairments decreased. This effect was more pronounced in patients who received sildenafil. In addition, patients had an improvement in sexual function. During follow-up, there was no adverse effects of sildenafil on hemodynamic parameters (blood pressure, heart rate). CONCLUSION: Our results allow to recommend sildenafil in order to restore sexual function postoperatively in patients with BPH, including those with concomitant cardiovascular disorders.

Replacement relations for a viscoelastic material containing multiple inhomogeneities.

Classical replacement relations provide a connection between elastic properties of a porous material and the same material with fluid or solid infill of the porous space. We derive such relations for the case when both skeleton and infill materials are viscoelastic. For this goal, we use formalism of compliance/stiffness contribution tensors that lead to replacement relations for anisotropic elastic materials that, in the case of isotropy, coincide with classical Gassmann equation (Gassmann, 1951). We rewrite these relations using creep and relaxation contribution tensors that describe effect of individual inhomogeneities on the overall viscoelastic properties of a heterogeneous material. Explicit analytical expressions are obtained using elastic-viscoelastic correspondence principle and Laplace transform. It becomes possible when viscoelastic properties are expressed in terms of fraction-exponential operators of Scott Blair-Rabotnov. Results are obtained in closed explicit form.

Estrogen therapy for osteoporosis in the modern era.

Menopause predisposes women to osteoporosis due to declining estrogen levels. This results in a decrease in bone mineral density (BMD) and an increase in fractures. Osteoporotic fractures lead to substantial morbidity and mortality, and are considered one of the largest public health priorities by the World Health Organization (WHO). It is therefore essential for menopausal women to receive appropriate guidance for the prevention and management of osteoporosis. The Women's Health Initiative (WHI) randomized controlled trial first proved hormonal therapy (HT) reduces the incidence of all osteoporosis-related fractures in postmenopausal women. However, the study concluded that the adverse effects outweighed the potential benefits on bone, leading to a significant decrease in HT use for menopausal symptoms. Additionally, HT was not used as first-line therapy for osteoporosis and fractures. Subsequent studies have challenged these initial conclusions and have shown significant efficacy of HT in various doses, durations, regimens, and routes of administration. These studies support that HT improves BMD and reduces fracture risk in women with and without osteoporosis. Furthermore, the studies suggest that low-dose and transdermal HT are less likely associated with the adverse effects of breast cancer, endometrial hyperplasia, coronary artery disease (CAD), and venous thromboembolism (VTE) previously observed in standard-dose oral HT regimens. Given the need for estrogen in menopausal women and evidence supporting the cost effectiveness, safety, and efficacy of HT, we propose that HT should be considered for the primary prevention and treatment of osteoporosis in appropriate candidates. HT should be individualized and the once "lowest dose for shortest period of time" concept should no longer be used. This review will focus on the prior and current studies for various HT formulations used for the prevention and treatment of osteoporosis, exploring the safety profile of low-dose and transdermal HT that have been shown to be safer than oral standard-dose HT.

Status of the Microcirculatory Network as a Factor of Prognosis and Evaluation of Therapeutic Efficiency in Prostate Cancer Treated by High-Intensity Focused Ultrasound in Combination with Androgen Deprivation.

Immunohistochemical and morphometric analysis of the microcirculatory bed in the tumor and non-tumor parenchyma of the prostate was carried out with the use of endothelial cell marker CD34 in patients treated by high-intensity focused ultrasound (HIFU). The numerical density of microvessels in the adenocarcinoma focus did not correlate with the degree of its differentiation, while high values of this parameter were associated with lower incidence of local progression after HIFU. Effective HIFU ablation led to progressive fibrosis and significant reduction of the microcirculatory bed in zones of intact non-tumor glands in control samples; an inverse relationship between the degree of reduction of the microcirculatory bed and the probability of relapse was revealed. The use of HIFU in combination with androgen deprivation was associated with a decrease in numerical density of microvessels in zones of tumor and non-tumor parenchyma in patients with relapses.

[Morphological changes in tumor and nontumor tissue in the treatment of prostate adenocarcinoma with high-intensity focused ultrasound in combination with androgen deprivation]. / Morfologicheskie izmeneniia opukholevoi i neopukholevoi tkani pri lechenii adenokartsinomy predstatel'noi zhelezy vysokointensivnym fokusirovannym ul'trazvukom v sochetanii s androgennoi deprivatsiei.

OBJECTIVE: To investigate structural changes in the tumor and nontumor tissues of the prostate in patients with its cancer (PC) after treatment with high-intensity focused ultrasound (HIFU) in combination with androgen deprivation to clarify criteria for evaluating the efficiency of treatment. SUBJECT AND METHODS: Comparative morphological, immunohistochemical, and morphometric analyses were carried out to examine 253 pre- and postoperative biopsy specimens, as well as transurethral resection specimens from 32 patients with localized PC and with or without a local recurrence within 3 years after a HIFU session. RESULTS: HIFU ablation was accompanied by coagulation necrosis and progressive pancreatic fibrosis with complete tumor regression or by a reduction in the number of positive columns (by an average of 58%) in cases with recurrence. An inverse relationship was found between the degree of a reduction in the nontumor parenchyma in the control specimens and the probability of a recurrence - a less than 20% reduction in the non-tumor glands corresponded to a 3.4-fold increased risk of tumor progression. The development of recurrence was associated with less differentiated PC (GS ≥4+3) and the presence of cribriform structures in the pretreatment samples. Combined androgen deprivation as the maximum blockade was associated with the most pronounced signs of therapeutic pathomorphism, with a reduction of the microcirculatory bed in the focus of residual tumor, and a decrease in the frequency of local progression. CONCLUSION: Neoadjuvant hormone therapy contributes to the enhanced efficiency of HIFU treatment for PC. A less than 20% reduction in nontumor parenchyma volumes in the control biopsy specimens may indicate insufficient ablation in pancreatic tissue and serve as a marker for increased risk of local progression.

Improvement in quality of oocytes in polycystic ovarian syndrome in programs of in vitro fertilization.

Inositol therapy is aimed at improving the quality of oocytes during preconception care in patients with polycystic ovarian syndrome (PCOS), a cause of infertility and reproductive dysfunction. The objectives of this observational comparative multicentre study were to evaluate the effectiveness of inositol in improving the quality of oocytes/embryos and IVF cycle outcome. Group 1 patients (N = 133) received inositol 1000 mg (Inofert or Nutrilinea) + folic acid 0.1 mg. Group 2 consisted of patients with preserved ovarian reserve without PCOS (N = 137), not administered inositol prior to pregnancy. Effectiveness criteria were numbers of mature oocytes and good quality embryos, pregnancy rates per ET, 'take home baby' index and miscarriage rates. Pregnancy rates per ET (87.0% vs. 87.4%), 'take home baby' index (79.6% vs. 89.4%) and miscarriage rates (14.3% vs. 10.6%) were comparable. Use of inositol in patients with PCOS during preconception care is an effective method allowing improvement of oocytes quality and positively affecting IVF cycle prognosis. High pregnancy rates per ET and 'take home baby' index after treatment are justifying inositol usage in patients with PCOS and infertility.

Ventricular tachycardia in "end stage" hypertrophic cardiomyopathy: a role of dronedarone.

Hypertrophic cardiomyopathy (HCM) occurs in 1 in every 500 individuals. It represents the most common cause of sudden cardiac death in those under the age of twenty-five. 3-5% patients with HCM go on to develop the dilated, hypokinetic end stage (ES) HCM with systolic failure. They have a higher incidence of heart failure, sudden deaths and defibrillator shocks. To the best of our knowledge this is first report of successful use of dronedarone for suppression of VT associated with ES HCM.

The neuronal repressor REST/NRSF is an essential regulator in medulloblastoma cells.

Medulloblastoma is the most malignant pediatric brain tumor. It is believed to originate from the undifferentiated external granule layer cells in the cerebellum, but the mechanism of tumorigenesis remains unknown. Here we studied three types of human medulloblastoma cells that express markers corresponding to different levels of neuronal differentiation. They expressed the neuronal repressor element 1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF; refs. 7-10) at very high levels compared with either neuronal progenitor NTera2 (NT2) cells or fully differentiated human neuron teratocarcinoma (hNT cells). To counter the effect of REST/NRSF, we used a recombinant transcription factor, REST-VP16, constructed by replacing repressor domains of REST/NRSF with the activation domain of viral protein (VP16). Transient expression of REST-VP16 in medulloblastoma cells was able to compete with the endogenous REST/NRSF for DNA binding and stimulate neuronal promoters. High-efficiency expression of REST-VP16 mediated by adenovirus vectors (Ad.REST-VP16) in medulloblastoma cells was able to counter REST/NRSF-mediated repression of neuronal promoters, stimulate expression of endogenous neuronal genes and trigger apoptosis through the activation of caspase cascades. Furthermore, intratumoral injection of Ad.REST-VP16 in established medulloblastoma tumors in nude mice inhibited their growth. Therefore, REST/NRSF may serve as a new target for therapeutic interventions for medulloblastoma through agents such as REST-VP16.

Overexpression of E2F-1 in glioma triggers apoptosis and suppresses tumor growth in vitro and in vivo.

The transfer of apoptosis genes to tumors is one of the most promising strategies for cancer gene therapy. We have shown that massive apoptosis occurs when wild-type p53 expression is induced in glioma cells carrying a p53 gene mutation. However, adenovirus-mediated p53 gene transfer is ineffective in causing apoptosis in glioma cells that retain a wild-type p53 genotype. We evaluated the effect of E2F-1 overexpression on the growth of gliomas in vitro and in vivo. In the in vitro study, the adenovirus-mediated transfer of exogenous E2F-1 protein precipitated generalized apoptosis in gliomas. The treatment with Ad5CMV-E2F-1 of nude mice carrying subcutaneous gliomas arrested tumor growth. Our results indicate that E2F-1 has anti-glioma activity in vitro and in vivo.

[Changes of blood rheological properties and its correction under surgical and drug treatment in patients with phlegmons of maxillofacial area].

Blood theological properties in patients with phlegmons of maxillofacial area before treatment, immediately after surgical treatment and after surgical treatment combined with reamberin therapy were examined in the study. Negatively changed theological profile values somewhat improved after operation, mainly because of blood and serum viscosity decrease by 10-11% and blood transport capability enhancement. But significant positive macro- and microrheological changes was only received by surgical treatment combined with reamberin. Reed blood cells (RBC) incubation with reamberin proved direct microrheological effect of reamberin due to RBC deformability increase (by 10%, p < 0.05) and aggregation decrease (by 11%, p < 0.05). Positive theological changes associated with favorable clinical outcome.

Two phase II trials of temozolomide with interferon-alpha2b (pegylated and non-pegylated) in patients with recurrent glioblastoma multiforme.

BACKGROUND: Because of the poor outcomes for patients with recurrent glioblastoma multiforme (GBM), and some laboratory and clinical evidence of efficacy using interferon in GBM, we assessed the toxicity and efficacy of temozolomide (TMZ) combined with either short-acting (IFN) or long-acting (pegylated) interferon alpha2b (PEG) in two single-arm phase II studies, and compared the results to 6-month progression-free survival (PFS-6) data from historical controls. METHODS: Two single-arm phase II studies were carried out in adults with GBM. Patients were treated with the standard regimen of TMZ (150-200 mg m(-2) per day x 5 days every month) combined with either 4 million units per m(2) subcutaneously (SQ) three times weekly of IFN or 0.5 microg kg(-1) SQ weekly of PEG. Physical exams and imaging evaluations were carried out every 8 weeks. RESULTS: On the IFN study, 34 adults (74% men) were enrolled, and 29 adults (55% men) on the PEG study; median Karnofsky performance status was 80 and 90 for the IFN and PEG studies, respectively. Grade 3 or 4 toxicities were common, leucopoenia and thrombocytopoenia occurring in 35-38% and 18-21% of patients, respectively. Grade 3 or 4 fatigue occurred in 18% of patients on both studies. Lymphopoenia was infrequent. PFS-6 was 31% for 29 evaluable patients in the IFN study and 38% for 26 evaluable patients in the PEG study. CONCLUSION: In recurrent GBM patients, both studies of standard dose TMZ with either IFN or PEG showed improved efficacy when compared to historical controls, or reports using TMZ alone. Even though the TMZ+PEG study met criteria for further study, the results of both of these studies must be considered in light of the standard of care (TMZ plus radiotherapy) for newly diagnosed GBM, which has evolved since the inception of these studies. Despite the results of the current studies being eclipsed by the new GBM standard of care, these results can still inform the development of newer approaches for GBM, either in an earlier, upfront setting, or by extrapolation of the results and consideration of the use of PEG or IFN in conjunction with other antiglioma strategies.

Cerebrospinal fluid production by the choroid plexus and brain.

The production of cerebrospinal fluid and the transport of (24)Na from the blood to the cerebrospinal fluid were studied simultaneously in normal and choroid plexectomized rhesus monkeys. Choroid plexectomy reduced the production of cerebrospinal fluid by an average of 33 to 40 percent and the rate of appearance of (24)Na in the cerebrospinal fluid and its final concentration were proportionately reduced. In both normal and plexectomized animals, (24)Na levels were found to be markedly greater in the gray matter surrounding the ventricles and in the gray matter bordering the subarachnoid space. That sodium exchanges in these two general areas of the brain may be linked to the formation of the cerebrospinal fluid is discussed here.

Ha-ras(val12) induces HSP70b transcription via the HSE/HSF1 system, but HSP70b expression is suppressed in Ha-ras(val12)-transformed cells.

Heat shock proteins (Hsps) are overexpressed in many tumors, but are downregulated in some tumors. To check for a direct effect of Ha-Ras(val12) on HSP70 transcription, we transiently expressed the oncoprotein in Rat1 fibroblasts and monitored its effect on HSP70b promoter-driven reporter gene. We show that expression of Ha-Ras(val12) induced this promoter. Promoter analysis via systematic deletions and point mutations revealed that Ha-Ras(val12) induces HSP70b transcription via heat shock elements (HSEs). Also, Ha-Ras(val12) induction of HSE-mediated transcription was dramatically reduced in HSF1-/- cells. Yet, residual effect of Ha-Ras(val12) that was still measured in HSF1-/- cells suggests that some of the Ha-Ras(val12) effect is Hsf1-independent. When HSF1-/- cells, stably expressing Ha-Ras(val12), were grown on soft agar only small colonies were formed suggesting a role for heat shock factor 1 (Hsf1) in Ha-Ras(val12)-mediated transformation. Although Ha-ras(Val12) seems to be an inducer of HSP70's expression, we found that in Ha-ras(Val12-)transformed fibroblasts expression of this gene is suppressed. This suppression is correlated with higher sensitivity of Ha-ras(val12)-transformed cells to heat shock. We suggest that Ha-ras(Val12) is involved in Hsf1 activation, thereby inducing the cellular protective response. Cells that repress this response are perhaps those that acquire the capability to further proliferate and become transformed clones.

Regulation of ornithine decarboxylase during oncogenic transformation: mechanisms and therapeutic potential.

The activity of ornithine decarboxylase (ODC(1)), the first enzyme in polyamine biosynthesis, is induced during carcinogenesis by a variety of oncogenic stimuli. Intracellular levels of ODC and the polyamines are tightly controlled during normal cell growth, and regulation occurs at the levels of transcription, translation and protein degradation. Several known proto-oncogenic pathways appear to control ODC transcription and translation, and dysregulation of pathways downstream of ras and myc result in the constitutive elevation of ODC activity that occurs with oncogenesis. Inhibition of ODC activity reverts the transformation of cells in vitro and reduces tumor growth in several animal models, suggesting high levels of ODC are necessary for the maintenance of the transformed phenotype. The ODC irreversible inactivator DFMO has proven to be not only a valuable tool in the study of ODC in cancer, but also shows promise as a chemopreventive and chemotherapeutic agent in certain types of malignancies.

[The role of factors determining rheological properties of blood in mechanisms of adaptation and damage in water imbalance].

The study was made of hematological, rheological and biochemical blood parameters of white male rats in daily intramuscular injection of 0.02 mcg of desmopressin and regular periodic hyperhydration of the organism achieved by introduction of 10% water loading within 3, 6, 9 days. The results evidence for significant action of desmopressin on liquid homeostasis not only by antidiuretic effects on the kidneys, by changing the condition of connecting tissue of the matrix as shown by a marked rise of acid GAG in plasm but also by influence on rheological properties of blood which is an important element of management of transcapillary exchange in tissue microregions.

Dianhydrogalactitol (NSC-132313): pharmacokinetics in normal and tumor-bearing rat brain and antitumor activity against three intracerebral rodent tumors.

Dianhydrogalactitol (DAG; NSC-132313), a hexitol epoxide, was used to treat intracerebral rodent tumors. DAG was most active against the murine ependymoblastoma [treated/controls (T/C)greater than 440%], less active against murine glioma 26 (T/C approximately 112-150%), and least active against rat 9L gliosarcoma (T/C approximately 100%). Application of a two-compartment open model for plasma disappearance of 14C-DAG in rats gave a volume of distribution at steady state of approximately 872 ml, a clearance of approximately 9.4 ml/minute, and an elimination constant of 0.025/minute. Entry of 14C-DAG was more rapid into the 9L tumor than into the normal brain. When a two-compartment series model for brain and tumor entry was applied, the t1/2 (half-time) for compartmental equilibrium was approximately 22 and 105 minutes in the brain, and 4 and 56 minutes in the 9L tumor. The drug rapidly entered the brain and tumor intracellular compartments. Binding to RNA was linear with time, and the absolute amount of binding was approximately six times greater for RNA than for DNA.

Treatment of recurrent gliomas with eflornithine.

BACKGROUND: Oral eflornithine in combination with intravenous mitoguazone (methylbisguanylhydrazone) has shown activity against recurrent anaplastic gliomas. Eflornithine alone, however, has not been evaluated against recurrent gliomas. PURPOSE: This study compared the antitumor activity of oral eflornithine with that of oral eflornithine combined with intravenous mitoguazone in the treatment of patients with recurrent or progressive glioblastoma multiforme as well as nonglioblastoma anaplastic gliomas. METHODS: During the 1st year of therapy with eflornithine alone, the drug was given at a dose of 3.6 g/m2 on days 1-14, 22-35, and 43-56 every 8 hours; cycles were repeated every 63 days until progression. For the 2nd year, the drug was given on days 1-14, 29-42, and 57-70, with 84 days between cycles. For the 1st and 2nd years of eflornithine-mitoguazone therapy, eflornithine was given at 1.8 g/m2 on the same schedule. Mitoguazone was given intravenously at 200 mg/m2 on the final day of each 2-week sequence of eflornithine therapy. Response was determined by evaluating changes in the size of contrast-enhanced neuroimages. RESULTS: Because of two cases of lethal hepatic necrosis, the initial random allocation of patients to the eflornithine-mitoguazone arm was stopped after 23 patients had been accrued. Ninety-eight patients were entered in the eflornithine arm; 80 patients (36 glioblastoma multiforme patients and 44 anaplastic glioma patients) were assessable for response. Antitumor activity (partial response, minor response, and stable disease) was seen in 45% of the patients with anaplastic gliomas, for a median of 49 weeks, but in only 17% of patients with glioblastoma multiforme (median not attained). Twenty-one (20%) of the patients with anaplastic glioma and 33% of the patients with glioblastoma multiforme were removed from the study before completing the first 8-week course of therapy because of neurological deterioration and tumor progression by the 5th week of treatment. CONCLUSION: This study suggests that eflornithine alone is an effective palliative therapy for recurrent anaplastic gliomas. Additional studies are needed to confirm our finding.