Meta-analysis of the Relationship Between Neutrophil to Lymphocyte Ratio and Nasal Polyps.

Our study aimed to enhance understanding of nasal polyp pathophysiology by reviewing the data for variations of NLR values between patients with nasal polyp and healthy controls. We searched Web of Science, PubMed, ProQuest, and Scopus up to 2 April 2023. The search strategy was not limited to any specific language. Twelve studies were included in our study. Of them, ten studies, involving 898 nasal polyp patients and 590 control patients, were included in the meta-analysis. The NLR levels in nasal polyp patients were statistically greater than in the control group (SMD = 0.56; 95%CI 0.04-1.08, P = 0.036). Subgroup analysis based on study design yielded that patients with nasal polyp exhibited significantly higher NLR levels than healthy controls in retrospective studies (SMD = 0.83; 95%CI 0.30-1.35, P = 0.002) but not in prospective studies (SMD = 0.10; 95%CI = -1.03 to 1.23, P = 0.85). Also, we found that the NLR levels in nasal polyp patients were significantly higher than healthy controls in high-quality studies (SMD = 1.00; 95%CI 0.38-1.62, P = 0.002) but not in low-quality studies (SMD = 0.11; 95%CI = -0.69 to 0.91, P = 0.79). A total of 312 patients with recurrence and 550 patients without recurrence were included in the study. The combined results revealed that NLR levels in nasal polyp recurrence patients were significantly higher than those of the nasal polyp without recurrence group (SMD = 0.06, 95% CI 0.39-0.81, P = 0.000). These results showed the relationship between the NLR in nasal polyps and can help medical doctors to predict the recurrence of the disease in such patients.

Association of inflammatory biomarkers with overall survival in burn patients: a systematic review and meta-analysis.

INTRODUCTION: The inflammatory response to burn injuries can lead to organ dysfunction that ultimately results in increased mortality and morbidity. This meta-analysis was conducted to determine the efficacy of inflammatory biomarkers, including the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), procalcitonin (PCT), and C-reactive protein (CRP) as predictive tools of mortality among burn patients. MATERIAL AND METHODS: The biomarker levels of survivors and non-survivors were consolidated according to guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Three main databases were searched electronically: PubMed, Web of Science, and Scopus, on December 8, 2022. The Newcastle-Ottawa Quality Assessment Scale (NOS) was used to evaluate and score the methodological quality of the included studies. The standard mean difference (SMD) with a 95% confidence interval (CI) was utilized. RESULTS: Twenty-four studies were included in our systematic review and meta-analysis, (3636 total burn patients), of whom 2878 survived. We found that deceased burn patients had elevated levels of NLR (SMD = 0.60, 95% CI; 0.19-1.00, P < 0.001), CRP (SMD = 0.80, 95% CI; 0.02-1.58, P = 0.04), and PCT (SMD = 0.85, 95% CI; 0.45-1.24, P < 0.001), compared to survivors. However, we found no association between PLR and mortality among burn patients (SMD = 0.00, 95% CI; -0.14-0.15, P < 0.001). In addition, CRP was significantly higher in non-survivors (SMD = 0.80, 95% CI; 0.02-1.58, P =0.04). Similar results were also found about PCT (SMD = 0.85, 95% CI; 0.45-1.24, P < 0.001). When we analyzed the PCT data, collected in the first 24-48 hours, we found similar results; the PCT level was significantly higher in non-survivors in the immediate postinjury-period (SMD = 0.67, 95% CI; 0.31-1.02, P < 0.001). There was no publication bias among studies on the role of NLR in burn (Egger's test P = 0.91). The based cut-off values for NLR (13), CRP (71), and PCT (1.77) yielded sensitivities of 69.2%, 100%, and 93.33%, and specificities of 76%, 72.22%, and 72.22% respectively. DISCUSSION/CONCLUSIONS: PCT is a marker of sepsis, therefore its elevated level is presumably associated with a higher incidence and severity of sepsis among non-survivors. In addition, NLR and CRP are promising biomarkers for predicting and guiding prevention against burn deaths in clinical settings.

Prognostic Role of Neutrophil to Lymphocyte Ratio in Allergic Rhinitis: A Systematic Review and Meta-analysis.

One of the crucial triggers of allergic diseases is an inflammatory reaction and neutrophil to lymphocyte ratio (NLR) is one of the systemic inflammation biomarkers. Our review aimed to evaluate role of NLR in predicting severity and comorbidities of allergic rhinitis (AR). We systematically searched Scopus, Web of Science, and PubMed to find relevant studies. Standardized mean difference (SMD) with a 95% confidence interval (CI) was reported. Due to the high levels of heterogeneity, the random-effects model was used to generate pooled effects. Eleven articles were included in the systematic review, among which ten were included in meta-analysis including 1122 healthy controls and 1423 patients with AR. We found that patients with AR had a significantly higher level of NLR than healthy controls (SMD = 0.19, 95%CI = 0.03-0.36, P = 0.03). In addition, patients with moderate to severe AR had significantly higher levels of NLR compared to those with mild AR (SMD = 0.41, 95%CI = 0.20-0.63, P < 0.001). Interestingly, it was found that NLR could associate with some comorbidities of AR, like asthma. Our results confirmed that NLR could assist clinicians in predicting the severity and comorbidities of AR. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-023-04148-8.

Prognostic Role of Neutrophil to Lymphocyte Ratio in Contrast-Induced Nephropathy: A Systematic Review and Meta-analysis.

This meta-analysis assessed the use of the neutrophil-to-lymphocyte ratio (NLR) as a means of early detection of contrast-induced nephropathy (CIN) following diagnostic or therapeutic procedures. We used Web of Science, PubMed, and Scopus to conduct a systematic search. There was no limitation regarding language or date of publication. We reported standardized mean difference (SMD) with a 95% confidence interval (CI). Due to high heterogeneity, a random-effects model was used, and the Newcastle-Ottawa scale was used for quality assessment. Thirty-one articles were included in the analysis. Patients in the CIN group had elevated levels of NLR compared with those in the non-CIN group (SMD = 0.78, 95% CI = 0.52-1.04, P < .001). Similar results were observed in either prospective (SMD = 1.03, 95% CI = 0.13-1.93, P = .02) or retrospective studies (SMD = 0.70, 95% CI = 0.45-0.96, P < .001). The pooled sensitivity of NLR was 74.02% (95% CI = 66.54%-81.02%), and the pooled specificity was 60.58% (95% CI = 53.94%-66.84%). NLR shows potential as a cost-effective biomarker for predicting CIN associated with contrast-involved treatments. This could help implement timely interventions to mitigate CIN and improve outcomes.

Neutrophil to lymphocyte ratio in odontogenic infection: a systematic review.

BACKGROUND: We conducted this systematic review to compile the evidence for the role of neutrophil to lymphocyte ratio (NLR) in odontogenic infection (OI) and to determine whether NLR is elevated in patients with OI. This was done to aid physicians in better understanding this condition for clinical management. METHODS: The search was conducted on PubMed, Scopus, and Web of Science libraries on March 30, 2023. Two reviewers independently screened the studies using Endnote software. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the studies. RESULTS: A total of nine studies were included in the review. Among patients with OI, positive and statistically significant correlations of NLR were seen with more severe disease, a prolonged hospital stay, postoperative requirement of antibiotics, and total antibiotic dose needed. In the receiver operating characteristics (ROC) analysis, the optimum cut-off level of NLR was 5.19 (specificity: 81, sensitivity: 51). In addition, NLR was correlated with preoperative fever (p = 0.001). Among patients with Ludwig's Angina, NLR could predict disease severity and length of stay in the hospital (p = 0.032 and p = 0.033, respectively). In addition, the relationship between the NLR and mortality was statistically significant (p = 0.026, specificity of 55.5%, and sensitivity of 70.8%). Among patients with severe oral and maxillofacial space infection, a positive correlation was found between IL-6 and CRP with NLR (rs = 0.773, P = 0.005 and rs = 0.556, P = 0.020, respectively). Also, a higher NLR was considered an essential predictor of organ involvement (P = 0.027) and the number of complications (P = 0.001). However, among diabetes mellitus (DM) patients afflicted with submandibular abscesses, NLR had no association with therapeutic response. CONCLUSIONS: Many people around the world suffer from OI, and a cheap and fast biomarker is needed for it. Interestingly, inflammation plays a role in this infection, and elevated NLR levels can be a good biomarker of inflammation and, as a result, for OI progression.

Neutrophil to lymphocyte ratio as an assessment tool to differentiate between uterine sarcoma and myoma: a systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis aimed to determine the potential value of neutrophil to lymphocyte ratio (NLR) as an assessment tool in the clinical distinction between uterine sarcoma and uterine leiomyoma. METHODS: We comprehensively searched Web of Science, Scopus, and PubMed for relevant papers published before March 19, 2023. The standardized mean difference (SMD) was provided, along with a 95% confidence interval (CI). The random-effects model was employed to derive pooled effects due to the high levels of heterogeneity. The Newcastle-Ottawa scale was used for the quality assessment. Our study was registered in PROSPERO (CRD42023478331). RESULTS: Overall, seven articles were included in the analysis. A random-effect model revealed that patients with uterine sarcoma had higher NLR levels compared to those with uterine myoma (SMD = 0.60, 95% CI = 0.22-0.98; p = 0.002). In the subgroup analysis according to sample size, we found that patients with uterine sarcoma had elevated levels of NLR compared to those with uterine myoma in either large studies (SMD = 0.58, 95% CI = 0.04-1.13; P < 0.001) or small studies (SMD = 0.64, 95% CI = 0.33-0.96; P = 0.32). In the sensitivity analysis, we found that the final result was not significantly changed when single studies were removed, suggesting that the finding of this meta-analysis was stable. The pooled sensitivity of NLR was 0.68 (95% CI = 0.61-0.73), and the pooled specificity was 0.64 (95% CI = 0.59-0.69). CONCLUSION: NLR might be utilized as an assessment tool in clinics to help clinicians differentiate between patients with uterine sarcoma and those with myoma.

Systematic review and meta-analysis of oxidative stress and antioxidant markers in recurrent aphthous stomatitis.

BACKGROUND: We performed this systematic review and meta-analysis to synthesize all studies that reported the level of oxidative and antioxidative markers in recurrent aphthous stomatitis (RAS) patients compared to controls. METHODS: We registered our study in PROSPERO (CRD42023431310). PubMed, ProQuest, Scopus, EMBASE, Google Scholar, and Web of Science were searched to find relevant publications up to June 5, 2023. The standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated. We included 30 articles after multiple stags of screening. RESULTS: We found that erythrocyte superoxide dismutase and Glutathione peroxidase activity were significantly lower in patients with RAS compared to healthy controls (SMD = - 1.00, 95%CI = -1.79 to -0.21, p = 0.013, and SMD = - 1.90, 95%CI = -3.43 to -0.38, p = 0.01, Respectively). However, there was not any difference between patients with RAS and healthy controls in erythrocyte Catalase (SMD = - 0.71, 95%CI = -1.56-0.14, p = 0.10). The total antioxidant status (TAS) level, in serum was significantly lower in patients than healthy controls (SMD = - 0.98, 95%CI = -1.57 to -0.39, p = 0.001). In addition, RAS patients had higher levels of serum Malondialdehyde (MDA), Serum total oxidant status, and serum oxidative stress index than healthy controls (SMD = 2.11, 95%CI = 1.43-2.79, p < 0.001, SMD = 1.53, 95%CI = 0.34-2.72, p = 0.01, and SMD = 1.25, 95%CI = 0.25-2.25, p = 0.014, Respectively); However, salivary MDA and TAS, and serum uric acid, vitamin E and C, and reduced glutathione levels of patients with RAS were not different from that of healthy controls. CONCLUSIONS: The relationship between oxidative stress and RAS is well established in this meta-analysis. Although the molecular processes underlying the etiology of this pathology remain unknown, evidence indicating oxidative stress has a significant role in the pathogenesis of RAS has been revealed.

Evaluating the effect of vitamin D supplementation on serum levels of 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D, parathyroid hormone and renin-angiotensin-aldosterone system: a systematic review and meta-analysis of clinical trials.

BACKGROUND: Vitamin D, one of the most essential micronutrients, is crucial in various health outcomes. However, previous studies showed conflicting results and uncertainty about vitamin D supplementation's optimal dosage and duration. In this study, we aimed to evaluate the vitamin D supplements efficiency on serum levels of 25-hydroxy vitamin D (25(OH)D), 1,25-dihdroxy vitamin D (1,25(OH)2D), parathyroid hormone (PTH) and renin-angiotensin-aldosterone system (RAAS) in adults. METHODS: A systematic analysis of eligible and relevant randomized-controlled trials (RCT) published before April 2023 assessing the effect of vitamin D supplementations applied. The studies were identified by searching several databases, including Pubmed, Scopus, Web of Science, ProQuest, and Cochrane Register of controlled trials. RESULTS: Five eligible RCTs with 346 participants in the intervention and 352 participants in the control group were assessed in our project. According to the results, there was a substantial change in 25(OH)D (SMD: 2.2, I2: 92.3, 95% Confidence Interval (CI): 1.38-3.02, P-value: 0.048) and 1,25(OH)2D (SMD:1.23, I2: 86.3, 95% CI: 0.01- 2.44, P-value < 0.010) affected by vitamin D intervention. Regarding Parathyroid hormone (PTH), however, vitamin D intervention showed a remarkable decrease (SMD: -0.75, I2: 82.4, 95% CI: (-1.3)-(-0.18), P-value < 0.010). Moreover, sensitivity analysis showed significant publication bias in terms of 25(OH)D. CONCLUSION: Vitamin D supplements significantly increase the serum levels of 25(OH)D and 1,25(OH)2D and decrease PTH levels. While some studies reported decreasing effect of vitamin D supplements on RAAS activity, some reported no changes.

Diagnostic significance of neutrophil to lymphocyte ratio in endometriosis: a systematic review and meta-analysis.

BACKGROUND: The purpose of this systematic review and meta-analysis was to compile existing evidence on the significance of the NLR in predicting endometriosis in order to aid clinical decision-making and outcomes. METHODS: We searched ProQuest, Web of Science, and PubMed for related studies published before January 2, 2023. Standardized mean difference (SMD) with a 95% confidence interval (CI) was reported for each outcome. Because a significant level of heterogeneity was found, we used the random-effects model to calculate pooled effects. We used Newcastle-Ottawa Scale (NOS) for quality assessment. RESULTS: Overall, 18 article with were included in the analysis. A random-effect model revealed that patients with endometriosis had elevated levels of NLR compared to healthy controls (SMD = 0.79, 95% CI = 0.33 to 1.25, P < 0.001). Patients with endometriosis had elevated levels of NLR compared to those with other benign tumors (SMD = 0.85, 95% CI = 0.17 to 1.53, P = 0.014). In addition, NLR level of patients with stage III and IV endometriosis was not different from that of patients with stage I and II endometrioma (SMD = 0.30, 95% CI = -0.14 to 0.74, P = 0.18). However, NLR level was not different between endometriosis patients with and without peritoneal lesions (SMD = -0.12, 95% CI = -0.34to 0.10, P = 0.28), between patients with and without endometrioma (SMD = 0.20, 95% CI = -0.15 to 0.55, P = 0.26) and between endometriosis patients with and without deep lesions (SMD = 0.04, 95% CI = -0.20 to 0.28, P = 0.72). The pooled sensitivity of NLR was 0.67 (95% CI = 0.60-0.73), and the pooled specificity was 0.68 (95% CI, 0.62-0.73). CONCLUSIONS: NLR might be utilized in clinics as a possible predictor to help clinicians diagnose endometriosis in affected women.

Recent advance on nanoparticles or nanomaterials with anti-multidrug resistant bacteria and anti-bacterial biofilm properties: A systematic review.

Objective: With the wide spread of Multidrug-resistant bacteria (MDR) due to the transfer and acquisition of antibiotic resistance genes and the formation of microbial biofilm, various researchers around the world are looking for a solution to overcome these resistances. One potential strategy and the best candidate to overcome these infections is using an effective nanomaterial with antibacterial properties against them. Methods: and analysis: In this study, we overview nanomaterials with anti-MDR bacteria and anti-biofilm properties. Hence, we systematically explored biomedical databases (Web of Sciences, Google Scholar, PubMed, and Scopus) to categorize related studies about nanomaterial with anti-MDR bacteria and anti-biofilm activities from 2007 to December 2022. Results: In total, forty-one studies were investigated to find antibacterial and anti-biofilm information about the nanomaterial during 2007-2022. According to the collected documents, nineteen types of nanomaterial showed putative antibacterial effects such as Cu, Ag, Au, Au/Pt, TiO2, Al2O3, ZnO, Se, CuO, Cu/Ni, Cu/Zn, Fe3O4, Au/Fe3O4, Au/Ag, Au/Pt, Graphene O, and CuS. In addition, seven types of them considered as anti-biofilm agents such as Ag, ZnO, Au/Ag, Graphene O, Cu, Fe3O4, and Au/Ag. Conclusion: According to the studies, each of nanomaterial has been designed with different methods and their effects against standard strains, clinical strains, MDR strains, and bacterial biofilms have been investigated in-vitro and in-vivo conditions. In addition, nanomaterials have different destructive mechanism on bacterial structures. Various nanoparticles (NP) introduced as the best candidate to designing new drug and medical equipment preventing infectious disease outbreaks by overcome antibiotic resistance and bacterial biofilm.

Neutrophil to lymphocyte ratio in parkinson's disease: a systematic review and meta-analysis.

BACKGROUND: The goal of this research was to explore the role of Neutrophil to lymphocyte ratio (NLR) in Parkinson's disease (PD). METHODS: From inception to 4 June 2023, PubMed, Web of Science, and ProQuest were searched for papers comparing NLR in PD to healthy individuals. Standardized mean difference (SMD) with a confidence interval (CI) of 95% were calculated. RESULTS: A random-effect model revealed that PD patients had elevated NLR values compared to healthy individuals (SMD = 0.81, 95% CI = 0.47 to 1.14, P < 0.001). The results of subgroup analysis were as follows: (1) study design: We observed that patients with PD had higher levels of NLR than healthy controls in either retrospective (SMD = 1.12, 95% CI = 0.58 to 1.66, P < 0.001) or prospective (SMD = 0.43, 95% CI = 0.18 to 0.68, P = 0.001) studies. (2) Ethnicity: We noticed that individuals with PD had higher levels of NLR than healthy controls, whether they were East Asian (SMD = 0.93, 95% CI = 0.22 to 1.63, P = 0.010) or Caucasian (SMD = 0.75, 95% CI = 0.40 to 1.10, P < 0.001).The pooled sensitivity of NLR in the prediction of PD was 0.67 (95% CI = 0.61-0.73), and the pooled specificity was 0.66 (95% CI, 0.61-0.70). CONCLUSIONS: Increased levels of NLR is highly related with the presence of PD. Further research is needed to determine the potential clinical benefits of this simple and low-cost biomarker in the PD diagnosis.

Diagnostic value of the neutrophil lymphocyte ratio in discrimination between tuberculosis and bacterial community acquired pneumonia: A meta-analysis.

Background: We conducted a systematic review and meta-analysis, based on Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, to evaluate current literature on diagnostic value of neutrophil to lymphocyte ratio (NLR) in discrimination between tuberculosis (TB) and bacterial community acquired pneumonia (B-CAP). Methods: Literature search was conducted from July 20, 2023 using Scopus, PubMed, and Web of Science databases. STATA software (version 12.0; Stata Corporation) was used for all analyses. Results: We found that patients with TB had significantly lower levels of NLR compared to those with B-CAP (SMD = -1.09, 95 %CI = -1.78- -0.40, P = 0.002). In the quality subgroup analysis, we found that patients with TB had significantly lower level of NLR compared to those with B-CAP consistent in moderate (SMD = -0.86, 95 %CI = -2.30, 0.57, P = 0.23) and high-quality studies (SMD = -1.25, 95 %CI = -2.07, -0.42). In the subgroup analysis based on continent, we found that patients with TB had significantly lower level of NLR compared to those with B-CAP in studies performed in Asian populations (SMD = -1.37, 95 %CI = -2.13, -0.61, P < 0.001), but not on African population (SMD = -0.02, 95 %CI = -1.06, 1.02, P = 0.97). The result of this study did not change after execution of sensitivity analysis. The pooled sensitivity of NLR was 0.86 (95% CI = 0.80, 0.91), and the pooled specificity was0.88 (95% CI = 0.69, 0.95). Conclusion: Patients with TB had a significantly lower NLR levels compared to those with B-CAP, so we utilized this biomarker for distinguishing between the disorders.

Face-to-face, online, or blended: which method is more effective in teaching electrocardiogram to medical students.

BACKGROUND: Electrocardiogram (ECG) remains an important medical diagnostic and screening tool. This study aimed to compare the effectiveness of online classes instead of traditional face-to-face or blended methods in medical students' ECG learning. METHODS: Two hundred and fifteen medical students (including 105 (48.8%) males and 110 (51.2%) females) were studied from February 2021 to February 2022. Regardless of their grade, participants were divided into three groups: online, face-to-face, and blended. Then all participants sat for an ECG interpretation exam, and their results were compared. RESULTS: Twenty-six (12.1%) participants were residents, and 189 (87.9%) were interns. Thirty-five (16.3%), 85 (39.5%), and 95 (44.2%) participants were taught ECG through face-to-face, online, and blended methods, respectively. Regarding participants' preferences on teaching methods, 118 (54.9%) preferred face-to-face learning, and the remaining 97 (45.1%) chose online learning (p < 0.001). The blended method seemed more promising in almost half of the exam questions regarding teaching method effectiveness. The mean total exam score was also significantly higher in participants who were taught blended than in the others (7.20 ± 1.89, p = 0.017). Face-to-face (5.97 ± 2.33) and online teaching methods (6.07 ± 2.07) had similar efficacy according to the mean total score (p = 0.819). CONCLUSION: While most students preferred face-to-face learning to online learning, a blended method seemed more promising regarding students' skill enhancement to interpret ECG.

Traumatic arteriovenous fistula mimicking cutaneous leishmaniasis: A case report.

INTRODUCTION: Traumatic arteriovenous fistula (TAVF) may be challenging to diagnose and can be misjudged as skin lesions or ulcers, including cutaneous leishmaniasis. Here, we present a patient with TAVF misdiagnosed and treated as cutaneous leishmaniasis. CASE PRESENTATION: A 36-year-old male presented with a non-healing venous ulcer in his left leg, which was misdiagnosed and treated as cutaneous leishmaniasis. He was referred to our clinic, where color Doppler sonography showed arterial flow in the left great saphenous vein, and Computed tomographic (CT) angiography revealed left superficial femoral artery fistula to the femoral vein. The patient had a history of shotgun injury six years ago. Surgical closure of the fistula was done. The ulcer healed completely one month after the surgery. DISCUSSION AND CONCLUSION: TAVF may present as skin lesions or ulcers. Our report emphasizes the importance of thorough physical examination and history taking and the use of color Doppler sonography in order to avoid unnecessary diagnostic and therapeutic modalities.

Systematic review of the diagnostic role of neutrophil to lymphocyte ratio in sarcoidosis.

BACKGROUND AND AIM: To outline the observations of studies evaluating the prominence of Neutrophil to Lymphocyte Ratio (NLR) in sarcoidosis. METHODS: The search was performed on PubMed, Scopus, and web of science up until November 21, 2021. Eventually, a number of 17 papers were incorporated into this review. RESULTS: The results of this analysis showed no significant difference of NLR values between sarcoidosis patients and tuberculosis patients (SMD=-0.36, 95% CI= -0.92-0.21). The results showed high heterogeneity (I2=90.83%, p<0.001). So, we used random-effects model. However, NLR can be utilized to identify the radiological severity and staging of pulmonary sarcoidosis due to statistically significant variations. An elevation in NLR values may assist both sarcoidosis diagnosis and lung parenchyma involvement. Also, extra-pulmonary involvement was just more probable to be found in individuals diagnosed with sarcoidosis inhibiting high rates of NLR. High NLR levels were found to be associated with an accelerated rate of progression, revealing that NLR might be used to detect Pulmonary Hypertension (PH) as a complication of sarcoidosis. CONCLUSIONS: In the visualizations of the disease, NLR was revealed to be a beneficial and straightforward fundamental laboratory biomarker connected to disease severity and requirement for therapy.