Although the prognosis of essential thrombocythemia (ET) is generally favorable, the risk of disease progression to secondary myelofibrosis (SMF) or acute myeloid leukemia (AML) increases over time, which makes their prevention particularly important for patients diagnosed at a younger age , 2.Treatment with hydroxyurea (HU) or anagrelide (ANA) aims at normalizing the platelet (PLT) count and decreasing the risk of vascular complications. However, long-term intake of HU is associated with multiple side effects leading to discontinuation in half of the patients . FurtherPegylated formulations of IFN (pegIFN) reduce treatment-related adverse events and allow for the extension of the application intervals. However, the accessibility to pegIFN is currently limited to PV patients due to a lack of approval in ET.n = 20), and (iii) the time of follow-up was limited .In a recent meta-analysis of 30 ET studies conducted between 1990 and 2014, data on the use of IFN were promising, including complete hematologic response rates of 59% and an annual discontinuation rate due to adverse events of 9% [To investigate the clinical benefits of pegIFN in ET, we here report the results from a retrospective analysis of a large cohort of 127 ET patients treated in routine clinical practice at seven academic centers. All patients provided written informed consent to the German Study Group-Myeloproliferative Neoplasms (GSG-MPN) registry (NCT03125707). ET was diagnosed after bone marrow biopsy in all cases based on the latest WHO classification at that time.JAK2 V617F, 32% CALR, and 5% MPL mutated. According to the International Prognostic Score of thrombosis in ET (IPSET-thrombosis), 37% were low-, 31% intermediate-, and 30% high-risk (2% unknown) [The median age of patients at ET diagnosis was 37.0 years ; 67% were female and 33% were male Table . Median unknown) . SplenomAccording to the high-risk definition of the European LeukemiaNet (ELN) cytoreductive treatment was indicated in patients at age >60 years, with a history of thrombosis or major bleeding, and/or PLT count >1500/nL . Median Since 31 patients (24%) had ≥2 lines of treatment (LOT) with pegIFN, overall 161 LOT were recorded in 127 patients Fig. . PegIFN-According to ELN response criteria, 89% of patients achieved clinicohematologic response at any time point during pegIFN treatment, which was complete in 54% and partial in 35% of patients  . The medNotably, just one disease progression to SMF and no transformation to sAML occurred in 469 pegIFN treatment years. Major vascular complications were also rare, with three arterial and five venous events resulting in an incidence of 0.6% and 1.1% per patient and year, respectively. Of interest, all arterial events were thromboembolic myocardial infarctions, whereas 4/5 venous complications were abdominal vein thromboses (one pulmonary embolism). Flu-like symptoms occurred in 41%, elevated liver function tests in 16% and depression in 14% of LOT (grading and time points of events not assessed).JAK2 mutation status, and sex  before and during pegIFN treatment [JAK2 V617F VAF measurements under pegIFN treatment was 5 years (2–8).In addition, we performed digital droplet PCR measurements with a sensitivity of 10reatment . In totaJAK2 V617F quantification in 14 patients showed a median VAF of 30.5% (7.2–48.1) at pegIFN baseline, 8.3% after 4 years, and 18.1% after 8 years of pegIFN treatment . Only one of the responders showed a VAF <1% (0.99%) at the last follow-up.ent Fig. . There wIn 10/127 patients (8%), pegIFN-2b was stopped due to market withdrawal. Based on preliminary data showing that treatment-free remissions may be achieved in a subset of long-term pegIFN-treated patients, they were not immediately switched to an alternative drug as they had been treated for a median of 9.5 years (6–18) . While 7JAK2 V617F positive and all four patients showed an allele burden of >5% at the time of pegIFN discontinuation: 5.6%, 16.7%, 19.9%, and 41.7% . In contrast, 2/3 of patients maintaining complete hematologic response had undetectable JAK2 V617F (<0.1%), while 1/3 was at 0.1% at pegIFN stop in 2017. In this patient, JAK2 V617F rose slowly to 0.54% after 4 years of follow-up without medication although PLT count remained normal. These three patients were not included in Fig. JAK2 V617F allelic burden. Bone marrow biopsies were performed in 2/3 of patients who maintained normal blood cell counts over 1.5 and 4.5 years after pegIFN discontinuation, respectively. It is instructive that, in both cases, histomorphologic remission of ET was demonstrated.Interestingly, 4/7 patients with loss of complete hematologic response were In summary, our data on 127 WHO-defined ET patients treated in routine clinical practice confirms the high efficacy of pegIFN in achieving a clinicohematologic response. Our study stands out for its unique sample size, a very long follow-up time of a subset of patients, and shows low rates of adverse events, vascular complications, and disease progressions. In the absence of randomized clinical trials and approval, our data support the use of pegIFN in ET patients. It is important to note that in individual cases it still remains difficult to distinguish ET from prefibrotic/early primary MF (prePMF). Therefore, one cannot fully exclude the possibility that some patients in our study had prePMF.JAK2 allele burden monitoring and defining thresholds for planned treatment discontinuation in PV patients treated with ropegIFN are currently ongoing, and the results will be instructive for the management of ET as well [CALR remains an additional challenge in ET treated with pegIFN.Prospective studies assessing  as well . In cont


BackgroundThe present study aims to evaluate the response of locally advanced breast carcinoma (LABC) to neoadjuvant chemotherapy (NACT) using image-guided clip placement based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.MethodsThirty-four patients with LABC were included in the study. Consent for three-dimensional titanium clip placement (400/300/200 mm Liga clips) under local anesthesia with USG guidance was obtained. Serial sonographic/X-ray evaluations of tumor bed size were conducted before every cycle of NACT. All data were recorded in millimeters of concentric tumor regression/non-regression. Tumor regression in a concentric or Swiss cheese pattern and non-responders were evaluated. Assessment of the response to NACT was performed using RECIST criteria, dividing it into four categories. Tumor response was confirmed with computerized tomography (CT) conducted before and after the completion of NACT. Patients underwent surgical management, mostly modified radical mastectomy (MRM), as they had locally advanced breast carcinoma. Following MRM, the clips in the specimen guided the original site of the tumor for histopathological evaluation and response to chemotherapy.ResultsTumor response was classified into four types: complete response (CR), partial response (PR), progressive disease (PD), and stable disease. RECIST 1.1 criteria were elaborated and defined. Data for all patients were entered into an Excel sheet  to prepare a master chart, and the following observations were made and analyzed using SPSS software. The duration of chemotherapy for the study population ranged from 32 to 206 days, with a mean (±SD) of 111.82 (± 52.64) days and a median (IQR) of 81  days. The mean period between clip insertion and completion of NACT was 111.82 days. The baseline sum diameters and post-NACT diameters of the tumors were 70.50 (±13.60) mm before NACT and 17.75 (±17.20) mm after NACT. Hence, the mean size of the lump was statistically significantly lower after NACT, with a mean difference of 52.75 (p<0.05). The mean rate of reduction in tumor diameter was found to be 74.32% (±23.44%) based on RECIST 1.1 criteria. Pathological response was observed in all patients except for 8.8% of the patients. Clinical complete response was seen in 35.29% of patients, and partial response was observed in 52.92% of the patients based on RECIST 1.1 criteria. The study thus demonstrates the effectiveness of NACT in LABC, with a mean reduction in tumor diameter of 74.32%, assessed with the help of RECIST 1.1 criteria.ConclusionNACT for patients with LABC has shown a significant reduction in tumor size. NACT should be the initial mode of management for patients with LABC. RECIST 1.1 criteria are effective and can be used to assess tumor response to NACT. This has aided in the stratification of the response of NACT for further management through systemic therapy (adjuvant chemotherapy) after the surgical excision of the tumor. Breast carcinoma occurs after puberty but with increasing frequency as age advances, with more disability-adjusted life years (DALYs) by females due to breast cancer globally than any other cancer . Breast The incidence of breast cancer is due to various factors, but factors such as genetic factors, environmental factors, significant family history, and lifestyle factors are the most important ones. Factors such as parities, lactation, and exercise reduce the risk of the disease . ScreeniBased on histological characteristics, breast cancer is divided into two types: in situ cancer and invasive breast carcinoma, with the most common invasive cancer being ductal cancer, which accounts for 70-85% of cases. The hormonal status of the patient helps in understanding the etiology of the disease and the response to treatment, with the choice of treatment depending on the expression of individual receptors .Neoadjuvant chemotherapy (NAC) is the initial treatment modality for operable patients and inoperable breast cancer. This has reduced mortality and has improved surgical options for management by converting inoperable cases to operable ones . ClinicaPhysical examination, mammography, and sonography are part of the triple assessment used for therapy assessment. Many studies have shown that MRI provides a more accurate determination of the response to chemotherapy than other modalities, and extensive research has been conducted on this . The radThere is the availability of many breast markers commonly used for tumor localization before NACT. Among the most commonly used are the inexpensive titanium-based metallic clip markers placed using either mammography or sonography. A preliminary report on sonographically guided implantation of metallic clips to permanently localize the tumor bed showed a complete mammographic or sonographic response in 42% of patients ,15,16. RThe Response Evaluation Criteria in Solid Tumors (RECIST) criteria are globally accepted for evaluating the tumor response to NACT and are divided into four categories. RECIST provides a set of rules for image interpretation and assessing tumor reduction ,18. PatiThis study was conducted in the Department of General Surgery at Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India. It was designed as an observational cohort study, which took place over a period of 18 months, from December 2020 to May 22, and the study population consisted of patients clinically diagnosed with locally advanced carcinoma breast who were planned for neoadjuvant chemotherapy.Inclusion and exclusion criteriaThe study included patients diagnosed with locally advanced carcinoma breast who were planned for neoadjuvant chemotherapy. Patients with a history of previous radiation treatment, previous breast surgery, or recurrent disease were excluded from the study.Sample sizeThe study conducted by Shalaby et al.  examinedCalculationThe formula used is: Zα is the value of Z at a two-sided alpha error of 0.5%, P is the proportion, Q is (100 - P), and i is the incidence rate.where 2 = 23.986 = 24 (approx.)n ≥ ((0.000348 × (1 - 0.000348))/(0.005/1.96))We have taken a minimum of 30 samples; hence sample size was 30.MethodologyIn this study, a comprehensive assessment of patients was conducted, which included gathering demographic information, medical history, and assessing signs and symptoms. A thorough clinical evaluation was carried out, encompassing a triple assessment involving clinical, radiological, and histopathological assessments. Routine investigations such as chest X-ray, ECG, and routine blood tests were also performed. Pathological assessment was done through FNAC (fine needle aspiration cytology) and core needle biopsy, including the evaluation of ER, PR, and Her2 neu status, along with identifying the type of breast cancer.Patients who met the inclusion criteria and were planned for neoadjuvant chemotherapy based on metastatic workup were included in the study. Consent was obtained for the placement of three-dimensional titanium clips (400/300/200 mm Liga clips) under local anesthesia with USG guidance. A sonographic assessment of tumor size and margins was conducted. A surgical tray was prepared, including 16-gauge cannula needles (4), antiseptic draping material, Liga clips of various sizes, local anesthesia, syringe, and a needle with a sterile cover for the ultrasound probe to facilitate the placement of the clips  scans taken before and after completion of NACT. Patients were subjected to surgical management, mostly modified radical mastectomy (MRM), as patients in the study group had locally advanced breast carcinoma. Following MRM, the clips in the specimen guided the original site of the tumor for histopathological evaluation and response to chemotherapy.Statistical analysisCategorical variables were presented in number and percentage and continuous variables were presented as mean ± SD and median. A diagnostic test was used to calculate sensitivity, specificity, PPV, and NPV. Inter-rater kappa agreement was used to find out the strength of agreement between the predicted response and the actual response. A p-value of <0.05 was considered statistically significant. The data was entered in an MS Excel  spreadsheet and analysis was done using IBM SPSS Statistics for Windows, Version 21 . The type of the study was an observational cohort study.A total of 34 patients were included in the study. The age of the study population ranged from 32 to 70 years, with a mean (± SD) of 48.79 (± 10.87) years and a median (interquartile range (IQR)) of 47  years. Of these patients, 55.9% were younger than 50 years and 44.1% were 50 years or older. In terms of symptoms, 38.2% of the patients had a lump, 50% had a lump with pain, and 11.8% had a lump with pain and nipple discharge. The median (IQR) lump size was found to be 6×5  cm.The age at menarche of the study population ranged from 12 to 16 years, with a mean (± SD) of 13.29 (± 1.12) years and a median (IQR) of 13  years. Specifically, 58.8% of the patients experienced menarche at ages 12 to 13, and 41.2% at ages 14 to 15.Regarding menopausal status, 55.9% of the patients were pre-menopause and 44.1% were post-menopause. For those in post-menopause, the age at menopause ranged from 45 to 54 years, with a mean (± SD) of 50.20 (± 2.48) years and a median (IQR) of 50  years. The number of pregnancies was one for 20.6% of the patients, two for 58.8%, three for 17.6%, and four for 2.9%.According to the BIRADS score, 2.9% were graded as 4C, indicating high suspicion for malignancy; 67.6% were graded as 5, highly suggestive of malignancy; and 29.4% were graded as 6, signifying known biopsy-proven malignancy. The surrogate molecular classes were as follows: 29.4% were HER2/neu-enriched, 2.9% were luminal A, 44.1% were luminal B, and 23.5% were triple-negative.The duration of clip to NAC 1 ranged from 1 to 18 days, with a mean (± SD) of 5.71 (± 3.74) days and a median (IQR) of 5  days. The duration of chemotherapy ranged from 32 to 206 days, with a mean (± SD) of 111.82 (± 52.64) days and a median (IQR) of 81  days  was lost to follow-up  size of the lump before NACT was 70.50 (±13.60) before NACT, whereas it was 17.75 (±17.20) mm after NACT. Hence the mean size of the lump was statistically significantly lower after NACT as compared to before NACT with a mean difference of 52.75 (p < 0.05) , partial response (PR), progressive disease (PD), and stable disease (SD).In the study by Shalaby et al. , tumor rThe overall stage of the disease was determined by considering clinical tumor size, lymph node status, and distant metastasis. In our study, 8.8% were in clinical stage 3A, 67.6% in stage 3B, and 23.5% in stage 4. According to the BIRADS score, 67.6% were graded as 5, indicating they were highly suggestive of malignancy, while 29.4% were graded as 6, signifying known biopsy-proven malignancy. These results align closely with the study by Shalaby et al. , where aImmunohistochemical evaluations of receptors were conducted on all 34 breast tumor specimens. The surrogate molecular class was HER2/neu-enriched for 29.4% of the patients, luminal A for 2.9%, luminal B for 44.1%, and triple-negative for 23.5%. All the lesions were invasive ductal carcinoma of non-specific type. A related study by Minella et al.  includedClip localization was performed on all patients in our study group (n = 35). No complications related to clip placement were observed during the study period, and there was no evidence of clip migration during post-procedural follow-up, post-NACT, or in surgical specimens. Similar outcomes were reported in the study by Youn et al. , which aThe time interval between clip insertion and the first cycle of NACT in our study population ranged from 1 to 18 days, with a mean (±SD) of 5.71 (±3.74) days and a median (IQR) of 5  days. The duration of chemotherapy ranged from 32 to 206 days, with a mean (± SD) of 111.82 (± 52.64) days and a median (IQR) of 81  days. The mean period between clip insertion and completion of NACT was 111.82 days. According to a study by Youn et al., the time intervals between clip insertion, post-chemotherapy cycles, and surgery were similar, with mean periods of 47.1±14.7 days and 128.6±34.4 days, respectively [Surgery was scheduled approximately 2 to 4 weeks after the completion of NACT, in line with current guidelines. Using CT, the baseline sum of tumor diameters was 70.50 (±13.60) mm before NACT and reduced to 17.75 (±17.20) mm after NACT. This represented a statistically significant reduction in tumor size, with a mean difference of 52.75 mm (p < 0.05). The rate of reduction in tumor diameter was found to be 74.32 (±23.44)%, based on RECIST 1.1 criteria. Treatment response, as measured by CT and evaluated through RECIST 1.1, showed CR in 12 patients (35.28%), PR in 18 patients (52.92%), stable disease in 2 patients (5.8%), and progressive disease in 1 patient (2.94%). One patient (2.9%) was lost to follow-up. A similar study by Kitajima et al. showed a comparable rate of tumor diameter reduction of 69.9±31.6% . These fIn this study, the pathological response was observed in all patients except for 5.8%. A complete response was seen in 35.29% of patients, and a partial response in 52.92% based on RECIST 1.1 criteria. A study by Oh et al. showed a similar pathological response in all but 3.8% of the patients .In this study, radiological rCR was found in 35.29% of the patients, all of whom had surgical clip insertion done. Clips were visible sonographically in 100% of the patients after NACT. All patients underwent MRM based on patient choice. These results were similar to the study by Minella et al., which showed that rCR was found in 53.7% of the patients. Of these, clip insertion was done in 65%, and clips were visible in 91% of the patients after NACT. Following NACT, 26 patients underwent breast conservative surgery, while the remainder underwent mastectomy based on patient choice .This study showed a cCR and an rCR in 35.29% of cases with the surrogate molecular class of triple-negative or basal cell variant. This is similar to the study by Xia et al., which showed a pCR rate of 35% among 36,480 triple-negative patients receiving neoadjuvant chemotherapy .Strong relationships exist between the response of locally advanced breast carcinoma to primary systemic therapy (neoadjuvant chemotherapy) and oncological outcomes. Patients are stratified based on pathological response . This stStratification of the response to neoadjuvant chemotherapy was done based on the latest NCCN guidelines. It is broadly divided into two groups: tumors with pCR and tumors with partial response, stable disease, or progressive disease.After stratification into various groups, patients were referred to the Department of Medical Oncology for assessment and further management, including adjuvant chemotherapy Tables , 5.The duration of NACT in the study population was adequate, ranging from three to six months. The impact of NACT on tumor size was assessed using standard RECIST 1.1 criteria, which showed a statistically significant reduction in tumor diameter. Only approximately 8% of the study population showed no response to NACT, while about 35% experienced a complete response with no residual tumor noted. Therefore, the study demonstrates the effectiveness of NACT in locally advanced breast carcinoma, with a mean reduction in tumor diameter observed to be 74%, as assessed by RECIST 1.1 criteria. This implies that NACT should be the initial mode of management for patients with locally advanced breast carcinoma. This has aided in the stratification of the NACT response for further systemic therapy following surgical excision of the tumor, thereby improving the oncological outcomes for patients.


The permanence of microorganisms in the root canal system represents the main cause of endodontic failure. Considering the impossibility of effective action of the endodontic files in ramifications of the main canal and mainly inside the dentinal tubules, a better understanding of the irrigation dynamics to enhance endodontic prognosis is essential. Objective: To evaluate the depth of intratubular penetration values of sodium hypochlorite (NaOCl) (dependent variable) by comparing different concentrations, methods of irrigation, and root canal thirds (independent variables) and to investigate the existence of interactions among them, capable of influencing the dependent variable. p< 0.05). 40 roots from extracted human maxillary central incisors were stained and instrumented according to four irrigation protocols (n. 10): conventional irrigation (CI) at each use or change of instrument, and final irrigation with 5ml of 2.5% or 5.25% NaOCl, with or without passive ultrasonic irrigation (PUI), respectivelly. Measurements based on stereomicroscopic images were obtained, and the data were subjected to statistical analysis (The highest depth values of intratubular penetration of NaOCl were observed in the cervical third, at 5.25%, and by PUI. When only two independent variables were analyzed in association, the highest penetration depth values of NaOCl were obtained at 5.25%, regardless of irrigation method, at 5,25%, in the cervical third, and; in the cervical third, despite of irrigation method. Considering the three independent variables simultaneously, the highest depth values of intratubular penetration of NaOCl were observed in the cervical third, at 5.25%, no matter the irrigation method. The interaction between the independent variables on the penetration depth values of NaOCl was only confirmed considering the irrigation method and root canal third. Intratubular penetration of NaOCl was influenced by the three independent variables individually and when the irrigation method and root canal third were considered simultaneously. Key words:Dentinal tubules, Depth, Disinfection, Irrigation, Root canal system, Sodium hypochlorite. The main goal of Endodontics is to keep natural teeth by preserving or restoring the health of periapical tissues. In necrotic teeth, the pulp cells are compromised, thus favoring root canal system (RCS) infection . Even ifThe biomechanical preparation is the main factor responsible for endodontic infection control . It is pAntimicrobial strategies during endodontic interventions are much more effective in the main root canal. However, the maintenance of remnants of microorganisms, including in the dentinal tubules, has previously been evidenced by several studies ,7, beingPassive ultrasonic irrigation (PUI) is one of the most studied methods to optimize the disinfection of the RCS. The energy released by inserts during PUI produces cavitation and acoustic streaming, resulting in microbubbles and hydrodynamic waves that promote agitation of the liquid against the root canal walls, favoring their cleaning and the penetration of the irrigating solution into the dentinal tubules .et al.  to evaluate the depth of intratubular penetration values of NaOCl (dependent variable), comparing two concentrations (2.5 and 5.25%) and two irrigation methods (CI and PUI) in the three root canal thirds  (independent variables), and; 2) to investigate whether there were interactions between these variables, capable of influencing the depth of penetration of the irrigant, by using a comprehensive statistical analysis performed with data obtained by the histochemical method proposed by Pécora, et al. . Bearing-Approval by the Research Ethics Committee, selection, and preparation of specimensFor the development of this study, after authorization issued by the Research Ethics Committee of the Ribeirão Preto School of Dentistry – FORP/USP (CAAE: 14962013.4.0000.5419), 40 extracted human maxillary central incisors were selected. The teeth were supplied by the Tooth Bank of the same Institution and had a single canal, complete rhizogenesis, without abrupt curvatures, resorption processes, or previous endodontic treatments. These characteristics were confirmed visually and on radiographs taken in the mesiodistal and buccolingual directions. The specimens selected were stored in 0.1% thymol solution at 48°C and washed in running water for 24 hours before use . After tAfter the canal was irrigated with 5 ml of distilled and deionized water using a Navitip needle and a 5 ml plastic syringe , it was initially explored through an n. 20 K-FlexoFile . Then, the specimens were placed in a vacuum desiccator  for 120 minutes to allow complete dehydration. After this, they were immersed in a copper sulfate solution and placed in a desiccator coupled to a vacuum pump  for 15 minutes to remove air from the main canal to enable more extensive penetration of the solution mentioned above. Subsequently, the specimens remained immersed in this solution for another 75 minutes at ambient atmospheric pressure, and the root surface and the canal were then dried with paper towels and n. 20 absorbent paper cones (Dentsply-Maillefer), in that order. Finally, all specimens were immersed in a rubeanic acid solution, transferred to and stored in the desiccator coupled to a vacuum pump, and exposed to ambient atmospheric pressure for 15 and 225 minutes, respectively.-Biomechanical preparation Before performing biomechanical preparation, each root was wrapped with a thin layer of hydrophilic vinyl imprint vinyl polysiloxane  to simulate the periodontal ligament space and embedded in acrylic resin blocks   to avoid• CI with 5ml of 2.5% NaOCl at each use or change of instrument, and final irrigation with 5ml of 2.5% NaOCl for 30 seconds*;• CI with 5ml of 2.5% NaOCl at each use or change of instrument*, and PUI** with 5ml of 2.5% NaOCl for 30 seconds*;• CI with 5ml of 5.25% NaOCl at each use or change of instrument, and final irrigation with 5ml of 5.25% NaOCl for 30 seconds*;• CI with 5ml of 5.25% NaOCl at each use or change of instrument*, and PUI** with 5ml of 5.25% NaOCl;*Procedure performed with a Navitip irrigation tip (Ultradent) inserted at -2mm from the WL.**Procedure performed with an Irrisonic ultrasonic insert (Helse), inserted at -2mm from the WL, at a power of 20kHz.Subsequently, the root canal was dried with absorbent paper cones (Dentsply-Maillefer) with a diameter corresponding to the final instrument used during the biomechanical preparation.-Analysis of intratubular penetration values of NaOClEach specimen was sectioned horizontally at 2, 8, and 14mm from the apex using a low-speed steel cutting disc . Three slices per root were obtained, resulting in 120 slices. A standard polishing procedure using SiC paper  followed by three μm diamond paste was employed on the cervical surface of each slice to produce a high-reflection surface, and each slice was observed in a high-resolution stereomicroscope to acquire images at 1048x1048 pixels, covering the entire root surface. For each image, the areas corresponding to discolored dentin and the perimeter of the root canal were measured using the AxioVision Software 4.11 . By subtracting the area corresponding to the perimeter of the root canal from the region corresponding to the discolored dentin, intratubular depth penetration of the irrigant was determined in mm2.-Statistical analysisp > 0.05). Therefore, the 3-way parametric analysis of variance (ANOVA) test  was applied to identify statistical differences concerning the mean values of the dependent variable studied (intratubular penetration depth of NaOCl), according to independent variables: concentration (2.5% and 5.25%); irrigation method (CI and PUI) and root canal third , as well as to analyze the paired and associated interaction between them. Since there were statistically significant differences, the Tukey HSD and Games-Howell parametric tests for multiple comparisons were applied for homogeneous and heterogeneous variances. The Levene test was used to identify the homogeneity of variances in the depth of intratubular penetration values of NaOCl among the irrigation protocols. The significance level was set at 0.05, and all analyses were performed using the IBM SPSS Statistic 25.0 software   .-Data availabilityThe complete statistical analysis of this research can be ac-cessed at: https://1drv.ms/f/s!AnuvHAhxDtNGg75jJv8e-jlJeQcGcqg?e=qNqX9X.-Depth of intratubular penetration values of NaOCl, considering the irrigation method, concentration, and root canal third, individuallyp < 0.01, with a test power of 99.99% determined based on the sample size. Thus, the existence of statistically significant differences was proved by comparing concentrations of the irrigant (2.5% and 5.25%), irrigation methods (CI and PUI), and root canal thirds evaluated . The highest depth values of intratubular penetration of NaOCl were observed in the cervical root canal thirds (0.72 ± 0.28 mm2), using the product at the concentration of 5.25% (0.68 ± 0.31 mm2) and in an activated manner (PUI) (0.63 ± 0.30mm2) (p < 0.01). The lowest values occurred in the apical root canal thirds (0.38 ± 0.32mm2), with no statistically significant differences in comparison to the middle root canal thirds (0.48 ± 0.20mm2) (p ˃ 0.05)  test . This test showed F values of 68.88, 29.41, and 28.46, respectively, and -Depth of intratubular penetration values of NaOCl, considering concentration/irrigation method, concentration/root canal third, and irrigation method/root canal thirdp < 0.01, with a test power of 99.99% determined based on the sample size. The highest penetration depth values of NaOCl were obtained by the following combinations, without significant statistical differences between them (p ˃ 0.05): 5.25%/PUI (0.78 ± 0.31mm2) and 5.25%/CI (0.58 ± 0.28mm2); 5.25%/cervical root canal third (0.90 ± 0.26mm2), and; CI/cervical root canal third (0.64 ± 0.30mm2) and PUI/cervical root canal third (0.79 ± 0.26mm2)  test , showed F values of 21.33, 19.71 and 12.01, respectively, and -Depth of intratubular penetration of NaOCl considering the irrigation method, concentration, and root canal third, simultaneouslyp < 0.01, with test power considering the sample size of 99.99%, indicating that there were statistically significant differences. The highest depth values of intratubular penetration of the irrigant were observed in the cervical root canal thirds, using it at the concentration of 5.25%, without statistically significant differences between irrigation methods ; PUI/2.5%: 0.64 ± 0.10mm2; CI/2.5%: 0.43± 0.13mm2). (p < 0.05). In the middle root canal third, there was no statistically significant di-fference when irrigation methods and concentrations of irrigant were compared  (p < 0.05). In the apical root canal third, the highest penetration depth values of NaO-Cl were obtained when it was used in higher concentration (5.25%), regardless of the irrigation method (PUI or CI) (p < 0.01)  , Fig. 3.-Interaction between the irrigation method, concentration, and root canal third on the intratubular penetration depth of NaOClp > 0.05)   , Fig. 4Cp > 0.05)  , Fig. 4DIn most cases, endodontic failure is caused by remaining microorganisms inside the RCS , which can even reach up to half the distance between the root canal walls and the cementum-dentin junction . Consideet al. ; therefore, the first null hypothesis established was rejected. Virdee, et al.  reported . However, the trend towards achieving higher penetration depth values of NaOCl rose significantly because of its activation . Furthermore, the proven interaction between the irrigation method and root canal third demonstrated that PUI promoted relevant increases in the depth values of intratubular penetration of the irrigant in all root canal thirds, which were considerably higher in the apical third (0.35 mm2); therefore, leading to rejection of the second null hypothesis established.Considering concentration/irrigation method, concentration/root canal third, and irrigation method/root canal third, the highest penetration depth values of NaOCl were obtained by the following combinations, without statistically significant differences between them: 5.25%/PUI (0.78 ± 0.31mm2) and 5.25%/CI 0.58 ± 0.28mm2); 5.25%/cervical root canal third (0.90 ± 0.26mm2), and; CI/cervical root canal third (0.64 ± 0.30mm2) and PUI/cervical root canal third (0.79 ± 0.26mm2). When assessing the impact of the three independent variables together on the depth of intratubular penetration of the irrigant, the highest values were observed in the cervical root canal third of the specimens irrigated with 5.25% NaOCl, with no relevant statistical differences between PUI (0.94 ± 0.28mm2) and CI (0.86 ± 0.25mm2). Because of the higher volume and larger diameter of the dentinal tubules present in the cervical root canal third, the use of 5.25% NaOCl only, with the consequent release of a larger quantity of chlorine ions .• Regarding concentration/irrigation method, concentration/root canal third, and irrigation method/root canal third, the highest penetration depth values of NaOCl were obtained by: 5.25% NaOCl, regardless of the irrigation method (PUI or CI), 5.25% NaOCl in the cervical root canal third, and cervical root canal third, despite of the irrigation method.• Considering the three independent variables simultaneously, the irrigant’s highest depth values of intratubular penetration were observed in the cervical root canal thirds, using it at the concentration of 5.25%, without statistically significant differences between irrigation methods. In the middle root canal third, there was no statistically significant difference when irrigation methods and concentrations of irrigant were compared. In the apical root canal third, the highest penetration depth values of NaOCl were obtained by PUI, using it at the concentration of 5.25% with significant statistical differences compared to the other combinations. In CI, the highest penetration depth values of the irrigant were also observed using it in the higher concentration, with significant statistical differences compared to the other combinations.• Analysis of the interaction between the concentration of NaOCl and irrigation method and NaOCl and root canal third on the intratubular penetration depth of the irrigant, indicating their absence. An interaction was identified by considering the irrigation method and root canal third on penetration depth values of the irrigant. Investigating the interaction among all independent variables simultaneously on the depth of intratubular penetration values of NaOCl, no interaction was proven.


ObjectiveThis study aims to report an immediate change in intraocular pressure (IOP) after the first injection of bevacizumab.Materials and methodsAn interventional case series was carried out at Isra Postgraduate Institute of Ophthalmology, Al-Ibrahim Eye Hospital, Karachi, from November 2018 to April 2020. All patients with various chorioretinal diseases requiring anti-VEGF treatment were included in the study. Patients with a history of previous anti-VEGF or steroid injections and personal or family history of glaucoma were excluded. Bevacizumab in a dose of 1.25 mg (0.05 ml) was injected intravitreally under topical anesthesia maintaining sterile aseptic conditions in the operating room. IOP was checked one hour prior to the injection, and hourly monitoring of it was continued for the next six hours. Data were analyzed using SPSS Statistics to compare the mean IOP readings before and after injection.ResultsA total of 191 eyes of 147 patients were included in the study. Among them, 92 (62.58%) were male and 55 (37.41%) were female with a mean age of 45.5 ± 8.8 years. The mean pre-injection IOP was measured as 12.12 ± 2.11 mmHg. The frequency of IOP elevation of ˃ 21 mmHg was observed in 169 (88.5%) eyes at five minutes, 104 (54.5%) eyes at 30 minutes, 33 (17.3%) eyes at one hour, and 16 (8.4%) eyes at two hours. The raised mean post-operative IOP was 30.44 ± 6.53 mmHg at five minutes, 26.27 ± 4.65 mmHg at 30 minutes, 26.12 ± 3.31 mmHg at one hour, and 25.63 ± 3.03 mmHg at two hours. The IOP reduced to pre-injection value at three hours measuring 12.12 ± 2.11 mmHg and continued to stay at that level for the next three hours.ConclusionsThe majority of the eyes receiving first-time intravitreal bevacizumab injection showed a significant increase in IOP level within five minutes to two hours post-injection. Anti-VEGF agents have been the treatment of choice for many choroidal and retinal vascular diseases. Bevacizumab  is a humanized monoclonal antibody to vascular endothelial growth factor approved for the treatment of colorectal cancer. It has been used off-label intravitreally since 2005 and is one of the common anti-VEGF agents used extensively due to its low cost and comparative usefulness ,2. The wThe transient and sustained rise in IOP can be expected with intravitreal injections due to an increase in vitreous volume and the toxic effect of the injected drug on the trabecular meshwork . Any sigWith the introduction of other anti-VEGF compounds available in the market for the treatment of various chorioretinal disorders, Bakri et al. used triamcinolone, pegaptanib, and bevacizumab intravitreally. They recorded an immediate rise (at 10 minutes) of more than 10mmHg in IOP in 27.6% of eyes receiving bevacizumab, 33.3% of eyes receiving triamcinolone, and 36.2% of eyes receiving pegaptanib .The sustained rise in IOP after repeated intravitreal anti-VEGF agents was first reported by Adelman in 2010 . In his Since then, multiple reports have followed, showing a transient and sustained rise in IOP following anti-VEGF injections -9. HowevVarious researchers have investigated a variety of risk factors for the potential rise in IOP. This includes multiple injections, the absence of post-injection sub-conjunctival reflux, smaller needles, tunneled injection technique, and previous diagnosis of glaucoma . Bracha To keep the multiple arrays of suggestions, we wanted to find out the change in IOP when an intravitreal injection is given for the first time in non-glaucomatous patients.We, therefore, conducted this prospective study to monitor the immediate change (up to six hours) in IOP of patients receiving bevacizumab injection for the first time.An interventional study was conducted at the Isra Postgraduate Institute of Ophthalmology, Al-Ibrahim Eye Hospital, Karachi from November 2018 to April 2020. The study was approved by the Ethical Review Committee of the institute and was performed in accordance with the Declaration of Helsinki. The sample size was drawn through OpenEpi online sample calculator by using an expected population of 1500 patients receiving intravitreal injection per year, and the difference between the mean pre-IOP (16.9 mmHg) and post-IOP (33.9 mmHg) after injection was calculated at 17 mmHg as the anticipated frequency, keeping 95% confidence interval and 5% margin of error . The reqAll enrolled patients underwent a complete ocular examination including best-corrected visual acuity, slit-lamp biomicroscopic examination of the anterior segment, gonioscopy, and recording of IOP by Goldmann Applanation Tonometer. A dilated fundus examination was carried out with a + 90 Diopter lens  and an indirect ophthalmoscope. Ancillary tests like optical coherence tomography, optical coherence tomography angiography, and fundus fluorescein angiography were obtained in all patients.All injections were performed under aseptic conditions in the operating theater under topical anesthesia . A dose of 1.25 mg (0.05 ml) was injected intravitreally 3.5 mm from the limbus using a half-inch-long 29-gauge needle in the superior-temporal quadrant.  After injection, a sterile cotton swab was placed on the injection site to prevent reflux of the given drug. A drop of 5% povidone-iodine was instilled before and after the procedure. All procedures were performed between 10:00 to 11:30 AM.The IOPs of all patients were checked one hour before receiving intravitreal bevacizumab injection and subsequently at five minutes, 30 minutes, and one, two, three, four, and six hours post-injection. The IOPs were recorded by the same observer throughout the study period.We injected bevacizumab in both eyes of 44 patients as no cross-over effect of the drug in the other eye causing a rise in IOP is described. The pressure spike was found to be similar in patients whose both eyes were injected.Data were analyzed using SPSS Statistics version 23.0 . All continuous variables were presented in Mean±SD, and categorical variables were presented as frequency and percentages. The chi-square test or Fisher’s exact test was used to check the association between two categorical variables. To compare the mean IOP of diagnosis for each time interval, repeated measures ANOVA was used. The baseline and postoperative IOP at each follow-up were analyzed using paired sample t-tests. P-values of ≤ 0.05 were considered statistically significant.One hundred and ninety-one eyes of 147 patients were included in this study. Out of 147 patients, 92 (62.58%) were male and 55 (37.41%) were female, with a male-to-female ratio of 1.67:1. The mean age of patients was 54.5 ± 8.8 years (range 35- 5 years). The distribution of our patients with primary diagnosis is shown in Figure Out of 191 eyes, 119 62.3%) were phakic and 72 (37.7%) were pseudophakic. The frequency of IOP elevation >21 mmHg following intravitreal bevacizumab was observed in 169 eyes (88.5%) at five minutes, 104 eyes (54.5%) at 30 minutes, 33 eyes (17.3%) at one hour, and 16 eyes (8.4%) at two hours, with no increase in IOP observed at three, four, and six hours , followed by proliferative diabetic retinopathy (PDR), whereas the least increase in IOP was seen in patients with posterior uveitis p < 0.001) (Table  (Table 1The mean IOP one hour before injection was recorded at 12.12 ± 2.11 mmHg. It increased to 30.44 ± 6.53 mmHg (p < 0.001) after five minutes, 26.27 ± 4.65 mmHg (p < 0.001) after 30 minutes, 26.12 ± 3.31 mmHg (p < 0.001) after one hour, and 25.63 ± 3.03 mmHg (p < 0.001) after two hours post-injection . This was 18 mmHg higher than the baseline level of 12.12 ± 2.11 mmHg. A study conducted to see the immediate post-injection IOP rise by Lemos-Reis et al. in 2014 found a mean rise of 28.6 ± 13.8 mmHg in the absence of sub-conjunctival reflux and only 7.7 ± 10.3 mmHg in the presence of reflux . Our stuThe post-injection IOP spike is generally transient, with pressure returning to normal in a few hours post-injection. In the present study, the IOP returned to less than 21 mmHg three hours after the injection. A meta-analysis of 46 articles by De Varies et al. reported a mean rise of 23.4 mmHg returning to baseline after one week . On the In the current study, the mean IOP at five minutes for patients with DME was 27.41 mmHg, which decreased to 11.24 mmHg in the sixth hour after the injection. Similarly, the mean IOP in patients with PDR at five minutes was 28.94 mmHg and decreased to 11.59 mmHg at six hours (Table 5). The most common reasons for receiving intravitreal injections in this study were DME (36.1%) and PDR (18.8%), which is why the rise in IOP was seen more in these conditions. The patient cohort in other studies mentioned in this discussion is mostly ARMD patients, which involves a different patient cohort.The study being discussed here reported a pressure spike in 88.1% of patients in the first five minutes after injection, which is much higher than the study by Lemos-Reis et al. (32% of patients) and Kim et al. (36% of patients) ,16. As mIn our study, the average age of patients was 54.5 ± 8.8 years, which is much younger than the mean age of 75 years in the study by Lemos-Reis et al. and the mean age of 69 in a study by Sobaci et al. ,24. The Intravitreal anti-VEGF treatment is here to stay until we find other possible routes of drug delivery in the retina. An IOP spike is a reality in the majority of patients after intravitreal drug delivery, and the height of IOP can be alarming, as seen in our study and others. Patients with a history of glaucoma are at real risk of this pressure spike, as sudden increases in IOP can have a deteriorating effect on optic disc function.One limitation of our study is that we did not consider the axial length of the eyes in which the intravitreal drug was deposited.The initial administration of bevacizumab via intravitreal injection may cause a transient elevation in IOP, which typically resolves within a few hours. However, patients with pre-existing glaucoma or those who undergo multiple injections may experience permanent impairments of the retinal nerve fiber layer. In these cases, medical or surgical interventions should be employed to mitigate pressure spikes.


We included 193 patients. Premaquick® had a sensitivity close to 89%, equivalent to QuikCheck fFN™, but a higher statistical specificity of 49.5% against 38.6% for QuikCheck fFN™. We found no superiority of Premaquick® over QuickCheck fFN™ in terms of PPV (6.6% vs. 7.9%), with NPV being equivalent in predicting childbirth within 7 days in cases of TPL (98.6% vs. 98.9%). Nevertheless, the combination of positive native and total IGFBP-1 and the combination of all three positive markers were associated with a higher PPV. Our results, though non-significant, support this combined multiple-biomarker approach to improve testing in terms of predictive values. We conducted a prospective double-blind study to compare two vaginal diagnostic methods in singleton pregnancies with threatened preterm labor (TPL) at the University Hospital of Clermont-Ferrand (France) from August 2018 to December 2020. Our main objective was to compare the diagnostic capacity at admission, in terms of positive predictive value (PPV) and negative predictive value (NPV), of Premaquick According to the latest national perinatal health survey published in 2021, 4.8% of women living in metropolitan France are hospitalized during their pregnancy for threatened preterm labor (TPL) . They caTPL is a real public health issue. Obstetricians need reliable tools to assess the real risk of a premature birth. Today, this assessment is based on the ultrasound measurement of cervix length, in particular, to predict childbirth within 7 days . Various® . IGFBP-1 is a marker of cervical ripening. Its presence in vaginal secretions in the absence of ruptured membranes indicates a significant lysis of the decidual cells of the cervix and a diffusion of amniotic fluid during contractions. The presence of fragmented forms of IGFBP-1 reflects a significant local proteolytic activity and fetal stress caused by contractions. The third marker, IL-6, signals inflammation or infection of the amniotic cavity and the cervicovaginal area. Combining the biomarkers of myometrium activity, ripening of the cervix and inflammation/infection, Premaquick® encompasses the principal pathogenic mechanisms for preterm labor. One study found that this test had an NPV comparable to Quikcheck fFN™ [p > 0.99) but Premaquick® had a higher PPV  [® had 95.1% sensitivity, 97.5% specificity, 97.5% positive predictive value, 95.2% negative predictive value, and 96.3% overall accuracy in predicting premature birth [Nevertheless, most of the biological diagnostic tests used to detect TPL are qualitative tests that detect fetal fibronectin (fFN) from cervico-vaginal secretions via immunochromatographic assay. Of these, the QuikCheck fFN™  test (Hologic) has a negative predictive value (NPV) of approximately 99% for no childbirth within 7 days and about 96–97% for no childbirth within 14 days [eck fFN™ . It was  > 0.99) . Anotherre birth .® and QuikCheck fFN™ to predict delivery within 7 days from admission in the event of TPL in a population with an ultrasound cervical length < 30 mm. Our secondary objectives were to assess the ability of these tests to predict an unfavorable outcome within 14 days  and to evaluate the diagnostic capacity of Premaquick® in terms of PPV and NPV according to the number of positive or negative markers .Our main hypothesis was that the combined detection of IL-6, total IGFBP-1, and native IGFBP-1 on admission would improve the prediction of premature birth (in terms of PPV and NPV) in cases of TPL. Our main objective was to compare the ability of Premaquick®. Patients were included consecutively at the University Hospital of Clermont-Ferrand, France.This was an exploratory double-blind study comparing two diagnostic methods in the context of TPL: QuikCheck fFN™ vs. PremaquickThe inclusion criteria were age over 18 years and admission for TPL with intact membranes between 24 + 0 GW and 34 + 6 GW. TPL was defined as symptomatic uterine contractions documented on an external cardiotocographic recording associated with a shortened cervix . Patients were covered by French social security and gave their informed consent.Non-inclusion criteria were the presence of cervical dilation ≥ 4 cm, multiple pregnancy, ROM, uterine malformation, polyhydramnios, fetal malformation, placenta previa, profuse bleeding, earlier participation in the study for a previous episode of TPL during the same pregnancy, or if the patient was under guardianship or curatorship. Enrolled patients underwent double simultaneous swab vaginal secretion sampling at the level of the posterior vaginal fornix under speculum. They were assessed for temperature, hemogram, CRP level, and urine and vaginal bacteriological culture. The usual management for TPL was unchanged . Antenatal corticosteroids for fetal maturation were administered according to the national guidelines: betamethasone given as two 12 mg intramuscular injections 24 h apart. Data were collected and managed using the REDCap (Research Electronic Data Capture) tool hosted at the University Hospital of Clermont-Ferrand . REDCap ®) were carried out by technicians at the central laboratory, following the supplier’s instructions (see The immunochromatographic tests for (i) fetal fibronectin detection (QuikCheck fFN™) and (ii) IL-6, total IGFBP-1, and native IGFBP-1  and test areas (T) for the three markers. The presence of three control bands (C) in the result reading windows was a condition for the test to be valid. The presence or absence of the test band T (even when of low intensity) for each parameter was scored as follows: 3 for a test band T for the IGFBP-1 N marker, 2 for a test band T for the IGFBP-1 marker, 1 for a test band T for the IL-6 marker, and 0 for no test band T. The scores were summed to give the total score see . A totalThe test results were not disclosed to the clinician or the patient before delivery and so did not affect management.® and QuikCheck fFN™ for delivery within 7 days in cases of TPL, the primary analysis was based on (i) the McNemar test for paired proportions for PPV and (ii) an analysis of the 95% confidence interval for the non-inferiority study of NPV. The same statistical analyses were conducted to evaluate the diagnostic ability to predict an unfavorable 14-day outcome in terms of delivery, PROM, re-hospitalization, and repeat tocolytic therapy. Comparisons of continuous variables  between Premaquick® and QuikCheck fFN™ results were made using Student’s t-test or the Mann–Whitney test if the criteria for applying the t-test were not met. The equality of variances was analyzed with the Fisher–Snedecor test. For categorical variables , chi-squared or Fisher’s exact tests were used. Statistical analyses were performed with Stata software  for a two-sided type I error of 5%.The objective of this study was to compare positive and negative predictive values of Premaquick©  and Quikcheck fFN™ (detection of fibronectin) at admission to predict delivery within 7 days in cases of threatened preterm birth. More precisely, a non-inferiority assumption was proposed for NPV, whereas a difference for PPV was expected. It was proposed to include 200 patients in order to guarantee a satisfactory statistical power to highlight (i) a non-inferiority limit of 4% concerning the negative predictive value for 99% expected NPV for the detection of fibronectin (Quikcheck fFN™) with at least 95% statistical power and one-sided type I error at 5%, i.e., 170 patients for an intra-individual correlation at 0.5, and (ii) an absolute difference of at least 20% for the following PPV values—50% for fibronectin detection (Quikcheck fFN™) and 70% for the Premaquick© test) for a power greater than 80%, i.e., 56 patients for an intra-individual correlation at 0.5. The continuous variables were expressed as mean and standard-deviation or as median and interquartile range. The normal distribution assumption was checked using the Shapiro–Wilk test. To compare the diagnostic capacity on admission of Premaquick® and QuikCheck fFN™. We included 193 singleton pregnancies between 21 August 2018 and 21 December 2020. All included patients underwent a double simultaneous swab with Premaquick® or QuikCheck fFN™ (p > 0.05).Population characteristics and obstetric history are listed in ® and QuikCheck fFN™ were positive. This difference was statistically significant for the two tests, with, respectively, p = 0.04 and p = 0.02 .In the 160 patients admitted, the mean hospital stay was 3.98 ± 2.5 days. In 79% of cases, weekly or bi-weekly monitoring was set up by a home midwife; 81.1% of included patients underwent a fetal lung maturation cure via an injection of betamethasone. There was no significant difference in the proportion of women who received betamethasone between patients with a positive or negative test result  and intravenously in 28.6% of cases (atosiban) . The mea® was positive for eight of these test patients, as was QuikCheck fFN™. The PPV of Premaquick® to predict a premature delivery within 7 days in cases of TPL was 7.9% with an NPV of 98.9%, a sensitivity of 88.9%, and a specificity of 49.5%. For QuikCheck fFN™, 7-day PPV was 6.6% with an NPV of 98.6%, a sensitivity of 88.9%, and a specificity of 38.6% , but we found no difference in PPV (p = 0.71).In our study, nine (4.7%) patients gave birth within 7 days. Premaquickof 38.6% . Premaqu® test. The PPV of Premaquick® to predict a premature delivery within 14 days in the event of TPL was 10.9% with an NPV of 96.7%, a sensitivity of 78.6%, and a specificity of 49.7%. For QuikCheck fFN™, PPV was 10.7% with an NPV of 98.6%, a sensitivity of 92.9%, and a specificity of 39.7%  patients gave birth within 14 days; 13 had a positive fetal fibronectin test, and 11 had a positive Premaquickof 39.7% .® test. The PPV of Premaquick® to predict a premature delivery before 37 weeks in cases of TPL was 20.8% with an NPV of 84.8%, a sensitivity of 60%, and a specificity of 49.4%. For Quikcheck fFN™, PPV was 21.5% with an NPV of 87.5%, a sensitivity of 74.3%, and a specificity of 39.9%  gave birth before 37 weeks; 26 had a positive fetal fibronectin test, and 21 had a positive Premaquickof 39.9% . p = 0.12 for Premaquick® and p = 0.84 for QuikCheck fFN™). In our study, the mean time to re-hospitalization was 19 days; 17 patients required re-hospitalization for TPL within 14 days of inclusion; 14 had a positive fetal fibronectin test (p = 0.08) and eight had a positive Premaquick® test (p = 0.65). These two tests were not statistically significant in predicting re-hospitalization within 14 days. Statistically significant results were not found for predicting the repetition of tocolytic treatment within 14 days. Only 21 patients received a new tocolysis within 14 days; 16 patients had a positive fetal fibronectin test (p = 0.18), and 10 had a positive Premaquick® test (p = 0.65). No difference was found for other secondary outcomes: six patients presented a PROM within 14 days of their inclusion. These two tests were not statistically significant in predicting the premature rupture of membranes within 14 days , 30.8% for a delivery in 14 days , and 30.8% before 37 weeks . NPV was 96.7% for predicting a delivery within 7 days , 94.4% for a delivery in 14 days , and 82.8% for a delivery before 37 weeks .When all three markers were positive, which was the case for 13 patients, there were three deliveries in 7 days, four in 14 days, and four before 37 GW. The PPV was 23.1% for a delivery in 7 days (vs. 7.9% for positive Premaquick® and Quikcheck fFN™ to predict a premature delivery within 7 days in cases of TPL (7.9% vs. 6.6%). In terms of NPV, there was also a non-inferiority of Premaquick® compared with Quikcheck fFN™ (98.9% vs. 98.6%). In the study of Eleje et al. [® versus fFN tests were, respectively, 96.3% vs. 51.9%, 97.6% vs. 98.4%, 89.7% vs. 87.5%, 99.2% vs. 90.3%, and 97.3% vs. 90.0% for preterm delivery within 14 days; fFN had higher specificity , but Premaquick® had higher PPV . Our results conflict with the PPVs and NPVs found in these two studies, which nevertheless present a prematurity rate close to ours. We hypothesize that this difference is due to the evaluation methods used for the tests. In our study, the analysis of the results was carried out in a centralized and standardized mode in a biochemistry laboratory, blinded to the clinician and the patient, to avoid a potential bias of evaluation that can occur when the tests are performed at the patient’s bedside.In our study, 158 (81.9%) patients treated for TPL gave birth after 37 weeks. This is in line with data classically published in the literature ,20. Accoe et al.  183 wome® test in detecting TPL [Another team compared 122 pregnant women admitted for TPL before 37 weeks with 122 controls to evaluate the accuracy of the Premaquickting TPL . They foting TPL . These r®. Each of the markers had strong NPV but low PPV. Native IGFBP-1 was never positive alone. The literature reports many similar results for the diagnostic capacity of biomarkers, with strong NPVs but highly variable and often weak PPVs. In 2002, Lembet et al. studied the effectiveness in 36 patients of a rapid phosphorylated-IGFBP-1 detection test in vaginal secretions, the ActimPartus test, to predict premature delivery in cases of TPL. The PPV and NPV of this test were, respectively, 83.3% and 94.1% to predict delivery within 7 days [® test case . For the detection of IGFBP-1, Cooper et al., in 2011, found a PPV of 24% to predict premature delivery < 37 GW. Compared with fetal fibronectin, like in our analysis (PPV 21.5%), no difference was observed [We examined the diagnostic capacity of each of the three biomarkers present in Premaquickn 7 days . Ting etn 7 days . These vp = 0.05) but not for the Quikcheck fFN™ test (p = 0.47). Since 2010, French official guidelines have recommended cervix measurement via endovaginal ultrasound to identify patients requiring specific care, with either TPL or identified risk factors for preterm delivery [We demonstrated a statistically significant difference concerning cervical length measured using ultrasound for a positive or negative Premaquick© test , but associated infections and inflammation are often explored as they are theoretically accessible to prevention or therapy. We set out to study the usefulness of inflammation biomarkers including IL-6 to predict the risk of premature delivery. Both infectious and sterile inflammation have been clearly established as important actors linked to premature childbirth. IL-6 is rapidly and abundantly upregulated upon an infectious stressor and initiates an immune response mediated by neutrophil, macrophages and lymphocytes cells during preterm birth . A studyMany studies have looked at combinations of several biomarkers to improve the diagnostic capacity of these tests ,30. The In 2011, Menon et al. published a meta-analysis on the biomarkers of spontaneous prematurity analyzed over the past 40 years. About 120 biomarkers were described among the 217 studies analyzed. Two-thirds of these studies were carried out in North America and in Europe. There was marked heterogeneity in the design of these studies. No biomarker emerged as a predictor of preterm delivery . Likewis® was more statistically specific for predicting premature delivery within 7 days than Quikcheck fFN™ (49.5% vs. 38.6%). The NPVs of Premaquick® and Quikcheck fFN™ were strong and equivalent in predicting delivery within 7 and 14 days (98.9% vs. 98.6%). In the event of a negative Premaquick®, it would thus seem reasonable to consider ambulatory care and limit excessive treatment . As the two tests performed similarly, cost may be a factor in the choice. We found no difference in terms of PPV for the two tests studied. Premaquickn = 193), with only nine patients who gave birth within 7 days.Our study has several strengths. It was a prospective study, conducted in a double-blind fashion for both clinicians and patients, ensuring that clinical decisions at admission, such as orientation  and the use of antenatal betamethasone or tocolysis, were not impacted by the test results. All patients benefited from the same management according to the protocol of the obstetrics department of the University Hospital. No patients were lost to follow-up and there were very few missing data. A limitation of our study is that it was a single-center study. Another weak point of our analysis was the sample size (We found no superiority of Premaquick© over Quikcheck fFN™ in terms of positive predictive value, with negative predictive value equivalent for predicting childbirth within 7 days in cases of TPL, and likewise for our secondary objectives within 14 days: childbirth, premature rupture of membranes, re-hospitalization, and repeat tocolytic treatment. Nevertheless, the combination of positive native and total IGFBP-1 and the combination of all three positive markers were associated with the highest PPV. Though non-significant, our results support multiple-marker approaches to improve the predictive capacity of biological diagnostic tests.


In contrast, the bead standard replicates for modified McMaster variants dispersed from the regression curve, causing a lower R2. The Mini-FLOTAC method seems less influenced by the choice of floatation solution and has better repeatability parameters and linearity for bead standard recovery. For FEC tests with high R2 (>0.95) but that underestimated the true bead count, a correction factor (CF) was determined to estimate the true count. Finally, the validity of CF was analyzed for 5 tests with R2 > 0.95 to accurately quantify intestinal strongyle eggs from 40 different horses. Overall, this study identified FEC methodologies with the highest diagnostic performance. The limitations in standardizing routine FEC tests are highlighted, and the importance of equalization of FEC results is emphasized for promoting uniformity in the implementation of parasite control guidelines.The American Association of Equine Practitioners strongly advocates evidence-based intestinal strongyle control in horses. It recommends targeted treatment of all heavy egg shedders (>500 eggs per gram (EPG) of feces), while the low shedders (0–200 EPG) are left untreated. As 50–75% of adult horses in a herd are low shedders, preventing them from unnecessary anthelmintic exposure is critical for tackling resistance. There are various fecal egg count (FEC) techniques with many modifications and variations in use, but none is identified as a gold standard. The hypothesis of the study was that the diagnostic performance of 12 commonly used quantitation methodologies (three techniques with four variants) differs. In this regard, method comparison studies were performed using polystyrene beads as proxy for intestinal strongyle eggs. Mini-FLOTAC-based variants had the lowest coefficient of variation (CV%) in bead recovery, whereas McMaster variants had the highest. All four variants of Mini-FLOTAC and the NaNO Strongylus vulgaris, more than five decades of suppressive control programs have triggered the unexpected emergence of anthelmintic resistance in cyathostomins /2 g} .This technique was based on a published protocol using the commercially available kit ,25. BrieTo one gram of fecal sample in a wax paper cup, the desired number of beads from a vial was dispensed and mixed in 15 mL of tap water. Vials were cross-checked to rule out incomplete dispensing. After sieving through a metal strainer, the filtrate was dispensed into a 15 mL glass tube and centrifuged at 2000 rpm for 10 min. The supernatant was poured off and the sediment was homogenized with ≈15 mL of the desired float solution using a wooden applicator stick. The floatation solution was added to the brim of the glass tube to form a slightly positive meniscus before a glass coverslip (22 × 22 mm) was placed onto it. After centrifuging at 2000 rpm for 10 min, the coverslips were removed and placed on a glass slide. Beads or eggs under the coverslips were counted manually using a compound microscope (100× magnification) and expressed as beads/eggs per gram of feces ,24.2) of the linear fit indicates the suitability of that particular test to perform linearly over the biologically important range of intestinal strongyle egg quantitation. Subsequently, a correction factor (CF) was deduced from the Deming regression forced through a 0 intercept for tests that showed a sufficiently high coefficient of determination in the Deming regression (R2 > 0.95).Deming regression was performed to identify a test’s suitability to quantify the intestinal strongyle eggs present in a given fecal sample over a plausible range (low to high). Deming regression is a widely accepted method for this purpose  due to t2 > 0.95. Secondly, the CF was applied. Pearson correlation between each pair of tests was determined. FEC results were then categorized into low, moderate, and high shedders. Contingency analysis was performed to determine the kappa agreement before and after adjusting with CF.Firstly, fecal samples from 40 different horses were analyzed to verify whether FEC differed between the quantitation techniques with R4 (1.18 SPG) and sugar (1.33 SPG). Spiked beads were detected using light microscopy in 100× magnification (4 solution retrieved an average of 452 beads (range 250–598) from six horses, whereas sugar solution retrieved 552 beads (range 528–618).Polystyrene beads (520 ± 33 in 12.5 µL) spiked into fecal sediments of six different horses were retrieved under coverslips after mixing and floatation in ZnSOfication . ZnSO4 sResults of the repeatability assay on 12 replicates for each test for selected bead standards  are depicted in 3 1.33 SPG, sugar 1.33 SPG, and ZnSO4 1.18 SPG were 40.25, 44.2, 28.14, and 32.49, respectively. The average CV% for the modified McMaster test variants (same order as above) were 45.5, 40.48, 41.59, and 29.19. Similarly, for Mini-FLOTAC, the average CV% were 21.45, 23.95, 28.31, and 26.74. Among the 12 tests, Mini-FLOTAC NaCl 1.20 SPG had the lowest CV%, indicating its precision in the mean number of beads recovered for the three bead standards. In general, the Mini-FLOTAC-based variants had the lowest CV%, whereas the McMaster variants had the highest.The average CV% for the modified Wisconsin test variants NaCl 1.20 SPG, NaNO3 1.33 SPG, 71.26% for sugar 1.33 SPG, and 65% for ZnSO4 1.18 SPG. The average percentage recoveries of beads for the modified McMaster method variants were 95.7% for NaCl 1.20 SPG, 51.1% for NaNO3 1.33 SPG, 90.3% for sugar 1.33 SPG, and 92.06% for ZnSO4 1.18 SPG. Some variants of the modified McMaster method overestimated the spiked bead standards. For example, a replicate of 125 spiked beads was estimated as 350 by NaCl 1.20 SPG. Similarly, a replicate of 1000 beads was estimated as 1100 by both NaCl 1.20 SPG and sugar 1.33 SPG. A significant impact of floatation solution in bead recovery (51.1%) was noted for the NaNO3 1.33 SPG variant compared to the other three variants of modified McMaster. The average percentage recoveries of beads for the modified Wisconsin method variants were 44.63% for NaCl 1.20 SPG, 47.63% for NaNO3 1.33 SPG, 62.8% for sugar 1.33 SPG, and 46.63% for ZnSO4 1.18 SPG.The average percentage recovery of three bead standards for the Mini-FLOTAC method variants was 76.3% for NaCl 1.20 SPG, 66.4% for NaNO2 = 1, or a slope = 1. All variants of Mini-FLOTAC and modified Wisconsin NaNO3 1.33 SPG bead counts followed a linear fit with R2 > 0.95. The bead standard replicates for the modified McMaster variants dispersed from the regression curve, causing a lower R2. For the modified Wisconsin variants, bead standard replicate values were tighter for the lower number of spiked beads  but dispersed from the regression curve for higher numbers (500 and 1000). Similarly, Mini-FLOTAC variants (NaCl 1.20 SPG and sugar 1.33 SPG) as well as the modified McMaster variants (sugar 1.33 SPG and ZnSO4 1.18 SPG) had slope < 1.3 (closer to 1).Bivariate analysis and linearity of the regression curve were determined by Deming regression . The reg2 and slope of linear regression were analyzed to determine the goodness-of-fit for each of the 12 tests (2 and slope) indicates good fit. Four tests had a slope < 1.30 . Five tests had R2 > 0.95 .R12 tests . A value2 > 0.95 was tested using 40 fecal samples (4 1.18 SPG had the highest number of correlations ≥ 0.90 with other methods and variants. Mini-FLOTAC ZnSO4 had the highest correlation (0.9682) with Mini-FLOTAC NaCl.The Pearson correlation for five method modifications with R samples . The corThe raw estimates as well as the corrected estimates of FEC from 40 horses were categorized based on strongyle egg shedding categorization (based on the cut-offs as per AAEP guidelines see ). ContinPolystyrene beads were used as a proxy for intestinal strongyle eggs to overcome the difficulty of procuring extracted/purified eggs for such a large-scale study. Initial validation to assess beads’ compatibility with horse fecal matrix and their ability to float in various floatation solutions of differing SPG proved their usefulness for such a study. One major hurdle was aliquoting the desired number of beads via manual titrations as performed in prior studies using strongyle eggs ,27. Howe4 and improved recovery of >90% for all variants except NaNO3. The superiority of the modified McMaster technique in the apparent recovery of a higher number of beads is attributed to its bigger multiplication factor [3 1.33 SPG negatively affected bead recovery using the modified McMaster method but sugar 1.33 SPG positively impacted the modified Wisconsin method. Nevertheless, the Mini-FLOTAC method seems less influenced by the choice of floatation solution and has better repeatability parameters, indicating its reliability for bead counts. The processing of fecal samples using Fill-FLOTAC associated with Mini-FLOTAC is credited for its better diagnostic performance [An initial assay to determine the repeatability of all three FEC methods and their variants was performed using three select bead standards . Accurate recovery of spiked beads and minimal coefficient of variations (CV%) among replicates must indicate the repeatability of the assays. In general, low repeatability was observed for all 12 tests as none had CV% closer to zero or recovered 100% of the spiked beads. Mini-FLOTAC had a comparatively better CV% (average < 28.3) and bead recovery average of >65% among the three methods. Our result corroborated the findings of other studies that confirmed less variance for Mini-FLOTAC ,30. The n factor . All varformance .2 (0.977) and slope (1.2057563) that are closer to 1. However, most replicates of Mini-FLOTAC underestimated the bead count. For the modified McMaster method, most replicates tended to disperse away from the slope. However, many replicates overestimated spiked beads, indicating a potential threat of false counts [The regression curve assessment (linear behavior) of the 12 tests to recover the bead standards proved that no test was linear as the slopes were not passing through zero . The foue counts . The mode counts .3 1.33 variant of modified Wisconsin had R2 > 0.95. Other tests had poor R2 values. Mini-FLOTAC sugar 1.33 performed better as the R2 value, and the slope was closer to but not equal to 1. This may preclude it from being designated as the gold standard test. Despite its good repeatability, Mini-FLOTAC variants were unable to estimate 100% of the spiked beads. Nonetheless, the correction factor (CF) determined for each test can be applied to the raw estimate to yield an adjusted estimate that should be closer to the expected count.Regression analysis (coefficient of determination) determined the suitability of each of the 12 tests to recover beads mimicking the plausible range of strongyle FEC referred to in the AAEP parasite control guidelines. All variants of Mini-FLOTAC and the NaNO2 (>0.95 < 1) to help standardize FEC. We applied CF to FEC from 40 horse fecal samples, determined by five different method modifications with R2 > 0.95. Pearson correlation on the adjusted FEC pointed out the Mini-FLOTAC method variants (ZnSO4 and NaCl) having the most correlations with others. Although the five method variants correlated positively, the CF adjustments did not equalize the EPG counts . Alternatively, the agreement between the five methods based on egg-shedding categories  was determined as per AAEP guidelines, before and after CF adjustments. Interestingly, the FEC categories equalized to some extent between the five tests after CF adjustments. Equalizing the FEC based on AAEP egg-shedding categories allows for a standardization of FEC methods. Further, this will facilitate meaningful approaches for targeted control of intestinal strongyle infection and effective management of anthelmintic resistance.An accurate FEC test  does not need a CF. A FEC test that is not sensitive  but precise  needs CF. Indeed, CF was intended for tests with high R3 1.33 SPG, sugar 1.33 SPG, and ZnSO4 1.18 SPG) differed considerably. Using polystyrene beads as a proxy for strongyle eggs proved that no method modifications behaved linearly in detecting bead standards mimicking the plausible range of FEC for horses. Regression analysis pointed out five tests  with R2 and slope closer to 1 as suitable for FEC. Despite their suitability, the raw FEC estimate differed, and a correction factor determined for each test based on regression analysis was applied to standardize methodologies. Furthermore, equalizing the FEC results based on egg-shedding categories  outlined in AAEP guidelines helped with standardization efforts. Selecting a suitable test with the application of the CF is the key to determining FEC. Adjusted FEC should form the basis for controlling and management of equine strongylosis.The diagnostic performance of FEC methods  and their variants (based on the choice of floatation solutions: NaCl 1.20 SPG, NaNO


To assess the value of intrauterine PRP to improve IVF outcome in women with previous implantation failure.Screening of Pubmed, Web of Science, and other databases from inception to August 2022 using the keywords related to “platelet-rich plasma” OR “PRP” AND “IVF” “implantation failure.” Twenty-nine studies (3308 participants) were included in our analysis, 13 were RCTs, 6 were prospective cohorts, 4 were prospective single arm, and 6 were retrospective analyses. Extracted data included settings of the study, study type, sample size, participants’ characteristics, route, volume, timing of PRP administration, and outcome parameters.Implantation rate was reported in 6 RCTs (886 participants) and 4 non-RCTs (732 participants). The odds ratio (OR) effect estimate was 2.62 and 2.06, with 95% CI of 1.83, 3.76, and 1.03–4.11, respectively. Endometrial thickness was compared in 4 RCTs (307 participants) and 9 non-RCTs (675 participants), which showed a mean difference of 0.93 and 1.16, with 0.59–1.27 and 0.68–1.65 95% CI, respectively.PRP administration improves implantation, clinical pregnancy, chemical pregnancy, ongoing pregnancy, live birth rates, and endometrial thickness in women with previous implantation failure.The online version contains supplementary material available at 10.1007/s10815-023-02781-4. IVF failure is mostly related to implantation failure. Successful implantation requires a precisely synchronized development of both endometrium and blastocyst . OptimizThese changes include the replacement of the endometrial stromal cells by the decidual cells. The latter is characterized by the development of apical projections (pinopodes), glandular growth, and the development of microvilli on the endometrial luminal epithelial surface . These cVarious interventions have been tried to improve implantation, especially for those with repeated implantation failure (RIF). These interventions include endometrial scratch injury , hysteroPlatelet-rich plasma (PRP), also known as autologous conditioned plasma, is a concentrate of platelet-rich blood prepared through centrifugation of fresh whole blood to remove red and white blood cells. The resultant precipitate is rich in growth factors and cytokines  released from activated platelets α-granules . PRP hasIt was first applied to improve refractory endometrium by Chang in 2015 . Since tA prospectively prepared protocol that follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for meta-analysis was registered at PROSPERO. The registration number was CRD42022327811.Two authors  searched Pubmed, Web of Science, Scopus, and the Cochrane Central Register of Controlled Trials electronic databases from inception to August 2022 using the keywords “platelet-rich plasma” OR “PRP” OR “autologous platelet-rich plasma”) AND “IVF” “ICSI” “implantation failure” OR “thin endometrium” and their MeSH terms. Abstracts of conferences, Google Scholar, and reference and citation lists of the subject-related studies were checked for any additional studies. Contacting the authors was done if any clarifications or additional data were needed through emails. Details about the search strategy are provided in Supplementary Table All available studies—with no language limitations—involved PRP administration around the time of embryo transfer in IVF/ICSI cycles. The types of studies included randomized controlled trials (RCTs) mainly. A separate analysis for cohort or single-arm studies, whether prospective or retrospective, was done. Studies compared PRP to no intervention, placebo, or granulocyte colony-stimulating factor (GCSF) were included. All routes of administration, whether intrauterine or subendometrial, were also included. Excluded studies included in vitro (cell culture) studies, animal studies, case reports, and studies with an inadequate methodology or unclear outcomes (and cannot be clarified by author correspondence).Two authors (AM and NS) examined the search results titles and abstracts according to the predetermined eligibility criteria and then evaluated the full articles of the related studies. Any disagreement between the 2 authors regarding inclusion was discussed with other co-authors. Data from selected articles were extracted independently by 2 authors (AM and NS), and disagreement was dealt with in the same way as inclusion. Extracted data included settings of the study, sample size, participants’ inclusion and exclusion criteria, intervention characteristics, outcome parameters, registration, and funding data. The authors were contacted to clarify any vague or missed data.Quality assessment of the included RCTs was done following the Cochrane Handbook of Systematic Reviews recommendations by two investigators (AM and MF), and disagreements were discussed further with other investigators. All studies were assessed for random sequence generation, allocation concealment, blinding of participants and outcome assessors, incomplete outcome data, selective reporting, and other bias were done.Quality assessment of non-RCTs was done using the Newcastle–Ottawa scale (NOS). This “star system” is based on three main perspectives: the selection of the study groups (exposed and non-exposed); the comparability of the groups (cohorts or cases and controls) on the basis of the design or analysis; the ascertainment of exposure or outcome (length and adequacy of follow-up). Absent and unclear data were checked by contacting the corresponding author or other coauthors.The GRADE system was used to assess the quality of evidence. GRADE included the risk of bias in the included studies due to inconsistency, indirectness, imprecision, and publication bias. Serious concerns in each item decrease the evidence by 1 level, while very serious ones decrease the evidence by 2 levels.The levels were high, moderate, low, or very low if we were very confident, moderately confident, have limited confidence, or very limited confidence that the true effect is close to the effect estimate, respectively.The odd ratio and the corresponding 95% CI were calculated for all dichotomous data, and the mean difference with the corresponding 95% CI was calculated for continuous data. The effect size was obtained using the random effect model by the Mantel–Hansel method.p-value of < 0.05 in the Q-test or I2 > 40%. A separate analysis was done for RCTs and non-RCTs, and subgroup analysis of the studies according to inclusion criteria of participants (previous implantation failure or thin endometrium), the volume of transferred PRP (ranged from 0.5 to 40 ml), and types of transferred embryos (fresh or frozen). All statistical analysis was performed with the Review Manager (RevMan) version 5.4.1 .The heterogeneity of studies included was evaluated by I2 statistic and Cochran’s Q test. Heterogeneity was considered significant at a Our search yielded 2398 studies through databases , 985 of them were screened after the removal of duplicates, 50 screened for full text, and 29 studies were included in quantitative and qualitative synthesis  was reported in 6 RCTs with 886 participants. The odd ratio effect estimate was 2.62 with a 95% CI of 1.83, 3.76]. Subgroup analysis reported IR in 3 studies (338 women) with repeated implantation failure and revealed an overall estimated OR of 1.95 and 95% CI of 0.95–4.01. IR was reported in 2 and 1 studies (418 and 130 women) with previous implantation failure and thin endometrium and revealed overall estimated OR of 3.32 and 2.60 with 95% CI of 2.06–5.35 and 0.93–7.27, respectively. IR was reported in 5 and 1 studies (698 and 188 women) with frozen and both frozen and fresh embryo transfer and revealed overall estimated OR of 2.54 and 2.67 with 95% CI of 1.57–4.11 and 1.47–4.83, respectively. IR was evaluated in 3 non-RCTs with 587 participants and revealed an overall estimated OR of 2.88 with a 95% CI of 1.14–7.25 . Subgroup analysis reported CPR in 5 studies (416 women) with repeated implantation failure and revealed an overall estimated OR of 2.54 and 95% CI of 1.61–4.02. CPR was reported in 4 and 2 studies (730 and 143 women) with previous implantation failure and thin endometrium and revealed overall estimated OR of 1.88 and 5.02 with 95% CI of 0.35–10.02 and 1.13–22.29, respectively. CPR was reported in 9 and 2 studies (1113 and 176 women) with frozen and both frozen and fresh embryo transfer and revealed overall estimated OR of 2.37 and 2.95 with 95% CI of 0.91–6.20 and 1.35–6.43, respectively. Subgroup analysis of CPR according to the volume of PRP injected revealed that 0.5–1 ml , 1.5 ml , and 2 ml  had a CPR OR of 2.31, 3.35, and 3.53 and 95% CI of 0.89–5.96, 0.63–17.74, and 1.44–8.67, respectively. CPR was evaluated in 10 non-RCTs with 1452 participants and revealed an overall estimated OR of 2.39 with a 95% CI of 1.47–3.90 . Subgroup analysis reported OPR in 2 studies 165 women) with repeated implantation failure and revealed an overall estimated OR of 1.79 and 95% CI of 0.37–8.53. OPR was reported in 2 and 1 studies (240 and 83 women) with previous implantation failure and thin endometrium and revealed overall estimated OR of 4.13 and 2.34 with 95% CI of 1.79–9.56 and 0.77–7.08, respectively. OPR was reported in 4 and 1 studies (408 and 80 women) with frozen and both frozen and fresh embryo transfer and revealed overall estimated OR of 2.62 and 5.57 with 95% CI of 1.26–5.47 and 0.62–50.03, respectively. Subgroup analysis of OPR according to the volume of PRP injected revealed that 0.5–1 ml  and 1.5 ml  had an OPR OR of 2.62 and 5.57 and 95% CI of 1.26–5.47 and 0.62–50.03, respectively. OPR was evaluated in 4 non-RCTs with 575 participants and revealed an overall estimated OR of 4.09 with a 95% CI of 1.02–16.38 . LBR was reported in 2 studies (130 women) with repeated implantation failure and 2 studies (393 women) with previous implantation failure and revealed overall estimated OR of 2.36 and 10.94 with 95% CI of 0.15–36.35 and 5.59–21.43, respectively. LBR was reported in 3 studies (563 women) with frozen embryo transfer and 1 study (80 women) with both frozen and fresh embryo transfer and revealed overall estimated OR of 3.47 and 12.55 with 95% CI of 0.93–12.91 and 0.67–235.00, respectively. Subgroup analysis of LBR according to the volume of PRP injected revealed that 0.5–1 ml  and 1.5 ml  had an LBR OR of 3.47 and 12.55, and 95% CI of 0.93–12.91 and 0.67–235.00, respectively. LBR was evaluated in 4 non-RCTs with 701 participants and revealed an overall estimated OR of 4.18 with a 95% CI of 1.61–10.86 [1 study (40 women) was prospective single arm and had 11.18 OR and 0.56–222.98 95% CI and 3 studies (661 women) were retrospective and had 3.85 OR and 1.37–10.81 95% CI . They concluded that PRP injection is effective in women with refractory “thin” endometrium and decreased uterine artery hemodynamics.Two prospective cohort studies by Apolikhina et al. [21] and Noushin et al.  evaluatep = 0.004]. They reported a similarly higher clinical pregnancy rate . They concluded that PRP improves the outcome of frozen embryo transfer cycles with no difference between subendometrial injection and intrauterine infusion.Noushin et al. study  includedThis meta-analysis found a beneficial effect of PRP administration on implantation, clinical pregnancy, chemical pregnancy, ongoing live birth rates, and endometrial thickness. These effects on IVF outcomes were constant with changing types of participants, types of embryos transferred, and volume of PRP injected in both RCTs and non-RCTs. However, the quality of evidence of these findings was very low regarding live birth rate (only 4 studies with 523 participants), low in endometrial thickness (4 studies with 307 participants), and clinical pregnancy rate (high risk of bias with the inconsistency of results), moderate in implantation rate and high in chemical pregnancy rate.The possible mechanisms of the beneficial effects of PRP include synchronization of immunological interactions between the endometrial and embryo development during the implantation window. PRP decreases inflammatory cytokines such as IL-6 and 8 and increases IL-1 β, which is crucial in successful implantation .However, the exact mechanism is still not clear, and these beneficial effects may result from mechanical endometrial injury caused by intrauterine catheter simulating endometrial injury effects, as in most of the included studies, the control group had no intervention.It is to be noted that the CI is passing through 1 in LBR, endometrial thickness, and chemical pregnancy rate.Our meta-analysis is the first comprehensive one focusing on the effects of PRP in women with previous implantation failure. It included all the available studies reached by extensive searching of all available databases and the gray literature, trial registration sites, and a reference list of all related studies. A separate analysis for RCTs and non-RCTs was done. Adequate subgroup analysis according to participants’ characteristics, route, and volume of PRP injected for all the available outcomes.This meta-analysis is not without limitations. Only 11 RCTs were included. Most of them had a high risk of bias, especially in blinding and allocation concealment. The most important outcome (live birth rate) was reported in 4 studies only. Most of the included studies did not describe accurate details about PRP preparation. The exact cause of previous implantation failure was not clarified in most studies except those that described thin endometrium. The studies describing thin endometrium failed to describe the exact method of measuring the endometrial thickness and the presence of any intra- or inter-observer variability. The exact timing and number of PRP administrations were not clear in most of the studies. These led to marked heterogeneity. We tried to compensate for that by using the random effect method for comparison.There are many systematic reviews evaluating the effects of PRP in orthopedic, ophthalmic, and dermatological fields. Few ones were done in gynecology. Some evaluated its role in Asherman syndrome and others evaluated it in premature ovarian failure. Only 1 systematic review studied its role in implantation.P < 0.001, I2 = 16%), chemical pregnancy , and implantation rates . They also reported more increase in endometrial thickness in women who received PRP compared to the control group . They concluded that PRP could be used as an accessory strategy in women with RIF and thin endometrium. However, this review included only 3 RCTs and 4 cohort studies. So, the subgroup analysis was defective.Maleki-Hajiagha and colleagues  evaluateThis systematic review showed an increase in all outcomes of IVF cycles, namely implantation, clinical pregnancy, chemical pregnancy, ongoing pregnancy, and live birth rates. It also reported a significant increase in endometrial thickness in women with refractory thin endometrium. However, the quality of evidence was generally low, as the number of well-designed RCTs was inadequate to provide strong evidence, and there was marked heterogeneity among the included studies. More RCTs with adequate blinding, low risk of bias, with precise inclusion criteria considering the possible causes of implantation failure and other markers of endometrial receptivity besides the endometrial thickness should be conducted to provide the needed evidence.ESM 1:Supplementary Tables