Morin is a naturally occurring flavonoid with anti-inflammatory and antioxidative properties. Therefore, we hypothesized that morin may prevent inflammatory bone loss by reducing oxidative stress. To investigate the effect of morin on inflammatory bone loss, mice were injected with lipopolysaccharide (LPS). Osteoclasts (OCs) were analyzed by tartrate-resistant acid phosphatase (TRAP) staining and actin ring formation. Micro-computerized tomography analysis indicated that morin prevented LPS-induced bone loss in mice. In vivo TRAP staining indicated that morin decreased the number and surface of the OCs that were increased in LPS-treated mice. Furthermore, in vitro experiments indicated that morin decreased the number and activity of OCs upon LPS stimulation. Morin decreased actin ring-containing OCs with decreased activation of c-Src (Y416)/vav guanine nucleotide exchange factor 3/Ras-related C3 botulinum toxin substrate 1 compared with LPS alone. Morin decreased cytosolic reactive oxygen species (ROS), thus preventing the oxidation of Src homology region 2 domain-containing phosphatase 1 (SHP-1), followed by the inactivation of c-Src via direct interaction with SHP1. Conversely, SHP1 knockdown abolished the inhibitory effect of morin on OCs. Therefore, our findings suggest that morin disrupted cytoskeletal reorganization via an ROS/SHP1/c-Src axis in OCs, thereby granting protection from LPS-induced bone loss, which demonstrates its therapeutic potential against inflammatory bone loss. The occurrence of inflammatory diseases  near bone tissues leads to focal erosion coupled with severe bone loss ,2,3. MorVβ3 integrin, which plays a critical role in cytoskeletal organization. The absence of αVβ3 integrin has been demonstrated to impair cytoskeletal organization, resulting in increased bone density with disrupted bone resorption by OCs [OC precursors are originated from hematopoietic cells and differentiate into bone-resorbing cells through several processes. Functional OCs are characterized by their unique morphological features. OC activation requires adhesion to the bone and subsequent cytoskeletal reorganization. The activity of OCs depends on the specialized cytoskeleton organization of an actin ring structure that forms the backbone of the bone resorption apparatus . Therefon by OCs . The tyrn by OCs , and then by OCs . The c-Sn by OCs ,20,21. Maclura pomifera [Morin  is a natural bioflavonoid that is isolated from pomifera . This copomifera . Morin epomifera ,25,26. Mpomifera .In this study, we investigated the therapeutic potential of morin against LPS-induced bone loss in mice. Collectively, our findings provide insights into the molecular mechanisms through which morin attenuates LPS-induced cytoskeletal organization in OCs.All mice were handled in accordance with the guidelines of the Institutional Animal Care and Use Committee (IACUC) of the Immunomodulation Research Center (IRC), University of Ulsan. All animal procedures were approved by the IACUC of the IRC. The approval ID for this study is #HSC-21-020.N-acetyl-l-cysteine (NAC), and Hoechst 33258 were purchased from Sigma Chemical . Rhodamine phalloidin and N-(biotinoyl)-N′-(iodoacetyl) ethylenediamine (BIAM), Lipofectamine 3000, and Mito-SOX red were purchased from Molecular Probes  and Invitrogen , respectively. Antibodies against MCP-1 for coating and detection were obtained from R&D Systems, Inc. NE-PER nuclear and cytoplasmic extraction reagents were acquired from Pierce . Regarding primary antibodies, antibodies specific for phospho-tyrosine (4G10) were purchased from Upstate USA Inc. , and antibodies for Vav guanine nucleotide exchange factor 3 (Vav3) were obtained from Abcam . c-Src-Y416 and c-Src antibodies were obtained from Cell Signaling Technology  and ECM Biosciences , respectively. β-Actin (A5441) and SHP1 (sc-287) antibodies were obtained from Sigma Chemical and Santa Cruz Biotechnology , respectively. Following the manufacturer’s protocol, active Rac1 was measured using the Rac1 activation kit from Thermo Scientific . HRP-conjugated secondary antibodies and 2′,7′-dichlorofluorescein diacetate (H2DCFDA) were obtained from Thermo Fisher Scientific . Small interfering RNA (siRNA) against SHP1 (sc-29479) and scrambled siRNA  were obtained from Santa Cruz Biotechnology. M-MLV reverse transcriptase and SYBR Green Real-Time PCR Master Mixes were purchased from Promega . QIAzol reagent was purchased from Qiagen . Morin was purchased from Tokyo Chemical Industry Ltd. . Recombinant mouse macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANKL) were obtained from R&D Systems, Inc. . The assay kits for RatLaps EIA, osteocalcin EIA, alkaline phosphatase, and OxiSelectTM hydrogen peroxide were obtained from Immunodiagnostic Systems Inc. , Biomedical Technologies Inc. , BioAssay Systems , and Cell Biolabs Inc. , respectively. LPS, MTT -2,5-diphenyltetrazolium bromide), leukocyte acid phosphatase (TRAP) assay kit, toluidine blue, n = 4), vehicle + morin 5 mg/kg (n = 4), LPS (n = 6), and LPS + morin 5 mg/kg (n = 6). LPS  was injected into mice in 200 μL of phosphate-buffered saline (PBS) once a week for 3 weeks [2 chamber at the end of the treatment period. The femur was scanned using a high-resolution Micro CT (CT) SkyScan 1176 System  to measure bone mineral density (BMD) and microarchitecture, as described in Park et al. [2O2 assay kit, respectively. Sandwich ELISA using the recommended antibodies was used to assess serum MCP-1, following the manufacturer’s instructions.Female C57BL/6J mice (10 weeks old) were housed in the IRC’s pathogen-free animal facility. Four groups of mice were randomly separated: vehicle control  was used to assess viable cells at 37 ℃ for 3 h. After MTT removal, insoluble formazan products were dissolved in 100 μL of dimethylformamide (DMSO), and absorbance was measured using a microplate reader at 540 nm. Bone marrow-derived macrophages (BMMs) were plated into 96-well plates. After generating pre-OCs, they were treated with LPS in the presence or absence of morin. MTT . The primer sequences were 5′–CTC CAA CAA GGT GCT TGG GA–3′ and 5′–GAA GCA GTA GAT AGT CGC CA–3′ ; 5′–GAC CAC CTT GGC AAT GTC TCT G–3′ and 5′–TGG CTG AGG AAG TCA TCT GAG TTG–3′ (TRAP); 5′–GTG GGT GTT CAA GTT TCT GC–3′ and 5′–GGT GAG TCT TCT TCC ATA GC–3′ (cathepsin K); 5′–AGA CGT GGT TTA GGA ATG CAG CTC–3′ and 5′–TCC TCC ATG AAC AAA CAG TTC CAA–3′ (DC-STAMP); 5′–TTC AGT TGC TAT CCA GGA CTC GGA–3′ and 5′–GCA TGT CAT GTA GGT GAG AAA TGT GCT CA–3′ (ATP6v0d2); 5′–ATC AAT GCC AAC TAC GTG AAG AAC–3′ and 5′–GGC TGG CGA TGT AGG TCT TAGA–3′ (SHP1); and 5′–ATC AGA GAG TTG ACC GCA GTT G–3′ and 5′–AAT GAA CCG AAG CAC ACC ATA G–3′ (RPS).Isolation of total RNAs was performed with QIAzol reagent, as described previously . The exp4OH and stained with 1% (w/v) toluidine blue in 0.5% sodium borate. The resorbed area was measured through ImageJ software, 1.37 v.To assess the bone resorption activity in vitro, mature OCs were generated with M-CSF for growth and RANKL for differentiation for 3–4 days in 24-well plates. Then, an equal number of obtained mature OCs were seeded on dentin discs . The celTo examine the actin ring within the OCs, mature OCs were washed and incubated under the indicated conditions for 6 h to examine filamentous polymer actin (F-actin) distribution as previously described . OCs werTotal proteins from the cultured cells were extracted on ice with lysis buffer , separated by SDS-PAGE, and transferred to nitrocellulose membranes. After blocking with 5% skim milk for 1 h at room temperature, the membranes were then incubated overnight with primary antibodies against c-Src (Y416), c-Src, Vav3, SHP1, and β-actin at 4 ℃. After washing with 1× TBS-T, the membranes were incubated with HRP-conjugated secondary antibodies for 1 h and developed using chemiluminescent substrates. 2DCFDA). BMMs were prepared and incubated with M-CSF and RANKL for 40 h, washed thoroughly, incubated further for the indicated periods and conditions, harvested, suspended in PBS, loaded with H2DCFDA, and incubated at 37 °C for 30 min. Intracellular ROS were measured using an FACS Calibur flow cytometer .Intracellular ROS and mitochondria-generated ROS were detected using the fluorescent probe 2′,7′-dichlorofluorescein diacetate (HN-(biotinoyl)-N′-(iodoacetyl) ethylenediamine (BIAM)-containing lysis buffer . The buffer was rendered oxygen-free by bubbling nitrogen gas through the buffer at a low flow rate for 20 min. The sulfhydryl-modifying chemical BIAM selectively detects the reduced form of cysteine [BMMs were incubated for 40 h with M-CSF (30 ng/mL) for growth and RANKL (40 ng/mL) for differentiation and further incubated with M-CSF and LPS in the presence or absence of morin (200 μM) for 16 h. The medium was then removed, and the cells were frozen rapidly in liquid nitrogen. The frozen cells were transferred to 100 µM cysteine . After bThe Rac1 pulldown assay was performed as indicated by the manufacturers. Briefly, cells were washed with PBS and harvested in the lysis buffer included in the kit. Next, 500 µg of cell lysates were mixed with GST–Pak1–PDB fusion protein in the presence of glutathione resin. The samples were then separated by SDS-PAGE (15% gel) and detected by immunoblotting using Rac1-specific antibodies.After treatment with M-CSF and RANKL for 40 h, the BMMs were transfected with either a small interfering RNA (siRNA) against SHP1 or scrambled siRNA (scRNA) using Lipofectamine 3000. Downstream procedures were conducted as described by Park et al. . t-test, whereas multiple group comparisons were conducted via one-way ANOVA followed by the Bonferroni post hoc test. Two-way ANOVA was used when two variables were analyzed. A p-value less than 0.05 was considered statistically significant. All experiments were repeated at least three times. The data are expressed as the mean ± standard deviation. Pairwise comparisons were conducted using Student’s To investigate whether morin protected from inflammatory bone loss induced by LPS, µCT scans of femurs from mice injected with morin after LPS stimulation were analyzed. A 5 mg/kg dose of morin provided maximum protection compared to 2.5 and 10 mg/kg doses, as demonstrated by X-ray radiogram analysis A. There Since OCs played a critical role in the protective effect of morin against LPS-induced bone loss, as demonstrated by the data from in vivo TRAP staining, the effects of morin on OCs were investigated after LPS stimulation in vitro. Addition of LPS to RANKL-pretreated OC precursor cells induced their differentiation into OCs with maximum activation after 48 h of exposure, as evaluated by counting TRAP-positive MNCs. Morin reduced the surface area and maximum diameter of OCs and the fusion index that was calculated on the basis of the number of nuclei per OC in a concentration-dependent with a modest decrease in the number of TRAP-positive MNCs A. FurtheGiven that morin affected the surface area of OCs more dramatically compared with the number of OCs, we hypothesized that morin disrupts cytoskeleton reorganization in OCs. To evaluate whether morin decreases the actin ring formation necessary for bone resorption in OCs, mature OCs were generated on a plastic well and incubated with M-CSF and LPS in the presence or absence of morin, after which the cells were stained with rhodamine-phalloidin to visualize the actin ring. As shown in Next, in vitro bone resorption activity was evaluated using dentine slices to assess whether morin affected OC function. Mature OCs were generated from cells treated with morin in the presence of LPS. Combined treatment of morin lowered the total pit area/number of OCs in the LPS-treated cells B. Vβ3 integrin to activate canonical signaling pathways consisting of c-Src, Vav3, and Rac1, which enable the cells to form actin rings [S-transferase (GST) pulldown assay. While activated form of Rac1-GTP was found after 5 min of exposure to M-CSF and LPS, the addition of morin attenuated its activation  phosphorylation , and thaOur findings demonstrated that morin, a natural bioflavonoid, protected mice against LPS-induced inflammatory bone loss. Three weeks after LPS injection, the mice exhibited a marked reduction in bone mineral density, which was accompanied by an increase in the number and surface area of OCs without affecting the expression of in vivo bone formation markers, suggesting that OCs play critical roles in LPS-induced bone loss. Morin injection reduced the number and surface area of OCs, as well as serum CTX-1 levels, which were enhanced in LPS-treated mice. No changes in serum ALP and osteocalcin were observed, indicating that the bone-sparing effect of morin was mainly due to its effects on OCs. Morin decreased TRAP-positive MNCs at high concentrations. Consistent with these findings, morin reduced OC survival by enhancing apoptosis, although it did not affect the differentiation of OCs. Moreover, morin reduced the surface area, maximum diameter, and fusion index of OCs that were increased by LPS in vitro, suggesting that morin attenuated the function of OCs. In line with these findings, morin inhibited bone resorption activity in dentine slices. This was attributed to a decrease in OC-specific cytoskeletal reorganization, which is critical in bone resorption. In agreement with our results, the protective effects of morin on osteoporosis have been reported in glucocorticoid-induced osteoporosis via osteogenic effects  and in oThe plasma level of morin was reported to be ~1.4 μg/mL after 2–4 h of i.v. injection (2 mg/kg) in rats . Since tTo investigate the molecular mechanisms involved in the protective effect of morin in OCs, we determined whether morin affected signaling pathways associated with cytoskeletal reorganization. After 5 min of exposure, morin decreased LPS/M-CSF-induced signaling for cytoskeletal reorganization by blocking the activation of c-Src/Vav3/Rac1, an effect that has also been reported for M-CSF stimulation . Given tTaken together, our findings demonstrated that morin granted protection against LPS-induced inflammatory bone loss by decreasing the number and area of OCs in bone without affecting bone formation . In vitr


This paper is dedicated to video coding based on a compressive sensing (CS) framework. In CS, it is assumed that if a video sequence is sparse in some transform domain, then it could be reconstructed from a much lower number of samples  than the Nyquist–Shannon theorem requires. Here, the performance of such a codec depends on how the measurements are acquired (or sensed) and compressed and how the video is reconstructed from the decoded measurements. Here, such a codec potentially could provide significantly faster encoding compared with traditional block-based intra-frame encoding via Motion JPEG (MJPEG), H.264/AVC or H.265/HEVC standards. However, existing video codecs based on CS are inferior to the traditional codecs in rate distortion performance, which makes them useless in practical scenarios. In this paper, we present a video codec based on CS called CS-JPEG. To the author’s knowledge, CS-JPEG is the first codec based on CS, combining fast encoding and high rate distortion results. Our performance evaluation shows that, compared with the optimized software implementations of MJPEG, H.264/AVC, and H.265/HEVC, the proposed CS-JPEG encoding is 2.2, 1.9, and 30.5 times faster, providing 2.33, 0.79, and 1.45 dB improvements in the peak signal-to-noise ratio, respectively. Therefore, it could be more attractive for video applications having critical limitations in computational resources or a battery lifetime of an upstreaming device. The veryslow profile corresponds to the maximum possible optimization of the codec parameters such that the compression performance is the highest while the encoding speed is the lowest. In contrast, the ultrafast profile corresponds to the maximum possible encoding speed. In [ultrafast profile, while having better compression performance?In recent years, more and more applications where a video upstreaming device is limited by its resources, such as the battery lifetime and the platform performance, have been developed. Examples include deep space missions , wirelespeed. In , it was 1.DVC based on syndrome coding ,12 or ov2.DVC based on compressive sensing (CS) .One of the promising video coding concepts that can potentially provide lower encoding complexity is distributed video coding (DVC), where the coding complexity is shifted from the encoder to the decoder . There akey frames) are intra-encoded via conventional video coding based on H.264/AVC in Intra mode. The remaining frames  frames) are divided into non-overlapped blocks for which a 2D discrete cosine transform (DCT) is performed. The resulting DCT coefficients are converted into several binary vectors. Then, a syndrome of an error-correcting code is computed for each vector and transmitted to the decoder. At the decoder side, already-reconstructed frames are used in order to obtain the interpolated version of the decoded frame . Then, the received syndromes and the side information are used for syndrome decoding, considering the binary vectors extracted from the side information as a sum of the vectors obtained at the encoder and some errors in a virtual channel. Several works [ultrafast profile.In the first implementation , some fal works ,12,13 real works  encoder ultrafast profile. In CS, it is assumed that if a video sequence is sparse in some transform domain, then it could be reconstructed from a much lower number of samples  than the Nyquist–Shannon theorem requires [This paper is dedicated to DVC based on CS, which potentially could provide lower encoding complexity compared with x264 in an requires ,15. The requires , we proprequires , DCVS [1requires , MH-BCS requires , and MC-requires . Howeverrequires  has the requires , a videorequires  is too srequires , a fast requires ,21 as we1.We introduce an accurate rate control algorithm based on packet dropping which does not lead to a noticeable increase in encoding complexity.2.We propose fast randomized thresholding for the ISTA, which pseudo-randomly selects the shrinkage parameters at each iteration and shows that compared with the ISTA with VBM3D ,23, it i3.ultrafast profiles. The comparisons demonstrate that the CS-JPEG codec provides much faster encoding and more accurate rate control. Moreover, it shows better compression performance for video sequences with low and medium motion levels.We show detailed comparisons of the proposed CS-JPEG codec with conventional optimized competitors, such as MJPEG, x264 (Intra), and x265 (Intra)  .First, the block-based sensing approach allows calculating the measurements separately for each block . Second, for the same reason, the recovery process can be performed in parallel as well. However, this approach has the following disadvantages:L-level Haar transform, which is needed to compute low-resolution images of a size Algorithm 1: Forward (inverse) DNTInput: 1:2:for do3:   4:   5:   6:end for 7:for do8:for do   9:     10:     11:     12:     13:end for   14:end forIn order to overcome the disadvantages mentioned above, in , we intr) matrix . The opeFirst, the DNT can be applied only for a 1D vector of a power of two samples. Therefore, in , we propsion, in , we propL-level Haar transform can be also performed without division and multiplication, the considered measurements matrix in Equation . The quantized and subsampled DNT coefficients are binarized and compressed via a context-adaptive binary range coder (CABRC) , which ilization . Here, o1.A sparsifying transform with a matrix 2.The hard threshold transform coefficients 3.A hard threshold block is calculated as In , we propshown in , such deSince each pixel can be estimated by the hard thresholding of different 3D blocks, operator 1.A sparsifying transform with matrix 2.A shrinkage coefficients 3.A resulting block is calculated as Video frames obtained at the first stage are used at the second stage as estimates of the noise-free frames in order to find similar blocks Here, the final estimate of each pixel is calculated as a weighted sum of all the estimates as well, where a weight coefficient for each estimate is computed as As was shown in , the resL, sensing rate R, and quantization step Q for DNT coefficients. At the decoder side, there are only two parameters: an initial threshold value K. In general, the problem of the codec parameter selection can be formulated as follows. For a given bit rate, we need to choose a triple K and performed encoding and decoding for all pairs There are three parameters in the CS-JPEG encoder: the number of levels for the Haar transform fore, in , we propFinally, for the selected triples vered in , Input: 1:2:for do3:for do   4:for do     5:        6:        7:        8:for do        9:          10:          11:          12:end for        13:end for     14:end for   15:end for16:for do17:   18:end forLet us introduce the following basic soft thresholding, presented in Algorithm 2. First, for a current reference block on (HME) . HME rethrinkage  is perfok. Moreover, in the motion estimation, we are not searching for the most similar blocks within the same frame. Both of these approaches allow reducing the computational complexity. Version 1. One can see that the complexity is still too high and should be reduced.In contrast to VBM3D, Algorithm 2 does not have the first stage, where the frames 1.s is randomly selected from a set Version 2, we propose usingK is high enough, this allows us to use almost all combinations of the reference blocks during the whole recovery process, providing the closest approximation to Version 1  and noticeable PSNR improvement when the motion level is low (see `Container’). This can be explained in the following way. At initial iterations, the current estimates Version 3 and VBM3D.A further reduction in complexity can be achieved by avoiding motion estimation at all for some iterations . In on 4 see . Figure 4.Version 5, we propose collecting F blocks from F frames, which have the maximum similarity, so that more than one block for a given frame can be selected in the thresholding. This allows us to achieve a noticeable improvement in PSNR but with almost double the complexity compared with Version 4.Since some videos have a high level of non-local similarities between the blocks within a frame, following VBM3D in In this paper, we propose the following four modifications of the basic soft thresholding:N is better for a flat area, while the smaller ones are better for areas with many details. From the temporal sparsity point of view, smaller N and F values allow finding more similar blocks in the neighbor frames when the motion level is medium or high, while for a low-motion area, a larger F value is better. The sparsity level, achieved through 3D DCT for a block of size of As could be expected, different block sizes provide different results for different videos. In this paper, we propose exploiting the advantages of different transform sizes in the following way. At each iteration, we randomly select the transform size using equal probabilities. This approach does not increase the complexity. At the same time, Following the reasoning described above, Y) component was considered. The test sequences were selected so that they had very different motion levels. In order to measure this numerically, let us introduce the following temporal similarity level S:f and the motion-compensated frame f, respectively.The performance evaluation was obtained for 27 test video sequences available in . All theS. Here, the sequences `Bridge-close’, `Container’, and `Bridge-far’ had the highest S values , while `Football’, `Mobile’, and `Flower’ had very low similarity due to heavy motion of the camera and the objects.https://github.com/eabelyaev/csjpeg, accessed on 3 December 2022) with the corresponding algorithms in the most famous intra-frame encoders such as MJPEG [ultrafast means that the x264 or x265 encoder is used in its fastest preset, while veryslow corresponds to the full RD optimization. Since MJPEG does not contain any rate control, we implement the following rate control based on a virtual buffer. For frame i, we select the JPEG quality factor In this paper, we compare the proposed rate control for the CS-JPEG codec .f, respectively.Let us compare the rate distortion performance of the considered codecs using the peak signal-to-noise ratio (PSNR) as an objective visual quality metric. The PSNR is defined asContainer’, `Hall’, `Foreman’, and `Soccer’. One can see that for `Container’ and `Hall’, the proposed CS-JPEG codec outperformed all the block-based codecs, while for `Foreman’ and `Soccer’, it provided similar or even worse results. This could be explained in the following way. The recovery performance of CS-JPEG highly depends on the statistical properties of a video sequence. On one hand, CS-JPEG exploits the temporal similarity between neighboring frames . On the other hand, if the temporal similarity is low, then the traditional block-based intra codecs could provide better performance, since they exploit the spatial similarity of the pixels within a frame more efficiently.As a reference, x264-veryslow and MJPEG2000. If For objective visual quality evaluation, we also used the Structural Similarity Index (SSIM) , which mBridge-far’) compared with the other block-based codecs, while in some cases, wavelet-based MJPEG2000 had the lowest flickering level.The objective PSNR and SSIM metrics are calculated for only a single frame. Therefore, these metrics are not always good enough for quality assessment of a video sequence. Let us also evaluate inter-frame flickering, which is a commonly seen video coding artifact. It is perceived mainly because of the increased inter-frame difference between neighboring frames after compression compared with the corresponding difference in the original video. As a result, flicker is more easily seen in static areas. Container’, `Hall’, `Foreman’, and `Soccer’ at a target bit rate In this paper we summarized the CS-JPEG codec with intra-frame encoding and inter-frame decoding inspired by compressive sensing. We demonstrated that when compared with the traditional block-based intra codecs, it is significantly less complex and provides a higher level of scalability. Moreover, for video sequences with low and medium motion levels, it also provided better rate distortion performance. This makes CS-JPEG more attractive for video applications having significant limitations in computational resources or battery lifetime for an upstreaming device.


P <.001). Evaluating the score by each type of content, videos containing personal experiences  scored significantly lower than videos containing other content such as explanations of the disease  and surgical procedures . Analysis according to the source, the number of views and video power index was significantly higher in the videos uploaded by the nonmedical group (P < .05). YouTube is currently not an appropriate source for patients to gain information on endometriosis. Credible videos with accurate information and clear, high-quality operative clips with proper scientific commentary should be uploaded by medical professionals and medical institutions to critically and rapidly appraise the quality of online video-disseminated information on endometriosis. In addition, advanced filtering using categories by YouTube’s staff appears to be necessary.Many patients seek information online, including on social media, regarding various health topics. This study aimed to investigate whether YouTube videos on endometriosis could be a useful source for the general population, surgical trainees, and specialists. A YouTube search was conducted on December 26, 2021, using the search terms “endometriosis,” “endometrioma,” and “endometriotic cyst.” Videos were sorted by view count, and the 100 videos with the highest view counts were chosen. After excluding 48 videos for various reasons, 52 were included in the final analysis. The number of views, duration, likes and dislikes, content type, and source of each video were recorded. We referred to a previous study to evaluate video quality. The 52 videos related to endometriosis had a total of 35,220,141 views . Based on authorship, the videos were categorized into videos uploaded by the medical group and the nonmedical group. The medical group mainly uploaded videos directly related to endometriosis, such as explanations or detailed surgical procedures for endometriosis , whereas the nonmedical group mainly uploaded videos about personal experiences and others (24/25, 96%;  Endometriosis appears to be one of the most common benign gynecological proliferations in premenopausal women since it is estimated that 10%–15% of reproductive-age women suffer from pelvic endometriosis. The prevalence of this disease increases up to 30% in patients with infertility and up to 45% in patients with chronic pelvic pain.,4 There are currently no diagnostic markers with adequate reliability for clinical use. Although a noninvasive diagnostic test for endometriosis is desirable and could help avoid the need for surgery in establishing a definitive diagnosis, no such test is available currently. Endometriosis is a chronic disease that requires sustained treatment; this key educational point must be reinforced in discussions with patients. As endometriosis has a common prevalence and its diagnosis is not easy, it is important to consult a gynecologist. However, when treatment is difficult, patients attempt to obtain information regarding the condition elsewhere.Endometriosis is a debilitating disease characterized by chronic inflammation and the presence of functional endometrial glands and stroma outside the uterine cavity. YouTube, one of the most common Internet-based visual information and entertainment platforms, boasts more than 2 billion video views every day. In addition, there is a high level of information posted by experts. However, because YouTube does not question the credibility of video creators, information that is inappropriate (or lacks expertise) is often posted. Although researchers representing various specialties have analyzed the accuracy of YouTube videos on various topics, controversy regarding the reliability of these videos due to the lack of peer review persists.–14 There is one study on endometriosis and YouTube analyzing endometrioma surgery video, but there is no study on videos regarding general endometriosis. Because many endometriosis patients with increasing levels of anxiety, it is important to use reliable YouTube videos with appropriate information from video uploaders who do not lack expertise.The internet provides access to a wide range of online medical and visual educational resources.The primary purpose of this study was to analyze the content of the most viewed videos of endometriosis on YouTube to identify the features of endometriosis-related videos that were watched by the public. In addition, we evaluated the quality of videos related to endometriosis on YouTube to determine whether accurate and important information was delivered.A YouTube search was conducted on December 26, 2021, using the terms “endometriosis,” “endometrioma,” and “endometriotic cyst.” The inclusion criteria for the videos were as follows: (1) English language used, (2) primary content related to endometriosis, and (3) acceptable audiovisual quality. The exclusion criteria were as follows: (1) languages other than English, (2) absence of audio or visual stimuli, and (3) duplicate videos.A new account was created to avoid YouTube’s view of history-based video recommendations. The videos were sorted by the view count. For each search term, the top 50 of the 100 initial videos were included for review, as determined by the “relevance” filter, according to YouTube’s algorithm. A total of 48 videos were excluded . Finally, 52 YouTube videos were found using the keywords “endometriosis,” “endometrioma,” and “endometriotic cyst” and were included in the final analysis , total number of “likes” as depicted by the “thumbs up” icon, and purpose and type of content. Based on the contents of the video, they were categorized into 4 groups: explanations of the disease , surgical procedures , personal experiences , and others . Based on the source of upload, videos were classified into 5 basic groups: academics (authors were affiliated with a university), physicians (authors were not affiliated with a university but were physicians), patients (women who have been diagnosed with endometriosis and are currently undergoing treatment or have been treated), commercial establishments (attention to a product or service), and paramedical . We further categorized the videos uploaded by academic and physician groups into the medical group and those uploaded by patients, commercial establishments, and paramedical groups into the nonmedical group Table .–20 The evaluation factors were divided into the part that evaluated the general quality of the video, whether important information on endometriosis was included and explained, and how much scientific evidence was specified. For general video quality and flow of video content, each parameter was scored on a scale of 1 to 3: poor, 1 point; moderate, 2 points; and good, 3 points. The information on endometriosis was divided into 5 elements  and evaluated as follows depending on the degree of explanation: 0 points, not mentioned; 1 point, mentioned briefly; and 2 points, mentioned in detail. For videos based on scientific evidence, there were 2 subdivided items: 0 points were given if there was no mention and 1 point was given if there was any mention. Thus, the total score of the 5 items ranged from a minimum of 2 to a maximum of 18 points. Three physicians independently evaluated the quality of each video, and the average of the 3 scores was used for the 3 scores.Because there are no established standards for evaluating video quality, we prepared an arbitrary scoring system based on a previous study.To assess the popularity of the videos, we used the like ratio (like×100/like), view ratio (number of views/day), and video power index (VPI) (like ratio × view ratio/100). In previous studies, dislike was included in the video evaluation index; however, due to YouTube’s recent policy, the number of dislikes was not indicated.U test. Comparisons of the difference in uploaded contents between the medical and nonmedical groups were analyzed using Fisher’s exact test. Statistical analysis was conducted using the SPSS software . A P value of < .05 was considered statistically significant. The reliability between YouTube videos and the 3 physicians scored on the criteria for the items was assessed using intraclass correlation coefficients (ICC).Data on video characteristics, including source, intent, and number of views since posting, were collected. Data were shown as median (range) for continuous variables and n (%) for categorical variables. Comparisons were made between the medical and nonmedical groups using the Mann–Whitney The need for institutional review board approval was waived for this study because only publicly available data were used.The 52 videos related to endometriosis had a total of 35,220,141 views . The descriptive features of endometriosis-related videos on YouTube are shown in Table P < .001). To evaluate whether the videos related to endometriosis contained accurate and important information and whether scientific evidence was presented, we created a detailed scoring method. The median score was 8 (range 2–18); the video with the highest score was a video containing a well-organized general explanation of endometriosis, and the video with the lowest score was mainly composed of personal experience without including contents related to endometriosis. When evaluating the score by each type of content, videos containing personal experience  scored significantly lower than videos containing other content, such as explanations of the disease  and surgical procedures . There was a high degree of correlation between reviewers . Then, we created and analyzed the like ratio, view ratio, and VPI to evaluate which videos people were interested in and liked. The video with the highest VPI was a short video posted by Beeston Fam, which was a short video of only 12 s. In addition, the title of this video is when the only treatment for endometriosis is to get pregnant over and over #shorts, but this video had nothing to do with endometriosis. We further analyzed how videos related to endometriosis uploaded on YouTube differed according to the uploaded content, source, and time when the video was uploaded to YouTube. We compared videos uploaded by the end of 2018 and videos uploaded after 2018, which was time to compare by dividing the number of uploaded videos in half. We also compared videos based on the source. When analyzed according to the source (Table (P < .05). However, videos uploaded by the medical group showed significantly higher scores than those by the nonmedical group . When analyzed according to the date when the video was uploaded (Table Table  These 2 videos showed the highest VPI values among the 52 videos, except for 1 video. The video with the highest VPI was uploaded in 2021 by the Beeston Fam; an individual belonging to the nonmedical group, and it was difficult to find a correlation with endometriosis in the video. Reflecting these results, VPI, which is a comprehensive indicator of popularity, was significantly higher in the non-medical group than in the medical group. However, video scores were significantly higher in the medical than in the nonmedical group. This shows that VPI does not reflect the quality and reliability of the information provided by YouTube videos and that laypeople expressed their preferences regardless of the quality of the video. These results are similar to those of previous studies. Kunze et al reviewed 50 videos regarding menisci and found that information on meniscus found in YouTube videos was of low quality and reliability. Ferhatoglu et al recently reported an association between high VPI scores and low DISCERN scores in their review of cardiopulmonary resuscitation videos on YouTube.We identified that the most viewed video about endometriosis was uploaded in 2018 by Drugs.com, which is a website that provides information on prescription drugs. This is a well-organized video containing information on the cause of endometriosis. The second most viewed video was uploaded in 2013 by Nucleus Medical Media, which is the same company that uploaded the video with the highest number of views and VPI even during a YouTube study related to cesarean section.There was no significant difference in the scores of the groups or videos uploaded before and after 2018, whereas the number of likes, view ratio, and VPI, which are indicators of the popularity of videos, were significantly higher in the group of videos uploaded after 2018. Considering that there is no difference in scores between the 2 groups and the increase in the number of video uploads after 2018, this can be interpreted as YouTube becoming more popular and laypeople can easily access and produce content.,23–29 However, recent studies on the benefits of YouTube are also increasing.–32 Therefore, in the future, providing high-quality medical information using YouTube in the field of obstetrics and gynecology is a possibility.It can be seen that the search volume of endometriosis using websites or YouTube is gradually increasing Figs. ,3. In thThis study has some limitations. We analyzed only 52 YouTube videos identified using the keywords “endometriosis,” “endometrioma,” and “endometriotic cyst.” It was classified according to the number of views, and only videos in English were included; thus, a sampling bias may have occurred. The scoring system was based on previous studies; however, there is still no unified standard for evaluating videos. Thus, more verification is needed to ensure that the assessment method is suitable for accurately evaluating the quality of endometriosis videos.Our study found that YouTube videos regarding endometriosis were misleading or inaccurate and presented a risk of harmful consequences. The results suggest that the quality of information in videos on endometriosis is poor, and YouTube is currently not an appropriate source of such information for patients with endometriosis. Credible videos with accurate information and clear, high-quality operative clips with proper scientific commentary should be uploaded by medical professionals and medical institutions to critically and rapidly appraise the quality of online video-disseminated information on endometriosis. In addition, advanced filtering using categories by YouTube’s staff appears to be necessary.Conceptualization: Kyong-No Lee, Sung-Ho Park.Data curation: Kyong-No Lee, Hyun-Jin Tak, So-Yoon Park.Formal analysis: Kyong-No Lee, Hyun-Jin Tak, So-Yoon Park.Funding acquisition: Sung Taek Park, Sung-Ho Park.Investigation: Hyun-Jin Tak, So-Yoon Park, Sung Taek Park.Methodology: Sung-Ho Park.Project administration: Kyong-No Lee, Sung-Ho Park.Resources: Hyun-Jin Tak, So-Yoon Park, Sung Taek Park.Supervision: Sung Taek Park, Sung-Ho Park.Validation: Sung Taek Park, Sung-Ho Park.Visualization: Hyun-Jin Tak, So-Yoon Park.Writing – original draft: Kyong-No Lee, Sung-Ho Park.Writing – review & editing: Kyong-No Lee, Hyun-Jin Tak, So-Yoon Park, Sung Taek Park, Sung-Ho Park.


Treating arteriovenous malformation (AVM) is challenging because of the high recurrence rate and because incomplete resection or embolization can induce aggressive growth. However, a standard strategy is not fully established. Although transcatheter arterial embolization (TAE) is currently almost always part of the treatment, in many cases, single treatment is not curative and only palliative. Additionally, the success and complication rates associated with TAE alone are unclear, and there has been limited study of staged TAE for facial AVMs. Furthermore, few reports have described the details of the procedure.We report two cases of AVM of the upper lip in patients who were successfully treated by staged super-selective TAE at several-month intervals using ultra-thin microcatheters and n-butyl-2-cyanoacrylate.Staged and super-selective TAE may prevent complications and provide high curability and might be a useful treatment in cases of AVM. Arteriovenous malformation (AVM) is a rare vascular anomaly. Approximately half of extracranial AVMs occur in the head and neck , and the left infraorbital artery and left ophthalmic artery, and the AVMs drained into bilateral facial and angular veins. The lesion was diagnosed in accordance with Cho’s classification as type IIIb AVM, indicating multiple shunts between the arterioles and venules, with dilated fistulae  was inserted via bilateral femoral arteries simultaneously, and the sheath was advanced into bilateral ECAs. A 5-F balloon catheter (Medtronic) was placed in the proximal ECA for flow control. A thin microcatheter with a 1.3-F tip  and microwires  was coaxially navigated via the balloon catheter into the feeding artery as far distally as possible. A 20% nBCA-lipiodol mixture was injected through the microcatheter with plug and push technique under arterial balloon occlusion until filling of the draining veins close to the shunted points was achieved. The embolized feeders in each session were as follows: right (rt.) superior labial artery, first session (20% n-BCA); left superior labial artery, second and third session (20% n-BCA). Subsequent carotid arteriography showed devascularization of the AVM (Fig. The treatment of AVM remains challenging owing to the high rate of recurrence, which is reported in up to 80% of patients (Fernández-Alvarez false, Cho et al. (Cho false, The complications associated with AVM therapy comprise mucosal necrosis requiring surgical repair, permanent nerve injury, and transient subcutaneous edema (Griauzde false, The main goal of AVM treatment is to occlude the arteriovenous shunts. Embolization of proximal arteries may lead to lesional growth with the development of collateral flow, which makes further interventions difficult. For successful embolization, it is essential to deliver embolic agents properly into both the shunting points and the draining veins, sparing the normal arterial branches supplying adjacent areas. The use of ultra-thin catheters allows approaching the distal feeding arteries, and injecting n-BCA from the level closest to the shunted points might result in high curability.Few reports of the successful use of staged TAE for head and neck AVMs have been published, although a few case reports have described the details of the procedure (Melia false, Staged TAE might be safe thanks to the intervals between sessions, which allow for repair of any tissue damage and prevention of irremediable conditions. Staged TAE may prevent complications and provide high curability and might be a useful treatment in cases of AVM.


They play an important role in pH regulation and in the balance of body fluids and are involved in several functions such as homeostasis regulation and cellular respiration. For these reasons, they have been studied as targets for the development of agents for treating several pathologies. CA inhibitors have been used in therapy for a long time, especially as diuretics and for the treatment of glaucoma, and are being investigated for application in other pathologies including obesity, cancer, and epilepsy. On the contrary, CAs activators are still poorly studied. They are proposed to act as additional (other than histidine) proton shuttles in the rate-limiting step of the CA catalytic cycle, which is the generation of the active hydroxylated enzyme. Recent studies highlight the involvement of CAs activation in brain processes essential for the transmission of neuronal signals, suggesting CAs activation might represent a potential therapeutic approach for the treatment of Alzheimer’s disease and other conditions characterized by memory impairment and cognitive problems. Actually, some compounds able to activate CAs have been identified and proposed to potentially resolve problems related to neurodegeneration. This review reports on the primary literature regarding the potential of CA activators for treating neurodegeneration-related diseases.Carbonic anhydrases (CAs) are a family of ubiquitous metal enzymes catalyzing the reversible conversion of CO The compounds of series 18, ureas or thioureas 19 . . 34–36 h34–36) and natural (37–39) derivatives were assayed as activators of four human isoforms of CA, namely hCA I, II, IV, and VII. Most of compounds 34–39 activated hCA I and VII in the micromolar range, with KA values ranging between 0.12 µM and 34.7 µM, whereas they were shown to be weak activators of hCA IV (KA 53.4–80.5 μM) and not active towards hCA II . In this series, two natural compounds, L-(+)-ergothioneine (37) and melatonin (38), are noteworthy and deserve to be further developed as they were shown to be selective and quite potent hCA VII activators . Instead, spinacine (39) was shown to be the best hCA I activator with a KA value of 7.21 μM that, unfortunately, is higher than the histamine one . . 41) and41a,b,d and four Schiff bases 42a–d were synthetized and tested as activators on hCA I, II, IV, and VII isoforms, as reported in Three bis-spinaceamines 41a,b,d are the most interesting compounds since they can be considered as quite potent and selective activators , regardless of the spacer (X) that featured. Instead, bis-histamine Schiff bases 42a–d display moderate  activity on all four isoforms with compound 42d (furyl substituted), which selectively activates the hCA VII isoform (KA 85 nM) [The data obtained evinced that hCA VII is the most sensitive isoform to be activated by all the tested compounds. In particular, the three bis-spinaceamines A 85 nM) . 7, histidine 2  and carnosine methyl ester (47) were derivatized, introducing electron-withdrawing halogens, and obtaining mono (X2 = H)- and di-halogenated  analogues  and46 and 47 resulted in activating in a diverse manner the hCA I, II VII, XII, and XIV isoforms tested. The most interesting results are summarized in The obtained compounds of series The differences in the activation properties of the synthetized compounds can be correlated both to the size of the halogens inserted into the molecular structure and their electron-withdrawing properties, as they modify the distribution of electrons into the ring and, in turn, the nucleophilicity and the basicity of the entire molecule that could interfere with the ability to activate the enzyme. 46 are more effective hCA I and II activators compared to the L-Car-OMe 47 counterparts, but are less effective than the corresponding histamine derivatives , which is a mono-halogenated Boc-substituted derivative. Its analogue with the deprotected amine  or the corresponding di-halogen derivative  are instead less effective activators of hCA I and II. This general trend is observed for all the compounds of the series.The best hCA I and II activator is compound 46a, namely 47a, weakly activated hCAI and II , while it showed to be an effective activator of isoform VII (KA 0.81 μM), which is more effective than the corresponding L-His-OMe derivative 46d (KA 9.7 μM). In fact, in general, L-Car-OMe derivatives 47 proved to be effective activators of the cerebral isoform hCA VII, which is weakly activated by L-His-OMe derivatives 46 and also by the corresponding histamine derivatives , which is a di-halogenated derivative; the relative Boc- analogue 47c is instead a less effective hCA VII activator (KA 4.0 μM). Thus, series 47 displayed an opposite trend with respect to series 46 for what concerns the activation of hCA I and II isoforms.The best-performing hCA VII activator is compound 46 and 47, with values of KA, aside for very few exceptions, in the range of 0.83–64.7 μM for hCA XII and 0.92–40.8 μM for hCA XIV [hCA XII and XIV are both little activated by the two series 43  compounds for this isoform. Isoform hCA II was poorly activated (KA > 76.6 μM) by all the compounds tested. Also, hCA VA was shown to be weakly activated (KA 6.4–52.8 μM), and the most active compound for this isoform was shown to once again be carnicine 48b (KA 6.4 μM).In general, compounds ide 48a,  and carnA 1.14–50.2 μM), with L-anserine 48c (A 1.14 μM) being the best and most selective activator of this isoform [In the end, the hCA IX isoform was a little better activated  and ex-vivo  of all the CA isoforms tested.Compounds This is the first example of enzyme activation with nanoparticles and may lead to interesting biomedical applications . 52, selenium 53, and tellurium 54 , hCA VA (KA 5.2–23.3 μM), and the brain-associated cytosolic CA isoform, hCA VII (KA 78.9–44.9 μM), without distinction about the presence of S (52), Se (53), or Te (54); hCA II was not activated by these compounds  (All the synthesized compounds of series  100 μM) .53 and 54 antioxidant compounds able to inhibit the formation of ROS metabolites, thus preventing cellular stress and damage, which are characteristics of neurodegenerative diseases. More specifically, they were tested as mimics of glutathione peroxidase and the best compounds were the aminotellurides (54). For this reason, these compounds can be considered able to contrast the progression of neurodegenerative processes due to their dual action: inhibition of oxidative stress (thanks to tellurium and selenium properties) and strengthening of synapses and neuronal activity (thanks to CAs activation) [In addition, the presence of Se and Te makes derivatives of series ivation) . Several drugs already used in therapy for other aims and carrying proton-shuttling groups in their structure such as timolol  and propThese compounds feature a central heterocyclic scaffold, which is not directly correlated to histamine or histidine, functionalized with an amino group linked to an alkyl spacer.55 , establishing a ternary complex with the enzyme and the substrate. It binds at the entrance of the active site, where His64 is located, and in a different position compared to the substrate, as timolol binding does not impact on the affinity of the substrate to its target, only increasing maxv in enzymatic kinetics [Timolol 55  is an ankinetics . 56, sertraline 57, and citalopram 58  and fluoxetine 56 (175% at 1.0 μM), instead of hCA II, which is better activated by citalopram 58 (170% at 1.0 μM), and phenylalanine 1 (175% at 1.0 μM). Sertraline is the weaker activator of both hCA I and hCA II . These data are important because they pave the way to a new therapeutic approach that is particularly direct against Alzheimer’s disease associated with major depression [All three SSRIs lanine 1 . In partpression . 59 NHR’, and, as reported, this type of amine could effectively activate CAs [Many psychoactive substances possess the phenethylamine scaffold and the general formula Ar–CHvate CAs ,35.60, methamphetamine 61, phentermine 62, mephentermine 63, and chlorphenteramine 64 , while they moderately activate hCA XIII and XIV . Isoform hCA IX resulted not significantly activated by the amines investigated in this study, while the other tumor-associated isoform hCA XII demonstrated to be significantly activated by amphetamine 60, methamphetamine 61, and chlorphenteramine 64 with KA values in the range of 0.64–0.94 μM, but less activated by the other amines (KA range 3.24–6.12 μM). The most activated isoform is hCA IV . In particular, the best hCA IV activators are methamphetamine 61 and chlorphenteramine 64 with KA values of 51 nM and 55 nM, respectively, followed by phentermine 62 and amphetamine 60 with KA values of 74 nM and 94 nM, respectively. Isoforms hCA VA and VB are effectively activated by compounds 60–64 with KA values in the range of 0.24–2.56 μM and, particularly, the best activator of hCA VA showed to be chlorphenteramine 64 with a KA 310 nM; the best activator of hCA VB demonstrated to be mephentermine 63 with a KA 240 nM. The data obtained .Of note, the cerebral isoform hCA VII was successfully activated by all five compounds with KSince some CAs  are abundant in the brain, some of the cognitive effects of these psychoactive compounds might be related to the activation of these enzymes, bringing new light to the intricate relationship between CA activation by these substances and their multitude of pharmacologic activities . 1, H2, H3, and H4) agonists/antagonists towards four hCA isoforms expressed in the human brain, namely hCA I, II, IV, and VII, were investigated [Very recently, the CAs activating effects of a series of histamine receptor  were tested, and they were all shown to be moderate activators of hCA I (KA range from 52 nM to >100 μM), hCA II (KA range from 82 nM to >100 μM), hCA IV (KA range from 1.02 μM to >100 μM), and hCA VII , the thiazole derivative 68 (KA 0.87 μM), burimamide 69 (KA 0.88 μM), metiamide 70 (KA 0.98 μM), and impromidine 71 (KA 0.72 μM), which are structurally related to histamine as they all bear the imidazole ring in their structure, except for compound 68, which has a thiazole ring. In particular, 1-methyl histidine 67 has an additional proton transfer group represented by the carboxyl moiety, thus resulting in being much more potent (KA 52 nM).In particular, 30 compounds , followed by other compounds ranging between 0.11 and 7.05 μM. In particular, some interesting SARs were observed for this isoform, resulting from the presence of more lipophilic groups  able to promote a greater and more selective hCA VII activation [Interestingly, hCA VII showed to be the most activated isoform, and impromidine tivation . 75 and di-urea 76 compounds  or for modifying lipophilicity and, in turn, the activity of the enzyme (in series 75). Fourteen derivatives were synthetized, in which R and R′ can both be alkyl and aryl groups, introduced for modulating the linker-length between the two triazole moieties  and 76b (KA 0.94 nM) (75 is compound 75a (KA 6.1 nM). Moreover, for series 75, it was proven that the activity for hCA I diminishes with the increasing of the chain-length; SARs are instead more complex for series 76. In general, regarding hCA I activation properties, KA values are influenced by the length of the chain for series 75 and by the linker between the two rings for series 76 [Mono-ureas 0.94 nM) . Whereaseries 76 . 75 and 76, with KA values in the range of 0.05–6.7 μM. In particular, in series 75, the best hCA II activator is compound 75a (KA = 1.7 nM), as well as for hCA I (KA 6.1 nM), whereas compounds that activate the most hCA II belong to series 76. The best hCA II activator showed to be 76b (KA 0.05 nM), which also strongly activates hCA I (KA 0.94 nM), resulting in a very potent dual hCA I/II activator. In this series, also compound 76c, with the 1,4-phenylene linker and the amino group, well activated the hCA II isoform (KA 0.12 nM). Even the hCA II isoform results in being well activated by the compounds of the two series 76b is the most effective hCA II activator (KA 0.05 nM) ever reported, and has shown to be a lead compound for the development of clinical candidates in cognitive impairment or other diseases characterized by a deficit of hCA I and hCA II isoforms, such as Alzheimer’s disease or aging [Interestingly, compound or aging . 55  with respect to hCA I and IV (KA range from 10- to 100-fold higher), with hCA IV being the less-activated isoform (KA 1.01–12.9 μM).All amino alcohol derivatives of series 77a (A 79 nM) of this study, while the iso-propylamines 77b and 77c  and 10- to 100-fold selectivity with respect to the other CA isoforms tested [In particular, compounds belonging to the tert-butylamino series turned out to better activate isoforms hCA I and II compared to those belonging to the iso-propylamino one. In fact, tert-butylamine 77a  is the m and 77c  showed ps tested .78  with potency in the micromolar range, while it was inactive on hCA II. In particular, clonidine showed to best activate hCA VII and XIII isoforms with KA values of 8.4 μM and 7.8 μM, respectively [Imidazoline ring is considered a bioisoster of the imidazole moiety and it is present in the antihypertensive agent clonidine 78 . In 202078  and, as clonidine, they showed to be inactive on hCA II, while resulting good activators of hCA I, VA, VII and XIII isoforms  were derived for these compounds that can be applied all over the hCA isoforms: the substitution with methyl at N-1 (R1 = CH3) improves the performance of compounds with respect to the unsubstituted ones (R1 = H), as well as the alkyl aryl chain compared to the alkyl one (R2). Finally, the amino or methylamino group is preferable to S as a linker (X) between the heterocycle and the alkyl-aryl chain. In addition, some other SAR were obtained and showed to be different on the various isoforms, suggesting that, in series 79, it could be possible to develop new compounds more selective for a particular CA isoform. In particular, the most interesting compounds are 79a and 79b, showing to be potent (KA 0.9 μM) and quite selective activators of hCA V and VII, respectively.In general, from the data obtained, it is evinced that most of the derivatives of series In an effort to improve both potency and selectivity, in 2022, Chiaramonte et al. developed histamine-related compounds by replacing the imidazole ring with several five-membered heterocycles , and changing the length of the aliphatic chain that leads to the primary amino group . 7 , while the other isoforms were activated with higher KA values .According to these modifications, 23 compounds were synthetized and biologically tested on hCA I, II, VA, VII, and XIII isoforms, but only a few of them demonstrated to activate these isoforms better than the lead compound histamine 7 . In gene80, 81, and 82 showed an interesting selectivity for activating hCA I over hCA II, VA, VII, and XIII  for all tested compounds. Some derivatives, 84b (R = p-OH-C6H4), 85a (R = CH3), and 85c (R = CH2CH2COOH) activated the hCA VII isoform with KA in the low micromolar range , but without a clear correlation between enzyme activation and chemical structure. The most activated isoform was hCA I with KA values ranging from 9.0 to 6.39 μM for all compounds 83–87: of note, the 1H-indazole series 84 , with compound 84b (R = p-OH-C6H4) being the best hCA I activator (KA 9 nM). Moreover, compounds 85b (KA 15 nM towards hCA I), which also displayed the best percentage of nNOS inhibition, thus showing to be a dual agent able to perform a selective nNOS inhibition and hCA I activation. Derivative 85b is therefore a promising lead compound to develop new drug candidates for the therapy of neurodegeneration [Anyhow, the most encouraging compound is the indazole derivative neration . 88–90, In 2021, Barresi et al.  develope88–90 were decorated at N1 with a benzyl group in all series, while different substitution patterns at 3- and 5-positions were exploited. Specifically, in series 88 and 89, 3-position features a glyoxylamide (88) or carboxamide (89) moiety in which the N-atom is substituted (R1) with polar (hydroxypropyl or hydroxyethyl), protonatable groups (dimethylaminopropyl or diethylaminoethyl) or with a benzyl group; conversely, in series 90 an ethyl ester is present at 3-position of the scaffold. The indole 5-position is substituted with hydroxyethyl or with protonatable groups (dimethylaminopropyl or dimethylaminoethyl or diethylaminoethyl) [The indole-based derivatives noethyl) . A values ranging between 69.1 μM and values > 100 μM. Isoform hCA VA demonstrated to be quite activated by all the tested compounds with KA values in the range of 24.4–59.8 μM. The cerebral isoform hCA VII proved to be the most sensitive to the activation by all compounds with KA values ranging between 7.2 and 10.8 μM, independently from the position of the basic group, leading to speculation that what matters is its presence, rather than its position at the scaffold. The best hCA VII activators belong to series 89 and 90, namely compounds 89a, 90a, and 90b, with KA values of 7.5, 7.2, and 8.2 μM, respectively [Nine compounds were synthetized and tested on the main isoforms expressed in human brain, namely hCA I, II, VA, and VII. Isoforms hCA I and II showed not to be significantly activated by all compounds, with Kectively . Due to 89a, 90a, and 90b were first tested for their cytotoxicity on microglial cells by treating human C20 cells with micromolar concentrations of the target compounds and, then, cell viability was evaluated by MTS assay. The data obtained revealed that, while compounds 90a and 90b caused a slight reduction in cell viability, compound 89a did not induce cytotoxicity in the human microglial cell line C20 at any tested concentration.In particular, compounds 89a was selected for further determination of its capability to produce BDNF (brain-derived neurotrophic factor) on the same cell line and, interestingly, it showed to induce the production of BDNF as good as microglia [Given these results, compound icroglia ,75.Going deeper, there is a link between the process of activating CAs and the process which leads to the release of BDNF, and this link is the correct acidification process. Indeed, it is important for activating CAs because an activator behaves as an additional proton shuttle towards His64 and so it must have a protonatable moiety in its molecular structure; in addition, it is also important for releasing BDNF from secretory granules, since correct acidification is a fundamental step during the release of BDNF . 89a was found to possess the physicochemical parameters suitable for reaching the CNS.Furthermore, Carbonic anhydrases activators (CAAs) are still poorly studied compared to carbonic anhydrases inhibitors (CAIs). Indeed, while CAIs are already used in therapy for the treatment of a number of pathologies such as glaucoma, epilepsy, and obesity, CAAs to date, have not shown relevant pharmacological applications and are still under study. CAAs are proposed to participate in the proton transfer, acting as additional proton shuttles towards His64 in the rate-limiting step of CA catalytic cycle, that is, the generation of the active hydroxylated state of the enzyme from the inactive acid form. In this respect, CAAs must feature two main structural requirements: to be a small molecule suitable for the active site and to possess at least a protonatable basic moiety with pKa values in the range of 6.5–8.0 for participating in the proton transfer. Interest in CAAs has increased thanks to recent findings reporting an involvement of CAs in cognitive and memory disorders, suggesting that the activation of this enzyme may represent a potential effective strategy for the strengthening of synaptic efficacy. In particular, cerebral isoforms of CAs  could be a valid target for the development of new agents useful for the treatment of neurodegenerative pathologies such as Alzheimer’s disease in which these isoforms showed to be less expressed. Indeed, it was demonstrated that the administration of an activator to experimental animals determined the enhancement of synaptic efficiency and the consolidation of cognition, spatial memory, and learning. Based on these findings, a number of CAAs are under study as potential candidates for the development of new drugs for the treatment of disorders in which memory and cognition are impaired. In this context, this paper reviewed the current state of the art concerning CAAs, focusing attention on those compounds that potently and selectively activate CAs, with particular regard to cerebral isoforms, and for which preliminary biological evaluations were carried out in order to evaluate their potential application in therapy. A) values in the very low nanomolar range.Amino acids and amine represent the most investigated compounds in the field of CAs activation. In fact, many of the compounds here described were obtained using histamine or histidine as lead compounds, and involved, thanks to previous SAR studies, the modification of either the heterocyclic ring, the amino portion, or the introduction of portions that could improve the activity and selectivity for the CA isoforms of interest. Some of them showed to strongly activate hCAI, hCA II, and/or hCA VII isoform with activation constant (KAs a summary, the hCA activation properties of the most interesting compounds reviewed are highlighted in In conclusion, in the present review we highlighted the peculiar decorations of CAAs, describing their involvement in the proton shuttling in the rate-limiting step of the CA catalytic cycle. Furthermore, this report provides an exciting outlook on existing data that might help the medicinal chemist in the design and development of more efficient and selective new leads for future in vitro and in vivo studies, so that novel drug candidates can be unveiled and introduced onto the market and into the clinical pipeline.


To understand a dialogue, we need to know the topics that are being discussed. This enables us to integrate our knowledge of what was said previously to interpret the current dialogue. This study involved a large-scale behavioral experiment conducted online and a separate fMRI experiment, both testing human participants. In both, we selectively manipulated knowledge about the narrative content of dialogues presented in short videos. The clips were scenes from situation comedies that were split into two parts. The speech in the part 1 clips could either be presented normally or spectrally rotated to render it unintelligible. The part 2 clips that concluded the scenes were always presented normally. The behavioral experiment showed that knowledge of the preceding narrative boosted memory for the part 2 clips as well as increased the intersubject semantic similarity of recalled descriptions of the dialogues. The fMRI experiment replicated the finding that prior knowledge improved memory for the conclusions of the dialogues. Furthermore, prior knowledge strengthened temporal intersubject correlations in brain regions including the left angular gyrus and inferior frontal gyrus. Together, these findings show that (1) prior knowledge constrains the interpretation of a dialogue to be more similar across individuals; and (2), consistent with this, the activation of brain regions involved in semantic control processing is also more similar between individuals who share the same prior knowledge. Processing in these regions likely supports the activation and integration of prior knowledge, which helps people to better understand and remember dialogues as they unfold. Understanding a conversation involves knowing what was previously said, especially when picking up a conversation after a break. Here we manipulated prior knowledge about the topic of conversation while participants watched dialogues between two people. Participants watched video clips for which they either had heard the preceding dialogue normally or as incomprehensible jumbled speech. Even in the conversations with jumbled speech, the general situation was clear . Prior knowledge resulted in better memory for the dialogues and also more similar recalled descriptions of the conversations across participants. Furthermore, the coherence of brain activity in language regions was increased across participants who shared the same prior knowledge.Understanding an unfolding narrative, such as a conversation from a television show, requires multiple inter-related cognitive processes, yet it is something that we typically accomplish with remarkable ease . In addiA fruitful method of investigating the brain regions engaged during relatively lifelike situations is to scan participants while they listen to stories, or watch video clips, and measure the degree to which brain activity is synchronized across individuals  was acquired with the following parameters: FOV, 256 mm; TR, 2.73 s; TE, 3.57 ms; 1.0 × 1.0 × 1.0 mm voxel size.All EPI images were preprocessed using SPM 12 . Field maps were used to correct for image distortions and susceptibility-by-movement effects using the Realign and Unwarp option . All EPIBehavioral data were analyzed using R, and mixed-effects models were fitted using the lme4  and lmerWe fitted separate linear mixed-effects models for the subjective memory ratings in experiments 1 and 2. We used condition as a fixed effect and allowed its slope to vary across participants and videos, and we also included a random intercept for subject and video . Note that, because of convergence issues in experiment 2, we dropped the random slope term. We used logistic mixed-effects models for the free-recall trials in experiment 1 and the short memory questions in experiment 2. We used the logit link function and modeled the responses as coming from a binomial distribution. We used condition as the fixed effect with random slopes and intercepts for subject and videos .For the free-recall data collected in experiment 1, we scored each trial as either remembered or not. Trials on which participants did not provide any correct details of the video or did not provide information that was not present in the memory cue video were rated as not remembered and scored 0. Trials on which participants correctly remembered the gist of the clip and provided some details about the clip were scored 1 . Importantly, the free-recall data allowed us to examine whether participants provided more consistent descriptions for the HC videos when compared with the LC videos. We used the Google Universal Sentence Encoder USE;  to examip-value.After embedding each recollected trial into this semantic space, for each video we extracted the recall responses that were given by participants who saw the video in the HC condition and by the other participants who saw the same video in the LC condition. For example, for video 1, 74 participants correctly remembered it and had seen it as HC video, and another 71 participants correctly remembered it and had seen it as LC video. For each video, we created two average semantic vectors, one for the HC condition and one for the LC condition. We then computed the similarity between each participant’s embedded recall description and the average description of the same video seen in the same condition. We used the Pearson correlation coefficient to compute similarity between the embedded recall descriptions. Note that the average descriptions were always recalculated to not include the description of the current participant (using a “leave-one-subject-out” procedure). For instance, for video 1, we would compute the similarity between the response of participant 1 for that video and the average responses of all other participants who remembered that video in the same condition. We then Fisher transformed and averaged these similarity scores across participants to result in two average consistency scores per video (one for the HC condition and one for the LC condition). We then compared for each video for whether participants on average provided more consistent responses for the HC condition than for the LC condition using a nonparametric permutation test. We flipped the sign of the difference between HC and LC videos 5000 times, which is effectively permuting the conditions the videos are in. This allowed us to construct a null distribution with which to compare the observed HC and LC difference and obtain a www.bobspunt.com/bspmview), which implements the MNI coordinates from the Anatomical Automatic labeling 2 toolbox for SPM 12. Significance was tested with a one-sample random-effects t test against zero. Unless otherwise stated, images were whole-brain cluster corrected for FWE at p < 0.05 at a voxel height-defining threshold of p < 0.001.Data were analyzed with SPM 12, the CoSMoMVPA toolbox , and cusA single task regressor for each of the four conditions  of each video were removed to remove transient onset effects that can lead to artificially high ISCs .To examine the general ISC effect, for each participant and each video we computed the following: (1) the correlation between their own video clip-specific time course and the average time course for the rest of the participants watching the same video clip; and (2) the correlations between their own video clip-specific time course and the average time course for the rest of the participants watching the other video clips shown within the same run . This resulted in a total of 100 correlations of interest per participant: 20 ISCs while watching the same video clip, and 80 correlations while watching different video clips. The key contrast is the difference in ISCs when watching the same video clip versus the ISCs when watching different video clips . There were 9 and 10 people in the two condition lists. For each participant, we computed the correlation between their own video clip-specific time course and the average time course for the rest of the participants in the same condition list watching the same video clip. This resulted in 20 time course correlations for each participant: 10 from the HC video clips and 10 from the LC video clips. For this analysis, the key contrast was for the correlations from the HC video clips versus the LC video clips , the raw correlations were Fisher transformed before the contrasts of interest were computed. The contrasts were conducted for each participant, resulting in 19 brain maps of the difference in correlations that were used in the group analyses. Since these brain maps are not necessarily independent , we usedhttps://osf.io/f9jd4/).We additionally conducted ISC analyses of the data from the part 1 video clips to identify brain regions that are more synchronized across participants watching videos with intelligible speech, compared with unintelligible speech. These analyses do not address our experimental hypotheses but are presented in supplementary materials for completeness (see https://osf.io/f9jd4/).We also conducted exploratory intersubject analyses using the spatial patterns of brain activity [intersubject pattern similarity (ISPS)] averaged over the whole of the video clips, rather than the temporal ISC. These were conducted for the same contrasts as the ISC analyses described above. Full details of the methods and results of these analyses are described in the supplementary materials (see https://osf.io/f9jd4/).Finally, based on recent studies examining reinstatement effects in hippocampus when participants were listening to stories referring to previously heard information , we examt(24.02) = 6.62, p < 0.001). Participants also found the HC videos to be more coherent  = 8.79, p < 0.001). Similarly in experiment 2, participants rated their memory for the HC compared with the LC videos to be more vivid (t(323.04) = 4.42, p < 0.001). They also found the HC versus the LC videos to be more coherent (t(324.86) = 4.83, p < 0.001) and more engaging (t(323.86) = 4.62, p < 0.001; Participants in experiment 1 rated their memory for the HC videos as more vivid compared with the LC clips . In experiment 2, participants were able to answer 72.2% of the memory questions, which is a high level of performance, given the fact that the questions were open ended . The main purpose of the online study was to examine the semantic consistency across participants of their recalled descriptions of second-half clips. We also used the Google USE to quantify the semantic similarity of free-recall responses for the videos in HC and LC conditions. Specifically, we examined how similar individual participants’ free-recall responses were to the group average free-recall responses, and, critically, whether the similarity was higher when the group had watched the video in the HC condition compared with the LC condition. Consistent with the view that the provision of prior knowledge guides and constrains how the content of the concluding part of the dialogue is interpreted and represented, we found that second-half descriptions were more similar across participants when the videos were seen in the HC condition when compared with the LC condition (t(19) = 3.71, p = 0.001; see Participants freely recalled on average 76.8% of the video clips and performed better on the HC videos when compared with the LC videos . This is consistent with previous studies using videos . For further discussion, see https://osf.io/f9jd4/ .The contrast of watching videos versus the active baseline task revealed higher activation in visual, auditory, medial, and anterior temporal cortices . Key behavioral results replicated closely across the two studies: prior knowledge resulted in better memory for the dialogues as well as increased subjective ratings of vividness and coherence. In the online behavioral experiment, using automated text-based measures, we showed that across participants, the recalled descriptions of the HC clips were semantically more similar to each other compared with the LC clips. In the fMRI experiment, we identified a number of brain regions that showed higher ISCs in the HC condition, particularly those associated with the semantic network of the brain .Our results extend and clarify the findings of In both our online behavioral experiments and fMRI experiments, prior knowledge improved cued-recall memory accuracy for details from the part 2 clips. It also increased subjective ratings of how coherent and engaging the part 2 clips were as well as how vividly they could be remembered. These effects are consistent with previous studies , 2021. NUnderstanding something as complex as a scene from a television sitcom requires the activation and integration of numerous different semantic concepts. Providing that the first part of the conversations provides a framework that can help interpret what is said during the second part. To give an example, in one of the part 2 videos, a character claims that penguins once “filled the skies” but are now unable to fly because they lack the confidence to do so. Participants viewing this clip in the HC condition can relate this discussion back to the first part in which the characters discuss how low self-esteem had a negative effect on a colleague’s work. However, participants in the LC condition do not have this background context to draw on and tend to form more idiosyncratic interpretations of the scene.Our first experiment used a universal sentence encoder to investigate whether knowing the content of the dialogue from the first half of the video resulted in greater similarity between people’s descriptions of the second half of the videos. This was found to be the case, suggesting that prior knowledge constrained the elements of the events that were recalled to be more similar across participants. Since these effects were seen when recalling the clips after several minutes, we cannot be sure whether the greater alignment across participants happened during recall, or when initially watching the second half clips. However, given that we also observed greater neural ISCs when participants watched the second-half clips in the HC condition, it is likely that prior knowledge constrained how participants interpreted the dialogues and encoded them to memory.https://osf.io/f9jd4/, Supplementary Materials) We additionally found higher ISCs in four brain regions while participants viewed videos in the HC condition, including two regions identified in the earlier study—the left AG and IFG. The fact that activity is more synchronous in these regions across participants who share the same prior knowledge suggests that processing in these regions is modulated by this knowledge. Consistent with the conclusion of In an earlier study with a similar design, we found that HC clips were associated with increased activity in the AG, IFG, and MTG . Our preThe brain regions where ISCs were modulated by prior knowledge have been particularly associated with “semantic control”—the selection and retrieval of appropriate semantic information in the face of competing but irrelevant information . A numbeThese empirical findings mesh well with recent theoretical accounts of processing with DMN structures. The inferior lateral parietal cortex has been viewed as supporting a “buffer” for episodic information  or for lIt is possible that our fMRI ISC results are caused by alignment of other cognitive processes beyond semantic processing. Sharing knowledge of the preceding dialogue might lead people to allocate attention to the second-half video in a more consistent manner or engage more similar emotional processes. However, our design aimed to minimize the likelihood of this. The part 1 clips in both HC and LC conditions were visually identical and therefore people can readily see the characters in the videos, what they were doing, their emotional states and where the videos were set. The key information that participants lacked in the LC condition was the content of the part 1 conversations. It remains possible that the contents of the dialogues themselves elicit emotional or empathic responses that differ in the HC and LC conditions. Further research may be able to tease apart the processing of the semantic concepts that comprise a narrative and the emotional responses to that narrative.How is the information from the part 1 clips stored before it is used to process the continuation of the conversations in the second-half clips? Since we used filled intervals between the first and second halves of the clips, it is unlikely that the information is actively held in working memory, either in the classic sense of a short-term buffer  or held https://osf.io/f9jd4/). Two previous studies have also implicated the right, but not the left, hippocampus, in the integration and differentiation of narrative storylines  ongoing semantic processing of events as they unfold and (2) the content of what can be later recalled about these events. Our findings highlight a role for the angular gyrus and inferior frontal gyrus in the processing of concepts necessary to understand a complex dialogue. These results provide new insights into how the brain represents and updates narrative information.


Inflammation of the rectal remnant may affect the postoperative outcome of ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis (UC). We aimed to determine the extent of inflammation in the anastomotic area during IPAA and to investigate the impact of proctitis on postoperative complications and long-term outcomes.Three hundred thirty-four UC patients with primary IPAA were included in this retrospective case–control study. The histopathologic degree of inflammation in the anastomotic area was graded into three stages of no proctitis (“NOP”), mild to medium proctitis (“MIP”), and severe proctitis (“SEP”). Preoperative risk factors, 30-day morbidity, and follow-up data were assessed. Kaplan–Meier analysis was performed in the event of pouch failure.n = 40; 28.2%, p = 0.017), pouchitis , and pouch failure . The time interval to pouch failure was 5.0 (4.0–6.9) years among NOP, and 1.2 (0.5–2.3) years in SEP (p = 0.036). ASA 3, pouchitis, and pouch fistula were independent risk factors for pouch failure.The prevalence of proctitis was high . During follow-up, the incidence of complications was highest among SEP: resulting in re-intervention (Proctitis at the time of IPAA is common. A high degree of inflammation is associated with poor long-term outcomes, an effect that declines over time. In addition, a higher degree of proctitis leads to earlier pouch failure. Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the gold standard in the surgical treatment of ulcerative colitis . Accordin = 31) , insufficient histopathologic (n = 26), or follow-up data (n = 17). Three hundred thirty-four UC patients with primary IPAA and sufficient documentation were included in this retrospective case–control study. The results of the study were reported according to the “Strengthening the Reporting of Observational Studies in Epidemiology” (STROBE) guidelines [A prospectively maintained database containing the records of 457 patients who had received IPAA in our tertiary referral center between 2000 and 2020 was screened for study participation. Of those, 390 (85.3%) patients were diagnosed with UC. Figure All two- and three-staged IPAA procedures were included. In patients exhibiting a high activity of UC, under high-dose of steroid immunosuppression, reduced general condition, and nutritional status, or in all emergency procedures, a three-staged approach was chosen , 9. The All patients included in the study had a complete histologic workup of their resected bowel specimens. In two-staged IPAA, the area of the distal resection margin of the proctocolectomy specimen was considered as the region of interest for this study. In three-staged IPAA, the rectal remnant that was resected before IPAA creation during the second step was analyzed. Several scoring systems for histologic chronicity and activity of UC had been developed, such as the Geboes score , or morep value < 0.05, marked with two asterisks**. A p value < 0.1 was considered a trend and marked with one asterisk*. Multivariate analysis was performed through logistic regression. Covariates were included in the model stepwise using forward selection based on the likelihood ratio and the Akaike information criterion. Kaplan–Meier analysis and log-rank tests were used to compare the degree of inflammation and pouch survival.In this retrospective study, clinical data, postoperative complications, and follow-up parameters were collected from a prospective patient database. Statistical analysis was performed with IBM SPSS, v27 . Unless otherwise indicated, measures of location and variability are reported as the median and interquartile range (IQR), as most of the continuous variables were not normally distributed in Shapiro–Wilk tests. Categorical variables were compared by means of chi-square tests or with Fisher’s exact test in cases with group size < 5. Continuous outcome variables were compared by a nonparametric Kruskal Wallis test. A statistically significant difference was assumed for a n = 235; 70.4%), colorectal cancer or high-grade dysplasia , and emergency events  . One hundred eighty patients (53.9%) were male, the median age at the time of IPAA was 36.8 (29.2–48.1) years. The portion of three-staged operations was 62.9% (n = 210). In three-staged IPAA, the subtotal colectomy took place 5.0 (3.0–8.0) months prior to the IPAA. There were 234 (70.1%) laparoscopic procedures, and hand-sewn anastomoses were created in 179 cases (53.6%). During the late years of the study, most IPAA were stapled anastomoses. Epidemiologic and procedural details are given in Table Three hundred thirty-four UC patients with primary IPAA were included in this study. The study selection process is depicted in Fig. ng) n = 3; 9.3%. Op < 0.01).The histopathologic degree of inflammation was determined in the rectal remnant of all 210 three-staged IPAA, and in the distal resection area of the remaining 124 IPAA. No inflammation (“NOP group”) was found in 56 (16.8%) cases; mild to medium proctitis (“MIP group”) was found in 135 (40.4%), and severe proctitis (“SEP group”) in 143 cases (42.8%). The portion of three-staged IPAA was 51.8% in NOP, 57.0% in MIP, and 72.7% in SEP (p = 0.023). The 30-day morbidity of NOP, MIP, and SEP regarding Clavien-Dindo score, and specific surgical complications  did not differ between the three different proctitis groups, as you can see in Table n = 40; 28.2%, p = 0.017), pouchitis , and pouch failure . The time interval to pouch failure  was 5.0 (4.0–6.9) years among NOP and only 1.2 (0.5–2.3) years in SEP (p = 0.036). Details of univariate group comparisons of the outcome parameters are described in Table Prior to IPAA, the rate of patients that were treated with rectal local steroids or 5-ASA was 20.3% in SEP and only 12.5% in NOP, respectively (p < 0.05) for pouch failure during a 10-year follow-up after IPAA were ASA category 3, a severe degree of inflammation at the time of IPAA (SEP), pouchitis, and pouch fistula. In the multivariate regression, ASA, pouchitis, and pouch fistula were included in the model as significant independent variables (p < 0.01). Severe proctitis was not included in the model because of a significant degree of collinearity with pouchitis . The hazard ratios and the 95% confidence intervals can be found in Table Univariate risk factors (p = 0.058)   curves and life tables of 5- and 10-year pouch survival rates are depicted in Figs. 58) Fig. . Therefo45) Fig. ; howeverRestorative proctocolectomy is the gold standard in the definitive treatment of refractory UC and UC associated colorectal cancer, including its preliminary states . Determip = 0.023), but still, only every 5th of SEP patients had received this therapy, similar to the study of Wasmann et al. [In this retrospective, single-center study, we showed that rectal stump inflammation or inflammation in the distal anastomotic area is common, with mild to medium degree of proctitis (MIP) in 40.4% and severe proctitis (SEP) in 42.8 of our cases. This high rate of proctitis is similar to the rate found in one other recent study . In thatn et al. . Furthern et al. . To our Regarding postoperative complications, there is one study showing no influence of proctitis on the rate of anastomotic leakage . In our Pouch survival was shortest in severe proctitis; however, after 5 years, there was no difference to medium proctitis. After 10 years, there still was a difference in pouch survival between the groups with any degree of inflammation and with no proctitis, but the gap was closing over time. As in our study, the failure rate was highest during the first year in a large Cleveland Clinic study . From a n = 5) in the group without proctitis, raising the question of model stability. Due to the retrospective design, it cannot be shown if there is a beneficial effect of topical anti-inflammatory treatment or just a correlation. A weakness of the study’s design is that in three-staged IPAA, the influence of diversion colitis could not be determined exactly. A strength of the study is the single-center design in a tertiary referral center for inflammatory bowel disease with a homogenous way of diagnosing and treating UC. A possible implication for future studies could be the re-evaluation of the degree of proctitis and prescription of local anti-inflammatory treatments some time before IPAA, in order to evaluate a benefit for IPAA results.One limitation of the study is the relatively low number of pouch failures (Proctitis at the time of IPAA is associated with poor long-term outcomes, an effect that declines over time. In addition, a higher degree of proctitis leads to earlier pouch failure. This is caused by high comorbidity and inflammation of the pouch. There is no study or guideline addressing the question of preoperative optimization by topical enemas or suppositories. Further prospective studies are needed to evaluate the benefit of an intensified preoperative local anti-inflammatory therapy prior to IPAA.