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Anterior knee pain is a common musculoskeletal complaint that is often due to an excessively tight lateral retinaculum, which normally plays a role in patellar tracking and stabilization. Several etiologies underlie lateral soft-tissue tightness in the knee, including lateral patellar compression syndrome, patellofemoral arthritis, patellofemoral instability, and patellofemoral pain syndrome. Stretching the lateral retinaculum through conservative treatment may be helpful, but lateral retinacular lengthening may be indicated. Since this surgical procedure has classically been performed in an open fashion, the purpose of this Technical Note is to describe an arthroscopic technique designed to limit complications, improve patient outcomes, and reduce operative and recovery times.
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Octocrylene is a common sun filter ingredient used to protect the skin from damaging UV rays. Benzophenone is an impurity found in formulations containing octocrylene. [14C]-Benzophenone was spiked (0.1 g/L) into 2 commercial sunscreen formulations; Neutrogena® Beach Defense Sunscreen Spray Broad Spectrum SPF 70 Aerosol, Neutrogena® Ultra Sheer Body Mist Sunscreen Broad Spectrum SPF 30 Aerosol, and an acetone vehicle. The formulations were applied (ca 2 µL/cm2) to dermatomed human skin mounted in static diffusion cells in vitro. Receptor fluid was collected up to 24 h post dose. All samples were analyzed by liquid scintillation counting. The dermal delivery of [14C]-Benzophenone was 10.02, 9.04 and 5.19% for the 3 formulations. However, the [14C]-Benzophenone mass balances were low; 81.5, 85.3 and 8.02%, respectively. A volatility test was performed replacing skin with aluminum foil for the sunscreen formulations only. The [14C]-Benzophenone mass balance at dosing was 99% but fell to 56.9 and 60.6% at 24 h post dose, confirming the losses were due to [14C]-Benzophenone volatility. A conservative dermal absorption value of 12.42% was proposed to cover [14C]-Benzophenone containing formulations.
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Benzofenonas , Radioisótopos de Carbono , Absorção Cutânea , Pele , Protetores Solares , Benzofenonas/farmacocinética , Benzofenonas/administração & dosagem , Humanos , Protetores Solares/farmacocinética , Protetores Solares/química , Protetores Solares/administração & dosagem , Pele/metabolismo , Técnicas In Vitro , Acrilatos/química , Acrilatos/farmacocinéticaRESUMO
PURPOSE: To systematically review the literature to assess the heterogeneity of platelet-rich plasma (PRP) preparation and composition reporting for the treatment of musculoskeletal/orthopaedic pathologies. METHODS: A systematic review was performed by searching PubMed, the Cochrane Library, and Embase to identify Level I and Level II studies from 2016 to 2022 that evaluated the use of PRP therapy for musculoskeletal pathologies. The search phrase used was "platelet-rich plasma clinical studies." Studies were assessed based on their reporting of the PRP preparation methods and reporting of PRP composition. RESULTS: One hundred twenty-four studies (in 120 articles) met inclusion criteria for analysis. Of these studies, 15 (12.1%) provided comprehensive reporting, including a clear, well-described, and reproducible preparation protocol that future investigators can follow. Thirty-three studies (26.6%) quantitatively reported the final PRP product composition. CONCLUSIONS: Among the studies using PRP for the treatment of musculoskeletal/orthopaedic pathologies, less than 20% provided a clear, well-described, and reproducible PRP preparation protocol, and only one-fourth of studies reported on the final PRP product composition. CLINICAL RELEVANCE: A diverse current reporting of PRP composition between studies provides a high heterogeneity of the term "PRP," which becomes a limitation for a comparison of studies using PRP.
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Incomplete healing and/or functional failure following rotator cuff tear repair remains a challenging problem for both patients and surgeons. Augmentation strategies are growing to increase healing through biologic and mechanical mechanisms to improve functional results after arthroscopic rotator cuff repair. The majority of currently described augmentation techniques use allograft tissue. An alternative, low-cost, autograft option for augmentation is the use of the long head of biceps tendon autograft as a free functional graft. Here, we describe the use of autograft biceps tendon as a viable option for augmentation of double-row rotator cuff repair with knotless all-suture suture anchors.
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Isolated posterior instability is well described but relatively uncommon, accounting for less than 10% of all shoulder instability cases. When nonoperative management fails, surgical outcomes demonstrate improved patient-reported outcomes with a high level of return to sport. Knotless suture anchor and "all-suture" suture anchor technology are now available and used for instability procedures in the shoulder. This technical description describes knotless "all-suture" suture anchor fixation for isolated posterior labral tears.
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Arthroscopic subscapularis repair continues to improve with the advancement of surgical technique and critical focus on careful intraoperative evaluation. As identification of these tears increases, there is an expected increase in repair rates as well. Anatomically, the upper border of the subscapularis and the long head of the biceps (LHB) tendon are in close relation. Many surgeons have advocated concomitant LHB tenotomy versus tenodesis in conjunction with operative subscapularis tears. We hypothesized that in the setting of a preserved anatomic biceps pulley and no LHB pathology, isolated subscapularis repair would result in excellent clinical outcomes when compared with subscapularis repair and biceps tenotomy or tenodesis.
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Osteochondral and pure chondral lesions of the knee are common after patellar dislocations. There are multiple described techniques for the fixation of these lesions, including metallic screws, bioabsorbable screws, bioabsorbable implants, and suture devices. The purpose of this article is to describe a surgical technique for surgical fixation of a lateral condyle chondral lesion using knotless all-suture anchors, with second-look knee arthroscopy illustrating healing of the cartilage repair.
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Muscarinic acetylcholine receptors (mAChR), including M4, draw attention as therapeutic targets for several neurodegenerative diseases including Alzheimer's disease (AD). PET imaging of M4 positive allosteric modulator (PAM) allows qualification of the distribution as well as the expression of this receptor under physiological conditions and thereby helps to assess the receptor occupancy (RO) of a drug candidate. In this study, our aims were (a) to synthesize a novel M4 PAM PET radioligand [11C]PF06885190 (b) to evaluate the brain distribution of [11C]PF06885190 in nonhuman primates (NHP) and (c) to analyze its radiometabolites in the blood plasma of NHP. Radiolabeling of [11C]PF06885190 was accomplished via N-methylation of the precursor. Six PET measurements were performed using two male cynomolgus monkeys, where three PET measurements were at baseline, two after pretreatment with a selective M4 PAM compound CVL-231 and one after pretreatment with donepezil. The total volume of distribution (VT) of [11C]PF06885190 was examined using Logan graphical analysis with arterial input function. Radiometabolites were analyzed in monkey blood plasma using gradient HPLC system. Radiolabeling of [11C]PF06885190 was successfully accomplished and the radioligand was found to be stable in the formulation, with radiochemical purity exceeding 99% 1 h after the end of the synthesis. [11C]PF06885190 was characterized in the cynomolgus monkey brain where a moderate brain uptake was found at the baseline condition. However, it showed fast wash-out as it dropped to half of the peak at around 10 min. Change of VT from baseline was around -10% after pretreatment with a M4 PAM, CVL-231. Radiometabolite studies showed relatively fast metabolism. Although sufficient brain uptake of [11C]PF06885190 was observed, these data suggest that [11C]PF06885190 might have too low specific binding in the NHP brain to be further applied in PET imaging.
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Encéfalo , Tomografia por Emissão de Pósitrons , Animais , Masculino , Macaca fascicularis , Radioisótopos de Carbono/química , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/químicaRESUMO
Anatomical total shoulder arthroplasty in its modern form where it reproduces the normal shoulder has been utilized clinically for more than half a century. As the technology and the designs have changed to recreate the humeral and glenoid sides of the joint, the sophistication of design has resulted in the growing number of cases annually worldwide. This increase is due in part to the increasing number of indications that the prosthesis can treat with successful results. On the humeral side, there have been design changes to better reflect the proximal humeral anatomy, and humeral stems are increasingly placed safely without cement. Platform systems which allow conversion of a failed arthroplasty to a reverse configuration without stem extraction is another design change. Similarly, there has been increasing utilization of short stem and stemless humeral components. Extensive experience with shorter stem and stemless devices, however, has yet to demonstrate the purported advantages of these devices, as recent studies have demonstrated equivalent blood loss, fracture rates, operative times, and outcome scores. Easier revision with these shorter stems remains to be definitively established, with only one study comparing the ease of revision between stem types. On the glenoid side, hybrid cementless glenoids, inlay glenoids, cementless all-polyethylene glenoids, and augmented glenoids have all been investigated; however, the indications for these devices remain unclear. Lastly, innovative surgical approaches to implanting shoulder arthroplasty and the use of patient specific guides and computerized planning, while interesting concepts, still await validation before they are utilized on a widespread basis. While reverse shoulder arthroplasty has been increasingly used to reconstruct the arthritic shoulder, anatomic glenohumeral replacement maintains a significant role in the armamentarium of the shoulder surgeon.
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Artroplastia do Ombro , Prótese Articular , Prótese de Ombro , Humanos , Desenho de Prótese , Artroplastia do Ombro/métodos , PolietilenoRESUMO
The foundation of preventing and treating an on-field emergency is preparation and readiness. The sideline medical team should coordinate the utilization of an emergency action plan (EAP). A successful EAP is accomplished through attention to detail, rehearsal, and self-assessments. Every EAP should include site-specific implementation, personnel, equipment, communication, transportation, venue location, emergency care facilities, and documentation. Improvements and advancements can be made to the EAP by self-evaluation after each on-field emergency and yearly reviews. A competent sideline emergency medical team can enjoy the competition while being ready to respond to a catastrophic on-field emergency.
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Serviços Médicos de Emergência , Medicina Esportiva , Esportes , Humanos , EmergênciasRESUMO
Shoulder instability is the separation of the humeral head from the glenoid. Injury to the static and dynamic stabilizers can result in instability. Anterior shoulder instability is the predominant form of instability. It is usually a result of trauma. Posterior shoulder instability often presents with an insidious onset of pain. Multidirectional instability of the shoulder is symptomatic laxity in more than one plane of motion. The primary goal of rehabilitation is to restore pain-free mobility, strength, and functioning. Rehabilitation implements range of motion and strengthening exercises to restore proprioceptive control and scapular kinematics.
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Instabilidade Articular , Articulação do Ombro , Humanos , Ombro , Instabilidade Articular/terapia , Escápula , Modalidades de Fisioterapia , Amplitude de Movimento Articular , Fenômenos BiomecânicosRESUMO
Asbestos is a group of six major silicate minerals that belong to the serpentine and amphibole families, and include chrysotile, amosite, crocidolite, anthophyllite, tremolite and actinolite. Weathering and human disturbance of asbestos-containing materials (ACMs) can lead to the emission of asbestos dust, and the inhalation of respirable asbestos fibrous dust can lead to 'mesothelioma' cancer and other diseases, including the progressive lung disease called 'asbestosis'. There is a considerable legacy of in-situ ACMs in the built environment, and it is not practically or economically possible to safely remove ACMs from the built environment. The aim of the review is to examine the three approaches used for the sustainable management of hazardous ACMs in the built environment: containment, stabilization, and inertization or destruction. Most of the asbestos remaining in the built environment can be contained in a physically secured form so that it does not present a significant health risk of emitting toxic airborne fibres. In settings where safe removal is not practically feasible, stabilization and encapsulation can provide a promising solution, especially in areas where ACMs are exposed to weathering or disturbance. Complete destruction and inertization of asbestos can be achieved by thermal decomposition using plasma and microwave radiation. Bioremediation and chemical treatment (e.g., ultrasound with oxalic acid) have been found to be effective in the inertization of ACMs. Technologies that achieve complete destruction of ACMs are found to be attractive because the treated products can be recycled or safely disposed of in landfills.
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PF-05212377 (SAM760) is a potent and selective 5-HT6 antagonist, previously under development for the treatment of Alzheimer's disease. In vitro, PF-05212377 was determined to be a P-gp/non-BCRP human transporter substrate. Species differences were observed in the in vivo brain penetration of PF-05212377 with a ratio of the unbound concentration in brain/unbound concentration in plasma (Cbu /Cpu ) of 0.05 in rat and 0.64 in non-human primates (NHP). Based on pre-clinical evidence, brain penetration and target engagement of PF-05212377 was confirmed in NHP using positron emission tomography (PET) measured 5-HT6 receptor occupancy (%RO). The NHP Cpu EC50 of PF-05212377 was 0.31 nM (consistent with the in vitro human 5HT6 Ki : 0.32 nM). P-gp has been reported to be expressed in higher abundance at the rat BBB and in similar abundance at the BBB of non-human primates and human; brain penetration of PF-05212377 in humans was postulated to be similar to that in non-human primates. In humans, PF-05212377 demonstrated dose and concentration dependent increases in 5-HT6 RO; maximal 5-HT6 RO of â¼80% was measured in humans at doses of ≥15 mg with an estimated unbound plasma EC50 of 0.37 nM (which was similar to the in vitro human 5HT6 binding Ki 0.32 nM). In conclusion, cumulative evidence from NHP and human PET RO assessments confirmed that NHP is more appropriate than the rat for the prediction of human brain penetration of PF-05212377, a P-gp/non-BCRP substrate. Clinical trial number: NCT01258751.
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Encéfalo , Serotonina , Humanos , Ratos , Animais , Serotonina/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Primatas/metabolismoRESUMO
The US Food and Drug Administration (FDA) has publicly recognized the importance of improving drug development efficiency, deeming translational biomarkers a top priority. The use of imaging biomarkers has been associated with increased rates of drug approvals. An appropriate level of validation provides a pragmatic way to choose and implement these biomarkers. Standardizing imaging modality selection, data acquisition protocols, and image analysis (in ways that are agnostic to equipment and algorithms) have been key to imaging biomarker deployment. The best known examples come from studies done via precompetitive collaboration efforts, which enable input from multiple stakeholders and data sharing. Digital health technologies (DHTs) provide an opportunity to measure meaningful aspects of patient health, including patient function, for extended periods of time outside of the hospital walls, with objective, sensor-based measures. We identified the areas where learnings from the imaging biomarker field can accelerate the adoption and widespread use of DHTs to develop novel treatments. As with imaging, technical validation parameters and performance acceptance thresholds need to be established. Approaches amenable to multiple hardware options and data processing algorithms can be enabled by sharing DHT data and by cross-validating algorithms. Data standardization and creation of shared databases will be vital. Pre-competitive consortia (public-private partnerships and professional societies that bring together all stakeholders, including patient organizations, industry, academic experts, and regulators) will advance the regulatory maturity of DHTs in clinical trials.
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Disseminação de Informação , Poder Psicológico , Humanos , Preparações FarmacêuticasRESUMO
Regular monitoring and timely repair of concrete cracks are required to minimize further deterioration. Self-healing of cracks has been proposed as an alternative to the crack maintenance procedures. One of the proposed techniques is to use axenic cultures to exploit microbial-induced calcite precipitation (MICP). However, such healing agents are not cost-effective for in situ use. As the market for bio-based self-healing concrete necessitates a low-cost bio-agent, nonaxenic sulfate reducing bacterial (SRB) granules were investigated in this study through cultivation in an upflow anaerobic sludge blanket reactor. The compact granules can protect the bacteria from adverse conditions without encapsulation. This study investigated the microbial activities of SRB granules at different temperatures, pH, and chemical oxygen demand concentrations which the microbes would experience during the concrete casting and curing process. The attenuation and recovery of microbial activities were measured before and after the exposure. Moreover, the MICP yield was also tested for a possible use in self-healing bioconcrete. The results consistently showed that SRB granules were able to survive starvation, high temperature (50-60°C), and high pH (12), together with scanning electron microscope/energy dispersive spectrometry/X-ray diffraction analysis evidence. Microbial staining analysis demonstrated the formation of spores in the granules during their exposure to harsh conditions. SRB granule was thus demonstrated to be a viable self-healing nonaxenic agent for low-cost bioconcrete.
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Materiais de Construção , Sulfatos , Bactérias , Carbonato de Cálcio , Materiais de Construção/análise , Materiais de Construção/microbiologia , Esgotos/microbiologiaRESUMO
BACKGROUND: Monoacylglycerol lipase (MAGL) is a key serine hydrolase which terminates endocannabinoid signaling and regulates arachidonic acid driven inflammatory responses within the central nervous system. To develop [11C]PF-06809247 into a clinically usable MAGL positron emission tomography (PET) radioligand, we assessed the occupancy of MAGL by an inhibitor in the non-human primate (NHP) brain. Additionally, we measured the whole-body distribution of [11C]PF-06809247 in NHP and estimated human effective radiation doses. METHODS: Seven cynomolgus monkeys were enrolled for brain PET measurements. Two PET measurements along with arterial blood sampling were performed in each NHP: one baseline and one pretreatment condition with intravenous administration of PF-06818883, a pro-drug of a selective MAGL inhibitor (total of seven doses between 0.01 and 1.27 mg/kg). Kinetic parameters K1, k2 and k3 were estimated by a two tissue compartment (2TC) model using metabolite corrected plasma radioactivity as the input function. k4 was set as 0 according to the irreversible binding of [11C]PF-06809247. Ki by 2TC and Patlak analysis were calculated as the influx constant. The target occupancy was calculated using Ki at baseline and pretreatment conditions. Two cynomolgus monkeys were enrolled for whole-body PET measurements. Estimates of the absorbed radiation dose in humans were calculated with OLINDA/EXM 1.1 using the adult male reference model. RESULTS: Radioactivity retention was decreased in all brain regions following pretreatment with PF-06818883. Occupancy was measured as 25.4-100.5% in a dose dependent manner. Whole-body PET showed high radioactivity uptake values in the liver, small intestine, kidney, and brain. The effective dose of [11C]PF-06809247 was calculated as 4.3 µSv/MBq. CONCLUSIONS: [11C]PF-06809247 is a promising PET ligand for further studies of MAGL in the human brain.
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There is an evolution and increasing need for the utilization of emerging cellular, molecular and in silico technologies and novel approaches for safety assessment of food, drugs, and personal care products. Convergence of these emerging technologies is also enabling rapid advances and approaches that may impact regulatory decisions and approvals. Although the development of emerging technologies may allow rapid advances in regulatory decision making, there is concern that these new technologies have not been thoroughly evaluated to determine if they are ready for regulatory application, singularly or in combinations. The magnitude of these combined technical advances may outpace the ability to assess fit for purpose and to allow routine application of these new methods for regulatory purposes. There is a need to develop strategies to evaluate the new technologies to determine which ones are ready for regulatory use. The opportunity to apply these potentially faster, more accurate, and cost-effective approaches remains an important goal to facilitate their incorporation into regulatory use. However, without a clear strategy to evaluate emerging technologies rapidly and appropriately, the value of these efforts may go unrecognized or may take longer. It is important for the regulatory science field to keep up with the research in these technically advanced areas and to understand the science behind these new approaches. The regulatory field must understand the critical quality attributes of these novel approaches and learn from each other's experience so that workforces can be trained to prepare for emerging global regulatory challenges. Moreover, it is essential that the regulatory community must work with the technology developers to harness collective capabilities towards developing a strategy for evaluation of these new and novel assessment tools.
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Pesquisa Biomédica , Simulação por Computador , HumanosRESUMO
PURPOSE: A sensitive and specific imaging biomarker to monitor immune activation and quantify pharmacodynamic responses would be useful for development of immunomodulating anti-cancer agents. PF-07062119 is a T cell engaging bispecific antibody that binds to CD3 and guanylyl cyclase C, a protein that is over-expressed by colorectal cancers. Here, we used 89Zr-Df-IAB22M2C (89Zr-Df-Crefmirlimab), a human CD8-specific minibody to monitor CD8+ T cell infiltration into tumors by positron emission tomography. We investigated the ability of 89Zr-Df-IAB22M2C to track anti-tumor activity induced by PF-07062119 in a human CRC adoptive transfer mouse model (with injected activated/expanded human T cells), as well as the correlation of tumor radiotracer uptake with CD8+ immunohistochemical staining. PROCEDURES: NOD SCID gamma mice bearing human CRC LS1034 tumors were treated with four different doses of PF-07062119, or a non-targeted CD3 BsAb control, and imaged with 89Zr-Df-IAB22M2C PET at days 4 and 9. Following PET/CT imaging, mice were euthanized and dissected for ex vivo distribution analysis of 89Zr-Df-IAB22M2C in tissues on days 4 and 9, with additional data collected on day 6 (supplementary). Data were analyzed and reported as standard uptake value and %ID/g for in vivo imaging and ex vivo tissue distribution. In addition, tumor tissues were evaluated by immunohistochemistry for CD8+ T cells. RESULTS: The results demonstrated substantial mean uptake of 89Zr-Df-IAB22M2C (%ID/g) in PF-07062119-treated tumors, with significant increases in comparison to non-targeted BsAb-treated controls, as well as PF-07062119 dose-dependent responses over time of treatment. A moderate correlation was observed between tumor tissue radioactivity uptake and CD8+ cell density, demonstrating the value of the imaging agent for non-invasive assessment of intra-tumoral CD8+ T cells and the mechanism of action for PF-07062119. CONCLUSION: Immune-imaging technologies for quantitative cellular measures would be a valuable biomarker in immunotherapeutic clinical development. We demonstrated a qualification of 89Zr-IAB22M2C PET to evaluate PD responses (mice) to a novel immunotherapeutic.
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Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Zircônio , Animais , Biomarcadores , Linhagem Celular Tumoral , Camundongos , Camundongos SCID , Tomografia por Emissão de Pósitrons/métodos , Receptores de Enterotoxina , Linfócitos TRESUMO
Bio-concrete is known for its self-healing capacity although the corrosion resistance was not investigated previously. This study presents an innovative bio-concrete by mixing anaerobic granular sludge into concrete to mitigate sewer corrosion. The control concrete and bio-concrete (with granular sludge at 1% and 2% of the cement weight) were partially submerged in a corrosion chamber for 6 months, simulating the tidal-region corrosion in sewers. The corrosion rates of 1% and 2% bio-concrete were about 17.2% and 42.8% less than that of the control concrete, together with 14.6% and 35.0% less sulfide uptake rates, 15.3% and 55.6% less sulfate concentrations, and higher surface pH (up to 1.8 units). Gypsum and ettringite were major corrosion products but in smaller sizes on bio-concrete than that of control concrete. The total relative abundance of corrosion-causing microorganisms, i.e. sulfide-oxidizing bacteria, was significantly reduced on bio-concrete, while more sulfate-reducing bacteria (SRB) was detected. The corrosion-resistance of bio-concrete was mainly attributed to activities of SRB derived from the granular sludge, which supported the sulfur cycle between the aerobic and anaerobic corrosion sub-layers. This significantly reduced the net production of biogenic sulfuric acid and thus corrosion. The results suggested that the novel granular sludge-based bio-concrete provides a highly potential solution to reduce sewer corrosion.