Can an informatics tool improve detection of antibiotic allergic-type events?In this cohort study of 36 344 patients who underwent cardiovascular implantable electronic device procedures, an electronic algorithm with high positive predictive value was developed that can be used to measure the occurrence of periprocedural antibiotic allergic-type events in near real-time. Most antibiotic allergic-type reactions were moderate in severity.The algorithm developed in this study could be used to detect when antibiotic allergic-type reactions occur to provide direct clinician feedback about harms. This cohort study describes the development of an informatics tool to improve detection of periprocedural antibiotic allergy adverse events. Standardized processes for identifying when allergic-type reactions occur and linking reactions to drug exposures are limited.To develop an informatics tool to improve detection of antibiotic allergic-type events.This retrospective cohort study was conducted from October 1, 2015, to September 30, 2019, with data analyzed between July 1, 2021, and January 31, 2022. The study was conducted across Veteran Affairs hospitals among patients who underwent cardiovascular implantable electronic device (CIED) procedures and received periprocedural antibiotic prophylaxis. The cohort was split into training and test cohorts, and cases were manually reviewed to determine presence of allergic-type reaction and its severity. Variables potentially indicative of allergic-type reactions were selected a priori and included allergies entered in the Veteran Affair’s Allergy Reaction Tracking (ART) system , allergy diagnosis codes, medications administered to treat allergic reactions, and text searches of clinical notes for keywords and phrases indicative of a potential allergic-type reaction. A model to detect allergic-type reaction events was iteratively developed on the training cohort and then applied to the test cohort. Algorithm test characteristics were assessed.Preprocedural and postprocedural prophylactic antibiotic administration.Antibiotic allergic-type reactions.The cohort of 36 344 patients included 34 703 CIED procedures with antibiotic exposures ; median duration of postprocedural prophylaxis was 4 days . The final algorithm included 7 variables: entries in the Veteran Affair’s hospitals ART, either historic  or observed ; PheCodes for “symptoms affecting skin” , “urticaria” , and “allergy or adverse event to an antibiotic” ; keyword detection in clinical notes ; and antihistamine administration alone or in combination . In the final model, antibiotic allergic-type reactions were identified with an estimated probability of 30% or more; positive predictive value was 61% ; and sensitivity was 87% .In this retrospective cohort study of patients receiving periprocedural antibiotic prophylaxis, an algorithm with a high sensitivity to detect incident antibiotic allergic-type reactions that can be used to provide clinician feedback about antibiotic harms from unnecessarily prolonged antibiotic exposures was developed. Clostridioides difficile infection, acute kidney failure, and immunologically mediated hypersensitivity reactions.3 Antibiotics are among the most common drugs associated with hypersensitivity reactions in hospitalized patients.4 The downstream effects posed by an antibiotic allergy include increased length of stay and health care costs, use of broad-spectrum antibiotics, and mortality.7Adverse events associated with antibiotic use include 9 Despite clinical guidelines recommending against extending duration of prophylaxis following skin closure, prolonged postprocedural antibiotics are commonly prescribed in some clinical settings, increasing the risk of adverse events, including antibiotic allergic-type reactions.13 However, the rate of antibiotic-related adverse reactions and allergy events that occur in this context is unknown.Antibiotics that most commonly cause hypersensitivity reactions  are the same drugs commonly prescribed for surgical site infection prophylaxis.There is no current process for antibiotic drug reaction surveillance. Lack of adverse event detection prevents feedback to clinicians about direct patient harms of inappropriate antibiotic use. Thus, the aims of this retrospective, multicenter national cohort study were (1) to develop an electronic tool using structured and unstructured data elements available within the Veterans Affairs (VA) electronic health record (EHR) to identify incident antibiotic allergic-type reactions and (2) to characterize the nature and severity of these reactions.STROBE) reporting guidelines for cohort studies.The VA Boston Healthcare System institutional review board approved this as an exempt study with a waiver of informed consent given the retrospective and observational nature of the study. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology  procedures  performed at Veterans Health Administration (VHA) facilities from October 1, 2015, to September 30, 2019. Data were analyzed between August 1, 2021, and January 31, 2022. Individual CIED procedures were included in the study if they had received 1 or more antibiotic(s) within 1 day before or after their procedure.International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] diagnosis codes, procedure codes, patient characteristics), structured tables (orders and dispensed medications), and unstructured clinical text notes. Duration of antibiotic exposure following CIED procedure was calculated based on the number of days of documented antibiotic administrations (inpatient data) and/or the number of days of antibiotic fills (outpatient exposures). Patient comorbidities were extracted using the Agency for Healthcare Research and Quality Elixhauser Comorbidity Software.17EHR data were extracted from the VA Corporate Data Warehouse using SQL Server Management Studio 18 (Microsoft Corp). Data sources accessed include administrative files  system , allergy diagnosis codes , medications administered to treat allergic-type reactions , text searches of clinical notes for keywords and phrases indicative of a potential allergic-type reaction, and consults to allergy and dermatology  and the subsequent 45-day window period was completed. The surveillance period for antibiotic-associated allergic-type reactions was a maximum of 10 days after the last date of antibiotic exposure, which was calculated based on medication administration data, days of antibiotic dispensed, or both. Manually abstracted data included procedure date, adverse event date and type , triggered variable, culprit antibiotic, reaction noted, treatment received, and change in level of care . Each event was then classified into allergic-type reaction, adverse reaction, or other or no event occurrence. Allergic-type reactions were defined as allergic signs or symptoms that could be immune-mediated hypersensitivity reactions, such as rash, hives, or anaphylaxis occurring after antibiotic exposure.2 Adverse reaction was defined as a nonimmunologically mediated undesired response to an antibiotic .2 Among patients who experienced an allergic-type reaction, severity of allergies was classified as mild, defined as not requiring medication or change in level of care; moderate, defined as requiring medication but no change in level of care; and severe, defined as requiring medication and change in level of care or intubation.25The manual medical record review process included a standardized review tool.26 rather than ICD-10 codes  were selected using a generalized linear model with a logit link (via the SAS Procedure HPGENSELECT), with a least absolute shrinkage and selection operator (LASSO) regression analysis for variable selection (SAS Enterprise Guide version 8.2 [SAS Institute]). Potential factors were iteratively updated to increase estimated probability of identifying true antibiotic allergic-type reactions, eg, by adjusting keyword searches and using diagnosis phenotype codes (PheCodes)Different iterations of the model were subsequently tested using logistic regression to estimate odds ratios (ORs) for different variables and estimate the probability of an antibiotic allergic-type reaction. The final version of the model was selected based on the estimated probability cutoff with the highest positive predictive value (PPV) and C statistic. Unadjusted and adjusted (full model) ORs for the outcome and the receiver operating characteristic were calculated in the training data set using the final model.27After selecting a predictive model using the training medical record review sample, logistic regression coefficients were applied to the testing cohort to obtain estimated probabilities that an allergic-type reaction had occurred. The test medical record review sample was selected according to a predetermined but arbitrarily selected estimated probability distribution to oversample high-probability cases. After reviewing the sampled procedures from the testing cohort, we assessed criterion validity  of the final model and compared it with the model performance in the training medical record review sample. Criterion validity of the algorithm was assessed with criterion-standard manual medical record review.26A total of 36 344 patients underwent CIED procedures during the study period, and 34 703 (96%) had a periprocedural antibiotic exposure and were included in the study. The median duration of postprocedural antibiotic prophylaxis in the whole cohort was 4 days . The total population was divided into a training data set (17 350 participants) and a testing data set (17 353 participants). Most included patients were male (34 008 [98%]) and White (26 576 [77%]). The mean (SD) age was 72 (10) years .21,22,26ICD-10 code; and PheCodes for urticaria, adverse event to antibiotic and penicillin, and rash and skin eruption . In the training sample, the initial set of variables selected by the LASSO included observed ART flag; keywords documented in clinical notes; corticosteroid receipt; new eruption . PrespecThe final model included 7 variables indicative of an antibiotic allergic-type reaction during the 45-day period following antibiotic exposure  . The varThe logistic regression model from the training cohort was applied to the testing cohort of 17 353 participants. A total of 17 259 cases (99%) fell under the PPV threshold for detecting potential allergic-type reactions; 120 cases underwent manual review . In this sample, 87% of allergic-type reactions (27 cases) fell into the high probability category. The PPV of the final model in the test data set was 61% , and sensitivity was 87% . The ART flag alone had lower sensitivity but similar PPV as the more complex model .25 Among cases with allergic-type reactions, the median (IQR) duration of postprocedure exposure was 5 (2-7) days; the same time frame when most events (75 [72%]) occurred. The most frequently administered antibiotics associated with allergic-type reactions included cephalosporins (40%) and vancomycin (23%), the same antibiotics most frequently administered for periprocedural prophylaxis.Allergic-type reactions by class of antibiotic, intervention administered, and severity classification are presented in Among the manually reviewed cases from the whole cohort, 104 antibiotic allergic-type reactions occurred following 102 exposures . Of these, 96 were due to antibiotics administered for periprocedural prophylaxis, and 81 allergic-type reactions (84%) were attributed to antibiotics administered for longer than 24 hours following skin closure. Of the 96 antibiotic allergic-type reactions attributed to periprocedural prophylaxis, 60 (63%) had an observed ART flag, 23 (24%) had a historic ART flag, and 30 of 96 cases (38%) did not have the allergy listed in the electronic medical record.Most antibiotic allergic-type reactions detected in the inpatient setting and were moderate in severity, requiring administration of antihistamine, corticosteroid, or intravenous epinephrine or a combination but did not require change in level of care. Most cases that required change in level of care  were outpatients treated in the emergency department. Intubation or intensive care unit was not required for any of the reactions with cephalosporins or vancomycin. One patient who presented with pneumonia and received azithromycin developed anaphylactic shock, was intubated in the emergency department, and was admitted into the intensive care unit.7 Despite this, guideline-discordant prolonged prophylaxis lasting longer than 24 hours after skin closure remains common in some surgical and procedural settings, including the cardiac electrophysiology laboratory.28 Identification of allergic-type reactions in near real-time creates an opportunity for audit and feedback to clinicians about patient harms of antibiotic prescribing and an opportunity to encourage adoption of evidence-based practices regarding antibiotic administration for postprocedural prophylaxis. Systematic surveillance may be particularly important in outpatient and procedural settings, as many events may occur after discharge and thus clinicians remain unaware of preventable harm caused by inappropriate antibiotic administration. The algorithm developed and validated in this study helps close this gap and can potentially be used to enhance identification of allergic-type reactions and improve quality and safety of medical care.Antibiotics are one of the most common causes of medication adverse events.16 These findings highlight the importance of perioperative antibiotic stewardship to limit harms of unnecessary antibiotic exposures and the need for innovative strategies to provide audit and feedback to clinicians about patient harm caused by unnecessary antibiotic exposures.Most allergic-type reactions occurred shortly after antibiotic exposure  and were attributed to antibiotics administered for guideline-discordant, prolonged prophylaxis.30 The higher rate in our study is likely due to a combination of the duration of prophylaxis and exposure to different agents for prophylaxis . Importantly, given these procedures were performed among individuals without an underlying infection, we were able to identify allergic-type reactions without the need to distinguish allergic reactions from other entities that cause rash, such as viral exanthems.In our study, the rate of antibiotic allergic-type reactions occurring with prolonged postprocedural antibiotic use was higher than previously reported rates (0.9% for cefazolin and 1.1% for vancomycin).C difficile infection following a single exposure) are rare; however, when a broader array of outcomes is considered, incidence of overall harm to the individual patient increases and contributes more substantially to adverse patient outcomes. More research is needed to develop antibiotic-use harm metrics that fully capture all harms caused by antibiotics to better inform and adapt clinical practice.This study adds to previous literature about the harms of extending prophylaxis beyond the guideline-recommended period and can be used in future investigations to consider a composite adverse event risk metric from antibiotic exposure, rather than considering each harm individually. Antibiotic-associated adverse events when considered individually  fell below the probability threshold that would require manual adjudication. Ideally, the algorithm would assist with attributing an allergic-type reaction to a specific exposure. However, in our cohort, patients received more than 1 antibiotic during the specified period, and pinpointing the causative agent was not possible without manual adjudication.8 Mild reactions that did not require medical intervention are less likely to be detected, as they are less likely to require medical care and therefore documentation in the EHR. However, they are likely less important from a clinical standpoint. Severe reactions were also less likely to be identified, likely because they occur less frequently.31 However, it is possible that severe reactions are more common than was identified, as patients with severe reactions may be taken to the nearest emergency department, not necessarily to a VA medical center, and therefore, the events might not be documented in the VA EHR.The algorithm primarily detected allergic-type reactions of moderate severity. This may be due to moderate severity allergic-type reactions being more common, or due to inherent features of the algorithm. Cutaneous manifestations were the most commonly reported allergic-type reactions, and these are easily treated in the inpatient setting with diphenhydramine or steroids, which were included in the algorithm.ICD-10-DM codes  were copied forward in EHR documentation, even though no penicillin exposure occurred during the incident admission. Missing data due to inability to detect adverse reactions that are treated outside the VA is another limitation and may have affected the number of cases identified and the true severity distribution of antibiotic allergic-type reactions. Our validation method focused on oversampling high probability cases, which may have led to an underestimation of the true incidence of adverse events due to limited review of potentially false-negative cases. It is not clear how well the tool would perform outside of the closed VA health care system or other EHRs or applied to other clinical settings or more complex or prolonged surgical procedures.Our study is subject to the limitations of documentation in the EHR and sampling methodology. False-positive variable detection related to historic 32; thus, the absolute incidence of allergic-type reactions may be underestimated in this population relative to populations with more women. Additionally, manual review was completed on a relatively small sample of the total cohort, and by a single adjudicator.Another limitation is that this study was conducted within the VA health care system, and the cohort included predominantly older White male patients. Drug allergies are much more commonly reported in female than male patientsIn this cohort study, we developed and validated an informatics tool using 7 variables composed of structured and unstructured data for the detection of antibiotic allergic-type reactions. This model had a good PPV for detecting antibiotic allergic-type reactions and can be operationalized to provide clinicians with real-time audit and feedback about when allergic-type reactions occur to support efforts to reduce inappropriate and unnecessary antibiotic exposures that increase patient-level harm without improving outcomes.


Hispidoberyxambagiosus Kotlyar, 1981, is redescribed based on four specimens collected from Taiwan. Their sampling locality represents the northernmost record of the family, which extends the family’s distribution from the eastern Indian Ocean and the South China Sea to northeastern Taiwan in the northwestern Pacific Ocean. A detailed description of these specimens and the first description of its sagittal otoliths are provided. In addition, the specimens are compared with other known specimens. Intraspecific variation of some morphological characters are discussed.A rare spiny-scale pricklefish,  Beryciformes . After a detailed examination, these specimens are re-identified as H.ambagiosus based on their unique characteristics. These specimens represent the first record of the species, genus, and family from Taiwan, as well as the third formal record in history. A detailed description of these specimens and the first description of its sagittal otoliths are provided; these specimens are also compared to the data of other known specimens.Recently, four specimens initially identified as Classification of taxonomic rank follow SL) and/or as a percentage of head length (HL), except where otherwise indicated. Specimens are deposited atAcademia Sinica, Biodiversity Research Center, Taipei, Taiwan (ASIZP), and thePisces Collection, National Museum of Marine Biology and Aquarium, Pingtung, Taiwan (NMMB-P).The sagittal otoliths of ASIZP 81665 were taken and deposited at the marine paleontology lab, Biodiversity Research Center with catalog number CHLOL 969.Measurements were taken using 150 mm digital calipers or 300 mm calipers and rounded to the nearest 0.1 mm. Morphometric data were presented as a percentage of standard length : ASIZP 63512, 134.8 mm SL, bottom trawl, depth 650–800 m, 10 Jun. 1999, coll. D.-M. Chen. ASIZP 64539, 154.7 mm SL, bottom trawl, 28 Aug. 2002, coll. H.-C. Ho. ASIZP 76178, 153.5 mm SL, bottom trawl, 24 Apr. 2015, coll. M.-Y. Lee. ASIZP 81665, 162.0 mm SL, bottom trawl, 25 July 2020, coll. C.-H. Lin et al. All collected from Daxi fishing port , Yilan, northeastern Taiwan.ASIZP 81665.Otolith (a pair of sagittae): CHLOL 969, otolith length 2.2 (left) and 2.3 (right) mm, taken from Meristic and morphometric data are provided in Tables Dorsal-fin elements V, 10–11, first 2 spines fused in 2 specimens Fig. . PectoraSL, depth at dorsal- and anal-fin origins 3.6‒4.5 and 4.5‒5.5 in SL, respectively; body laterally compressed and oval in trunk section, its width 4.4‒4.7 in SL. Head somewhat oval, length 3.2‒3.3 in SL; its height 1.4‒1.5 in HL; upper profile of head nearly straight, gently curved to dorsal-fin origin; forehead flat, HF1 14.3‒20.3 and HF2 5.3‒5.9 in HL; eye diameter 4.8‒5.8 in HL; tip of snout slightly rounded, not extending before premaxilla, its length 3.3‒3.5 in HL; interorbital width 2.8‒2.9 in HL.Body slender for stephanoberycoid, greatest depth 3.4‒3.9 in HL; posterior end of maxilla rounded, reaching vertical through posterior margin of eye; lower jaw slightly larger than upper jaw and protruding before upper jaw, length 1.3‒1.5 in HL. Two nostrils at same horizontal through center of eye; both nostrils rounded, slightly oval, with posterior nostril much larger than anterior one; both nostrils immediately in front of eye. Tominaga’s organ .HL, height 3.7‒4.1 in HL. Light organs absent. No trace of swim bladder.Lateral line single, originating behind and slightly lower than posterior tip of posttemporal bone; its anterior portion slightly curved and raised, with downturn below dorsal-fin base, and nearly straight posterior portion; its end anterior to caudal-fin base. Anus situated immediately anterior to anal-fin origin. Caudal peduncle stout, length 1.3 in Fig. . OtoltihWhen fresh Fig. , entire SL  is a mature female with developing eggs, suggesting that it may mature at this size.This is a moderately small species of stephanoberycoid, attaining at least 181 mm Hispidoberyxambagiosus was originally described from the eastern Indian Ocean .In this study, we confirm that Tominaga’s organ is present in sus Fig. . The nashthyidae ; as the hthyidae , TominagH.ambagiosus have been both described and depicted for the first time ; slightly longer pelvic-fin‒anal-fin length (29.6‒32.1% SL vs 27.2‒29.8% SL); slightly longer dorsal-fin length (22.1‒24.0% SL vs 21.6‒22.1% SL); slightly longer anal-fin length (13.8‒15.4% SL vs 12.3‒13.8% SL); slightly longer longest gill-raker length (4.1‒5.0% SL vs 4.0‒4.4% SL); and a shorter postdorsal length , previously considered lost (S.-P. Huang pers. comm.), was relocated in the National Museum of Marine Science and Technology, Keelung Taiwan (NMMST) for exhibition (J.-F. Huang pers. comm.), and we identify that specimen here as B.rufa. Therefore, B.rufa is retained in the ichthyofauna of Taiwan.Although the specimens reported here as se fauna , anotherBarbourisiarufa: ASIZP 57678, 312 mm SL, Bashi Channel, 21°30'00"N, 120°47'59.99"E, depth 300–400 m, 20 Jan. 1991, bottom trawl, coll. J.-W. Chen. Gibberichthyslatifrons: NMMB-P37435, 100.7 mm SL, off Dong-gang fishing port , Pingtung, southwestern Taiwan, 26 Dec. 2022, bottom trawl, coll. K.-H. Wu.


The statistical model exhibited no indication of prediction bias and demonstrated a statistically significant outcome, with a p-value below 0.5. The present investigation aims to examine the mechanical and durability properties of concrete that has been reinforced with a waste printed circuit board (WPCB) towards a low-carbon built environment. It assessed the fresh and hardened characteristics of the low-carbon concrete reinforced with WPCB fibres, after a curing period of 7 and 28 days. The evaluation was done by quantifying slump, compressive strength, split tensile strength, flexural strength, sorptivity, rapid, and acid tests. It further analysed eleven discrete concrete mixes with WPCB fibres at a weight percentage ranging from 1 to 5% in the cement mixture. The results indicate that incorporating WPCB fibre into concrete improves its mechanical strength. The results revealed that incorporating 5% WPCB fibre yielded the most favourable outcomes. The properties of WPCB fibre-reinforced concrete have been theoretically validated through Response Surface Methodology (RSM), which employs various statistical and mathematical tools to analyse the experimental data. The results derived from RSM were compared with the experimental results. It was found that the RSM model demonstrated a high level of accuracy (R There have been many attempts to reuse waste products creating environmental hazards such as fibre and filler material in the construction industry. A brief literature Review indicates that studies have attempted to incorporate materials like rubber tree seed cells, textile-based carbon nanotube composites, waste marble powder, coconut fibre, recycled steel wire waste tyres, steel fibres, etc. There also has attempts to utilise material like used engine oil and thermoset plastic to develop sustainable concrete10. These studies have proved that enhancement in the performance characteristics can be achieved by reusing these waste materials providing an option for sustainable development through green products17. Massively, electronic waste (e-waste) is generated as millions of electronic gadgets are rendered obsolete yearly18. United Nations Environment Programme (UNEP) predicts that the quantum of e-waste generated in India could increase by 500% over the next decade. The global production of Waste Electrical Equipment (WEE) is rising owing to the rapid technological obsolescence of electronic products and the availability of newer products at reasonable prices. WEE contains numerous economically valuable and environmentally hazardous metals and synthetic compounds, but it also is composed of toxic substances that pose a significant hazard to the environment and society. Developed nations have incorporated reuse laws and regulations into their waste electrical and electronic management policies while developing countries lag19. In emerging economies, households discard WEE through improper disposal, leading to environmental pollution and health risks20. The waste materials are often discarded in nearby fields22. Mishandling e-waste leads to harmful composites contaminating the local environment, including soils, sediments, dust and plants23. Critical solid waste is also disposed of following improper disposal techniques24. The electronic waste generated from electrical and electronic devices industries and households consists of Liquid Crystal Display (LCD) screens (11.9%), Personal Computers (PCs) (18.8%), mobile phones (21.3%) and Cathode Ray Tube (CRT) Televisions (7%). Only 10% of electronic waste is recycled. This waste can be recycled using various technologies or disposed of directly in a landfill or an incinerator25. E-waste can be recycled or reused, but improper techniques and equipment for disposal may harm the environment and humans. Reuse is repurposing a product for a purpose other than its original design. Reusing can be done using various product life-extension strategies, such as repair, refurbishment and remanufacturing. Reusing e-waste can also extend the product's lifespan.In contemporary times, the issue of sustainability has emerged as a significant preoccupation for humanity, especially in the Eco-Friendly Built Environment (EFBE) in line with the requirements of the Conference of the Parties (COP27) and United Nations Sustainable Development Group (UNSDGs). Based on this premise, global resources are steadily diminishing due to housing demands while the human populace is experiencing a rapid surge. The efficient utilization of resources holds significant importance in this regard27. Waste Printed Circuit Boards (WPCBs) are an extremely heterogeneous product category in size, material composition and shape28. WPCBs contain many carbon and toxic substances, including heavy metals and brominated flame retardants, which are harmful to the environment if not properly treated. Constant technological advances have hastened the regular replacement of electrical and electronic devices, significantly increasing the quantity of discarded WPCBs29. In the recent past, WPCB manufacturing reached a global growth rate of 8.7%, while in Southeast Asia and China, WPCB manufacturing grew at 10.8% and 14.4%, respectively30 China currently produces 40% of the world's WPCBs. WPCBs contain many metals, including carbon, copper, aluminium, iron, tin and lead, and non-metals, such as thermosetting resins and glass fibres31. Metal extraction is done as part of WPCB recycling. Hydrometallurgical, pyrometallurgical and mechanical methods are used to recover metals from waste PCBs. The metals in waste PCBs are recycled/recovered using mature processes like Hydrometallurgical, pyrometallurgical and mechanical methods for industrial and commercial purposes as secondary raw material. Hydrometallurgical is a method which utilises various acid to recover metals from waste PCBs and has recovery efficiency of 60–70%34. Pyrometallurgical is a process using high temperatures to recover metals like gold, silver and copper etc. from waste PCBs and is has recovery efficiency of 85–95%37. Although the above-mentioned process and not environmentally friendly. Hydrometallurgical has the disposal problem40 and pyrometer is considered as an energy-intensive process42. The mechanical methods generate residue of waste PCB in various sizes, further worsening solid waste management. The above-mentioned are only concentrating on the recovery of metals present in the Waste PCB, the board which contains fibre which further increases the load on environmental pollution and intensifies the problem in solid waste management. However, reusing the substantial amounts of non-metals that comprise approximately 70% of WPCBs presents a formidable challenge43. Currently, non-metals reprocessed from waste WPCBs are generally disposed of in incinerators or landfills, which leads to hazardous environmental effects46. Reusing non-metals from WPCBs has become a significant challenge for e-waste management and a source of worry in environmental protection and resource recycling49. Yokoyama and Iji50 investigated the recycling of non-metals as fillers in resin-type building materials. Mechanical and Vicat Softening Temperature (VST) tests were employed to recycle non-metals used as reinforcing fillers in thermoplastic resin matrix composites51. Polypropylene (PP) composites show a maximum increase of tensile, tensile strength, flexural strength and flexural modulus by 62.9%, 28.4%, 87.8% and 133.0%, respectively. Without violating environmental regulations, 30% of non-metals recycled from WPCBs can be included in polypropylene composites. Hong and su52 utilized non-metallic fillers as reinforcements in polyester composites. Incorporating WPCBs altered the Unsaturated Polyester (UP) resin's free radical reaction and reduced the initial curing. Because of the energy dissipation effects of epoxy resins (rigid) and glass fibres in the WPCB, WPCB-modified UP resins had a high glass transition temperature (Tg). They were stronger and tougher than plain UP. Franz53 stated that using non-metals as a thermoplastic material would be an ideal recycling solution. The strategy involved reusing non-metals to create thermoplastic housing. Unfortunately, this approach runs counter to current product miniaturisation trends.Printed circuit boards (PCBs) provide electrical interconnections between elements and report for approximately 4% of all electronic waste56. Using waste materials in construction also prevents environmental degradation caused by their disposal and affirms sustainable construction practices62. The effective management of various waste production processes has come under increased scrutiny in recent years to make the building industry environmentally sustainable. One of the critical considerations of waste management strategies is using waste materials instead of natural materials as raw materials63. The primary benefits of recycling are decreasing the pollution released into the environment, reducing the amount of trash discarded and preserving natural resources67. Over the past few years, the response surface method (RSM) has been modified to solve various issues in civil engineering, such as forecasting different characteristics, evaluating concrete structures' capacity to support loads, modelling material behaviour, optimising and controlling structures and monitoring groundwater68. RSM is a statistical and mathematical tool set. It can model and evaluate practical problems69. Despite its everyday use in trial and optimization design, this tool set has seen restricted application in the concrete industry70. As per the literature reviewed by the investigators, research on WPCB fibre-reinforced concrete was focused primarily on using WPCB as a substitute for natural aggregates and cement73.WCPB wastes are non-biodegradable materials and could persist on the earth for hundreds or even thousands of years after they are discarded. Reusing these materials in the building and construction industry reduces the demand for raw materials extracted from natural sources74. The problem stated in support of this project is that the increased generation, management, and disposal of E-waste (WPCBs) causes various environmental and health issues. This study aims to use WPCBs as fibre as an alternative to conventional fibres, potentially lowering construction costs and demand for natural resources and reducing the environmental hazard to address and sustainably prevent the abovementioned problems. This investigation experimentally examines the durability characteristics and structural strength aspects of WPCB fibre-reinforced concrete of AR30 and AR40. It validates the experimental results by comparing them with the theoretical values for mechanical parameters of WPCB fibre-reinforced concrete obtained using the Response Surface Methodology.The viability of using WPCBs in concrete as fibre strips cut from WPCBs was investigated For Aspect Ratio (AR) 10 and 20 to enhance the mechanical properties75. Calcium oxide (CaO) was the main composition with a specific gravity of 3.14. Table 3. Coarse aggregate with a maximum particle size of 10 mm, a specific gravity of 2.72, fineness modulus of 7.11 and bulk density of 1548 kg/m3. All aggregates conformed to BIS 383-2016 standard76 Conplast SP430, a commercially available superplasticizer additive containing sulfonated naphthalene polymers, was used to achieve the desired workability that met the BIS 9103-1999 standards77. In addition, tap water was used to mix and cure the concrete.The 53-grade Ordinary Portland Cement (OPC) utilised in this research was procured locally and conformed to BIS 12269-2013 standard78. After cleaning, external components were extracted through desoldering using a heat gun. Once chips, diodes, and other metallic components, including mechanical disassembly and removal of components that can be reused or recycled, were removed, the unadorned waste PCB was transformed into fibers with dimensions specified in Table The FR4-type WPCB used in this study was sourced from a local recycling facility and obtained from old personal computers. It is essential to clean discarded Printed Circuit Boards (PCBs) to ensure their safe and effective disposal or reuse81.The main composition of the WPCB is silica, and its specific gravity is 2.68. The physical properties and dimensions of WPCB fibre are shown in Table 3). Two aspect ratios of the WPCB fibre (AR30 and AR40) were tested; therefore, ten unique mixtures were prepared by adding varying amounts of WPCB fibre to the weight of cement . In all these 11 different mixes, the proportion of the superplasticizer was fixed as 1% of the weight of the cement. Table In this study, the WPCB fibre concrete mix proportion was divided into three different mixes based on the percentage of added fibre. The control variables included cement, fine aggregates, coarse aggregates and three different weights of superplasticizers  test, and a cylinder of 100 mm diameter and 200 mm height were subjected to a split Tensile Strength (TS) test following BIS 1199-1959 standard82 A prism to test Flexural Strength (FS) was cast for 100 mm × 100 mm × 500 mm according to IS 1199-195982. The mechanical properties of PCB fiber-reinforced concrete were tested under loading conditions and limits. The testing was carried out in accordance with BIS 546-201883 .The WPCB fibre-reinforced concrete design mix was prepared and mixed in a drum-type tilting concrete mixer. After preparing wet mixing of concrete, fresh properties, such as slump, are determined per Indian Standard IS 1199-19592, R2 Adjusted, and R2 Expected numerals were used to calculate the significance of the model level using the RSM method. The F-value computed in this method determines the impact of the variables on the quantified outcomes. The greater F-value of a parameter, the larger effect on the experiment. The P-value indicates the significance of the model's output. For statistical significance, a P-value of less than 0.05 is required for the model or set of parameters to be valid85. The RSM strategy was implemented for this research using a demo version of Design Expert 13 software.The RSM is an experimental outcomes analysis method. The RA slump test was used to determine the workability of freshly mixed concrete reinforced with WPCB fibres. Before casting the specimens, each mix was subjected to the slump test three times (in a single batch). Figure The compression test results for 7-day and 28-day cured AR30 and AR40 WPCB fibre-reinforced concrete mixes are shown in Figs. 74. Figure For all the AR30 fibre mixes, the compressive strength at 28 days showed higher values than control concrete. The compressive strengths of all the AR30 WPCB fibre-reinforced concrete mixes are shown in Fig. 74. The resistance of the concrete against its elongation is its tensile strength. The tensile strength of the AR30 and AR40 WPCB fibre-reinforced concrete are shown in Figs. An earlier study also reported WPCB fibre-reinforced concrete's tensile strengthAdding 1%, 2%, 3%, 4%, and 5% of AR30 WPCB fibres to concrete increased the tensile strength of the resultant mixes by 17.18%, 33.74%, 46%, 57%, and 70.25%, respectively, when compared to control concrete. For example, from Fig. WPCB fibre improves the specimen's load-bearing capacity compared to the control specimen. This study demonstrated the similarity pattern between flexural strength and compressive strength. The flexural strength variations on adding 1%, 2%, 3%, 4% and 5% of AR30 WPCB fibre to the mix are shown in Fig. Chemical attacks on concrete can cause physical effects such as increased porosity and permeability, reduced strength, cracking and spalling. In most cases, the chemical and physical deterioration processes work together simultaneously, and one process may occasionally contribute to accelerating the other processes. Therefore, an acid attack test was conducted on WPCB fibre-reinforced concrete to determine its chemical resistance. A 5% hydrochloric (HCl) acid was used for this experiment, and a 100 mm cube cured for 28 days was employed. Then the samples were cured in HCl for 30 days. After 15 days, the solution was changed to retain its concentration. After 30 days, specimens were collected from acid and air-dried. The samples were evaluated to determine the loss in weight (%) and then tested using a CTM. Figure 86. The RCPT was conducted by subjecting the specimen to a 60 V direct current for 6 h as per ASTM C1202-201986. One reservoir has a solution of 3.0% NaCl, and the other has a solution of 0.3 M NaOH. Finally, a calculation is made of the total amount of charge passed. This test is widely reported in the literature and has been acknowledged as a standard87.A disc was cut from a 100 × 200 mm concrete cylinder with a thickness of 50 mm used for this experiment and cured for 30 days. The rapid chloride penetration test (RCPT) was performed following ASTM C1202-201986, the distribution of chloride penetration was modest, so all WPCB fibre-reinforced concrete mixes achieved better resistance to chloride penetration. With the addition of WPCB fibres, the amount of charge being conducted through the concrete samples decreased for all five mixes reinforced with AR30 and AR40 WPCB fibres, indicating that the permeability of the concrete decreased. The chloride penetration abilities of concrete mixes with WPCB fibres are lower than control concrete. All WPCB fibre-reinforced concrete mixes have a moderate capacity for chloride diffusion. The addition of fibre does not affect the porosity of concrete. The AR40 WPCB concrete mixes show comparatively more significant performance characteristics. The reduction in RCPT value can be attributed to the reduction in porosity with reduced chloride diffusion.Figure 88. The sorptivity test gives valuable information about the presence of pore structures in concrete89. The laboratory test measures the water absorption rate by concrete samples according to ASTM C1585-201390. The only requirements for this test are a pan of water, a stopwatch and a ruler. Then a specimen was cut from a 100 mm diameter cylinder with a thickness of 50 mm and cured for 28 days employed in the test. The sides of the specimen were insulated with electrical tape. The mass is initially recorded, and the specimen is immersed in water at a depth of 5–10 mm for 0.6 s. Samples were checked at 1, 2, 3, 4, 6, 9, 12, 16, 20, 25, 30 and 45 min and 1-h intervals. Then, the sample was taken out of the water at specified intervals.Sorptivity is the method for assessing the quantity of unsaturated flow of liquids into concrete on an unsaturated specimen or the capacity of a sample to absorb and transmit water through capillary action3 × 10–7/ min(1/2)), the graph is plotted between the square root of time and flow quantity. Figure The square root of the time elapsed versus the mass obtained per unit area relative to water density was plotted. The slope for the best-fitting line (after eliminating the origin) was interpreted as sorptivity. For analysing the sorptivity index (mThis investigation uses a response surface model (RSM), which is trained to predict the properties like tensile strength, compressive strength and flexural strength of WPCB fibre-reinforced concrete. The accuracy of each of their predictions is measured and compared.92. The RSM polynomial model as a function of the input variable 93.The functional relationships between the response of interest mentclass2pt{minimIn this study, eight performance indicators were chosen to evaluate prediction results obtained from RSM. The metrics consist of the coefficient of determination . It was found that R2 from being artificially inflated by introducing new variables, an adjustment or modification known as the adjusted R2 has been developed . It is desirable if the modified p-value of less than 0.5 implies that it is statistically significant94.Table Figures The 3D surface plots of the strength parameters also clearly show that the increase in fibre content tends to increase the mechanical properties of WPCB fibre-reinforced concrete. The RSM model's main weakness is that it is aliased, which means estimating a factor's influence affects the element.The closeness of the predicted and actual responses is demonstrated by the actual and predicted response values. The residual plots did not show any significant deviation from normality; the plots clearly show that the chosen model could predict properties and connections between the materials used.Mechanical properties such as compressive strength, tensile strength and flexural strength were assessed for WPCB fibre-reinforced concrete in various proportions  for two different aspect ratios of AR30 and AR40 of WPCB fibres. Compared to control concrete, the compressive strength of WPCB fibre-reinforced concrete increased by 32.8% for AR30 and 40.8% for AR40 of WPCB fibres due to more fibres in the composite.In AR30, tensile strength is 70% and 80.1% for AR40 of WPCB-reinforced concrete compared to conventional concrete. The trend is nearly identical to compressive strength test results obtained for tensile strength and flexural, which could be strongly linked with increased WPCs fibres in the AR40 concrete mixes.Acidic environment's bond breakdown between WPCB fibres and the cement matrix, it is revealed that the AR30 concrete mixes were found to be more durable than AR40 concrete mixes due to the presence of a higher bonding area which requires a relatively more period for deterioration. The RCPT test confirmed that WPCB fibre conserved porosity, and the AR40 mixes performed much better, demonstrating that the WPCB fibre mix can produce high-performance concrete with low porosity and higher chloride resistance. The sorptivity index value drops for AR30 and AR40 mixes as the percentage of WPCB fibre increases. However, AR40 performed much better than AR30. Lower sorptivity numbers mean that the concrete is less likely to absorb water.The RSM accurately validated the mechanical properties of the WPCB fibre-reinforced concrete (Adding WPCB fibre improves the properties of fresh and hardened concrete significantly. The solid bonding strength between the fibre and matrix phase was the reason for the strength increase of WPCBs fibre-reinforced concrete.WPCBs converted as fibre is an alternative to conventional fibres, reducing the environmental hazards. WPCBs fibre-reinforced concrete mechanical properties were thoroughly investigated. The contribution of WPCB fibre to fresh and hardened concrete properties and durability properties was determined experimentally, and the experimental results were validated using a statistical model developed with RSM. The conclusions are drawn from this study:In conclusion, this research suggests that the utilization of hazardous WPCB as construction material with long term durability, could be effective waste management and reduce negative environmental impacts.Beyond 5% addition of WPCB fibre is cause the balling effect, which directly affects the workability nature of the concrete mix, which reduces the mechanical properties of the designed grade of concrete.The Balling effect may be avoided by decreasing the aspect ratios of the WPCB fibre, which increase the utilization of more WPCB fibre in concrete that may result in resisting the crack propagation in the concrete member.A limitation in the mechanical process has forced the investigators to study the properties of concrete by incorporating PCB Fiber with a width of 1 mm to 1.5 mm. a refinement in the process a manufacturing PCB fibre with a width of 0.1 to 0.5 mm can yield better results breeding the micro and macro cracks.The work was focused only on WPCB fiber addition in standard cement concrete; however, there were limitations in cutting the fiber to lower width/ thickness, making it challenging to maintain AR80 followed in conventional fiber-reinforced concrete.It is evident that WPCB might contains heavy metals in spite of removal external metal components and hence a comprehensive life cycle assessment would be helpful in assign the advantage and disadvantage in utilizing the same material in concrete as obsessed to traditional disposal methods.Fire resistance characteristics of reinforced WPCB concrete would prove beneficial as PCB contains epoxy materials


IgG4-related disease (IgG4-RD) is an emerging immune-mediated chronic fibrotic disease characterized by tumour-like mass formation. Reports of brain parenchymal involvement in IgG4-RD are rare and complete treatment-related remission of lesions has never been reported. Here, we present a woman in her mid-50s who developed headache and seizures. Brain magnetic resonance imaging revealed frontal bilateral pachymeningitis and a left frontal lobe parenchymal lesion, and pathologic findings were consistent with an IgG4-RD central nervous system manifestation. She had a history of tumour-like growth around the right optic nerve, orbital and maxillary cavities treated successfully with corticosteroids 28 years ago, and was receiving infliximab as a maintenance therapy for uveitis for the last 14 years. After initial high-dose corticosteroid treatment, the patient was treated with rituximab, and after 3 months, the patient presented with complete remission of IgG4-RD lesions and associated symptoms. This case illustrates the chronic, decades-spanning nature of IgG4-RD, and a complete response to rituximab even with intracerebral mass lesions that had emerged despite the use of infliximab, a therapy previously reported successful in IgG4-RD. The disease is characterized by mass-forming lesions consisting of lymphoplasmacytic infiltrates rich in IgG4-positive plasma cells and sclerosis, and in most patients, high-serum IgG4 levels. The most recognized presentations of IgG4-RD are type 1 autoimmune pancreatitis and salivary gland disease, but multiple organs are affected in 60−90% of all patients. Published cases of IgG4-RD have reported involvement of almost all organs, including descriptions of central nervous involvement in form of pachymeningitis, orbital pseudotumor, inflammatory enlargement of pituitary gland,6 pterygopalatine fossa, and cranial nerve enlargement. However, previous studies reporting involvement of brain parenchyma in IgG4-RD are scarce.IgG4-related disease (IgG4-RD) was defined only in 2003 as a clinical entity and is regarded an immune-mediated fibrotic disease with a progressive and chronic nature. The patient presented with spastic hemiparesis and dementia responding to high-dose corticosteroid treatment followed by rituximab. The treatment prevented the patient from having new lesions, but complete radiological or neurological recovery was not reported. More recently, De Maria and colleagues reported a case presenting with seizures and cerebral masses related to IgG4-RD. The patient showed favorable response to glucocorticoid treatment, but radiological or long-term outcomes were not reported.In 2014, Regev and colleagues reported a case of IgG4-RD with multiorgan involvement including several cortical and subcortical brain lesions.Here, we report the case of a woman in her mid-50s who presented with progressive headache and 3 months later with focal seizures that arrested speech production for the duration of 1 to 2 min. She was admitted to Helsinki University Hospital neurology ward in January 2022. Twenty-eight years earlier, the patient had presented with tumour-like growth around the right optic nerve, orbital, and maxillary cavities. Two separate biopsies via craniotomy revealed fibrotic inflammatory proliferation and the patient was diagnosed with Tolosa-Hunt syndrome. Corticosteroids were administered with a good response. Fifteen years later, regrowth of the tumour was observed on imaging, but biopsy could confirm only fibrosis, and the specific diagnosis remained unclear. The patient responded well to treatment with corticosteroids and the observed tumour-like growth disappeared. Four years after the initial diagnosis of Tolosa-Hunt syndrome, the patient developed chronic bilateral iritis and uveitis. Due to chronic uveitis, the patient had been treated in Helsinki University Hospital Department of Ophthalmology with glucocorticoids, but cystoid macular edema (CME) persisted and steroid-sparing medication (methotrexate and azathioprine) were tried. Slowly, the situation subsided with intravitreous corticosteroid injections and regular infliximab-infusions for 14 years preceding admission to neurology ward.Upon admittance, no significant neurological findings were observed in the clinical evaluation, but during monitoring, the patient presented with a focal seizure that arrested her speech production for 1 to 2 min. Paraphasias, dysarthria, or accompanying sensorimotor symptoms were not observed. A brain magnetic resonance imaging (MRI) scan with MRI angiography was acquired that revealed frontal bilateral pachymeningitis and left frontal lobe parenchymal inflammatory infiltrate . The neuAn electroencephalogram showed widespread intermittent theta and delta wave abnormalities in the left hemisphere. While clear epileptiform activity was not observed, the clinical presentation was in concordance with symptomatic focal epilepsy due to the parenchymal findings. She was discharged and referred to the department of neurosurgery for a diagnostic biopsy and to neurological outpatient clinic for further care.Thereafter seizures reoccurred, and the patient was again admitted to the neurological ward. MRI scan showed that the previously observed pachymeningitis and left frontal lobe parenchymal inflammatory infiltrate had progressed and were now accompanied with oedema. Lacosamide was added to antiepileptic medication. A preponed biopsy was performed in the left frontal lobe lesion and the adjacent meninges followed by initiation of methylprednisolone treatment. The number of IgG4-positive plasma cells was increased (>10 cells per high-power field); however, IgG4 to IgG plasma cell ratio was <40%.The biopsy revealed thickened and fibrotic dura with dense lymphoplasmacytic inflammation . PerivasTo treat both the chronic uveitis and the observed central nervous system infiltrates, infliximab was replaced with rituximab, which was administered in 1000 mg given twice with a 2-week interval. During the follow-up, the patient remained seizure-free and the headache had resolved. After 3 months of rituximab-treatment, the previously observed brain parenchymal changes and pachymeningitis were no longer observable in the brain MRI with gadolinium enhancement nor had new lesions emerged . Extensi10 and true central nervous system involvement  even more so.11 The disease often responds well to corticosteroids, also when there are meningeal manifestations. However, in severe, refractory, and steroid-dependent cases inclusion of rituximab in the treatment regime has shown promise.13 In parenchymal infiltrates, such reports are scarce.11 To our knowledge, this is the first report of complete clinical and radiological remission of probable IgG4-RD pachymeningoencephalitis after rituximab treatment. Infliximab has also been reported beneficial in treating IgG4-RD but our patient had long-lasting infliximab-therapy with confirmed high blood concentration and no autoantibody production against the medication at admittance, thus suggesting suboptimal effect against preventing manifestations of the central nervous system.Central nervous system involvement in IgG4-RD is rare. The prevalence of meningeal involvement is approximately 2% of overall clinical manifestations in IgG4-RD, Characteristic histopathological findings include fibrosis, lymphoplasmacytic infiltration with IgG4-positive plasma cells and obliterative phlebitis. For meninges, a threshold of 10 IgG4-positive plasma cells per high-power field has been recognized as diagnostic,10 whereas higher thresholds might apply different organs, for example, 100 IgG4-positive plasma cells per high-power field in skin.Biopsy is considered the gold standard for establishing a diagnosis in meningeal or brain parenchymal IgG4-RD. supported also by our patient, and IgG4-RD is almost indistinguishable from Tolosa-Hunt syndrome in its ocular presentation, it remains unknown whether the case was IgG4-RD from the beginning. Infliximab-therapy was unable to prevent the central nervous system manifestations, although was successful in treating uveitis. Our findings show complete and maintained remission with rituximab in IgG4-RD affecting the brain parenchyma, supporting the role of CD20+ B cells as disease drivers. A recent finding of a highly clonal CD8 + T cell infiltration within an IgG4-RD brain parenchymal lesion suggests a close interplay of B and T cells, and thus the benefit of rituximab might be linked to decreased antigen presentation by memory B cells. Further prospective treatment trials with rituximab are warranted.Our case report highlights the chronic nature of IgG4-RD, with almost 30 years from the first likely manifestation to setting the diagnosis based on modern histopathological analysis. Initially, the patient was diagnosed with Tolosa-Hunt syndrome, which is a rare neuro-ophthalmic manifestation characterized by granulomatous inflammation. As neuro-ophthalmological manifestations are quite commonly observed in IgG4-RD,


Background: Mucociliary clearance is a pivotal physiological mechanism that protects the lung by ridding the lower airways of pollution and colonization by pathogens, thereby preventing infections. The fixed 20:1 combination of cafedrine and theodrenaline has been used to treat perioperative hypotension or hypotensive states due to emergency situations since the 1960s. Because mucociliary clearance is impaired during mechanical ventilation and critical illness, the present study aimed to evaluate the influence of cafedrine/theodrenaline on mucociliary clearance.Material and Methods: The particle transport velocity (PTV) of murine trachea preparations was measured as a surrogate for mucociliary clearance under the influence of cafedrine/theodrenaline, cafedrine alone, and theodrenaline alone. Inhibitory substances were applied to elucidate relevant signal transduction cascades.Results: All three applications of the combination of cafedrine/theodrenaline, cafedrine alone, or theodrenaline alone induced a sharp increase in PTV in a concentration-dependent manner with median effective concentrations of 0.46 µM , 408 and 4 μM, respectively. The signal transduction cascades were similar for the effects of both cafedrine and theodrenaline at the murine respiratory epithelium. While PTV remained at its baseline value after non-selective inhibition of β-adrenergic receptors and selective inhibition of β1 receptors, cafedrine/theodrenaline, cafedrine alone, or theodrenaline alone increased PTV despite the inhibition of the protein kinase A. However, IP3 receptor activation was found to be the pivotal mechanism leading to the increase in murine PTV, which was abolished when IP3 receptors were inhibited. Depleting intracellular calcium stores with caffeine confirmed calcium as another crucial messenger altering the PTV after the application of cafedrine/theodrenaline.Discussion: Cafedrine/theodrenaline, cafedrine alone, and theodrenaline alone exert their effects via IP3 receptor-associated calcium release that is ultimately triggered by β1-adrenergic receptor stimulation. Synergistic effects at the β1-adrenergic receptor are highly relevant to alter the PTV of the respiratory epithelium at clinically relevant concentrations. Further investigations are needed to assess the value of cafedrine/theodrenaline-mediated alterations in mucociliary function in clinical practice. All procedures involving animals were conducted in compliance with the European legislation for the protection of animals used for scientific purposes and the standards for animal experiments according to the German animal welfare law. The experiments were approved by the local committee for animal care of the regional council . After deep isoflurane  narcosis, animals were sacrificed by cervical dislocation. The following steps were performed immediately within 30 min after euthanasia. The trachea was dissected with a parasternal incision of the thorax and a median incision of the throat . The traAfter a 30-min resting period, subsequent 80-min observation period started, where repeated measurements of PTV were performed under the influence of the different drugs. During the first 72 min of the observation period, measurement of PTV was conducted every 3 min. Afterward, adenosine triphosphate (ATP) was applied to confirm the viability of the tracheal epithelium leading to a maximal increase in PTV; measurements of PTV were then performed every 2 min to the end of the experiment at minute 80. At each timepoint, short movie sequences were recorded with high sampling rates using TiLLvisION Imaging software , as described previously . In brie50) were calculated using the Hill equation. The Mann-Whitney U test was used to compare equivalent measurement points from the different experiments, while the Wilcoxon rank-sum test was used to compare paired variables. In general, two-tailed values of p < 0.05 were considered statistically significant, while issues with multiple comparisons were counteracted by adjusting the α level according to the Bonferroni correction.The absolute PTV value was standardized to 100% after the resting time and prior to the observation period. Tracheal preparations and PTV measurements were only included in the statistical analyses when tracheal preparations showed directed particle motion during the whole observation period, and a clear response to the application of ATP was detected at the end of the experiments, immediately resulting in normalized PTV values of more than 200%. However, when high concentrations were applicated to obtain the concentration-response relationship, maximum PTV was already reached and could not be further accelerated by ATP. In this case, tracheal preparations were still included when directed particle motion was preserved during the whole observation period, and replicate experiments yielded similar results. Absolute values of basal PTV per experimental group prior to the standardization are shown in 2, 11 mM glucose, 136 mM NaCl, and 2.2 mM MgCl2. NaOH was used to adjust the pH to 7.4 at 30°C. To realize the experiments in Ca2+-free solutions, CaCl2 was substituted with 1 mM ethylene glycol tetraacetic acid. The following drugs were applied during the experiments: 2-aminoethoxydiphenylborane , TOCRIS Bioscience, Bristol, United Kingdom), ATP , cafedrine , cafedrine/theodrenaline 20:1 , caffeine , CGP20712A , H-89 , ICI-118,551 , theodrenaline , and U-73122 . The reported drug concentrations were achieved during the experiments after applying the stock solution to the buffer solution in the recording chamber.The historically established 20:1 ratio of cafedrine/theodrenaline is related to mass but not molarity; therefore, due to the different molar masses of cafedrine (357.41 g/mol) and theodrenaline (375.38 g/mol), a 1 M solution of cafedrine/theodrenaline 20:1 with a molar mass of 7,882.98 g/mol consists of 1 M theodrenaline, and approximately 21 M cafedrine. Preparations and experiments were performed in HEPES solution consisting of 10 mM HEPES, 5.6 mM KCl, 2.2 mM CaClp < 0.001; 50 values of 0.46 µM  for cafedrine/theodrenaline . When cafedrine/theodrenaline, cafedrine alone, or theodrenaline alone were applied, PTV significantly increased almost immediately in all experiments  was evaluated to determine the overall influence of β-adrenergic effects on the alteration in PTV. ICI-118,551 alone did not alter the baseline value of PTV, however, the increase in PTV was already completely blocked in the presence of ICI-118,551 when cafedrine/theodrenaline , which alone reduced basal PTV , cafedrine  and theodrenaline  alone produced comparable PTV values. When phospholipase C (PLC) was inhibited using U-73122 (7.5 µM), baseline value of PTV remained unchanged; however, PTV still increased following the administration of cafedrine/theodrenaline, cafedrine alone, and theodrenaline alone  release as crucial mechanism changing the PTV after the application of cafedrine/theodrenaline, further experiments were carried out on the value and the origin of intra- and extracellular Ca2+.Since our experiments found the β2+-free buffer solution was used to distinguish the origin of Ca2+ during the following experiments. PTV in Ca2+-free buffer solution did not differ from the Ca2+-containing control . As most intracellular Ca2+ is stored in the endoplasmic reticulum, these stores were depleted by caffeine prior to the application of the three substances. Subsequently, a decline of the basal PTV was noted ; neither cafedrine/theodrenalin  nor cafedrine  or theodrenaline  alone were able to cause a significant rise in PTV compared with caffeine alone , and it is mediated by stromal-interacting molecules activating ORAI channels  of our tested drugs was preserved. Second, pharmacodynamics and pharmacokinetics might differ between murine tracheae and human lower airways, including the concentration-response relationship. Third, we used small sample sizes in each group; however, clear effects were observed, and larger sample sizes were prohibited by animal welfare regulations. Although clinically administered concentrations were comparable to the concentrations used in our experiments, further studies on human tissues are necessary to confirm the results of our study, and the clinical relevance of the observed effects should be assessed 1-adrenergic receptor-associated Ca2+ release that is ultimately triggered through IP3 receptor activation. We obtained evidence that the alteration in murine PTV observed after 20:1 cafedrine/theodrenaline is foremost induced by theodrenaline; however, their synergistic effects at the β1-adrenergic receptor are highly relevant to accelerate the PTV of the respiratory epithelium. Because the pharmacokinetics of cafedrine/theodrenaline remain unknown, further experiments including human tracheal epithelium and clinical studies are needed to evaluate the value of cafedrine/theodrenaline in altering mucociliary function in clinical practice.In conclusion, our experiments showed a sustained elevation in murine PTV when cafedrine/theodrenaline, cafedrine alone, or theodrenaline alone were applied. Both substances produce their effects via β


Opioid use disorder (OUD) is defined as a compulsion to seek and take opioids, loss of control over intake and the development of a negative emotional state when access to opioids is denied. Using functional magnetic resonance imaging (fMRI) data in a rat model of OUD, we demonstrate that the escalation of heroin self-administration (SA) and the increased heroin SA following an injection of an opioid receptor antagonist  are associated with changes in distinct brain circuits, centered on the cingulate cortex (Cg). Here, SA escalation score was negatively associated with changes in resting state functional connectivity (rsFC) between the Cg and the dorsal striatum. Conversely, increased heroin SA following naloxone injection, was associated with increased connectivity between the Cg and the extended amygdala and hypothalamus. Naloxone-induced increased SA was also positively associated with changes in the amplitude of low frequency fluctuations within the Cg, a measure of spontaneous neuronal activity. Characterizing the distinct brain circuit and behavior changes associated with different facets of addiction increases our understanding of OUD and may provide insight into addiction prevention and treatment. In 2019, 2.2% of the US population reported any lifetime use of heroin . Heroin Previous research from our group has identified the extended amygdala and the hypothalamus as responsive to odor cues previously associated with conditioned heroin withdrawal in heroin dependent rats . In thatTo measure individual differences in intrinsic circuits related to the behavioral characteristics of heroin dependence, rats with a history of heroin SA and naloxone administration under ShA or LgA conditions  underwenμg/kg/infusion) in 1-h sessions under a fixed-ratio 1 (FR1) schedule of reinforcement. Rats were randomly split into ShA (1 h/day) or LgA (12 h/day) SA groups and self-administered heroin over 10 sessions. The two groups were then injected with saline or naloxone  while being exposed to cues during 8 alternating SA sessions. The rats underwent fMRI scanning 24 h after the last SA session. Behavioral data are published in [Details about the experimental animals and heroin SA procedures have been previously described by Carmack et al. . The expFrom the behavior reported in , two beh®; Webster Veterinary) and isoflurane (Henry Schein), which has minimal interference on spontaneous brain oscillations [2, matrix size = 64 × 64 (0.547 mm in-plane resolution), slice thickness = 1 mm, 15 slices, 300 time points).Twenty-four hours following the last odor cue conditioning session, rats underwent fMRI scanning under light anesthesia using a combination of dexmedetomidine  software ,18 and tuncorrected < 0.01) was considered significant.Whole brain, seed-based, rsFC analyses used 3dMVM (AFNI) to compare groups (LgA versus ShA) and either escalation score or naloxone-induced increases in SA score  as a behavioral covariate. Average respiration rate was included as a covariate to account for differences between individual animal’s respiration rate, shown to be the most critical physiological parameter for fMRI data quality in anesthetized rats . The spaThe amplitude of low frequency fluctuations (ALFF) , measuriR studio 1.3.1073  was usedr=−0.098, P = 0.67, CI=−0.51 to 0.35). Given the lack of association between these two behavioral metrics, we considered them independent measures.On average, LgA rats had significantly higher escalation scores and self-administered more heroin following a low dose injection of naloxone than ShA rats (data published in ). The docorrected < 0.05; corrected < 0.05; We chose the previously observed  mid-hypo=6.05, p < 0.05). Increased ALFF in the Cg of LgA rats suggests increased spontaneous neuronal activity within and between elements in the Cg in dependent rats as naloxone-induced increases in heroin infusions increase. In contrast, there were no main effects of escalation score or heroin exposure group on Cg ALFF.Given that rsFC between the Cg and both the extended amygdala and hypothalamic seed regions increased with increasing naloxone-induced SA, we next asked whether intrinsic activity within the Cg changed as a function of heroin access and escalation score and/or naloxone-induced increases in heroin SA. We measured the amplitude of low frequency fluctuations (ALFF)  within tcorrected < 0.05; corrected < 0.001; Given that the intrinsic activity of the Cg was altered as a function of ShA and LgA treatment and individual differences in naloxone-induced SA, we next determined whether Cg connectivity with other brain regions was impacted by heroin access and the behavioral metrics of escalation score and/or naloxone-induced increases in heroin SA. Using the Cg , such that the CPu/BNST-Cg functional circuit strength increased with escalation score. Notably, no changes in rsFC between the LSN/TSN cluster and any other regions as a function of heroin access group (ShA versus LgA) or escalation score were observed (data not shown).Next, given that connectivity between the Cg and these clusters was associated with escalation score but not naloxone-induced increases in SA, we performed a second whole brain rsFC analysis using escalation score as a behavioral correlate with these two identified circuit clusters as seeds. For the CPu/BNST seed, we observed a significant interaction between escalation score and rsFC in a cluster within the Cg , we conUsing resting state BOLD signal to infer changes in functional connectivity along the trajectory of heroin dependence, we observed that two dependence associated behaviors  were associated with distinct cingulate cortex based neural circuits. To do this, we used a priori regions of interest from our previous findings of activity changes in the hypothalamus and extended amygdala that demonstrated differential responses to conditioned opioid withdrawal cues . IndepenEscalation of heroin SA occurs during the period in the addiction cycle where occasional drug use transitions from impulsive to compulsive use –28. HereConnectivity between the cingulate and striatum previously has been strongly implicated in nicotine dependence severity in humans ,38 and rαi/o-coupled receptors, leading to enhanced cAMP production [In addition to the Cg-dorsal striatal circuit’s relationship with initial drug use escalation, we observed that increased naloxone-induced heroin SA is associated with increased rsFC between two other Cg-based circuits, one with the eAmy and the other with the mHyp area -E. Naloxoduction . In thisoduction . This seoduction  and may oduction ,44. For oduction . In partoduction  and is hoduction . Additiooduction . TherefoThe extended amygdala, a region functionally connected to the hypothalamus , is simiAlthough heroin intake escalation and naloxone-induced increases in SA are associated with distinct neural circuits, these circuits appear to converge on the Cg. Moreover, chronic drug use-induced plasticity not only alters cingulate based circuits (as summarized above) but also modifies intrinsic circuits within the cingulate itself. Here, we assessed spontaneous brain activity fluctuations within the Cg and found that the amplitude of intrinsic low frequency fluctuations (ALFF) increased as naloxone-induced SA increased in LgA rats,whereas ALFF decreased in ShA animals. The Cg is involved in many functions including emotion formation and processing , decisioThe Cg, both as a component of the Salience Network and on its own, has been heavily implicated in drug addiction. For example, functional connectivity strength within the Salience Network increases as a function of exposure to a conditioned heroin withdrawal cue in rats with a history of heroin SA  and enviAlthough our data suggest that the distinct circuits, identified here, drive different behavioral facets of opioid dependence, they both converge on the Cg. We propose that as dependence develops, reward-associated Cg-dorsal striatal circuitry contributes to escalating drug taking behaviors. However, following increased opioid receptor sensitivity, Cg-limbic circuits, which are associated with negative emotional learning ,8, strenDespite the convergence of our findings, multiple study limitations remain. First and foremost, although our sample size was sufficient for the targeted analysis presented here, any network-based analysis would be underpowered and require larger group sizes. Additionally, the behaviors measured represent only a limited sample of addiction-related behaviors and were measured only in male rats. Although the LgA and ShA model of drug use has numerous advantages , it doesIn summary, using a LgA and ShA model of heroin SA, we demonstrate that escalation of SA and naloxone-induced increases in heroin infusions are associated with several neural circuits that center on the Cg, demonstrating its key role in heroin dependence. These results support the hypothesis that pivoting away from the current non-specific, pharmacologic therapeutic approach , and tow


The presence of peritoneal carcinomatosis in patients with advanced gastric cancer has important implications for the management of this disease. For this reason, staging laparoscopy plays an important role in the preoperative diagnosis of peritoneal dissemination in these patients. A review of the current literature was performed in order to summarize the indications, advantages, and future perspectives of staging laparoscopy and peritoneal cytology in the diagnosis and management of advanced gastric cancer.A significant proportion of patients diagnosed with gastric cancer is discovered with peritoneal metastases at laparotomy. Despite the continuous improvement in the performance of radiological imaging, the preoperative recognition of such an advanced disease is still challenging during the diagnostic work-up, since the sensitivity of CT scans to peritoneal carcinomatosis is not always adequate. Staging laparoscopy offers the chance to significantly increase the rate of promptly diagnosed peritoneal metastases, thus reducing the number of unnecessary laparotomies and modifying the initial treatment strategy of gastric cancer. The aim of this review was to provide a comprehensive summary of the current literature regarding the role of staging laparoscopy in the management of gastric cancer. Indications, techniques, accuracy, advantages, and limitations of staging laparoscopy and peritoneal cytology were discussed. Furthermore, a focus on current evidence regarding the application of artificial intelligence and image-guided surgery in staging laparoscopy was included in order to provide a picture of the future perspectives of this technique and its integration with modern tools in the preoperative management of gastric cancer. Staging laparoscopy (SL) is a minimally invasive diagnostic procedure used for gastrointestinal and gynecological tumor staging, including advanced gastric cancer (GC). During SL, a thorough exploration of the abdominal cavity is carried out to detect possible occult peritoneal metastases that might have been missed by preoperative imaging.SL plays a key role in the preoperative assessment of GC, as the detection of peritoneal carcinomatosis is considered as distant metastasis by the 8th International Union for Cancer Control/American Joint Committee on Cancer TNM classification, ranking the disease as stage IV ,2 and shNotwithstanding this, the importance of SL has long been debated since 1984. On the one hand, Shandall et al. questioned the value of laparoscopy, given the need for at least palliative surgery in a high percentage of patients . ConversNowadays, the employment of new chemotherapy regimens, the technological improvement in diagnostics and surgery, and the multi-disciplinary decision making have expanded the boundaries of advanced GC treatment, paving the way to patient-tailored strategies and improving overall and disease-free survival ,7,8,9. However, despite computed tomography (CT) currently representing the gold standard technique for preoperative GC staging, its performance in detecting peritoneal dissemination is suboptimal and often relies on many indirect signs of carcinomatosis, such as ascites and omental retraction . SL can provide supplementary information regarding GC peritoneal dissemination, also through peritoneal washing and cytological analysis . For this reason, SL is recommended for preoperative staging of GC by several international guidelines, including those published by the National Comprehensive Cancer Network (NCCN) , EuropeaThis review aims to provide an overview of SL for GC, its indications, benefits, limitations, and future perspectives.A literature search was performed by screening MEDLINE, Cochrane Library, and EMBASE from inception to 1st April 2023. Specific research equations were designed for each database, using the following search equation: ((staging laparoscopy) OR (diagnostic laparoscopy)) AND (gastric cancer). After a first screening based on titles and abstracts, thirty-seven articles were selected and underwent full-text analysis. Relevant articles were reviewed, and their references were also screened for additional relevant studies. Only English-language articles were included.The most important aim of SL is to detect occult peritoneal disease through direct intraperitoneal view or cytological analysis after peritoneal washing, which cannot be preoperatively diagnosed by conventional radiological imaging .The most important indications for SL according to National and International Guidelines are summarized in In Western countries, where the ratio of advanced–early GC is more common, there is a general indication for SL in the case of a resectable GC without distant metastases. In particular, according to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for GC , SL may As regards European Society for Medical Oncology (ESMO) guidelines , SL withAccording to the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) guidelines , SL is iIn Eastern countries, SL is carried out based on the results of two clinical trials of the Japan Clinical Oncology Group (JCOG), in which SL was systematically performed to confirm the eligibility criteria ,23. AccoSL is performed under general anesthesia with the patient in a supine position. To begin the procedure, open Hasson, or optical ports-based technique, as well as Veress needle insufflation, can be used according to the surgeon’s personal experience. After the carbon dioxide pneumoperitoneum induction, the inspection of the peritoneal cavity through a laparoscope can start, looking for any signs of advanced or metastatic GC disease. Ascitic fluid is collected for cytology if present. The liver, spleen, diaphragm, mesentery, and peritoneal surfaces are examined for the presence of metastatic disease . In caseAlthough the SL technique has been long described in the literature, a standardized “Four-Step Procedure” has not been proposed until 2018 by Liu et al. .The first step regards the exploration of the anterior abdominal wall and the surface of the visceral peritoneum. Specifically, the exploration of the anterior abdominal wall is performed with a circular clockwise orientation, starting from the diaphragmatic domes, the teres, and falciform ligaments, then proceeding towards the left side, the hypogastric, and the right side of the anterior abdominal wall. Conversely, the exploration of the surface of the abdominal viscera is performed according to an “S-shaped” sequence, starting from the anterosuperior surface of the left and right liver, proceeding to the greater omentum and the transverse colon, then to the left colon and the left paracolic gutter, finally ending with the surface of the small intestine, the right colon, and the right paracolic gutter.The second step aims to explore the pelvic parietal and visceral peritoneum. This step takes advantage of a 30° Trendelenburg position and requires the placement of two 5 mm trocars in order to take the intestine out of the pelvis. At this point, the bilateral iliac fossa  are exposed, and the pelvic floor and the peritoneal reflection can be examined after lifting the bladder fundus  and pulling the sigmoid colon.The third step concerns the inspection of the small intestine and mesentery. The 30° Reverse Trendelenburg or supine position is required. The greater omentum and the transverse colon are lifted up, and the transverse mesocolon, the Treitz ligament, and the duodenojejunal junction are examined. Subsequently, the whole surface of the intestinal mesentery, together with the surface of the small intestine, are explored from the Treitz region to the ileocecal valve.The fourth step regards the exploration of the stomach and the adjacent area. In the supine position, the greater omentum is replaced in its anatomical position to expose the anterior gastric surface and the greater curvature. Next, the stomach is lifted in order to evaluate the presence of posterior neoplastic infiltration. Then, the exploration of the lesser curvature and lesser omentum may require the lifting of the left liver. In the case of proximal GC, the distance between the tumor and cardia should be evaluated, while pylorus and duodenal bulb infiltration should be examined in the case of distal GC.Finally, after the exploration of the hepatorenal recess, the opening of the gastrocolic ligament and the inspection of the lesser sac should be considered for posterior GC.During the procedure, biopsies are performed when peritoneal dissemination is detected.PC represents a useful diagnostic tool for detecting GC spreading to the peritoneal cavity. In order to obtain samples for cytologic analysis, a peritoneal lavage is performed through the infusion of 150 mL of saline solution into hepatorenal and splenic recesses during the first step, and the infusion of 200 mL into paracolic gutters and the pelvis during the second step.Being a surgical procedure in every aspect, SL can be burdened by the same complications of other surgeries. Except for the anesthesiologic complications that may occur due to comorbidities and/or intolerance of the pneumoperitoneum, the perioperative course can still be complicated by inadvertent bowel perforation during manipulation, damage to other intra-abdominal structures, hemorrhage , infection, and incisional hernia. Nevertheless, the incidence of these complications is quite rare, and SL can be considered a safe procedure.SL can detect unknown metastatic diseases in up to three out of five GC patients despite negative staging imaging ,33,34,35Nowadays, the importance of SL is also enhanced by the possibility of assessing the Peritoneal Carcinomatosis Index (PCI) . PCI is Indeed, during recent decades, cytoreductive surgery followed by HIPEC ,42,43, ap = 0.0003) [PC can further improve the efficacy of SL for GC staging through the identification of occult carcinomatosis . Indeed, 0.0003) . NeverthStaging laparoscopy has some limitations that must be considered. It is an invasive procedure that carries a risk of complications, such as bleeding, infection, and injury to surrounding organs, albeit lower than the morbidity and mortality associated with nontherapeutic laparotomies ,61. MoreSL has become part of the standard preoperative assessment of GC staging during recent decades. However, the continuous technological progress of CT imaging in terms of accuracy and precision  and the A prospective study by Li et al.  analyzedMore recently, AI has been broadly investigated as a complementary tool due to its potential to overcome many limitations of SL and computed tomography for GC in terms of accuracy and safety ,82. The Dong et al.  improved2 CT image of the primary tumor to estimate the probability of occult peritoneal metastasis. The Peritoneal Metastasis Network model achieved an area under the curve of 0.92 with a sensitivity of 87.5% and a specificity of 98.2% in the external validation cohort. Moreover, this non-invasive model was an independent predictor of occult peritoneal metastases at the multivariable analysis, with better performance when compared to the conventional clinicopathological factors.Recently, Jiang et al.  analyzedInterestingly, Schnelldorfer et al.  tried toIn conclusion, AI may have the potential to revolutionize the staging of GC and redesign the role of SL. Furthermore, the development of image-guided surgical tools might integrate the AI application. In fact, while they have already been investigated to guide lymphadenectomy during resective surgery , the useSL is a key tool for preoperative GC staging, allowing an accurate assessment of disease extent and the detection of peritoneal metastases that may be missed by conventional preoperative imaging.The high sensitivity and specificity of SL, together with its negligible rate of complications, earned it a top-notch spot in GC clinical decision making, thanks to the possibility of preventing unnecessary laparotomy in case of metastatic disease and identifying all patients with advanced disease who will not benefit from curative surgery.The integration of new technologies into current clinical practice, such as AI-based models, has the potential to improve the accuracy of preoperative staging tools and might provide a more accurate patient selection for tailored treatment strategies.