Modification Of Protocol Research Articles

Impact of preanaesthetic electrocardiogram on decision making and modification of anaesthetic protocols in dogs.

This retrospective observational study explored the impact of preanaesthetic electrocardiogram (ECG) assessment on preoperative echocardiography requests and modifications to a standardised anaesthetic protocol in healthy dogs. A total of 228 healthy dogs with no previously diagnosed heart disease that underwent general anaesthesia at Complutense Veterinary Teaching Hospital from December 2017 to June 2018 were included. Preanaesthetic ECGs were assessed for abnormalities, and the findings were documented. The number of dogs requiring echocardiography, based on ECG findings, and the echocardiography results were recorded. All anaesthesia-related decisions were documented. Overall, 72 dogs (31.6%) exhibited ECG abnormalities. Echocardiography was requested for five dogs (2.2%). The anaesthetic protocol was changed in 11 dogs (15.3% of those with ECG abnormalities). P wave disturbances, ventricular premature complexes and impulse conduction issues were abnormalities that prompted echocardiography. Bradycardia and electrical impulse conduction abnormalities influenced protocol modifications. The limited sample size meant that it was not possible to investigate potentialcorrelations between demographics and ECG alterations. Preanaesthetic ECG screening was useful forpromoting echocardiography and influencing anaesthesia plans in a subset of dogs. Despite this, further assessment of the impact of routine use of non-targeted preoperative ECG on anaesthesia-related outcomes is warranted.

BEST FOR CAN – bringing empirically supported treatments to children and adolescents after child abuse and neglect: update to the study protocol

ABSTRACT Background: The implementation trial BESTFORCAN aims to evaluate the dissemination of Trauma-Focused Behavioural Therapy (TF-CBT) for children and adolescents in Germany with posttraumatic stress symptoms (PTSS) after child abuse and neglect (CAN) with a focus on supervision. Objective: This update to the study protocol outlines changes made due to practical reasons in the course of the ongoing trial while maintaining methodological quality. Method: The amendments to the original study protocol comprise (1) a more refined operationalisation of the primary outcome sufficiently adherent TF-CBT therapy (SATT), (2) changes in the study sites and (3) additional inclusion of one post-gradual psychotherapy training institute. Discussion: The adaptions to the original study protocol ensured high methodological quality through the transparent presentation of protocol modification: ensuring the recruitment of participating psychotherapists in training by including a further post-gradual training institute as well as an adaption of the measurement of SATT with high external validity. The objectives, diagnostic set, and secondary outcomes remained unimpaired by the amendment. Therefore, we expect the trial to provide evidence for the effect of model-specific trauma-focused supervision on the implementation outcomes of TF-CBT as compared to supervision as usual. Trial registration: German Clinical Trials Register identifier: DRKS00020516..

Modification of The Spectrophotometric Analysis Protocol by Sims D. and Gamon to Analyze Leaf Pigment Content using Green Spinach (Amaranthus hybridus) as a Model Plant

Modification of The Spectrophotometric Analysis Protocol by Sims D. and Gamon to Analyze Leaf Pigment Content using Green Spinach (Amaranthus hybridus) as a Model Plant

A statistical method for protocol modifications with heterogeneous population variances

During the course of a clinical trial, the procedure may need to be modified based on medical or practical results. For example, in trials with low recruitment rates, the data monitoring committee often changes the inclusion/exclusion criteria, the number of sites, the endpoint, or the protocol itself. When such changes occur, protocol amendments are needed. However, the actual patient population after protocol amendments may be slightly different from the target population. In this study, we focus on the scenario in which the populations have heterogeneous variances across the modifications of trial procedures due to protocol amendments. A statistical method based on the Satterthwaite approximation with corresponding sample size adjustments is developed to evaluate the treatment effect. Our simulation demonstrates that the proposed method controls the type I error rate and provides sufficient power.

Protocol modifications reduce risk of delayed pericardial effusions after vein of Marshall ethanol infusion: follow-up from the Maine experience.

While ethanol infusion into the vein of Marshall (VOM) as an adjunct to atrial fibrillation ablation has shown promise, adoption has been limited by the technical expertise required, unclear antiarrhythmic mechanism, and complication risk. Delayed pericardial effusions have been associated with ethanol infusion into the VOM in prior studies. Very little is known about how the procedural approach itself can impact the risk of delayed effusions. We sought to understand the incidence and influence of procedural technique on complications including delayed pericardial effusions from VOM ethanol infusion at a large single medical center. A total of 275 atrial ablation cases wherein VOM ethanol infusion was attempted were identified from the time of the program's inception in 2019 at Maine Medical Center (Portland, ME) until October of 2023. Cases were classified into phase I cases (early experience) and phase II cases (later experience) based upon temporal programmatic changes in the ethanol dose and infusion rate as well as the use of routine VOM venography. Procedural details and complications were adjudicated from the medical record. The overall VOM ethanol infusion success was 91.4%. Nine complications (3.3%) occurred in eight patients (2.9% of patients). These were more frequent in phase I (5.8%) compared to phase II (1.3%, p = 0.047). This difference was driven by a difference in delayed presentations of tamponade, which occurred in four patients in phase I (3.3%) and in no patients in phase II (0%, p = 0.037). Twelve-month estimated atrial arrhythmia freedom did not differ between groups (73.8% phase I vs 70.4% phase II, p = 0.24). In our single-center experience, adjustments to the procedural approach with lower ethanol infusion rate and dosage, combined with utilizing selective VOM venography, associated with a lowering of complication rates and in particular, delayed pericardial tamponade.

Evaluation of the Tolerability of Hedgehog Pathway Inhibitors in the Treatment of Advanced Basal Cell Carcinoma: A Narrative Review of Treatment Strategies.

Hedgehog pathway inhibitors (HHIs) have broadened the treatment options available for patients with advanced basal cell carcinoma (BCC) for whom traditional therapeutic approaches are not feasible or effective. Sonidegib and vismodegib are oral HHIs that were approved for treatment of patients with advanced BCC after demonstrating promising efficacy in the pivotal Phase II BOLT (NCT01327053) and ERIVANCE (NCT00833417) trials, respectively. However, the incidence and types of treatment-emergent adverse events (AEs) observed with these agents may limit continuous use of HHIs and ultimately impact clinical outcomes. In this review, we summarize the safety and tolerability profiles of sonidegib and vismodegib and discuss potential management strategies for HHI class-effect AEs, including muscle spasms, creatine phosphokinase increase, alopecia, and dysgeusia. These AEs primarily occur early in treatment and can lead to treatment discontinuation. Differences in the pharmacokinetic profiles of sonidegib and vismodegib may contribute to the variability noted in times to onset and resolution of these and other AEs. Evidence suggests that protocol modifications, such as treatment interruptions and dose reductions, are effective ways to manage AEs while maintaining disease control. Nonpharmacologic and pharmacologic interventions may also be considered as part of an AE management strategy. Overall, healthcare providers and patients with advanced BCC should be aware of the HHI class-effect AEs and plan effective management strategies to avoid treatment discontinuation and optimize therapeutic response.

Effects of Heart Rate Variability Biofeedback Training on Anxiety Reduction and Brain Activity: a Randomized Active-Controlled Study Using EEG.

Heart rate variability biofeedback (HRVBF) is a promising anxiety-reducing intervention that increases vagally-mediated heart rate variability (vmHRV) through slow-paced breathing and feedback of heart rhythm. Several studies have reported the anxiety-reducing effects of HRVBF; however, some studies have reported such training as ineffective. Furthermore, the effects of training and underlying brain activity changes remain unclear. This study examined the anxiety-reducing effects of HRVBF training and related brain activity changes by randomly assigning participants, employing an active control group, and measuring anxiety-related attentional bias using the emotional Stroop task and electroencephalography (EEG). Fifty-five healthy students with anxiety were randomly assigned to the HRVBF or control groups, and 21 in the HRVBF group and 19 in the control group were included in the analysis. Both groups performed 10 training sessions of 20min each within 3 weeks. They were assessed using resting vmHRV, event-related potential (ERP), time-frequency EEG, attentional bias, and the State-Trait Anxiety Inventory-JYZ (STAI-JYZ) before and after training. The results demonstrated increased resting vmHRV in the HRVBF group compared to the control group after training. However, no differences were observed in ERP, time-frequency EEG, attentional bias, and STAI-JYZ. Participants with higher pre-training resting vmHRV achieved higher heart rhythm coherence in HRVBF training and had reduced attentional bias. This study suggests that individuals with higher resting vmHRV are more likely to be proficient in HRVBF training and benefit from its anxiety-reducing effects. The findings contribute to participant selection to benefit from HRVBF training and modification of the training protocols for non-responders.Clinical trial registrationOrganization: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR), JapanRegistration number: UMIN000047096Registration date: March 6, 2022.

Stem cell therapy for interstitial cystitis/bladder pain syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic disease with limited treatment options. Current multidisciplinary approach targeting bladder inflammation and urothelial dysfunction has limited durable effect that major surgery is ultimately required for both Hunner and non-Hunner type IC. Various investigational attempts are underway to avoid such operations and preserve the urinary bladder. Stem cell therapy is a fascinating option for treating chronic illnesses. Stem cells can self-renew, restore damaged tissue, and have paracrine effects. The therapeutic efficacy and safety of stem cell therapy have been demonstrated in numerous preclinical models, primarily chemically induced cystitis rat models. Only one clinical trial (phase 1 study) has investigated the safety of human embryonic stem cell-derived mesenchymal stem cells in three Hunner-type IC patients. Under general anesthesia, participants underwent cystoscopic submucosal stem cell injection (2.0 × 107 stem cells/5 mL). No safety issues were reported up to 12 months of follow-up and long-term follow-up (up to 3 years). Although there were variations in therapeutic response, all patients reported significant improvement in pain at 1 month postoperatively. One patient underwent fulguration of the Hunner lesion after the trial, but others reported an overall improvement in pain. The analysis on phase 1/2a trial which had several modifications in protocol is currently ongoing. Despite several limitations that need to be overcome, stem cell therapy could be a potential therapeutic option for treating IC/BPS. Clinical outcome on phase 1/2a trial is important and might provide more insight into the clinical application of stem cell therapy for IC/BPS.

Divergent responses of human intestinal organoid monolayers using commercial in vitro cytotoxicity assays.

In vitro models, such as primary cells and continuous cell lines routinely used for evaluating drug candidates, have limitations in their translational relevance to human diseases. Organotypic cultures are increasingly being used to assess therapeutics for various cancers and infectious diseases. Monitoring drug cytotoxicity in cell cultures is crucial in drug development, and several commercially available kits for cytotoxicity assessment offer distinct advantages and limitations. Given the complexity of organoid cultures, including donor-driven variability, we investigated drug-treated, tissue stem cell-derived human intestinal organoid responses with commonly used cell cytotoxicity assay kits. Using seven different compounds, we compared the cytotoxicity assay performance of two different leaky membrane-based and two metabolism-based assays. Significant variability was seen in reported viability outcomes across assays and organoid lines. High baseline activity of lactate dehydrogenase (LDH) in four human intestinal organoid lines required modification of the standard LDH assay protocol. Additionally, the LDH assay reported unique resilience to damage in a genetically-modified line contrasting results compared to other assays. This study highlights factors that can impact the measurement of cell cytotoxicity in intestinal organoid models, which are emerging as valuable new tools for research and pre-clinical drug testing and suggest the need for using multiple assay types to ensure reliable cytotoxicity assessment.

Simultaneous assessment of human genome and methylome data in a single experiment using limited deamination of methylated cytosine.

Multiomics require concerted recording of independent information, ideally from a single experiment. In this study, we introduce RIMS-seq2, a high-throughput technique to simultaneously sequence genomes and overlay methylation information while requiring only a small modification of the experimental protocol for high-throughput DNA sequencing to include a controlled deamination step. Importantly, the rate of deamination of 5-methylcytosine is negligible and thus does not interfere with standard DNA sequencing and data processing. Thus, RIMS-seq2 libraries from whole- or targeted-genome sequencing show the same germline variation calling accuracy and sensitivity compared with standard DNA-seq. Additionally, regional methylation levels provide an accurate map of the human methylome.

Near-perfect precise on-target editing of human hematopoietic stem and progenitor cells.

Precision gene editing in primary hematopoietic stem and progenitor cells (HSPCs) would facilitate both curative treatments for monogenic disorders as well as disease modelling. Precise efficiencies even with the CRISPR/Cas system, however, remain limited. Through an optimization of guide RNA delivery, donor design, and additives, we have now obtained mean precise editing efficiencies >90% on primary cord blood HSCPs with minimal toxicity and without observed off-target editing. The main protocol modifications needed to achieve such high efficiencies were the addition of the DNA-PK inhibitor AZD7648, and the inclusion of spacer-breaking silent mutations in the donor in addition to mutations disrupting the PAM sequence. Critically, editing was even across the progenitor hierarchy, did not substantially distort the hierarchy or affect lineage outputs in colony-forming cell assays or the frequency of high self-renewal potential long-term culture initiating cells. As modelling of many diseases requires heterozygosity, we also demonstrated that the overall editing and zygosity can be tuned by adding in defined mixtures of mutant and wild-type donors. With these optimizations, editing at near-perfect efficiency can now be accomplished directly in human HSPCs. This will open new avenues in both therapeutic strategies and disease modelling.

Near-perfect precise on-target editing of human hematopoietic stem and progenitor cells

Precision gene editing in primary hematopoietic stem and progenitor cells (HSPCs) would facilitate both curative treatments for monogenic disorders as well as disease modelling. Precise efficiencies even with the CRISPR/Cas system, however, remain limited. Through an optimization of guide RNA delivery, donor design, and additives, we have now obtained mean precise editing efficiencies >90% on primary cord blood HSCPs with minimal toxicity and without observed off-target editing. The main protocol modifications needed to achieve such high efficiencies were the addition of the DNA-PK inhibitor AZD7648, and the inclusion of spacer-breaking silent mutations in the donor in addition to mutations disrupting the PAM sequence. Critically, editing was even across the progenitor hierarchy, did not substantially distort the hierarchy or affect lineage outputs in colony-forming cell assays or the frequency of high self-renewal potential long-term culture initiating cells. As modelling of many diseases requires heterozygosity, we also demonstrated that the overall editing and zygosity can be tuned by adding in defined mixtures of mutant and wild-type donors. With these optimizations, editing at near-perfect efficiency can now be accomplished directly in human HSPCs. This will open new avenues in both therapeutic strategies and disease modelling.

FLAG-IDA + venetoclax in newly diagnosed (ND) or relapsed/refractory (RR) AML.

6519 Background: We report the outcomes of a phase 2 study of FLAG-IDA+VEN in AML. Methods: Pts ≥18 with ND or RR AML / MDS-EB2 fit for intensive chemotherapy were eligible. Induction comprised fludarabine 30mg/m2 D2–6, cytarabine 1.5g/m2 D2–6, idarubicin 8 (6 if RR) mg/m2 D4–6 & filgrastim 5mcg/kg D1–7. VEN 400mg was administered D1–14 with CYP3A inhibitor dose adjustment until Jul 2023; following a protocol modification, VEN is now administered D1–7. The primary outcome was ORR (CR + CRh + CRi + MLFS + PR). Secondary outcomes were CRc (CR + CRh + CRi), overall survival (OS), event-free survival (EFS) & duration of response (DOR). Measurable residual disease (MRD) was assessed by flow cytometry. Results: As of Jan 2024, 134 pts have enrolled, 127 (68 ND & 59 RR) evaluable at data cut. Median age was 45 (18 – 73); 19 (15%) age ≥60. 13 (19%), 22 (32%) & 33 (49%) ND pts were ELN22 favorable, intermediate & adverse respectively. There were 7 (10%) secondary (s), including 4 hypomethylating agent failure, & 7 (10%) therapy-related (t) AML. In RR pts, 40 (68%) were in salvage 1 (S1), of whom 32 (54%) were TP53WT. 20 (34%) had prior stem cell transplant (SCT). Median of 2 cycles were given. In ND pts, ORR was 99%, (96% CRc, of whom 89% MRD negative [Table]). Similar responses were seen across ELN groups & s/tAML. At median follow-up (mFU) of 30 months (mo), the mOS, mEFS & mDOR were not reached. The 2yr OS, EFS & DOR were 75% (64 – 88), 68% (56 – 81) & 71% (59 – 85) respectively, with no differences among ELN groups. 57% went to SCT in CR1. 4/4 pts with TP53mut became CRc MRD–, but mDOR was only 8.2 mo (95% CI, 2.2 – NE), resulting in poor mOS (13.5 mo, 95% CI, 8.6 – NE). In RR pts, ORR was 70% (66% CRc, of whom 79% MRD negative [Table]). At mFU 27 mo, the mOS, mEFS & mDOR were 12 (7 – 33), 7 (4 – 23) & 21 (8 – NE) mo respectively. The 2yr OS, EFS & DOR were 40% (28 – 55), 34% (23 – 49) & 49% (35 – 68) respectively. 58% went to SCT. S1+ TP53WT pts had mOS of 34 mo (12 – NE), with 72% going to SCT. 30d & 60d mortality were 0% & 3%. Of the 4 deaths within 60d, 1 was sepsis-related in CR in a ND pt while 3 were disease-related in NR RR pts. The most frequent adverse event was infection. Grade ≥3 infections, gastrointestinal toxicities & bleeding occurred in 102 (80%), 20 (16%) & 9 (7%) pts respectively. The median time to neutrophil >1x109/L & platelet >50x109/L were 27d & 28d for C1, 39d & 67d for C2 & 35d & 50d for C3 respectively. Conclusions: FLAG-IDA+VEN results in high MRD negative response rates, leading to impressive survival outcomes across ELN risk groups in ND AML. It is an effective salvage regimen for RR AML, especially for S1+ TP53WT pts. Clinical trial information: NCT03214562 . [Table: see text]

Complications and revisions in metal-backed anatomic total shoulder arthroplasty: a comparative study of revision rates between stemless and stemmed humeral components

BackgroundThe primary objective of this study was to evaluate and compare the incidence of complications and revision surgeries between in two of convertible metal-back glenoid systems in total shoulder arthroplasty (aTSA) groups over a follow-up period of up to five years. MethodsA retrospective analysis included 69 shoulders from 65 patients with primary aTSA. Patients were divided into Group 1 (n=31), receiving convertible cementless stemmed aTSA (Lima SMR) and Group 2 (n=38), receiving humeral head replacement aTSA (Arthrex, Eclipse) both with metal-back glenoid components. Clinical and radiological assessments were conducted at 2, 5, and 10 years postoperatively. Assessments included the following: Constant Score, DASH, SPADI, SSV, Glenohumeral Distance, Critical Shoulder Angle and Lateral Acromion Index. In addition, we compared complications, revision rates and survival rates between groups using Kaplan-Maier curves and Log-Rank-test. ResultsBaseline demographics and preoperative outcome scores showed no significant differences between groups (p≥0.05). The overall revision rate did not significantly differ between groups (Group 1:32% vs. Group 2:24%, p=0.60), nor did the mean time to revision (p=0.27). The mean follow-up was 71±41 months (Group 1: 94±48 months, Group 2: 53±23 months, p<0.001). Kaplan-Meier analysis showed similar mid-term survival probabilities (p=0.94). Revision reasons included rotator cuff insufficiency (n=4 in Group 1, n=2 in Group 2) and glenoid wear/loosening (n=5 in Group 1, n=7 in Group 2). Interestingly, Group 1 demonstrated no occurrence of glenoid metal baseplate or humeral loosening, while complex revisions were more common in the Group 2. At 2 and 5 years, non-revised patients in both groups had similar outcome scores. ConclusionMetal-backed glenoid implants in combination with both stemless and stemmed humeral components in aTSA exhibit comparable revision rates and survival probabilities. Rotator cuff insufficiency and polyethylene wear are the two most common complications leading to revision. To facilitate ongoing monitoring and optimize patient safety, we implemented a modification in the follow-up protocol, transitioning to annual appointments or earlier when necessary. This study underscores the unsolved disadvantages in metal-back components and the importance of a mid- to long-term longitudinal assessment of those patients.

The safety of atezolizumab plus bevacizumab (atezo/bev) treatment in Chinese patients (pts) with hepatocellular carcinoma (HCC) with active hepatitis B virus (HBV) infection: Results from the TALENTop study.

e16168 Background: HCC pts with active HBV infection were excluded from most clinical trials involving immune checkpoint inhibitors because of safety concerns. We are aiming to evaluate the treatment safety of atezo/bev treatment in the TALENTop study (NCT04649489) which enrolled a large number of pts with active HBV infection. Methods: The TALENTop study is to clarify whether liver resection may provide additional benefits in Chinese HCC pts with macrovascular invasion who responded to conversion therapy with atezo/bev. After two versions of protocol modification, pts with active HBV infection were allowed. This study is ongoing, and the primary analysis is expected later. The current analysis is to evaluate treatment safety in pts with active HBV infection in the induction phase when pts received 3 cycles of atezo/bev and 1 cycle of atezo monotherapy. We compared the adverse events (AEs) between pts with active (baseline serum HBV-DNA ≥500 IU/mL) or inactive HBV infection (HBV-DNA &lt; 500 IU/mL). All pts with detectable HBV-DNA or positive hepatitis B surface antigen received oral antiviral therapy throughout the study. Results: From Apr 2021 to Sep 2023, 296 pts were enrolled and completed induction phase therapy of atezo/bev. 274 pts (92.6%) had HBV-related HCC, and 133 pts (44.9%) had active HBV infection. The baseline characteristics were mainly balanced between groups, except pts with active HBV infection were younger (52 vs 56 years, P = 0.024), had larger tumor size (the diameter of target lesion 88.3 vs 78.1 mm, P = 0.007), and had higher album-bilirubin score (-2.62 vs -2.80, P &lt; 0.001). In the induction phase, the AEs of any grade were higher in pts with active HBV infection (88.0% vs 73.6%, P = 0.002). However, the grade ≥3 AEs (20.3% vs 17.8%, P = 0.584), grade ≥3 treatment-related AEs (12.0% vs 12.3%, P = 0.950) and serious AEs (15.0% vs 13.5%, P = 0.706) were comparable between pts with active and inactive HBV infection. Additionally, the incidence of liver-related AEs was also comparable, including increased AST (17.3% vs 16.0%), increased ALT (17.3% vs 14.7%), and increased bilirubin (10.5% vs 12.9%). AEs leading to treatment withdrawal were also comparable (6.0% vs 6.1%, P = 0.966). In pts with active HBV infection, 20.8% remained serum HBV-DNA ≥500 IU/mL at the end of cycle 4. Conclusions: Active HBV infection did not compromise the safety of atezo/bev therapy. These findings could support that, with concurrent use of oral antiviral therapy, pts with active HBV infection should be not excluded from clinical trials or delayed for immunotherapy. Clinical trial information: NCT04649489 .

Optimal Node Routing Layouts in Mobile Adhoc Network

Mobile Adhoc Network (MANET) is a self-organizing network of various network devices responsible for communication. In MANET, new layouts are adopted for energy optimization, security implementation, traffic minimization and overhead reduction. MANET are aggressive in nature. This requires modification in network routing protocols for performance enhancement. This paper presents the detailed survey of different layouts involved in the implementation of network routing protocols in MANET. The survey is classified into four phases involved in MANET routing applications namely- routing protocols, neighborhood discovery, distributed or centralized hash tables, and bloom filter. Firstly, the classification of routing protocols based on various traffic models presents the MANET configuration. Secondly, a neighborhood discovery mechanism conveys the enhancement in the routing configurations. Thirdly, application of hash table operation (distributed/ centralized) to MANET to improve the matching efficiencies and computational speed. Finally, the application of bloom filter concept to improve service discovery rate and reduce the fake identities. Traditionally, the unpredictability occurs during the prediction of optimal node routing due to the dynamic nature of the MANET. Moreover, the presence of ejected malicious node in another cluster disgraced the link stability. This survey conveys the problems such as storage overhead, mobility nature, malicious nodes, and false positive rates in the traditional methods. The detailed survey leads to the stone of integration of Distributed Hash Table (DHT) with a bloom filter to reduce the problems in traditional research works. Index Terms – Performance Optimization, Bloom Filter, Centralized Hash Table (CHT), Distributed Hash Table (DHT), Energy Consumption, Mobile Ad- hoc Network (MANET), Quality of Service (QoS), Routing.

Is biochemical pregnancy loss associated with embryo or endometrium? A retrospective cohort study in frozen single embryo transfer of own and donated oocytes.

Does the use of preimplantation genetic testing for aneuploidies (PGT-A), personalized embryo transfer with endometrial receptivity assay (pET-ERA), or the use of donated oocytes modify the incidence of biochemical pregnancy loss (BPL) in frozen single embryo transfer (FSET)? Following FSET, BPL incidence does not differ between own and donated oocytes, and the use of PGT-A with euploid embryo transfer or pET-ERA results in a similar incidence of BPL compared to cycles without embryo or endometrial analysis. BPL occurs frequently after IVF, and many factors have been associated with its incidence. The etiology of BPL is not well known, but the most probable cause seems to be either a low-quality embryo or impaired endometrial maintenance. The impact of techniques diagnosing embryonic ploidy or endometrial receptivity on BPL incidence and the BPL incidence between own and donated oocytes have not been analyzed. This is a retrospective cohort study analyzing the incidence of BPL over 3741 cycles of FSET derived from own (2399 cycles) and donated (1342 cycles) oocytes between January 2013 and January 2022 in 1736 of which PGT-A, pET-ERA, or both were applied. We defined BPL as a pregnancy diagnosed only by serum β-hCG > 10 UI/l followed by a decrease that does not result in a clinical pregnancy. Clinical pregnancy was defined as the presence of gestational sac on transvaginal ultrasound. We compared BPL rates among patients undergoing 2399 FSETs from own oocytes, which comprised 1310 cycles of embryos analyzed by PGT-A, 950 cycles of untested embryos, 30 cycles of untested embryos with pET-ERA, and a subgroup of 109 cycles analyzed by both PGT-A and pET-ERA. We also included a total of 1342 FSET cycles from donated oocytes comprising 132, 1055, 140, and 15 cycles in the same groups, respectively. In FSET from own oocytes, the overall BPL rate per embryo transfer was 8.2% (95% CI [7.09-9.33]). In untested embryo transfers, the BPL rate was 7.5% [5.91-9.37]. In the PGT-A group, the BPL rate was 8.8% [7.32-10.47]. In the pET-ERA group, the rate was 6.7% [0.82-22.07]. In the PGT-A+ERA group, the rate was 6.5% [2.65-12.90]. No significant differences were found (P = 0.626). A multivariate analysis considering clinically meaningful variables that were significantly different among groups, taking the untested embryos/endometrium group as a reference, showed comparable incidences among groups. For PGT-A, the adjusted odds ratio (AdjOR) was 1.154 [0.768-1.735] (P = 0.49) and for PGT-A+ERA 0.885 [0.330-2.375] (P = 0.808). Because of a low number of registered cases in the pET-ERA group, and to prevent statistical errors and convergence issues, this group was excluded from further analysis. In FSET of donated oocytes, the overall BPL rate per embryo transfer was 4.9% [3.76-6.14]. In the PGT-A group, the BPL rate was 6.8% [3.16-12.55]. In the pET-ERA group, the rate was 5.0% [2.03-10.03]. In untested embryo transfers, the rate was 4.7% [3.46-6.10]. No cases occurred in the PGT-A+ERA group, and no significant differences were found (P = 0.578). The multivariate analysis showed comparable incidences among groups. For PGT-A the AdjOR was 1.669 [0.702-3.972] (P = 0.247) and for pET-ERA 1.189 [0.433-3.265] (P = 0.737). The PGT-A+ERA group was eliminated from the model to prevent statistical errors and convergence issues because no BPL cases were registered in this group. In the multivariate analysis, when the sources of oocytes were compared, own versus donated, no significant differences were found in the incidence of BPL. This was a retrospective cohort study with potential biases. In addition, we were unable to control differences among groups due to modifications in medical or laboratory protocols during this long time period, which may modify the relationships being addressed. Factors previously associated with BPL, such as immunological conditions other than thyroid autoimmunity, were not considered in this study. Limited sample sizes of some groups may limit the statistical power for finding differences that can be present in the general population. BPL may be related to a mechanism not associated with the chromosomal constitution of the embryo or the transcriptome of the endometrium. More studies are needed to explore the factors associated with this reproductive issue. No specific funding was available for this study. None of the authors have a conflict of interest to declare with regard to this study. This trial was registered at clinicaltrials.gov (NCT04549909).

Optimized Duplicate Address Detection for the Prevention of Denial-of-Service Attacks in IPv6 Network

In constrained IoT networks, Stateless Address Autoconfiguration (SLAAC) utilizes the Duplicate Address Detection (DAD) protocol to ensure the uniqueness of IPv6 addresses. However, the DAD employed in SLAAC is susceptible to various security vulnerabilities, including issues related to confidentiality, conflicting addresses, and spoofing attacks. Malicious nodes can exploit these weaknesses to perform Denial of Service (DoS) attacks by consistently claiming a tentative address, joining with conflicting address, or disclosing assigned address. Existing measures against DAD attacks have limitations, e.g. high computation, communication overhead, energy consumption, and major protocol modification. To address these challenges, this paper presents an innovative Optimized DAD (O-DAD) that is robust, scalable, and compliant with standard specifications. In O-DAD, the uniqueness of tentative IPv6 addresses is ensured in a way that neither new nor existing nodes have knowledge of each other's exact assigned addresses. O-DAD also hampers the ability of malicious nodes to spoof new/existing nodes. Experimental results demonstrate that the proposed solution effectively mitigates these attacks and exhibits superior performance in terms of Address Success Ratio (ASR), computational complexity, overhead, and energy consumption. When compared to Secure, Improved, and Standard DAD, the proposed scheme reduces overhead and energy by approximately 6%, 8%, and 15%, respectively.

Feasibility of hemoperfusion using extracorporeal therapy in the horse.

Develop, implement, and monitor for adverse effects of, a novel hemoperfusion therapy in adult horses. A prospective, observational feasibility study using three healthy adult horses from the North Carolina State University teaching herd. Health status was determined by physical exam, complete blood count, coagulation panel, and serum biochemistry. Each horse was instrumented with a 14 Fr × 25 cm double-lumen temporary hemodialysis catheter and underwent a 240 min polymer-based hemoperfusion session. Horses were administered unfractionated heparin to maintain anti-coagulation during the session. Given the novelty of this therapy in horses, each horse was treated as a learning opportunity that informed an iterative process of protocol development and modification. Our long-term goal is to investigate potential clinical applications of hemoperfusion in horses, including cytokine reduction in horses with severe SIRS/sepsis. Horses were monitored for changes in clinical exam, biochemistry and hematology parameters. Additionally, cytokines were quantified to determine whether extracorporeal hemadsorption therapy alone caused an inflammatory response. Our results show that hemoperfusion therapy was associated with decreased platelet counts and serum albumin concentration. There was no significant change in plasma cytokine concentrations with hemoperfusion therapy. In one horse, the cytokine concentrations decreased, as previously reported with hemoperfusion therapy in humans. We hypothesized that hemoperfusion therapy could be performed in healthy adult horses without significant adverse effects. Polymer-based hemoperfusion is a feasible extracorporeal therapy (ECT) modality for adult horses. Additional studies are needed to further establish clinical protocols, as well as establish efficacy of polymer-based hemoperfusion for treatment of various conditions in horses, including intoxications, immune-mediated conditions, and sepsis.

Research protocol and recruitment redesign of a study of pregnant women and their infants during the COVID-19 pandemic: Childhood Allergy and the NeOnatal Environment (CANOE)

BackgroundRecruitment for research studies is a challenging endeavor that was further complicated by the COVID-19 pandemic. We launched a new NIH-supported multi-center birth cohort, “Childhood Allergy and the NeOnatal Environment” (CANOE) in January 2020 across four sites. While the pandemic temporarily halted clinical research, we restructured the study and instituted novel recruitment methods that we hypothesized would enable brisk enrollment when research activities resumed. ObjectiveDevelop protocol modifications and recruitment methods that promote successful recruitment of diverse populations in clinical research despite a global pandemic. MethodsWhile study activities were suspended, we modified recruitment strategies to limit in-person contact, shifting toward alternative HIPAA-compliant methods like clinician referrals, institutional social media, and telemedicine screening and consent procedures. Protocol changes included reducing the frequency of in-person visits, leveraging clinical care visits to collect biospecimens, expanded self-collection of samples at home, and making study materials available online. ResultsRemote methods, including targeted social media posts, mailed letters, and email, combined with in-clinic recruitment with modifications for social distancing led to successful recruitment at all sites. Rates of consent have been similar across recruitment sites, with the highest rates of enrollment of mother-infant dyads realized by sites that implemented multiple recruitment strategies. ConclusionsStudy procedures that prioritize health and safety measures such as social distancing, study participant convenience, and diverse recruitment strategies enable successful enrollment of pregnant women and their newborns into clinical research while adhering to public health restrictions during a global pandemic.