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Background In fundoplication, mobilization of the distal oesophagus and proximal stomach is essential to obtain a sufficient tension‐free intra‐abdominal oesophageal length for creation of an efficient antireflux barrier. Most surgical literature and anatomical illustrations do not describe nerve branches running from the diaphragm to the stomach. After observing small nerve branches at laparoscopic fundoplication, penetrating the left crus of the diaphragm lateral to the hiatus and apparently running into the stomach, an anatomical cadaver study was undertaken to identify the origin and target organ of these nerves. Methods Fifty‐three human cadavers (23 men, 30 women; age range 35–103 years) were dissected with special attention to the nerves that penetrate the left crus of the diaphragm. The entire course of these nerves was documented with standardized drawings and photos. Results Small nerve branches penetrating the diaphragm lateral to the left crus of the hiatus were found in 17 (32 per cent) of the 53 cadavers. In 14 of these 17 cadavers, one or two splanchnic nerve branches were identified, and in ten of the 17 the nerve branches were found to be phrenic nerves. In seven of these 17 cadavers, two different nerve branches were found and assigned to both splanchnic and phrenic nerves. Conclusion Nerves penetrating the left crus with splanchnic origin or phrenic origin have been identified. Their function remains unclear and their relationship to postfundoplication symptoms remains to be determined.

This study presents a reduced version of the Perception of Family Support Scale (PFSS)--a measure of family support designed for research and clinical purposes--and examine construct validity, invariance, and reliability evidence for scores obtained from the instrument. Data collection occurred in 2019. Using exploratory and confirmatory factor analyses with college student samples from Australia, Brazil, Hong Kong, and Turkey (N = 1,256), we identified an oblique three-factor model corresponding to the original scale's internal structure (e.g. affective consistency, family maladaptation, and family autonomy). We also found configural, metric, and scalar invariance, good reliability coefficients, and significant relationships with distress (e.g. depression, anxiety, and stress) across the four studied countries. These results indicate good validity evidence for using the brief version of the PFSS. Applications of the PFSS and implications of the current results are discussed.

Abstract Background Variant interpretation is essential for identifying patients’ disease-causing genetic variants amongst the millions detected in their genomes. Hundreds of Variant Impact Predictors (VIPs), also known as Variant Effect Predictors (VEPs), have been developed for this purpose, with a variety of methodologies and goals. To facilitate the exploration of available VIP options, we have created the Variant Impact Predictor database (VIPdb). Results The Variant Impact Predictor database (VIPdb) version 2 presents a collection of VIPs developed over the past three decades, summarizing their characteristics, ClinGen calibrated scores, CAGI assessment results, publication details, access information, and citation patterns. We previously summarized 217 VIPs and their features in VIPdb in 2019. Building upon this foundation, we identified and categorized an additional 190 VIPs, resulting in a total of 407 VIPs in VIPdb version 2. The majority of the VIPs have the capacity to predict the impacts of single nucleotide variants and nonsynonymous variants. More VIPs tailored to predict the impacts of insertions and deletions have been developed since the 2010s. In contrast, relatively few VIPs are dedicated to the prediction of splicing, structural, synonymous, and regulatory variants. The increasing rate of citations to VIPs reflects the ongoing growth in their use, and the evolving trends in citations reveal development in the field and individual methods. Conclusions VIPdb version 2 summarizes 407 VIPs and their features, potentially facilitating VIP exploration for various variant interpretation applications. VIPdb is available at https://genomeinterpretation.org/vipdb

Many studies have analysed how goal directed movements are corrected in response to changes in the properties of the target. However, only simple movements to single targets have been used in those studies, so little is known about movement corrections under more complex situations. Evidence from studies that ask for movements to several targets in sequence suggests that whole sequences of movements are planned together. Planning related segments of a movement together makes it possible to optimise the whole sequence, but it means that some parts are planned quite long in advance, so that it is likely that they will have to be modified. In the present study we examined how people respond to changes that occur while they are moving to the first target of a sequence. Subjects moved a stylus across a digitising tablet. They moved from a specified starting point to two targets in succession. The first of these targets was always at the same position but it could have one of two sizes. The second target could be in one of two different positions and its size was different in each case. On some trials the first target changed size, and on some others the second target changed size and position, as soon as the subject started to move. When the size of the first target changed the subjects slowed down the first segment of their movements. Even the peak velocity, which was only about 150 ms after the change in size, was lower. Beside this fast response to the change itself, the dwell time at the first target was also affected: its duration increased after the change. Changing the size and position of the second target did not influence the first segment of the movement, but also increased the dwell time. The dwell time was much longer for a small target, irrespective of its initial size. If subjects knew in advance which target could change, they moved faster than if they did not know which could change. Taken together, these results suggest that the whole sequence is treated as one action, which can be corrected if the properties of any of the targets change. The precise nature and timing of the correction depends on how the change influences the task.

We are using molecular, biochemical, and genetic approaches to study the structural and regulatory genes controlling the assimilation of inorganic nitrogen into the amino acids glutamine, glutamate, aspartate and asparagine. These amino acids serve as the principal nitrogen-transport amino acids in most crop and higher plants including Arabidopsis thaliana. We have begun to investigate the regulatory mechanisms controlling nitrogen assimilation into these amino acids in plants using molecular and genetic approaches in Arabidopsis. The synthesis of the amide amino acids glutamine and asparagine is subject to tight regulation in response to environmental factors such as light and to metabolic factors such as sucrose and amino acids. For instance, light induces the expression of glutamine synthetase (GLN2) and represses expression of asparagine synthetase (ASN1) genes. This reciprocal regulation of GLN2 and ASN1 genes by light is reflected at the level of transcription and at the level of glutamine and asparagine biosynthesis. Moreover, we have shown that the regulation of these genes is also reciprocally controlled by both organic nitrogen and carbon metabolites. We have recently used a reverse genetic approach to study putative components of such metabolic sensing mechanisms in plants that may be conserved in evolution. These components include an Arabidopsis homolog for a glutamate receptor gene originally found in animal systems and a plant PII gene, which is a homolog of a component of the bacterial Ntr system. Based on our observations on the biology of both structural and regulatory genes of the nitrogen assimilatory pathway, we have developed a model for metabolic control of the genes involved in the nitrogen assimilatory pathway in plants.

There is limited data regarding the use of immunotherapy for patients with vulvar squamous cell carcinoma and coexisting autoimmune disease. Cemiplimab is a PD-1 inhibitor approved for use in patients with locally advanced and metastatic cutaneous squamous cell carcinoma. However, little is known about its efficacy in the setting of vulvar cancer. We present a case of advanced vulvar squamous cell carcinoma treated with induction chemotherapy and immunotherapy with cemiplimab followed by definitive chemoradiation in the setting of multiple autoimmune diseases. She achieved a complete clinical response and experienced no worsening of her autoimmune conditions despite cessation of her immunosuppressants and initiating an immune checkpoint inhibitor. We review existing data on neoadjuvant treatment of vulvar cancer and the use of cemiplimab in genital and inguinal squamous cell carcinomas. Ongoing exploration of cemiplimab’s efficacy in vulvar cancer and safety in immunosuppressed patients is critical.

Abstract Background A major obstacle faced by families with rare diseases is obtaining a genetic diagnosis. The average "diagnostic odyssey" lasts over five years and causal variants are identified in under 50%, even when capturing variants genome-wide. To aid in the interpretation and prioritization of the vast number of variants detected, computational methods are proliferating. Knowing which tools are most effective remains unclear. To evaluate the performance of computational methods, and to encourage innovation in method development, we designed a Critical Assessment of Genome Interpretation (CAGI) community challenge to place variant prioritization models head-to-head in a real-life clinical diagnostic setting. Methods We utilized genome sequencing (GS) data from families sequenced in the Rare Genomes Project (RGP), a direct-to-participant research study on the utility of GS for rare disease diagnosis and gene discovery. Challenge predictors were provided with a dataset of variant calls and phenotype terms from 175 RGP individuals (65 families), including 35 solved training set families with causal variants specified, and 30 unlabeled test set families (14 solved, 16 unsolved). We tasked teams to identify causal variants in as many families as possible. Predictors submitted variant predictions with estimated probability of causal relationship (EPCR) values. Model performance was determined by two metrics, a weighted score based on the rank position of causal variants, and the maximum F-measure, based on precision and recall of causal variants across all EPCR values. Results Sixteen teams submitted predictions from 52 models, some with manual review incorporated. Top performers recalled causal variants in up to 13 of 14 solved families within the top 5 ranked variants. Newly discovered diagnostic variants were returned to two previously unsolved families following confirmatory RNA sequencing, and two novel disease gene candidates were entered into Matchmaker Exchange. In one example, RNA sequencing demonstrated aberrant splicing due to a deep intronic indel in ASNS, identified in trans with a frameshift variant in an unsolved proband with phenotypes consistent with asparagine synthetase deficiency. Conclusions Model methodology and performance was highly variable. Models weighing call quality, allele frequency, predicted deleteriousness, segregation, and phenotype were effective in identifying causal variants, and models open to phenotype expansion and non-coding variants were able to capture more difficult diagnoses and discover new diagnoses. Overall, computational models can significantly aid variant prioritization. For use in diagnostics, detailed review and conservative assessment of prioritized variants against established criteria is needed.

Previous studies indicate an implication of the terminal complement complex (TCC) in disc degeneration (DD). To investigate the functional role of TCC in trauma-induced DD in vivo, the model of endplate (EP) drilling was first applied in rabbits using a C6-deficient rabbit strain in which no TCC formation was possible. In parallel the model of needle puncture was investigated. Using a minimally invasive surgical intervention, lumbar rabbit intervertebral discs (IVDs) were treated with EP drilling or needle puncture. Degenerative effects of both surgical interventions were assessed by Pfirrmann grading and T2 quantification of the IVDs based on high-resolution MRI (11.7 T), as well as radiographic determination of disc height index. Pfirrmann grading indicated significant degenerative effects after EP drilling. Contrary to our assumption, no evidence was found that the absence of TCC formation in C6-deficient rabbits reduces the development of DD compared to C6-sufficient animals. EP drilling was proven to be suitable for application in rabbits. However, results of the present study do not provide clear evidence of a central functional role of TCC within DD and suggest that TCC deposition in DD patients may be primarily considered as a marker of complement activation during DD progression.

A recent book by Romaric Jannel on the work of the 20th Century Japanese philosopher Yamauchi Tokuryū is reviewed as a prolegomenon in this journal to more detailed studies of Oriental philosophy. Emphasis is placed on the similarities and overlaps of Eastern and Western thought.

Rhinoceros species range from near threatened to critically endangered due to habitat loss and poaching. A sustainable ex situ breeding population is critically important to maintain genetic diversity and help ensure the survival of the species; however, not all populations under human care are self-sustaining. While rhinoceros reproductive physiology and pathology have been well studied, there is still a paucity of information describing the normal parameters of parturition and neonatal landmarks. Using video recordings, medical records, and keeper logs, we reviewed and compared data regarding the parturition of three rhinoceros species (black rhinoceros (BR) (Diceros bicornis), n = 4; greater one-horned rhinoceros (GOHR) (Rhinoceros unicornis), n = 21; and southern white rhinoceros (SWR) (Ceratotherium simum simum), n = 22) managed under human care in the United States. Using equine parameters as a model for comparison, we compiled the following data: the signs of impending parturition, durations of the parturition phases, calving presentation, frequency of dystocia or stillbirth, and time from birth to neonatal landmarks. Data from 47 births, including 26 videos, were examined. The durations of parturition phases I, II, and III had median lengths of 153 min (n = 18), 28 min (n = 21), and 205 min (n = 15), respectively. Anterior presentation of the calf was observed in 59% births, whereas posterior presentation occurred in 41% births. Posterior calving presentation was associated with a longer phase II of parturition (p = 0.04), although more data are needed to determine whether the posterior presentation of the calf carries a higher risk for stillbirth. Most (83%) stillbirths occurred in GOHR, indicating that this species might be at a higher risk for stillbirth compared to SWR (17%) (p = 0.07). The median time from birth to the calf standing was longer in the GOHR (64 min) compared to the SWR (30 min) (p = 0.02). Detailed descriptions of the parturition parameters and neonatal landmarks in rhinoceros will aid facilities with rhinoceros breeding programs to recognize abnormalities in the parturient or post-partum periods and guide indications for veterinary intervention.

Terminal complement complex (TCC) deposition was identified in human degenerated discs. To clarify the role of terminal complement activation in disc degeneration (DD), we investigated respective activating mechanisms and cellular effects in annulus fibrosus (AF) cells. Isolated cells from human AF, nucleus pulposus (NP), and endplate (EP) were stimulated with human serum alone or with zymosan and treated with either the C3 inhibitor Cp40 or the C5 antibody eculizumab. Complement activation was determined via anaphylatoxin generation and TCC deposition detection. Thereby, induced catabolic effects were evaluated in cultured AF cells. Moreover, C5 cleavage under degenerative conditions in the presence of AF cells was assessed. Zymosan-induced anaphylatoxin generation and TCC deposition was significantly suppressed by both complement inhibitors. Zymosan induced gene expression of ADAMTS4, MMP1, and COX2. Whereas the C3 blockade attenuated the expression of ADAMTS4, the C5 blockade reduced the expression of ADAMTS4, MMP1, and COX2. Direct C5 cleavage was significantly enhanced by EP conditioned medium from DD patients and CTSD. These results indicate that terminal complement activation might be functionally involved in the progression of DD. Moreover, we found evidence that soluble factors secreted by degenerated EP tissue can mediate direct C5 cleavage, thereby contributing to complement activation in degenerated discs.

The terminal complement complex (TCC) has been described as a potential driver in the pathogenesis of posttraumatic osteoarthritis (PTOA). However, sublytic TCC deposition might also play a crucial role in bone development and regeneration. Therefore, we elucidated the effects of TCC on joint-related tissues using a rabbit PTOA model. In brief, a C6-deficient rabbit breed was characterized on genetic, protein, and functional levels. Anterior cruciate ligament transection (ACLT) was performed in C6-deficient (C6−/−) and C6-sufficient (C6+/−) rabbits. After eight weeks, the progression of PTOA was determined histologically. Moreover, the structure of the subchondral bone was evaluated by µCT analysis. C6 deficiency could be attributed to a homozygous 3.6 kb deletion within the C6 gene and subsequent loss of the C5b binding site. Serum from C6−/− animals revealed no hemolytic activity. After ACLT surgery, joints of C6−/− rabbits exhibited significantly lower OA scores, including reduced cartilage damage, hypocellularity, cluster formation, and osteophyte number, as well as lower chondrocyte apoptosis rates and synovial prostaglandin E2 levels. Moreover, ACLT surgery significantly decreased the trabecular number in the subchondral bone of C6−/− rabbits. Overall, the absence of TCC protected from injury-induced OA progression but had minor effects on the micro-structure of the subchondral bone.

Immunotherapy for cancer is now a standard pillar in the armamentarium of treatments for many cancers. Immune checkpoint inhibitors, in particular, have resulted in significant therapeutic benefit and prolongation of survival in solid organ cancers, such as melanoma and lung cancer. However, the extent of benefit is not uniform. There are several groups studying predictors of benefit from these therapies. Recently, there has been a burgeoning interest in studying predictive biomarkers from the blood. These markers include circulating tumor DNA, circulating tumor cells, lymphocyte subpopulations, exosomes and metabolites to name a few. The logistics involved in such biomarker work are complex and rigorous with potential to impact a given study. Such pre-analytic components include development of a rigorous protocol, standard operating procedures for collection and storage of various blood components, ethics of patient consent, personnel involved as well as budget considerations. In this primer, we lay out representative aspects of each of the aforementioned components as a guide to blood-based biomarker research for immunotherapy studies in cancer.

This paper proposes an informational approach to probability based on a non-semantic, non-propositional and non-truth-functional logic of real processes and systems, according to which they interact and evolve—Logic in Reality, LIR. Its fundamental principle is that the contradictory or opposing informational elements of complex real processes move from states that are primarily potential to ones that are predominantly actual, alternately and reciprocally, without going to the abstract, ideal limits of zero or one. LIR provides a thread between the different sciences and constitutes a bridge between the ontological aspects of logic, science and philosophy.

Transplantation of xenogenic porcine chondrocytes could represent a future strategy for the treatment of human articular cartilage defects. Major obstacles are humoral and cellular rejection processes triggered by xenogenic epitopes like α-1,3-Gal and Neu5Gc. Besides knockout (KO) of genes responsible for the biosynthesis of respective epitopes (GGTA1 and CMAH), transgenic expression of human complement inhibitors and anti-apoptotic as well as anti-inflammatory factors (CD46, CD55, CD59, TNFAIP3 and HMOX1) could synergistically prevent hyperacute xenograft rejection. Therefore, chondrocytes from different strains of single- or multi-genetically modified pigs were characterized concerning their protection from xenogeneic complement activation. Articular chondrocytes were isolated from the knee joints of WT, GalTKO, GalT/CMAH-KO, human CD59/CD55//CD46/TNFAIP3/HMOX1-transgenic (TG), GalTKO/TG and GalT/CMAHKO/TG pigs. The tissue-specific effectiveness of the genetic modifications was tested on gene, protein and epitope expression level or by functional assays. After exposure to 20% and 40% normal human serum (NHS), deposition of C3b/iC3b/C3c and formation of the terminal complement complex (TCC, C5b-9) was quantified by specific cell ELISAs, and generation of the anaphylatoxin C5a by ELISA. Chondrocyte lysis was analyzed by Trypan Blue Exclusion Assay. In all respective KO variants, the absence of α -1,3-Gal and Neu5Gc epitope was verified by FACS analysis. In chondrocytes derived from TG animals, expression of CD55 and CD59 could be confirmed on gene and protein level, TNFAIP3 on gene expression level as well as by functional assays and CD46 only on gene expression level whereas transgenic HMOX1 expression was not evident. Complement activation in the presence of NHS indicated mainly effective although incomplete protection against C3b/iC3b/C3c deposition, C5a-generation and C5b-9 formation being lowest in single GalTKO. Chondrocyte viability under exposure to NHS was significantly improved even by single GalTKO and completely preserved by all other variants including TG chondrocytes without KO of xenoepitopes.