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The Combination Service for Time-variable Gravity fields (COST-G) operationally provides combinations of monthly Earth gravity field models derived from observations of the microwave ranging instrument of the GRACE Follow-on (GRACE-FO) satellite mission, applying the quality control and combination methodology originally developed by the Horizon 2020 project European Gravity Service for Improved Emergency Management for the data of the GRACE satellites. In the frame of the follow-up Horizon 2020 project Global Gravity-based Groundwater Product (G3P), the GRACE-FO combination is used to derive global grids of groundwater storage anomalies. To meet the user requirements and achieve optimal signal-to-noise ratio, the combination has been further developed and extended to incorporate: • new time-series based on the alternative accelerometer transplant product generated in the frame of the project by the Institute of Geodesy at the Graz University of Technology, which specifically improves the estimation of the C 30 coefficient and also reduces the noise at medium to short wavelengths, and • the new time-series AIUB–GRACE-FO–RL02 of monthly GRACE-FO gravity fields, which is derived at the Astronomical Institute of the University of Bern by applying empirical noise modelling techniques. The COST-G quality control confirms the consistency of the contributing GRACE-FO time-series concerning the signal amplitude of seasonal hydrology in large river basins and the secular mass change in polar regions, but it also indicates rather diverse noise characteristics. The difference in the noise levels is taken into account in the combination process by relative weights derived by variance component estimation on the solution level. The weights are expected to be inverse proportional to the noise levels of the individual gravity field solutions. However, this expectation is violated when applying the weighting scheme as developed for the GRACE combination. The reason is found in the high-order coefficients of the gravity field, which are poorly determined from the low–low range-rate observations due to the observation geometry and suffer from aliasing due to the malfunctioning accelerometer onboard one of the GRACE-FO satellites. Hence, for the final G3P-combination a revised weighting scheme is applied where the gravity field coefficients beyond order 60 are excluded from the determination of the weights. The quality of the combined gravity fields is assessed by comparison of the noise content and the signal-to-noise ratio with the individual time-series. Independent validation is provided by the COST-G validation centre at the GFZ German Research Centre for Geosciences, where orbit fits of the low-flying Gravity and steady-state Ocean Circulation Explorer satellite are performed that confirm the high quality of the combined GRACE-FO gravity fields. By the end of the G3P project, the new combination scheme is implemented by COST-G as the new COST-G–GRACE-FO–RL02 and continued to be used for the operational GRACE-FO combination. [ABSTRACT FROM AUTHOR]

Orbit determination of probes visiting Solar System bodies is currently the main source of our knowledge about their internal structure, inferred from the estimate of their gravity field and rotational state. Nongravitational forces acting on the spacecraft need to be accurately included in the dynamical modeling (either explicitly or in the form of empirical parameters) not to degrade the solution and its geophysical interpretation. In this study, we present our recovery of NASA GRAIL orbits and our lunar gravity field solutions up to degree and order 350. We propose a systematic approach to select an optimal parametrization with empirical accelerations and pseudo‐stochastic pulses, by checking their impact against orbit overlaps or, in the case of GRAIL, the very precise inter‐satellite link. We discuss how parametrization choices may differ depending on whether the goal is limited to orbit reconstruction or if it also includes the solution of gravity field coefficients. We validate our setup for planetary geodesy by iterating extended lunar gravity field solutions from pre‐GRAIL gravity fields, and we discuss the impact of empirical parametrization on the interpretation of gravity solutions and of their error bars. Plain Language Summary: We analyze the orbits of the twin GRAIL probes orbiting the Moon in 2012 to determine the lunar gravity field. The frequency shift of radio signals exchanged between GRAIL and Earth antennas, as well as an ultra‐precise inter‐satellite radio link, allow for an accurate determination of the absolute and relative spacecraft trajectories. As these trajectories mainly depend on the internal mass distribution of the Moon, their accurate knowledge provides important information about lunar gravity and internal structure. However, nongravitational forces acting on the probes, for example, caused by radiation from the Sun or the Moon, have to be modeled as well. An explicit modeling of these forces requires an accurate knowledge of spacecraft geometry and optical properties, which are often poorly known. Additional accelerations can be estimated from the data to absorb the effect of nongravitational forces and improve both orbit and gravity field determination. We propose a systematic approach to configure such estimated accelerations when dealing with the recovery of planetary probes' orbits and gravity fields, while also discussing collateral effects of employing them. Based on these findings we also present our independent solution of GRAIL orbits and the lunar gravity field, with a spatial resolution of 31 km. Key Points: We present a systematic approach to assess and select the optimal empirical parametrization for an orbit and gravity field recovery processWe provide an independent solution for the Moon's gravity field up to d/o 350 based on GRAIL Doppler and Ka‐Band Range Rate dataWe describe the planetary extension of the Bernese GNSS Software and its application to planetary geodesy [ABSTRACT FROM AUTHOR]

This paper applied cost-effectiveness analysis to the use of drug therapy in the treatment of AIDS. The empirical approach adopted overcame the facts that the samples of patients had varying clinical prognoses, had variable entry dates into the samples and, because AIDS is a terminal disease, had variable exit dates. Holding these variables constant, administration of the drug AZT proved to be a less costly alternative than other existing palliatives for AIDS. The sub-sample of patients treated with AZT had lower hospitalization costs, lower caring costs and sufferers had an increased ability to continue to participate for longer as economically active members of society. [ABSTRACT FROM AUTHOR]

Gene ontology analyses of high-confidence autism spectrum disorder (ASD) risk genes highlight chromatin regulation and synaptic function as major contributors to pathobiology. Our recent functional work in vivo has additionally implicated tubulin biology and cellular proliferation. As many chromatin regulators, including the ASD risk genes ADNP and CHD3, are known to directly regulate both tubulins and histones, we studied the five chromatin regulators most strongly associated with ASD (ADNP, CHD8, CHD2, POGZ and KMT5B) specifically with respect to tubulin biology. We observe that all five localize to microtubules of the mitotic spindle in vitro in human cells and in vivo in Xenopus. Investigation of CHD2 provides evidence that mutations present in individuals with ASD cause a range of microtubule-related phenotypes, including disrupted localization of the protein at mitotic spindles, cell cycle stalling, DNA damage and cell death. Lastly, we observe that ASD genetic risk is significantly enriched among tubulin-associated proteins, suggesting broader relevance. Together, these results provide additional evidence that the role of tubulin biology and cellular proliferation in ASD warrants further investigation and highlight the pitfalls of relying solely on annotated gene functions in the search for pathological mechanisms., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Copy number variants (CNVs) associated with neurodevelopmental disorders are characterized by extensive phenotypic heterogeneity. In particular, one CNV was identified in a subset of children clinically diagnosed with intellectual disabilities (ID) that results in a hemizygous deletion of multiple genes at chromosome 16p12.1. In addition to ID, individuals with this deletion display a variety of symptoms including microcephaly, seizures, cardiac defects, and growth retardation. Moreover, patients also manifest severe craniofacial abnormalities, such as micrognathia, cartilage malformation of the ears and nose, and facial asymmetries; however, the function of the genes within the 16p12.1 region have not been studied in the context of vertebrate craniofacial development. The craniofacial tissues affected in patients with this deletion all derive from the same embryonic precursor, the cranial neural crest, leading to the hypothesis that one or more of the 16p12.1 genes may be involved in regulating neural crest cell (NCC)-related processes. To examine this, we characterized the developmental role of the 16p12.1-affected gene orthologs, polr3e , mosmo , uqcrc2 , and cdr2 , during craniofacial morphogenesis in the vertebrate model system, Xenopus laevis . While the currently-known cellular functions of these genes are diverse, we find that they share similar expression patterns along the neural tube, pharyngeal arches, and later craniofacial structures. As these genes show co-expression in the pharyngeal arches where NCCs reside, we sought to elucidate the effect of individual gene depletion on craniofacial development and NCC migration. We find that reduction of several 16p12.1 genes significantly disrupts craniofacial and cartilage formation, pharyngeal arch migration, as well as NCC specification and motility. Thus, we have determined that some of these genes play an essential role during vertebrate craniofacial patterning by regulating specific processes during NCC development, which may be an underlying mechanism contributing to the craniofacial defects associated with the 16p12.1 deletion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lasser, Bolduc, Murphy, O'Brien, Lee, Girirajan and Lowery.)

We previously identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental outcomes, where severely affected probands carried an excess of rare pathogenic variants compared to mildly affected carrier parents. We hypothesized that the 16p12.1 deletion sensitizes the genome for disease, while "second-hits" in the genetic background modulate the phenotypic trajectory. To test this model, we examined how neurodevelopmental defects conferred by knockdown of individual 16p12.1 homologs are modulated by simultaneous knockdown of homologs of "second-hit" genes in Drosophila melanogaster and Xenopus laevis. We observed that knockdown of 16p12.1 homologs affect multiple phenotypic domains, leading to delayed developmental timing, seizure susceptibility, brain alterations, abnormal dendrite and axonal morphology, and cellular proliferation defects. Compared to genes within the 16p11.2 deletion, which has higher de novo occurrence, 16p12.1 homologs were less likely to interact with each other in Drosophila models or a human brain-specific interaction network, suggesting that interactions with "second-hit" genes may confer higher impact towards neurodevelopmental phenotypes. Assessment of 212 pairwise interactions in Drosophila between 16p12.1 homologs and 76 homologs of patient-specific "second-hit" genes (such as ARID1B and CACNA1A), genes within neurodevelopmental pathways (such as PTEN and UBE3A), and transcriptomic targets (such as DSCAM and TRRAP) identified genetic interactions in 63% of the tested pairs. In 11 out of 15 families, patient-specific "second-hits" enhanced or suppressed the phenotypic effects of one or many 16p12.1 homologs in 32/96 pairwise combinations tested. In fact, homologs of SETD5 synergistically interacted with homologs of MOSMO in both Drosophila and X. laevis, leading to modified cellular and brain phenotypes, as well as axon outgrowth defects that were not observed with knockdown of either individual homolog. Our results suggest that several 16p12.1 genes sensitize the genome towards neurodevelopmental defects, and complex interactions with "second-hit" genes determine the ultimate phenotypic manifestation., Competing Interests: The authors have declared that no competing interests exist.

The 1.6 Mbp deletion on chromosome 3q29 is associated with a range of neurodevelopmental disorders, including schizophrenia, autism, microcephaly, and intellectual disability. Despite its importance towards neurodevelopment, the role of individual genes, genetic interactions, and disrupted biological mechanisms underlying the deletion have not been thoroughly characterized. Here, we used quantitative methods to assay Drosophila melanogaster and Xenopus laevis models with tissue-specific individual and pairwise knockdown of 14 homologs of genes within the 3q29 region. We identified developmental, cellular, and neuronal phenotypes for multiple homologs of 3q29 genes, potentially due to altered apoptosis and cell cycle mechanisms during development. Using the fly eye, we screened for 314 pairwise knockdowns of homologs of 3q29 genes and identified 44 interactions between pairs of homologs and 34 interactions with other neurodevelopmental genes. Interestingly, NCBP2 homologs in Drosophila (Cbp20) and X. laevis (ncbp2) enhanced the phenotypes of homologs of the other 3q29 genes, leading to significant increases in apoptosis that disrupted cellular organization and brain morphology. These cellular and neuronal defects were rescued with overexpression of the apoptosis inhibitors Diap1 and xiap in both models, suggesting that apoptosis is one of several potential biological mechanisms disrupted by the deletion. NCBP2 was also highly connected to other 3q29 genes in a human brain-specific interaction network, providing support for the relevance of our results towards the human deletion. Overall, our study suggests that NCBP2-mediated genetic interactions within the 3q29 region disrupt apoptosis and cell cycle mechanisms during development., Competing Interests: The authors have declared that no competing interests exist.

Wolf-Hirschhorn syndrome (WHS) is a rare developmental disorder characterized by intellectual disability and various physical malformations including craniofacial, skeletal, and cardiac defects. These phenotypes, as they involve structures that are derived from the cranial neural crest, suggest that WHS may be associated with abnormalities in neural crest cell (NCC) migration. This syndrome is linked with assorted mutations on the short arm of chromosome 4, most notably the microdeletion of a critical genomic region containing several candidate genes. However, the function of these genes during embryonic development, as well as the cellular and molecular mechanisms underlying the disorder, are still unknown. The model organism Xenopus laevis offers a number of advantages for studying WHS. With the Xenopus genome sequenced, genetic manipulation strategies can be readily designed in order to alter the dosage of the WHS candidate genes. Moreover, a variety of assays are available for use in Xenopus to examine how manipulation of WHS genes leads to changes in the development of tissue and organ systems affected in WHS. In this review article, we highlight the benefits of using X. laevis as a model system for studying human genetic disorders of development, with a focus on WHS.

Neurons depend on the highly dynamic microtubule (MT) cytoskeleton for many different processes during early embryonic development including cell division and migration, intracellular trafficking and signal transduction, as well as proper axon guidance and synapse formation. The coordination and support from MTs is crucial for newly formed neurons to migrate appropriately in order to establish neural connections. Once connections are made, MTs provide structural integrity and support to maintain neural connectivity throughout development. Abnormalities in neural migration and connectivity due to genetic mutations of MT-associated proteins can lead to detrimental developmental defects. Growing evidence suggests that these mutations are associated with many different neurodevelopmental disorders, including intellectual disabilities (ID) and autism spectrum disorders (ASD). In this review article, we highlight the crucial role of the MT cytoskeleton in the context of neurodevelopment and summarize genetic mutations of various MT related proteins that may underlie or contribute to neurodevelopmental disorders.

Open radical cystectomy (ORC) remains the gold standard for treatment of muscle-invasive bladder cancer and certain cases of high-risk noninvasive bladder cancer. However, ORC is associated with significant morbidity, and there is promise of improved outcomes with the emergence of minimally invasive surgery. Because of the increased adoption of robotic radical cystectomy (RRC), we sought to review the current literature on the robotic approach. We explored the surgical techniques, perioperative and postoperative complications, oncologic and functional outcomes, and quality of life of patients with RRC versus ORC. Current data appear to favor RRC in perioperative outcomes and patient recovery, although RRC continues to be associated with longer surgical times and higher costs. Oncologic data are also promising, however data on long-term oncologic outcomes are insufficient. To date, there is evidence of similar functional outcomes between RRC and ORC continence, but there is a paucity of rigorous, standardized studies on health-related quality of life for continent versus incontinent diversion. Even as use of RRC steadily grows, there is a lack of consensus on the type of approach and urinary diversion that is optimal. We assessed the influence of surgeon experience on the totally intracorporeal urinary diversion and its feasibility to be widely adopted. We aimed to answer the question of whether there are significant benefits to RRC, and furthermore, of the effect of the approach on the choice of urinary diversion., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Bowel-related injuries are known complications of suprapubic tube (SPT) catheterization placement. A literature review was conducted to determine identifiable risk factors for bowel injury. Results on the analysis of 25 cases are presented along with a proposed algorithm to aid in choosing between open, percutaneous, and image-guided methods of placement.

Introduction: The application of robotic-assisted radical prostatectomy has increased considerably over the past decade, but there remains a paucity of standardized complications reporting associated with this procedure. The complications literature regarding robotic prostatectomy is wrought with limitations, variability, and bias making meaningful comparisons between surgical series difficult., Materials and Methods: From November 2006 to December 2010, a total of 575 patients were evaluated. Data were assimilated through an IRB-approved blinded prospective database by an independent third party committee. Patients were followed prospectively for 30 days postoperatively. The Modified Clavien system was utilized to grade complications. Grade I and II complications were classified as minor, while grade III, IV, and V were considered major complications. Multiple complications in individual patients were recorded as separate events. Our initial experience and that of our most recent were compared. Age, body mass index, American Society of Anesthesiologists score, Gleason grade, prostate specific antigen, prostate volume, and complications were evaluated., Results: Of the 575 patients, 482 (83.8%) had an ideal perioperative course. In the remaining 93 (16.2%) patients, there were 117 complications. Minor complications occurred in 84 (14.6%) and major complications arose in 15 (2.6%) patients. When the first 500 patients were divided into subsets of 100 patients, a linear regression analysis demonstrated no significant difference in overall complications among the five quintiles (p=0.17). The first quintile was found to have a significantly higher major complication rate compared with the second quintile (p=0.05). The subsequent quintiles exhibited no significant change in major complication rate., Conclusions: As a surgeon progresses through the learning curve, there is a stable overall complication rate with a drop in major complications after the first 100 cases.

The Federal Trade Commission and the Department of Justice have modified their views on what constitutes price fixing by integrated delivery systems. Recently released enforcement policy statements indicate that joint agreements on price between competing providers will not necessarily constitute price fixing, even without risk sharing, if the system is sufficiently integrated. The enforcement policy statements indicate that if integration arises from the combined efforts of previously competing providers, involves improvements in clinical efficiency or quality, and demonstrates no anticompetitive intent, it will be sufficient to withstand Federal scrutiny.

Haemophilus influenzae type b (Hib) infection is a major cause of severe bacterial infection in young children in South Africa and world-wide. These diseases can be prevented by immunisation with conjugate Hib vaccines. In South Africa, unlike some developed countries, Hib vaccines are not part of the routine immunisation schedule. The objective of this study was to measure the expected net benefits from a hypothetical programme of vaccination of the 1992 Cape Town birth cohort (N = 46,537). Costs were calculated by summing the estimated direct medical care costs together with the indirect costs of Hib disease. The latter were calculated by valuing human life using alternative, and conservative human capital and willingness-to-pay measures. The difference between Hib disease costs (i.e. the benefits which would be gained from a successful vaccination programme) and the costs of the vaccination programme itself (HibTITER, Praxis Biologicals) defined the expected net benefits. In the absence of an immunisation programme, the estimated economic costs of Hib disease in the 1992 Cape Town cohort ranged from R10.7 million to R11.8 million. The costs of introducing the vaccine would have amounted to R8.3 million. Had the vaccine been administered to the 1992 birth cohort, benefits would have exceeded costs by between R2.4 million and R3.5 million.

The development of the cerebral microvasculature of the rat was studied during three successive postnatal periods, namely: 1) neonatal period, i.e., 1 to 9 days after birth (capillary sprouting period); 2) myelinization period, i.e., 10 to 20 days; and 3) young adult period, i.e., 2 to 3 months. The survey covered structural aspects and distribution of binding sites for anionic or cationic probes and for albumin-gold complexes on the luminal surface of the microvascular endothelium. The salient results are: a) an extensive development of the endoplasmic reticulum of endothelial cells during the first period (presumably in relation with the production of basement membrane components); b) the high surface density of coated pits and coated vesicles that peaks during the myelinization period; c) the paucity of plasmalemmal vesicle and their differential distribution (their volume density is higher in the endothelium of arterioles than in that of capillaries and venules); d) the existence of an extensive smooth surface tubular system in the cytoplasm of endothelial cells, whose structural connections and functional significance remains to be established; and e) the presence of pericytes with elaborate interactions with endothelia in the early developmental periods. Labeling by perfused tracers indicates an uneven patchy distribution of binding sites for cationic ferritin (generally limited to the plasmalemma proper) and a more even distribution of binding sites for cationic and anionic hemeundecapeptides. Binding patterns did not change during the developmental periods studied. No binding sites were detected for albumin-gold complexes.

The ability of cyclic AMP to inhibit growth, cause cytolysis and induce synthesis of cyclic AMP-phosphodiesterase in S49.1 mouse lymphoma cells is deficient in cells selected on the basis of their resistance to killing by 2 mM dibutyryl cyclic AMP. The properties of the cyclic AMP-dependent protein kinase (ATP:protein phosphotransferase, EC 2.7.1.37) in the cyclic AMP-sensitive (S) and cyclic AMP-resistant (R) lymphoma cells were comparatively studied. The cyclic AMP-dependent protein kinase activity or R cells cytosol exhibits an apparent Ka for activation by cyclic AMP 100-fold greater than that of the enzyme from the parental S cells. The free regulatory and catalytic subunits from both S and R kinase are thermolabile, when associated in the holoenzyme the two subunits are more stable to heat inactivation in R kinase than in S kinase. The increased heat stability of R kinase is observed however only for the enzyme in which the catalytic and cyclic AMP-binding activities are expressed at high cyclic AMP concentrations (10(-5)--10(-4) M), the activities expressed at low cyclic AMP concentrations (10(-9)--10(-6) M) being thermolabile. The regulatory subunit of S kinase can be stabilized against heat inactivation by cyclic AMP binding both at 2-10(-7) and 10(-5) M cyclic AMP concentrations. In contrast, the regulatory subunit-cyclic AMP complex from R kinase is stable to heat inactivation only when formed in the presence of high cyclic AMP concentrations (10(-5)M). The findings indicate that the transition from a cyclic AMP-sensitive to a cyclic AMP-resistant lymphoma cell phenotype is related to a structural alteration in the regulatory subunit of the cyclic AMP-dependent protein kinase which has affected the protein's affinity for cyclic AMP and its interaction with the catalytic subunit.