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Background: Limited data are available describing the effects of SARS-CoV-2 breakthrough infections on the plasma proteome. Methods: PCR-positive SARS-CoV-2 patients, enrolled in a natural history study, underwent analysis of the plasma proteome. A prospective cohort of 66 unvaccinated and 24 vaccinated persons with different degrees of infection severity were evaluated acutely (within 40 days of symptom onset), and at three and ten months. Comparisons based on vaccination status alone and unsupervised hierarchical clustering were performed. A second cohort of vaccinated Omicron patients were evaluated acutely and at ten months. Results: Acutely, unvaccinated patients manifested overexpression of proteins involved in immune and inflammatory responses, while vaccinated patients exhibited adaptive immune responses without significant inflammation. At three and ten months, only unvaccinated patients had diminished but sustained inflammatory (C3b, CCL15, IL17RE) and immune responses (DEFA5, TREM1). Both groups had underexpression of pathways essential for cellular function, signaling, and angiogenesis (AKT1, MAPK14, HSPB1) across phases. Unsupervised clustering, based on protein expression, identified four groups of patients with variable vaccination rates demonstrating that additional clinical factors influence the plasma proteome. The proteome of vaccinated Omicron patients did not differ from vaccinated pre-Omicron patients. Conclusions: Vaccination attenuates the inflammatory response to SARS-CoV-2 infection across phases. However, at ten months after symptom onset, changes in the plasma proteome persist in both vaccinated and unvaccinated individuals, which may be relevant to post-acute sequelae of SARS-CoV-2 and other viral infections associated with post-acute infection syndromes. [ABSTRACT FROM AUTHOR]

Barnett responds to three articles that put the thought of Søren Kierkegaard in conversation with modern popular media. He argues that each of these pieces demonstrates that Kierkegaard's criticism of the burgeoning free press remains relevant today, particularly in the areas of journalistic practice, mental health, and political responsibility. At the same time, however, Barnett wonders if the radical nature of the Dane's critique has been fully considered. For Kierkegaard, in other words, it is not just that popular media have flaws in need of correction; it is that the media constitute "the evil principle in the modern world." [ABSTRACT FROM AUTHOR]

Purpose of Review: The endotracheal intubation of patients with pulmonary arterial hypertension (PAH) in respiratory distress is a highly morbid procedure that can precipitate hemodynamic collapse. Here we review our strategy for confronting this difficult clinical situation. Recent findings: There are no clinical trials that explore best practices in the management of patients with PAH and respiratory failure. Summary: Here we provide a practical approach to respiratory support, inopressor and pulmonary vasodilator selection, hemodynamic considerations, point-of-care ultrasound monitoring, and endotracheal intubation in patients with PAH in respiratory failure. [ABSTRACT FROM AUTHOR]

The article discusses the introduction of Medicare-funded reproductive genetic carrier screening (RGCS) in Australia and examines the country's readiness for this screening. RGCS is a preventive health strategy that identifies healthy individuals and couples who have an increased chance of having a child affected by a serious genetic condition. The article emphasizes the benefits of RGCS in allowing informed reproductive choices and reducing the chance of having an affected child. It also addresses the factors that have limited the uptake of RGCS, such as lack of awareness and understanding, and the cost of testing. The article provides information on the three genetic conditions included in the Medicare-funded screening and the complexities involved in pre- and post-test counseling. It highlights the importance of choice-based counseling and the need to provide individuals and couples with information about the limitations and potential implications of screening. The article concludes by discussing the reproductive options available to reduce the risk of an affected pregnancy and the demand for clinical genetics services in Australia. It also mentions the implementation and outcomes of Mackenzie's Mission, a study funded by the Australian Government Medical Research Future Fund, which aimed to assess the feasibility and acceptability of expanded carrier screening for Australian couples. Preliminary results showed that about 1 in 50 Australian reproductive couples would be identified as having an increased chance of carrying a genetic condition. The study underscores the need for ongoing education and resources to support the implementation of expanded carrier screening. [Extracted from the article]

Two novel oxides with Pb2Rh2O7 and Y2Rh2O7 compositions were synthesised using high pressure, high temperature techniques at 19 GPa and 8 GPa, respectively. Structurally, both compounds were determined to crystallise in the cubic pyrochlore structure, space group Fd3¯m, with no observed oxygen vacancies. Both oxides have effectively identical Rh–O bond lengths of 1.987 Å and a bond-valence sum (BVS) of 4.2 that confirm a Rh4+ oxidation state. Physical property measurements for Pb2Rh2O7 are consistent with a metallic ground state. This is similar to other Pb2M2O7 oxides where M = Ru, Ir, and Os. Y2Rh2O7 represents an unusual case of the lower density (6.356 g cm−3) pyrochlore structure being stabilised under high pressure conditions, while the analogous, higher density (7.031 g cm−3) perovskite YRhO3 is stabilised by synthesis under ambient pressure conditions. The Rh4+ state results in a S = ½ magnetic ground state. Magnetisation measurements suggest strong AFM coupling in Y2Rh2O7. However, long range AFM order is not observed down to 2 K presumably due to the geometric frustration of the pyrochlore lattice. Specific heat and resistivity measurements indicate a large electronic contribution to the heat capacity. The Wilson ratio of 4.78(11) is well above 2, indicating nearness to magnetism and the likely presence of Rh moments in the background of the conduction electrons. Catalytic activity indicated a greater correlation with other Rh pyrochlores as opposed to dependence on the Rh oxidation state. [ABSTRACT FROM AUTHOR]

Background: The disconnect between research and clinical practice leads to research evidence that is often not useful for clinical practice. Practice-based research networks are collaborations between researchers and clinicians aimed at coproducing more useful research. Such networks are rare in the physiotherapy field. We aimed to describe (i) clinicians' motivations behind, and enablers to, participating in a network, (ii) the process of network establishment and (iii) research priorities for a practice-based network of physiotherapists in the Hunter Region of New South Wales (NSW), Australia that supports research coproduction. Methods: We describe the methods and outcomes of the three steps we used to establish the network. Step 1 involved consultation with local opinion leaders and a formative evaluation to understand clinicians' motivations behind, and enablers to, participating in a network. Step 2 involved establishment activities to generate a founding membership group and codesign a governance model. Step 3 involved mapping clinical problems through a workshop guided by systems thinking theory with local stakeholders and prioritizing research areas. Results: Through formative evaluation focus groups, we generated five key motivating themes and three key enablers for physiotherapists' involvement in the network. Establishment activities led to a founding membership group (n = 29, 67% from private practice clinics), a network vision and mission statement, and a joint governance group (9/13 [70%] are private practice clinicians). Our problem-mapping and prioritization process led to three clinically relevant priority research areas with the potential for significant change in practice and patient outcomes. Conclusions: Clinicians are motivated to break down traditional siloed research generation and collaborate with researchers to solve a wide array of issues with the delivery of care. Practice-based research networks have promise for both researchers and clinicians in the common goal of improving patient outcomes. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) attacks the immune system and can cause acquired immunodeficiency syndrome. Thankfully, antiretroviral therapy is highly effective, and people infected with HIV can live long lives with proper adherence to therapy. One of the important noninfectious complications of HIV is the development of pulmonary arterial hypertension (PAH). This review will cover the epidemiology, pathogenesis, and clinical characteristics of HIV-associated PAH. It will also cover the current knowledge on use of vasodilator therapy in this population. [ABSTRACT FROM AUTHOR]

Case Presentation: A 16-year-old boy presented with 6 days of left iliac fossa pain. He had a medical history of right subtalar dislocation and appendicitis requiring laparotomy 3 years earlier, complicated by wound dehiscence. His family history was significant for his brother's sudden death 3 weeks prior after a 12-month illness with intermittent epigastric pain, weight loss, and hemoptysis. Travel history was significant for travel to the Philippines 3 years prior, in which he spent time in the hospital for appendicitis. [ABSTRACT FROM AUTHOR]

Background Few therapies are approved for hospitalized patients with severe coronavirus disease 2019 (COVID-19). Ibrutinib, a once-daily Bruton tyrosine kinase inhibitor, may mitigate COVID-19–induced lung damage by reducing inflammatory cytokines. The multicenter, randomized, double-blind phase 2 iNSPIRE study evaluated ibrutinib for prevention of respiratory failure in hospitalized patients with severe COVID-19. Methods Adult patients with severe COVID-19 requiring hospitalization and supplemental oxygen but without respiratory failure were randomized 1:1 (stratified by remdesivir prescription) to ibrutinib 420 mg or placebo once daily for up to 28 days plus standard of care (SOC), including remdesivir and/or dexamethasone. Results Forty-six patients were randomized to ibrutinib plus SOC (n = 22) or placebo plus SOC (n = 24). The primary endpoint (proportion of patients alive and without respiratory failure through day 28) was not met, with no statistically significant difference adjusting for remdesivir prescription (86% with ibrutinib plus SOC vs 79% with placebo plus SOC; adjusted difference, 5.8% [80% confidence interval, –9.2% to 20.4%]; P  = .599). Secondary endpoints also showed no statistically significant improvement with ibrutinib plus SOC. Median treatment duration was 14 days for ibrutinib and placebo. Adverse events were similar with ibrutinib plus SOC vs placebo plus SOC (overall: 55% vs 50%; serious: 18% vs 13%) and were consistent with the known safety profile of ibrutinib. Conclusions Addition of ibrutinib to SOC did not improve the proportion of patients alive and without respiratory failure through day 28 in hospitalized patients with severe COVID-19. Ibrutinib had a manageable safety profile, with similar safety to placebo. Clinical Trials Registration NCT04375397. [ABSTRACT FROM AUTHOR]

The inherited retinal dystrophies (IRDs) are a clinically and genetically complex group of disorders primarily affecting the rod and cone photoreceptors or other retinal neuronal layers, with emerging therapies heralding the need for accurate molecular diagnosis. Targeted capture and panel-based strategies examining the partial or full exome deliver molecular diagnoses in many IRD families tested. However, approximately one in three families remain unsolved and unable to obtain personalised recurrence risk or access to new clinical trials or therapy. In this study, we investigated whole genome sequencing (WGS), focused assays and functional studies to assist with unsolved IRD cases and facilitate integration of these approaches to a broad molecular diagnostic clinical service. The WGS approach identified variants not covered or underinvestigated by targeted capture panel-based clinical testing strategies in six families. This included structural variants, with notable benefit of the WGS approach in repetitive regions demonstrated by a family with a hybrid gene and hemizygous missense variant involving the opsin genes, OPN1LW and OPN1MW. There was also benefit in investigation of the repetitive GC-rich ORF15 region of RPGR. Further molecular investigations were facilitated by focused assays in these regions. Deep intronic variants were identified in IQCB1 and ABCA4, with functional RNA based studies of the IQCB1 variant revealing activation of a cryptic splice acceptor site. While targeted capture panel-based methods are successful in achieving an efficient molecular diagnosis in a proportion of cases, this study highlights the additional benefit and clinical value that may be derived from WGS, focused assays and functional genomics in the highly heterogeneous IRDs. [ABSTRACT FROM AUTHOR]

Prize giving has grown exponentially, with agencies like the World Bank and USAID using them to help solve critical development challenges in low-income countries. This paper draws on findings from a DFID programme that has been experimenting with a suite of global prizes, including in Ghana, Kenya, and Nepal. The paper reflects on prizes used to deliver social change: where they work, why, and for whom. We find that development impact can be enhanced when prizes are not implemented alone. Complementary support is often necessary to help innovators participate, overcome barriers, and support innovation that leads to social change. [ABSTRACT FROM AUTHOR]

The σ‐donating and π‐accepting properties of a series of N‐methylimidazolium‐derived N‐heterocyclic carbenes, systematically altered at the 4,5‐positions, were determined using two NMR‐based probe techniques. The sterically slight methyl substituent provided reliable probe data, free from through‐space effects, and reliable measures of the electronic properties. Correlations with established electronic parameters for the substituents show that the electronic properties of carbenes, when extraneous effects are controlled for, are indeed predictable. These correlations were compared with earlier data which revealed a previously unrecognised systematic deviation for N‐aryl substituents. [ABSTRACT FROM AUTHOR]

Electronic probes of ligands, particularly carbenes, are widely used in assessing electronic properties; the results inform the selection of a ligand for a given application. As such, it is important to ensure the data obtained is reliable and unaffected by other factors, such as the steric bulk of the ligand. The effects of such steric factors on two commonly used electronic probes (based on palladium and selenium) are investigated here, with the selenium adduct found to be particularly sensitive. It is hoped that this serves as a cautionary tale to always critically evaluate what a probe is measuring. [ABSTRACT FROM AUTHOR]

Preoperative cardiopulmonary exercise testing (CPET) is well validated for prognostication before advanced surgical heart failure therapies, but its role in prognostication after LVAD surgery has never been studied. VE/VCO2 slope is an important component of CPET which has direct pathophysiologic links to right ventricular (RV) performance. We hypothesized that VE/VCO2 slope would prognosticate RV dysfunction after LVAD. All CPET studies from a single institution were collected between September 2009 and February 2019. Patients who ultimately underwent LVAD implantation were selectively analyzed. Peak VO2 and VE/VCO2 slope were measured for all patients. We evaluated their association with hemodynamic, echocardiographic and clinical markers of RV dysfunction as well mortality. Patients were stratified into those with a ventilatory class of III or greater. (VE/VCO2 slope of ≥ 36, n = 43) and those with a VE/VCO2 slope < 36 (n = 27). We compared the mortality between the 2 groups, as well as the hemodynamic, echocardiographic and clinical markers of RV dysfunction. 570 patients underwent CPET testing. 145 patients were ultimately referred to the advanced heart failure program and 70 patients later received LVAD implantation. Patients with VE/VCO2 slope of ≥ 36 had higher mortality (30.2% vs. 7.4%, p = 0.02) than patients with VE/VCO2 slope < 36 (n = 27). They also had a higher incidence of clinically important RVF (Acute severe 9.3% vs. 0%, Severe 32.6% vs 25.9%, p = 0.03). Patients with a VE/VCO2 slope ≥ 36 had a higher CVP than those with a lower VE/VCO2 slope (11.2 ± 6.1 vs. 6.0 ± 4.8 mmHg, p = 0.007), and were more likely to have a RA/PCWP ≥ 0.63 (65% vs. 19%, p = 0.008) and a PAPI ≤ 2 (57% vs. 13%, p = 0.008). In contrast, peak VO2 < 12 ml/kg/min was not associated with postoperative RV dysfunction or mortality. Elevated preoperative VE/VCO2 slope is a predictor of postoperative mortality, and is associated with postoperative clinical and hemodynamic markers of impaired RV performance. [ABSTRACT FROM AUTHOR]

The electronic properties of a series of imidazolium‐derived N‐heterocyclic carbenes systematically substituted at the 4,5‐positions were investigated through NMR analysis of their palladium and selenone derivatives. This combined approach provided information on both the σ‐donating ability and the π‐accepting ability of the carbenes, allowing correlation with the electronic nature of the substituents on the carbene and providing an understanding of the structural features that affect these properties; in principle, this allows design of related ligands with known electronic parameters. Along with a greater understanding of the electronic properties of this series of carbenes, the work allows a comparison of the utility of both NMR probes based on the information gained, and the differences in requirements for preparation and acquisition. With this in mind, the selenone probe is proposed as being able to provide a wide range of electronic information, along with being relatively easily prepared. [ABSTRACT FROM AUTHOR]

Arrhythmias are commonly encountered in the intensive care unit as a primary admitting diagnosis or secondary to an acute illness. Appropriate identification and treatment of ventricular arrhythmias in this setting are particularly important to reduce morbidity and mortality. This review highlights the epidemiology, mechanisms, electrocardiographic features, and treatment of ventricular arrhythmias. [ABSTRACT FROM AUTHOR]

Objective: To assess Australian physiotherapists' knowledge about, attitudes towards, and self-reported use of shared decision making, as well as perceived barriers to its implementation in practice. Methods: Physiotherapists registered for a national Australian physiotherapy conference were invited via email and the conference app to complete a self-administered online questionnaire about shared decision making, including: a) knowledge, b) attitude to and reported approach in practice, c) behaviours used, d) barriers, e) previous training and future training interest. Responses were analysed descriptively and open-ended questions synthesised narratively. Results: 372 physiotherapists (71% female, mean age 45 years, mean experience 23 years) completed the survey. Respondents had a good level of knowledge on most questions, with correct responses ranging from 39.5% to 98.5% of participants, and a generally positive attitude towards shared decision making, believing it useful to most practice areas. Sixty percent indicated they make decisions with their patients and there was general agreement between how decisions should be made and how they are actually made. The behaviour with the lowest reported occurrence was explaining the relevant research evidence about the benefits and harms of the options. The main perceived barriers were patient knowledge and confidence, consequent fewer physiotherapy sessions, and time constraints. Most (79%) were keen to learn more about shared decision making. Conclusions: Shared decision making is of growing importance to all health professions and rarely studied in physical therapy. This sample of Australian physiotherapists had a generally positive attitude to shared decision making and learning more about it. Opportunities for providing such skills training at the undergraduate level and in continuing professional development should be explored. This training should ensure that the communicating evidence component of shared decision making is addressed as well as debunking myths about perceived barriers to its implementation. [ABSTRACT FROM AUTHOR]

Background: Periventricular nodular heterotopia (PNH) is a malformation of cortical development characterized by nodules of abnormally migrated neurons. The cause of posteriorly placed PNH is not well characterised and we present a case that provides insights into the cause of posterior PNH. Case presentation: We report a fetus with extensive posterior PNH in association with biallelic variants in LAMC3. LAMC3 mutations have previously been shown to cause polymicrogyria and pachygyria in the occipital cortex, but not PNH. The occipital location of PNH in our case and the proposed function of LAMC3 in cortical development suggest that the identified LAMC3 variants may be causal of PNH in this fetus. Conclusion: We hypothesise that this finding extends the cortical phenotype associated with LAMC3 and provides valuable insight into genetic cause of posterior PNH. [ABSTRACT FROM AUTHOR]

Axenfeld‐Rieger syndrome is a genetic condition characterized by ocular and systemic features and is most commonly caused by variants in the FOXC1 or PITX2 genes. Facial dysmorphism is part of the syndrome but the differences between both genes have never been systematically assessed. Here, 11 facial traits commonly reported in Axenfeld‐Rieger syndrome were assessed by five clinical geneticists blinded to the molecular diagnosis. Individuals were drawn from the Australian and New Zealand Registry of Advanced Glaucoma in Australia or recruited through the Genetic and Ophthalmology Unit of l'Azienda Socio‐Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda in Italy. Thirty‐four individuals from 18 families were included. FOXC1 variants were present in 64.7% of individuals and PITX2 variants in 35.3% of individuals. A thin upper lip (55.9%) and a prominent forehead (41.2%) were common facial features shared between both genes. Hypertelorism/telecanthus (81.8% vs 25.0%, p = 0.002) and low‐set ears (31.8% vs 0.0%, p = 0.036) were significantly more prevalent in individuals with FOXC1 variants compared with PITX2 variants. These findings may assist clinicians in reaching correct clinical and molecular diagnoses, and providing appropriate genetic counseling. [ABSTRACT FROM AUTHOR]

Cyclic conformational coordinates are essential for the distinction of molecular ring conformers as the use of Cremer-Pople coordinates have illustrated for five- and six-membered rings. Here, by tessellating medium rings into triangular planes and using the relative angles made between triangular planes we are able to assign macrocyclic pucker conformations into canonical pucker conformers such as chairs, boats, etc. We show that the definition is straightforward compared with other methods popularly used for small rings and that it is computationally simple to implement for complex macrocyclic rings. These cyclic conformational coordinates directly couple to the motion of individual nodes of a ring. Therefore, they are useful for correlating the physical properties of macrocycles with their ring pucker and measuring the dynamic ring conformational behavior. We illustrate the triangular tessellation, assignment, and pucker analysis on 7- and 8-membered rings. Sets of canonical states are given for cycloheptane and cyclooctane that have been previously experimentally analysed. [ABSTRACT FROM AUTHOR]

Iridium(III) half-sandwich complexes containing 7-chloroquinoline-1,2,3-triazole hybrid ligands were synthesised and their inhibitory activities evaluated against the Plasmodium falciparum malaria parasite. Supporting computational analysis revealed that metal coordination to the quinoline nitrogen occurs first, forming a kinetic product that, upon heating over time, forms a more stable cyclometallated thermodynamic product. Single crystal X-ray diffraction confirmed the proposed molecular structures of both isolated kinetic and thermodynamic products. Complexation with iridium significantly enhances the in vitro activity of selected ligands against the chloroquine-sensitive (NF54) Plasmodium falciparum strain, with selected complexes being over one hundred times more active than their respective ligands. No cross-resistance was observed in the chloroquine-resistant (K1) strain. No cytotoxicity was observed for selected complexes tested against the mammalian Chinese Hamster Ovarian (CHO) cell line. In addition, speed-of-action assays and β-haematin inhibition studies were performed. Through preliminary qualitative and quantitative cell-free experiments, it was found that the two most active neutral, cyclometallated complexes can act as transfer hydrogenation catalysts, by reducing β-nicotinamide adenine dinucleotide (NAD+) to NADH in the presence of a hydrogen source, sodium formate. [ABSTRACT FROM AUTHOR]

We report the first case of diffuse gastric cancer in an individual with familial blepharocheilodontic syndrome (BCD) due to a germline CDH1 likely pathogenic variant. To date, other BCD affected relatives are nonpenetrant for diffuse gastric cancer posing challenges to counseling regarding gastric and breast cancer surveillance, and preventative total gastrectomy. [ABSTRACT FROM AUTHOR]

Background Pseudodiastrophic dysplasia (PDD) is a severe skeletal dysplasia associated with prenatal manifestation and early lethality. Clinically, PDD is classified as a 'dysplasia with multiple joint dislocations'; however, the molecular aetiology of the disorder is currently unknown. Methods Whole exome sequencing (WES) was performed on three patients from two unrelated families, clinically diagnosed with PDD, in order to identify the underlying genetic cause. The functional effects of the identified variants were characterised using primary cells and human cell-based overexpression assays. Results WES resulted in the identification of biallelic variants in the established skeletal dysplasia genes, B3GAT3 (family 1) and CANT1 (family 2). Mutations in these genes have previously been reported to cause 'multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defects' ('JDSCD'; B3GAT3) and Desbuquois dysplasia 1 (CANT1), disorders in the same nosological group as PDD. Follow-up of the B3GAT3 variants demonstrated significantly reduced B3GAT3/GlcAT-I expression. Downstream in vitro functional analysis revealed abolished biosynthesis of glycosaminoglycan side chains on proteoglycans. Functional evaluation of the CANT1 variant showed impaired nucleotidase activity, which results in inhibition of glycosaminoglycan synthesis through accumulation of uridine diphosphate. Conclusion For the families described in this study, the PDD phenotype was caused by mutations in the known skeletal dysplasia genes B3GAT3 and CANT1, demonstrating the advantage of genomic analyses in delineating the molecular diagnosis of skeletal dysplasias. This finding expands the phenotypic spectrum of B3GAT3-related and CANT1-related skeletal dysplasias to include PDD and highlights the significant phenotypic overlap of conditions within the proteoglycan biosynthesis pathway. [ABSTRACT FROM AUTHOR]

Importance: Widespread adoption of rapid genomic testing in pediatric critical care requires robust clinical and laboratory pathways that provide equitable and consistent service across health care systems.Objective: To prospectively evaluate the performance of a multicenter network for ultra-rapid genomic diagnosis in a public health care system.Design, Setting, and Participants: Descriptive feasibility study of critically ill pediatric patients with suspected monogenic conditions treated at 12 Australian hospitals between March 2018 and February 2019, with data collected to May 2019. A formal implementation strategy emphasizing communication and feedback, standardized processes, coordination, distributed leadership, and collective learning was used to facilitate adoption.Exposures: Ultra-rapid exome sequencing.Main Outcomes and Measures: The primary outcome was time from sample receipt to ultra-rapid exome sequencing report. The secondary outcomes were the molecular diagnostic yield, the change in clinical management after the ultra-rapid exome sequencing report, the time from hospital admission to the laboratory report, and the proportion of laboratory reports returned prior to death or hospital discharge.Results: The study population included 108 patients with a median age of 28 days (range, 0 days to 17 years); 34% were female; and 57% were from neonatal intensive care units, 33% were from pediatric intensive care units, and 9% were from other hospital wards. The mean time from sample receipt to ultra-rapid exome sequencing report was 3.3 days (95% CI, 3.2-3.5 days) and the median time was 3 days (range, 2-7 days). The mean time from hospital admission to ultra-rapid exome sequencing report was 17.5 days (95% CI, 14.6-21.1 days) and 93 reports (86%) were issued prior to death or hospital discharge. A molecular diagnosis was established in 55 patients (51%). Eleven diagnoses (20%) resulted from using the following approaches to augment standard exome sequencing analysis: mitochondrial genome sequencing analysis, exome sequencing-based copy number analysis, use of international databases to identify novel gene-disease associations, and additional phenotyping and RNA analysis. In 42 of 55 patients (76%) with a molecular diagnosis and 6 of 53 patients (11%) without a molecular diagnosis, the ultra-rapid exome sequencing result was considered as having influenced clinical management. Targeted treatments were initiated in 12 patients (11%), treatment was redirected toward palliative care in 14 patients (13%), and surveillance for specific complications was initiated in 19 patients (18%).Conclusions and Relevance: This study suggests feasibility of ultra-rapid genomic testing in critically ill pediatric patients with suspected monogenic conditions in the Australian public health care system. However, further research is needed to understand the clinical value of such testing, and the generalizability of the findings to other health care settings. [ABSTRACT FROM AUTHOR]

Autosomal dominant (de novo) mutations in PBX1 are known to cause congenital abnormalities of the kidney and urinary tract (CAKUT), with or without extra‐renal abnormalities. Using trio exome sequencing, we identified a PBX1 p.(Arg107Trp) mutation in a deceased one‐day‐old neonate presenting with CAKUT, asplenia, and severe bilateral diaphragmatic thinning and eventration. Further investigation by droplet digital PCR revealed that the mutation had occurred post‐zygotically in the father, with different variant allele frequencies of the mosaic PBX1 mutation in blood (10%) and sperm (20%). Interestingly, the father had subclinical hydronephrosis in childhood. With an expected recurrence risk of one in five, chorionic villus sampling and prenatal diagnosis for the PBX1 mutation identified recurrence in a subsequent pregnancy. The family opted to continue the pregnancy and the second affected sibling was stillborn at 35 weeks, presenting with similar severe bilateral diaphragmatic eventration, microsplenia, and complete sex reversal (46, XY female). This study highlights the importance of follow‐up studies for presumed de novo and low‐level mosaic variants and broadens the phenotypic spectrum of developmental abnormalities caused by PBX1 mutations. [ABSTRACT FROM AUTHOR]

Although lentigines are usually benign, they can be associated with a number of genetic syndromes in which neoplasms and other multi‐system pathological processes occur. Here, we report the case of a 6‐year‐old girl who presented with atypical lentiginosis and hyperpigmentation caused by a de novo genetic variant in the KIT gene. [ABSTRACT FROM AUTHOR]