Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1‐related syndrome

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.     

Mechanoafferent neurons innervating tail of Aplysia. I. Response properties and synaptic connections

Mechanical, chemical, or electrical stimulation of the tail elicits a short-latency (less than 1 s) tail-withdrawal reflex that is graded with the intensity of the stimulus. The tail-withdrawal reflex is not elicited by stimulation of parts of the body outside of the tail region. Mechanoafferent neurons innervating the tail are located in a small subcluster within a large, homogeneous group of medium-size (40-80 micron) cells on the ventrocaudal (VC) surface of each pleural ganglion. The tail sensory neurons within this large VC cluster are activated by tactile pressure or by electrical stimulation of discrete regions of the tail. They adapt slowly to maintained stimulation and sometimes respond to stimulus offset as well. Both mechanical and electrical stimuli produce responses that are graded with the intensity of the stimulus. Cells in the VC cluster appear to be primary mechanoreceptors because they have axons in peripheral nerves (including nerves innervating the tail), they exhibit action potentials lacking prepotentials in response to tactile stimulation, and these action potentials are still produced by cutaneous stimulation when peripheral and central chemical synaptic transmission is blocked. Stimulation of fields all over the body surface evokes synaptically mediated hyperpolarizing responses in individual mechanoafferent neurons that may represent afferent inhibition. Hyperpolarizing responses lasting many seconds can be produced by brief cutaneous stimuli. The mechanoafferent neurons innervating the tail region make strong monosynaptic connections to tail motor neurons in the ipsilateral pedal ganglion, and through these connections this subpopulation of the VC neurons appears to make a substantial contribution to the short-latency tail-withdrawal reflex. In addition, the combined excitatory receptive fields of these mechanoafferents match the excitatory receptive field of the tail-withdrawal reflex. Mechanoafferent neurons in the VC cluster that have receptive fields on other parts of the body (outside the excitatory receptive field of the tail-withdrawal reflex) have not been observed to make monosynaptic connections to the tail motor neurons. The neurons innervating the tail are reliably found in a discrete region within the larger VC cluster. In addition to this gross somatotopic organization, there is evidence of a finer level of somatotopic organization between the position of the excitatory receptive field on the tail and the position of the cell soma in the tail subcluster.(ABSTRACT TRUNCATED AT 400 WORDS)     

Differential Susceptibility of Chlamydiae to Exogenous Fibroblast Interferon

Mouse fibroblasts (L cells) were incubated for 5 h with 1,000 U of murine fibroblast interferon (MuIFN α+ β) per ml and then were infected with either Chlamydia trachomatis (LGV 440), C. psittaci (6BC), or C. psittaci (Cal 10). Intracellular development of C. trachomatis was reduced 90% in interferon-treated cells 24 h after infection when compared with controls, whereas C. psittaci growth was not affected in interferon-treated cells.     

Housing type,housing location and mental health

A number of studies have suggested a connection between the type of dwellings which people occupy and their mental health. People who live in flats are usually shown to be more prone to mental illness than those who live in houses. Those who live in high-rise accommodation are shown to be particularly vulnerable. These conclusions were examined by comparing rates on an indicator of psychological distress, in different dwelling types located in good and bad council housing areas. The results suggest that psychological distress is more closely associated with the location of a dwelling than with dwelling type. High-rise flats located on inner-city problem estates are associated with high levels of psychological distress, while low levels are found in similar dwelling types located in the suburbs. These findings are consistent when the effect of age, health, sex and household class are taken into consideration.     

Beta-2-adrenoceptor agonists as inhibitors of lung vascular permeability to radiolabelled transferrin in the adult respiratory distress syndrome in man

Increased lung vascular permeability leading to increased plasma protein extravasation and accumulation (PPA) is a characteristic feature of acute lung injury. Using a previously described technique, PPA was monitored in the lungs of patients with the adult respiratory distress syndrome (ARDS) — an extreme example of acute lung injury in man. An external radiation probe detector was used to monitor the pulmonary accumulation of the plasma protein transferrin radiolabelled in-vivo with ^113mIn. Ten patients with ARDS exhibiting increased PPA indices (>1.0x10^-3/min) were given an intravenous infusion of terbutaline (7 g/kg) over 30 min. Of the four patients in whom the post-drug PPA indices remained within the ARDS range, none survived, whilst five of the six patients in whom the post-drug PPA indices were reduced to below 1.0x10^-3/min survived. PPA indices prior to the administration of terbutaline were not significantly different between the survivor (n=5) and non-survivor (n=5) groups. There was a significant decrease in the PPA indices following terbutaline in survivors (p<0.01) but not in non-survivors. Thus beta-2-agonists in therapeutic doses can inhibit increased lung vascular permeability in man. These findings may have prognostic and therapeutic implication for beta-2-agonists in ARDS.     

Editorial Commentary: Remember the Risk Factors During Individualized,Anatomic, Value-Based Anterior Cruciate Ligament Reconstruction

Understanding the etiology behind anterior cruciate ligament (ACL) reconstruction failure is a complex topic still being investigated heavily. The 3 classes of failure are technical, traumatic, and biologic. Technical errors are most common and most frequently reflect tunnel malposition. In addition, tibial slope has long been understood to be a risk factor for failed ACL reconstruction. Although not routinely performed at time of primary ACL reconstruction, osteotomy may be considered in the setting of failed ACL reconstruction. Relative quadriceps weakness is a risk factor, and we recommend sport-specific return-to-play testing as well as benchmarks for relative quadriceps strength before full return to activity. Revision ACL reconstruction is associated with both increased costs and worse patient outcomes, so every effort should be made to give patients the best chance of success after the index surgery. Whereas this begins with understanding the patient’s history and risk factors for failure, it crescendos with careful attention to the individually variable factors that make each case unique, tailoring one’s management to ensure that each patient receives an anatomic, individualized, and value-based ACL reconstruction.     

Trends and Outcomes in Simultaneous Liver and Kidney Transplantation in Australia and New Zealand

AimRates of simultaneous liver and kidney transplantation (SLKT) have increased, but indications for SLKT remain poorly defined. Additional data are needed to determine which patients benefit from SLKT to best direct use of scarce donor kidneys.MethodsData were extracted from the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) database for all SLKT performed until the end of 2017. Patients were divided by pretransplant dialysis status into no dialysis before SLKT (preemptive kidney transplant) and any dialysis before SLKT (nonpreemptive). Baseline characteristics and outcomes were compared.ResultsBetween 1989 and 2017, inclusive, 84 SLKT procedures were performed in Australia, of which 24% were preemptive. Preemptive and nonpreemptive SLKT recipients did not significantly differ in age (P = .267), sex (P = .526), or ethnicity (P = .870). Over a median follow-up time of 4.5 years, preemptively transplanted patients had a statistically equivalent risk of kidney graft failure (hazard ratio (HR) 1.83, 95% confidence interval [CI]: 0.36-12.86, P = .474) and all-cause mortality (HR 1.69, 95% CI: 0.51-5.6, P = .226) compared to nonpreemptive patients. Overall, 1- and 5-year survival rates for all SLKTs were 92% (95% CI: 86-96) and 60% (95% CI: 45-75), respectively.ConclusionKidney graft and overall patient survival were similar between patients with preemptive kidney transplant and those who were dialysis dependent.     

Identifying gaps in COVID-19 health equity data reporting in Canada using a scorecard approach

ObjectiveTo assess health equity-oriented COVID-19 reporting across Canadian provinces and territories, using a scorecard approach.MethodsA scan was performed of provincial and territorial reporting of five data elements (cumulative totals of tests, cases, hospitalizations, deaths, and population size) across three units of aggregation (province or territory level, health regions, and local areas) (15 “overall” indicators), and for four vulnerable settings (long-term care and detention facilities, schools, and homeless shelters) and eight social markers (age, sex, immigration status, race/ethnicity, healthcare worker status, occupational sector, income, and education) (180 “equity-related” indicators) as of December 31, 2020. Per indicator, one point was awarded if case-delimited data were released, 0.7 points if only summary statistics were reported, and 0 if neither was provided. Results were presented using a scorecard approach.ResultsOverall, information was more complete for cases and deaths than for tests, hospitalizations, and population size denominators needed for rate estimation. Information provided on jurisdictions and their regions, overall, tended to be more available (average score of 58%, “D”) than that for equity-related indicators (average score of 17%, “F”). Only British Columbia, Alberta, and Ontario provided case-delimited data, with Ontario and Alberta providing case information for local areas. No jurisdiction reported on outcomes according to patients’ immigration status, race/ethnicity, income, or education. Though several provinces reported on cases in long-term care facilities, only Ontario and Quebec provided detailed information for detention facilities and schools, and only Ontario reported on cases within homeless shelters and across occupational sectors.ConclusionOne year into the pandemic, socially stratified reporting for COVID-19 outcomes remains sparse in Canada. However, several “best practices” in health equity-oriented reporting were observed and set a relevant precedent for all jurisdictions to follow for this pandemic and future ones.Supplementary InformationThe online version contains supplementary material available at 10.17269/s41997-021-00496-6.     

Comments on an obstructed death -- a case conference revisited: commentary 1

The paper comments on Scott Dunbar's "An obstructed death and medical ethics," arguing contra Dunbar that we should not view truth-telling to the terminally ill as primarily governed by principles of veracity and respect for autonomy. All such rules are of limited value in medical ethics. We should instead turn to an ethics deriving from the centrality of moral relationships and virtues. A brief analysis of the connections between moral relationships and moral rules is offered. Such an ethics would lower the value that philosophical fashion places on truth-telling and autonomy and leave decisions about truth-telling and the terminally ill more dependent on the circumstances of particular cases.