A second individual with rhizomelic spondyloepimetaphyseal dysplasia and homozygous variant in GNPNAT1

Spondyloepimetaphyseal dysplasias (SEMDs) belong to a clinically and genetically heterogeneous group of inherited skeletal disorders defined by a defect in the growth and shape of vertebrae, epiphyses and metaphyses. Rhizomelic SEMD is characterized by a disproportionate small stature caused by severe shortening and deformation of the limbs’ proximal bones, with the cranio-facial sphere unaffected. We report a second individual, an 8-year-old girl, with autosomal recessive rhizomelic SEMD associated with a homozygous exonic missense variant, c.226G > A p.(Glu76Lys), in GNPNAT1 identified by trio genome sequencing. Our data corroborate the recent findings of Ain et al. and further delineate the clinical and radiographic features of this form of SEMD associated with rhizomelic dysplasia while outlining a potential hotspot in this newly described genetic disorder.     

Considerations in Critical-Care and Anesthetic Management of Adult Patients Living With Fontan Circulation

The Fontan procedure is a staged palliation for various complex congenital cardiac lesions, including tricuspid atresia, pulmonary atresia, hypoplastic left heart syndrome, and double-inlet left ventricle, all of which involve a functional single-ventricle physiology. The complexity of the patients’ original anatomy combined with the anatomic and physiologic consequences of the Fontan circulation creates challenges. Teens and adults living with Fontan palliation will need perioperative support for noncardiac surgery, peripartum management for labour and delivery, interventions related to their structural heart disease, electrophysiology procedures, pacemakers, cardioversions, cardiac surgery, transplantation, and advanced mechanical support. This review focuses on the anesthetic and intensive care unit (ICU) management of these patients during their perioperative journey, with an emphasis on the continuity of preintervention planning, referral pathways, and postintervention ICU management. Requests for recipes and doses of medications are frequent; however, as in normal anesthesia and ICU practice, the method of anesthesia and dosing are dependent on the presenting medical/surgical conditions and the underlying anatomy and physiologic reserve. A patient with Fontan palliation in their early 20s attending school full-time with a cavopulmonary connection is likely to have more reserve than a patient in their late 40s with an atriopulmonary Fontan at home waiting for a heart transplant. Each case will require an anesthetic and critical care plan tailored to the situation. The critical care environment is a natural extension of the anesthetic management of a patient, with complex considerations for a patient with Fontan palliation.     

Management of Orthostatic Hypotension in the Hospitalized Patient: A Narrative Review

Orthostatic hypotension is a frequent cause of falls and syncope, impairing quality of life. It is an independent risk factor of mortality and a common cause of hospitalizations, which exponentially increases in the geriatric population. We present a management plan based on a systematic literature review and understanding of the underlying pathophysiology and relevant clinical pharmacology. Initial treatment measures include removing offending medications and avoiding large meals. Clinical assessment of the patients’ residual sympathetic tone can aid in the selection of initial therapy between norepinephrine “enhancers” or “replacers.” Role of splanchnic venous pooling is overlooked, and applying abdominal binders to improve venous return may be effective. The treatment goal is not normalizing upright blood pressure but increasing it above the cerebral autoregulation threshold required to improve symptoms. Hypertension is the most common associated comorbidity, and confining patients to bed while using pressor agents only increases supine blood pressure, leading to worsening pressure diuresis and orthostatic hypotension. Avoiding bedrest deconditioning and using pressors as part of an orthostatic rehab program are crucial in reducing hospital stay.     

Biological Disease-Modifying Antirheumatic Drugs and Osteoporotic Fracture Risk in Patients with Rheumatoid Arthritis: A Danish Cohort Study

ObjectivesClinical trials have shown a beneficial effect from biological disease-modifying antirheumatic drugs (bDMARDs) on hand or axial bone loss in patients with rheumatoid arthritis; however, it is unclear if this translates to a reduced fracture risk. We investigated the effect of bDMARDs on osteoporotic fracture risk compared to no biological treatment in rheumatoid arthritis.MethodsA cohort of patients with rheumatoid arthritis aged 18+ from DANBIO was linked to population-based health registries in Denmark (2006-2016). Adopting a prevalent new-user design, we matched bDMARD users to bDMARD-naïve patients using time-conditional propensity scores. The risk of incident osteoporotic fractures (including hip, vertebrae, humerus, and forearm) was estimated among the matched patients by Cox proportional hazards models.ResultsOut of 24,678 patients with rheumatoid arthritis, 4265 bDMARD users were matched to the same number of bDMARD-naïve patients (mean age 56.2 years, 74% female). During follow-up, 229 osteoporotic fractures occurred among bDMARD users and 205 fractures among bDMARD-naïve patients (incidence rates 12.1 and 13.0 per 1000 person-years, respectively). The use of bDMARDs was not associated with a reduced risk of osteoporotic fractures among patients with rheumatoid arthritis (hazard ratio 0.97, 95% confidence interval 0.78-1.20), compared with no biological treatment. The risk estimates were similar for all osteoporotic fracture sites.ConclusionWe found no independent beneficial effect from using bDMARDs on reducing the risk of osteoporotic fractures in patients with rheumatoid arthritis.     

Bidirectional Association Between Sleep Quality and Low Back Pain in Older Adults: A Longitudinal Observational Study

ObjectiveTo investigate the bidirectional relationship by determining whether baseline sleep quality predicts pain intensity and whether baseline pain intensity predicts sleep quality in older individuals with chronic low back pain (LBP).DesignA prospective longitudinal cohort study with a 6-month follow-up period.SettingCommunity.ParticipantsOlder adults with LBP aged 60 years or older (N=215).InterventionNot applicable.Main Outcome MeasuresData collection occurred at baseline and at 6 months. Pain intensity and sleep quality were measured in both time points of assessment using the numeric pain rating scale (range, 0-10) and the Pittsburg Sleep Quality Index. At baseline, we also collected information on demographic anthropometric variables, cognitive status, depression, and comorbidities. Multivariable linear regression analyses adjusted for potential covariates were performed.ResultsA total of 215 individuals with LBP were recruited. Poor sleep quality at baseline predicted high pain intensity at 6 months (β coefficient, 0.18; 95% confidence interval [CI], 0.07-0.30). High pain intensity at baseline predicted poor sleep quality 6 months later (β coefficient, 0.14; 95% CI, 0.01-0.26).ConclusionOur findings give some support to the bidirectional relationship between pain and sleep quality in older individuals with LBP. This bidirectional relationship may be used as prognostic information by clinicians when managing patients with LBP.     

Deciphering the molecular landscape of microcephaly in 87 Indian families by exome sequencing

Microcephaly is a frequent feature of neurodevelopmental disorders (NDDs). Our study presents the heterogeneous spectrum of genetic disorders in patients with microcephaly either in isolated form or in association with other neurological and extra-neural abnormalities. We present data of 91 patients from 87 unrelated families referred to our clinic during 2016–2020 and provide a comprehensive clinical and genetic landscape in the studied cohort. Molecular diagnosis using exome sequencing was made in 45 families giving a yield of 51.7%. In 9 additional families probable causative variants were detected. We identified disease causing variations in 49 genes that are involved in different functional pathways Among these, 36 had an autosomal recessive pattern, 8 had an autosomal dominant pattern (all inherited de novo), and 5 had an X-linked pattern. In 41 probands where sequence variations in autosomal recessive genes were identified 31 were homozygotes (including 16 from non-consanguineous families). The study added 28 novel pathogenic/likely pathogenic variations. The study also calls attention to phenotypic variability and expansion in spectrum as well as uncovers genes where microcephaly is not reported previously or is a rare finding. We here report phenotypes associated with the genes for ultra-rare NDDs with microcephaly namely ATRIP, MINPP1, PNPLA8, AIMP2, ANKLE2, NCAPD2 and TRIT1.