Cutibacterium acnes septic arthritis of the nonoperated knee: A case report.

Abstract Cutibacterium (Propionibacterium) acnes, a gram-positive bacillus with low pathogenicity, is an uncommon but known cause of prosthetic joint infections, particularly related to shoulder surgery. C. acnes, however, is an extremely rare pathogen in the nonoperated knee joint. This report details an uncommon case of C. acnes septic knee arthritis after multiple intra-articular steroid injections in a 56-year-old male patient. After an indolent presentation and late diagnosis, the patient underwent surgical debridement with IV antibiotic management. This case illustrates that intra-articular corticosteroid injections for the management of osteoarthritis are not without risk. Literature supporting their use remains limited and clinicians should use proficient clinical judgment for appropriate patient selection for these injections. Vigilance following injections or aspirations of the knee should be maintained to identify the indolent clinical presentation of C. acnes septic arthritis.</jats:p

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Oral Dexamethasone Following Total Knee Arthroplasty: A Double-Blind, Randomized Controlled Trial

BACKGROUND: Intravenous dexamethasone has been shown to reduce pain in total joint arthroplasty. This double-blind, randomized, placebo-controlled trial investigated the postoperative effects and safety of oral dexamethasone as a potential augment to multimodal pain management in outpatient knee arthroplasty. METHODS: The authors prospectively randomized 109 consecutive patients undergoing primary total knee arthroplasty. Patients were assigned to Group A (57 patients) received 4 mg of dexamethasone by mouth twice per day starting postoperative day (POD) one for four days and Group B received placebo capsules. All healthcare professionals and patients were blinded to group allocation. The primary outcome was defined as postoperative pain scores. Secondary outcomes included 90-day postoperative complications, nausea and vomiting, daily opioid usage, assistance for ambulation, difficulty sleeping, and early patient reported outcomes. Demographics were similar between groups. RESULTS: The patients who received dexamethasone had statistically significant decrease in VAS scores when averaging POD 1 to 4 (P=0.01). The average VAS scores among individual days were significantly lower with dexamethasone on POD 2, 3, and 4. While taking dexamethasone, morning and mid-day VAS scores were significantly lower. There was no difference between the groups with opioid use, nausea or vomiting, 90-day complications, ability to walk with/without assistance, difficulty sleeping, and early patient reported outcomes. CONCLUSION: This double-blind, randomized, placebo-controlled trial demonstrated that oral dexamethasone following primary total knee arthroplasty can reduce postoperative pain. This may be a beneficial option in ambulatory surgery where intravenous limitations exist, but larger series are needed to further evaluate the safety profile in this population

Increased Accuracy in Templating for Total Knee Arthroplasty Using 3D Models Generated from Radiographs

Templating prior to total hip arthroplasty is a widely adopted practice that aims to improve operative efficiency and reduce clinical outliers. Predicting implant size before total knee arthroplasty (TKA), although less common, could increase operating room efficiency by reducing necessary equipment needed for the procedure. This study compared templating accuracy in TKA using two-dimensional (2D) digital radiographs to a novel imaging technology that generates a three-dimensional (3D) model from these 2D radiographs. Two hundred and two robotic-assisted primary TKA surgical cases using Persona Knee System (Zimmer Biomet, Warsaw, IN) were retrospectively analyzed. For all cases, 3D templating was completed preoperatively using a novel radiographic image acquisition protocol. Using the same radiographs, the knee was templated using a 2D digital templating program. All surgeons were blinded to the final implant sizes, and all templating was done independently. The accuracy of predictions within ± 1 from the final implant size was determined for the femoral and tibial components. The accuracy (within 1 size) of tibial size predictions was comparable between attending surgeons and residents (87 vs. 82%, p = 0.08), but attending surgeons more accurately predicted the femoral size (77 vs. 60%, p \u3c 0.05). The 2D to 3D imaging technology more accurately predicted both tibial and femoral sizes compared with the attending surgeons (99.5 vs. 87%, p \u3c 0.05; 84% vs. 77%, p \u3c 0.05). However, the imaging technology, attending surgeons, and residents were all more likely to overestimate femur size (p \u3c 0.05). Moreover, the 3D imaging technology predicted the exact tibial component size in 93.1% of cases, which was significantly greater compared with residents (40%, p \u3c 0.01) and attending surgeons (53%, p \u3c 0.01). The 2D to 3D imaging technology more accurately predicted tibial and femoral component sizes compared with 2D digital templating done by surgeons. All templating predictions were more accurate for the tibial implant size than for the femoral size. The increased accuracy of implant size predictions from this 3D templating technology has the potential to improve intraoperative efficiency and minimize costs and surgical time

Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health Short Forms Demonstrate Responsiveness in Patients Undergoing Knee Arthroplasty.

BACKGROUND: The Patient-Reported Outcomes Measurement Information System (PROMIS) is an alternative to legacy outcome metrics. We investigated the relationship between Knee Injury and Osteoarthritis Outcomes Score for Joint Replacement (KOOS-JR) and PROMIS Global Health forms of Physical Health (PH) and Mental Health (MH) in knee arthroplasty patients. METHODS: This is a retrospective cohort study of knee arthroplasty patients from December 2017 through April 2019 who had surveys collected preoperatively and postoperatively. We excluded patients undergoing revision surgery. Outcome scores were analyzed for responsiveness, effect size index (ESI), minimal clinically important difference (MCID), and correlation with each other through 12 months postoperatively. RESULTS: A total of 875 patients were included. Floor and ceiling effects were 0% for PROMIS-PH. Postoperative PROMIS-PH and KOOS-JR scores significantly correlated with one another and increased from baseline at each postoperative time point (P \u3c .001 for all). PROMIS-MH did not change between time points (P \u3e .05). PROMIS-PH showed moderate responsiveness at 1 and 3 months (ESI \u3e0.2) and excellent responsiveness at 6 and 12 months (ESI \u3e0.8), whereas KOOS-JR was responsive at all time points (ESI \u3e0.8). The MCID of PROMIS-PH correlated significantly with KOOS-JR, and a preoperative PROMIS-PH score of less than 32.5 predicted achieving MCID with 97% specificity. CONCLUSION: PROMIS global health forms are a valid metric which capture patient outcomes and correlate with KOOS-JR scores after knee arthroplasty. Although KOOS-JR may be more responsive in the early postoperative time period, both measures show excellent responsiveness at 6 and 12 months after knee arthroplasty

Intraocular Pressure Increases After Intraarticular Knee Injection With Triamcinolone but Not Hyaluronic Acid.

BACKGROUND: Intraarticular steroid injections are a common first-line therapy for severe osteoarthritis, which affects an estimated 27 million people in the United States. Although topical, oral, intranasal, and inhalational steroids are known to increase intraocular pressure in some patients, the effect of intraarticular steroid injections on intraocular pressure has not been investigated, to the best of our knowledge. If elevated intraocular pressure is sustained for long periods of time or is of sufficient magnitude acutely, permanent loss of the visual field can occur. QUESTIONS/PURPOSES: How does intraocular pressure change 1 week after an intraarticular knee injection either with triamcinolone acetonide or hyaluronic acid? METHODS: A nonrandomized, nonblinded prospective cohort study was conducted at an outpatient, ambulatory orthopaedic clinic. This study compared intraocular pressure elevation before and 1 week after intraarticular knee injection of triamcinolone acetonide versus hyaluronic acid for management of primary osteoarthritis of the knee. Patients self-selected to be injected in their knee with either triamcinolone acetonide or hyaluronic acid before being informed of the study. The primary endpoint was intraocular pressure elevation of ≥ 7 mm Hg 1 week after injection. This cutoff is determined as the minimum significant pressure change in the ophthalmology literature recognized as an intermediate responder to steroids. Intraocular pressure was measured using a handheld Tono-Pen® applanation device. This device is frequently used in intraocular pressure measurement in clinical and research settings; 10 sequential measurements are obtained and averaged with a confidence interval. Only measurements with a 95% confidence interval were used. Over a 6-month period, a total of 96 patients were approached to enroll in the study. Sixty-two patients out of 96 approached (65%) agreed. Thirty-one (50%) were injected with triamcinolone and 31 (50%) were injected with hyaluronic acid. Patients with osteoarthritis of the knee who were suitable candidates for either a steroid injection or hyaluronic acid injection were included in the study. Exclusion criteria included previous glaucoma surgery, previous corneal injury precluding use of a Tono-Pen, current acute or chronic steroid use, and diagnosis of glaucoma other than primary open-angle. Patients with elevated intraocular pressure at the 1-week timepoint were invited to return at 1 month for repeat measurement; however, only five of nine (55.6%) were able to do so. The mean age of the total population was 64.1 ± 11.65 years. There were 46 (74%) women and 16 men. Patient in the hyaluronic acid injection group were younger than the triamcinolone group, 59.5 ± 11.7 versus 68.7 ± 9.7 years of age (p \u3c 0.003). RESULTS: The mean intraocular pressure increased by 2.79 mm Hg 1 week after treatment with triamcinolone, but it did not change among those patients treated with hyaluronic acid (2.79 ± 9.9 mm Hg versus -0.14 ± 2.96 mm Hg; mean difference 2.93 mm Hg; 95% confidence interval, -0.71 to 6.57 mm Hg; p = 0.12). More patients who received triamcinolone injections developed an increase in intraocular pressure \u3e 7 mm than did those who received hyaluronic acid (29% [nine of 29] versus 0% [zero of 31]; p = 0.002). Of the nine patients who developed elevated intraocular pressure after a triamcinolone injection, five returned for reevaluation 1 month later, and four of them had pressures that remained elevated \u3e 7 mm Hg from baseline. CONCLUSIONS: There appears to be an associated intraocular pressure elevation found in patients who have undergone a triamcinolone injection of the knee. Further larger scale randomized investigations are warranted to determine the longevity of this pressure elevation as well as long-term clinical implications, including optic nerve damage and visual field loss. LEVEL OF EVIDENCE: Level II, therapeutic study

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities

Whole-genome sequencing of patients with rare diseases in a national health system

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare