STAC3 disorder: a common cause of congenital hypotonia in Southern African patients.

STAC3 disorder, or Native American myopathy, is characterised by congenital myopathy, hypotonia, musculoskeletal and palatal anomalies, and susceptibility to malignant hyperthermia. A STAC3 c.851 G > C (p.Trp284Ser) pathogenic variant, common in the Lumbee Native American tribe, has been identified in other populations worldwide, including patients of African ancestry. We report on the frequency of STAC3 c.851 G > C in a cohort of 127 patients presenting with congenital hypotonia that tested negative for spinal muscular atrophy and/or Prader-Willi syndrome. We present a clinical retrospective, descriptive review on 31 Southern African patients homozygous for STAC3 c.851 G > C. The frequencies of various phenotypic characteristics were calculated. In total, 25/127 (20%) laboratory-based samples were homozygous for STAC3 c.851 G > C. A carrier rate of 1/56 and a predicted birth rate of 1/12 500 was estimated from a healthy cohort. A common haplotype spanning STAC3 was identified in four patients. Of the clinical group, 93% had a palatal abnormality, 52% a spinal anomaly, 59% had talipes equinovarus deformity/deformities, 38% had arthrogryposis multiplex congenita, and 22% had a history suggestive of malignant hyperthermia. The novel finding that STAC3 disorder is a common African myopathy has important clinical implications for the diagnosis, treatment and genetic counselling of individuals, with neonatal and/or childhood hypotonia with or without arthrogryposis multiplex congenita, and their families. The spread of this variant worldwide and the allele frequency higher in the African/African-American ancestry than the Admixed Americans, strongly indicates that the STAC3 c.851 G > C variant has an African origin which may be due to an ancient mutation with migration and population bottlenecks.

Watch-sized 12 Tesla all-high-temperature-superconducting magnet.

We demonstrate the construction of 7 Tesla and 12 Tesla all high-temperature-superconducting (HTS) magnets, small enough to fit on your wrist. The size of the magnet reduces the cost of fabrication, decreases the fringe field to permit facile siting of magnets, and decreases the stored energy of high field magnets. These small HTS-based magnets are being developed for gyrotron microwave sources for use in high-field nuclear magnetic resonance applications. The 7 Tesla and 12 Tesla magnets employ a no-insulation winding technique and are cooled to 4.2 Kelvin in a liquid helium cryostat. The 7 Tesla magnet is a single pancake coil, made of only 9.4 m of HTS tape, with an inner diameter of 8 mm and an outer diameter of 24 mm. This magnet was charged up to 1168 Amperes, generating a field of 7.3 Tesla. The 12 Tesla magnet is comprised of two pancake coils (inner diameter of 10 mm and outer diameter of 27 mm) connected in series. This magnet reached its maximum field at a current of 850 Amperes.

Cryogenic-compatible spherical rotors and stators for magic angle spinning dynamic nuclear polarization.

Cryogenic magic angle spinning (MAS) is a standard technique utilized for dynamic nuclear polarization (DNP) in solid-state nuclear magnetic resonance (NMR). Here we describe the optimization and implementation of a stator for cryogenic MAS with 9.5 mm diameter spherical rotors, allowing for DNP experiments on large sample volumes. Designs of the stator and rotor for cryogenic MAS build on recent advancements of MAS spheres and take a step further to incorporate sample insert and eject and a temperature-independent spinning stability of ±1 Hz. At a field of 7 T and spinning at 2.0 kHz with a sample temperature of 105-107 K, DNP enhancements of 256 and 200 were observed for 124 and 223 µL sample volumes, respectively, each consisting of 4 M 13C, 15N-labeled urea and 20 mM AMUPol in a glycerol-water glassy matrix.

Infection and myelodysplasia: A case report of GATA2 deficiency in a South African patient.

Rare diseases often result in delays in diagnosis. It is important to recognize conditions that have features of both inborn errors of immunity and predispose to myeloid neoplasia. Here we report a patient with GATA2 deficiency that presented with disseminated non-tuberculous mycobacterial infection and pancytopenia secondary to myelodysplastic syndrome.

Deliberate delays in offering abortion to pregnant women with fetal anomalies after 24 weeks' gestation at a centre in South Africa.

South Africa has an abortion law which codifies the broad themes of reproductive rights set out in the Constitution of South Africa, other laws and national guidelines. Certain wording of the conditions in the Choice Act for abortion after 20 weeks' gestation, are open to interpretation, being 'severe malformation of the fetus' and 'risk of injury to the fetus'. From 24 weeks onwards, abortion is carried out by feticide/induced fetal cardiac asystole ('IFCA') and subsequent induction of labour in South Africa. Some maternal-fetal units have developed guidelines to assist clinicians and patients in decision-making around eligibility for abortion after 20 weeks' gestation, given the broad terms in the law. We consider the guideline used by an institution in the Western Cape for abortion after 23 weeks and 6 days gestation, in terms of its alignment with the law on reproductive rights and its compliance with fair and transparent procedures. We also note its effect on respect for patients and on staff professionalism.

Improving the sensitivity of MAS spheres using a 9.5 mm spherical shell with 219 µL sample volume spinning in a spherical solenoid coil.

Spherical rotors in magic angle spinning (MAS) nuclear magnetic resonance (NMR) experiments have potential advantages relative to cylindrical rotors in terms of ease of fabrication, low risk of rotor crash, easy sample exchange, and better microwave access. However, one major disadvantage so far of spherical rotors is poor NMR filling factor due to the small sample volume and large cylindrical radiofrequency (RF) coil. Here we present a novel NMR coil geometry in the form of a spherical coil. The spherical coil best fits the spherical sample to maximize sensitivity, while also providing excellent RF homogeneity. We further improve NMR sensitivity by employing a spherical shell as the rotor, thereby maximizing sample volume (219 µL in this case of 9.5 mm outer diameter spheres). The spinning gas is supplied by a 3D-printed ring stator external to the coil, thereby introducing a simplified form of MAS stators. In this apparatus, the RF field generated along the coil axis is perpendicular to the external magnetic field, regardless of rotor orientation. We observe a linear increase in sensitivity with increasing sample volume. We also simulate the RF performance of spherical and cylindrical solenoid coils with constant or variable pitch for spherical and cylindrical rotors, respectively. The simulation results show that spherical solenoid coils generate comparable B1 field intensities but have better homogeneity than cylindrical solenoid coils do.

Utility of genetic testing in children with developmental and epileptic encephalopathy (DEE) at a tertiary hospital in South Africa: A prospective study.

OBJECTIVES: The developmental and epileptic encephalopathies (DEE) are a heterogeneous group of rare neurodevelopmental disorders, characterised by early-onset seizures that are often intractable, electroencephalographic abnormalities, and developmental delay or regression. There is a paucity of data from sub-Saharan Africa on the genetic basis of DEE. The aim of this study was to investigate the genetic background of DEE using targeted next generation sequencing (NGS) analysis in a tertiary pediatric neurology outpatient department at Tygerberg Hospital, South Africa. In addition, we assessed the value of the genetic results to the parents and managing physicians. METHODS: A prospective cohort study of 41 consecutive children with DEE (onset before 3 years of age) that were recruited over a 2-year period (2019-2021). Pre- and post-test genetic counselling were offered to all study participants. The results were categorized as either: positive (pathogenic/likely pathogenic variant identified), inconclusive (variant(s) of unknown significance identified), or negative (no variants identified). Result interpretation and careful matching of the variant to the clinical phenotype was performed. Subsequently, questionnaires were administered to both the physicians and the parents. RESULTS: A genetic underlying cause for DEE was identified in 18 of 41 children (diagnostic yield 43.9%). Variants in SCN1A (n=7), KANSL1 (n=2), KCNQ2 (n=2) and CDKL5 (n=2) were identified in more than one patient. Rarer genes included IQSEC2, SMC1A and STXBP1. All of the identified pathogenic variants fully explained and matched the respective phenotypic description of the patient at the time of clinical diagnosis. In 26% of patients the genetic result facilitated precision medicine management changes to anti-seizure medication. Both parents and physicians expressed benefit of genetic testing in patients with DEE. CONCLUSION: Targeted NGS analysis proved an efficient diagnostic tool in detection of a genetic cause of DEE in a large proportion of South African children. The 43.9% diagnostic yield is similar to previously reported international pediatric cohorts. Additionally, the genetic findings proved useful for targeted therapeutic decision-making and accurate genetic counseling.

Luxembourg and Ireland in global financial networks: Analysing the changing structure of European investment funds.

Using a unique database on investment funds and the conceptual framework of global financial networks, this paper examines the spatial structure of the European investment fund industry, with particular focus on Luxembourg and Ireland. Grounded in financial and economic geography, the paper shows how these countries became the leading investment fund domiciles through a mixture of structural factors and agency enabling a fast and flexible implementation of the European Directive on the Undertakings for the Collective Investment in Transferable Securities (UCITS) of 1985, and the cultivation of the investment fund industry ever since. In the process, Luxembourg and Ireland have built on and developed their functions as offshore jurisdictions and international financial centres, both sustained by their governments and regulatory agencies. The analysis of the functional structure of investment funds and their networked geography reveals the increasingly dominant position of London as the investment management centre for the industry, and the increasing concentration of control by large asset management firms. Stripped to its basics, the geography of European investment fund networks is about large, mainly US, asset management firms, creating and managing funds in Luxembourg and Ireland, and investing money through London. As such, the rise of European investment funds can be seen as an example of European financial integration through Americanisation. The Luxembourg and Irish investment fund industry are connected mainly through London and New York, and thus function as satellites of the NY-LON axis, rather than a Luxembourg-Dublin axis in international finance. Overall, the paper demonstrates that studying this seemingly arcane industry, and the role of two small countries in it, reveals much about the nature of financial globalisation.

Targeted Gene Sanger Sequencing Should Remain the First-Tier Genetic Test for Children Suspected to Have the Five Common X-Linked Inborn Errors of Immunity.

To address inborn errors of immunity (IEI) which were underdiagnosed in resource-limited regions, our centre developed and offered free genetic testing for the most common IEI by Sanger sequencing (SS) since 2001. With the establishment of The Asian Primary Immunodeficiency (APID) Network in 2009, the awareness and definitive diagnosis of IEI were further improved with collaboration among centres caring for IEI patients from East and Southeast Asia. We also started to use whole exome sequencing (WES) for undiagnosed cases and further extended our collaboration with centres from South Asia and Africa. With the increased use of Next Generation Sequencing (NGS), we have shifted our diagnostic practice from SS to WES. However, SS was still one of the key diagnostic tools for IEI for the past two decades. Our centre has performed 2,024 IEI SS genetic tests, with in-house protocol designed specifically for 84 genes, in 1,376 patients with 744 identified to have disease-causing mutations (54.1%). The high diagnostic rate after just one round of targeted gene SS for each of the 5 common IEI (X-linked agammaglobulinemia (XLA) 77.4%, Wiskott-Aldrich syndrome (WAS) 69.2%, X-linked chronic granulomatous disease (XCGD) 59.5%, X-linked severe combined immunodeficiency (XSCID) 51.1%, and X-linked hyper-IgM syndrome (HIGM1) 58.1%) demonstrated targeted gene SS should remain the first-tier genetic test for the 5 common X-linked IEI.

Barriers and facilitators of alcohol abstinence during pregnancy.

Fetal Alcohol Spectrum Disorders (FASD) is a common and under-recognised health burden in South Africa. There is a limited understanding of why pregnant women drink in the South African context, particularly in rural settings, where the prevalence of FASD is highest. A purposive sample included eight women from a rural ante-natal clinic in the Northern Cape province of South Africa. Participants participated in a semi-structured interview. A process of thematic analysis was used to generate themes from the interviews. All participants were aware of the link between alcohol use during pregnancy and adverse fetal outcomes. Furthermore, most participants reduced drinking after pregnancy recognition. Participants described barriers and facilitators of alcohol abstinence. Barriers included social pressure, life stressors, and cravings and habits. Facilitators included the desire to avoid FASD, supportive relationships, availability of alternative activities. Addressing barriers at community and individual levels may aid women in reducing harmful drinking during pregnancy.

Chronic Anxiety- and Depression-Like Behaviors Are Associated With Glial-Driven Pathology Following Repeated Blast Induced Neurotrauma.

Long-term neuropsychiatric impairments have become a growing concern following blast-related traumatic brain injury (bTBI) in active military personnel and Veterans. Neuropsychiatric impairments such as anxiety and depression are common comorbidities that Veterans report months, even years following injury. To understand these chronic behavioral outcomes following blast injury, there is a need to study the link between anxiety, depression, and neuropathology. The hippocampus and motor cortex (MC) have been regions of interest when studying cognitive deficits following blast exposure, but clinical studies of mood disorders such as major depressive disorder (MDD) report that these two regions also play a role in the manifestation of anxiety and depression. With anxiety and depression being common long-term outcomes following bTBI, it is imperative to study how chronic pathological changes within the hippocampus and/or MC due to blast contribute to the development of these psychiatric impairments. In this study, we exposed male rats to a repeated blast overpressure (~17 psi) and evaluated the chronic behavioral and pathological effects on the hippocampus and MC. Results demonstrated that the repeated blast exposure led to depression-like behaviors 36 weeks following injury, and anxiety-like behaviors 2-, and 52-weeks following injury. These behaviors were also correlated with astrocyte pathology (glial-fibrillary acid protein, GFAP) and dendritic alterations (Microtubule-Associated Proteins, MAP2) within the hippocampus and MC regions at 52 weeks. Overall, these findings support the premise that chronic glial pathological changes within the brain contribute to neuropsychiatric impairments following blast exposure.

Clinical Utility of Whole Exome Sequencing and Targeted Panels for the Identification of Inborn Errors of Immunity in a Resource-Constrained Setting.

Primary immunodeficiency disorders (PIDs) are inborn errors of immunity (IEI) that cause immune system impairment. To date, more than 400 single-gene IEI have been well defined. The advent of next generation sequencing (NGS) technologies has improved clinical diagnosis and allowed for discovery of novel genes and variants associated with IEI. Molecular diagnosis provides clear clinical benefits for patients by altering management, enabling access to certain treatments and facilitates genetic counselling. Here we report on an 8-year experience using two different NGS technologies, namely research-based WES and targeted gene panels, in patients with suspected IEI in the South African healthcare system. A total of 52 patients' had WES only, 26 had a targeted gene panel only, and 2 had both panel and WES. Overall, a molecular diagnosis was achieved in 30% (24/80) of patients. Clinical management was significantly altered in 67% of patients following molecular results. All 24 families with a molecular diagnosis received more accurate genetic counselling and family cascade testing. Results highlight the clinical value of expanded genetic testing in IEI and its relevance to understanding the genetic and clinical spectrum of the IEI-related disorders in Africa. Detection rates under 40% illustrate the complexity and heterogeneity of these disorders, especially in an African population, thus highlighting the need for expanded genomic testing and research to further elucidate this.

Impacts of High Environmental Temperatures on Congenital Anomalies: A Systematic Review.

Links between heat exposure and congenital anomalies have not been explored in detail despite animal data and other strands of evidence that indicate such links are likely. We reviewed articles on heat and congenital anomalies from PubMed and Web of Science, screening 14,880 titles and abstracts in duplicate for articles on environmental heat exposure during pregnancy and congenital anomalies. Thirteen studies were included. Most studies were in North America (8) or the Middle East (3). Methodological diversity was considerable, including in temperature measurement, gestational windows of exposure, and range of defects studied. Associations were detected between heat exposure and congenital cardiac anomalies in three of six studies, with point estimates highest for atrial septal defects. Two studies with null findings used self-reported temperature exposures. Hypospadias, congenital cataracts, renal agenesis/hypoplasia, spina bifida, and craniofacial defects were also linked with heat exposure. Effects generally increased with duration and intensity of heat exposure. However, some neural tube defects, gastroschisis, anopthalmia/microphthalmia and congenital hypothyroidism were less frequent at higher temperatures. While findings are heterogenous, the evidence raises important concerns about heat exposure and birth defects. Some heterogeneity may be explained by biases in reproductive epidemiology. Pooled analyses of heat impacts using registers of congenital anomalies are a high priority.

Enhanced recovery pathway in adult patients undergoing thoracolumbar deformity surgery.

BACKGROUND CONTEXT: Enhanced recovery (ERAS) pathways can help hospitals maximize the incentives of bundled payment models while maintaining high-quality patient care. A key component of an enhanced recovery pathway is the ability to predictably reduce inpatient length of stay, as this is a critical component of the cost equation. PURPOSE: To determine the efficacy of an enhanced recovery pathway on reducing length of stay after thoracolumbar adult deformity surgery. STUDY DESIGN: Single surgeon retrospective review of prospectively-collected data. PATIENT SAMPLE: Forty adult deformity patients who underwent ≥5 levels of fusion to the pelvis (two to L5) with a single surgeon before and after implementation of an ERAS pathway. METHODS: The pathway involved participation by anesthesiology, hospital medicine, and physical therapy, and was designed to achieve goals previously associated with decreased LOS (eg, EBL<1200 mL, procedure time <4.5 hours, avoidance of ICU postoperatively, and mobilization POD0-1). Patients were propensity-score matched 1:1 to a historical cohort (enhanced recovery [ER] and historical [H] cohorts), based on demographics, medical comorbidities, radiographic alignment parameters, and surgical factors. Outcomes were compared to determine the effect of the enhanced recovery pathway. Primary outcomes included LOS and 90-day complications and readmissions. RESULTS: After matching, gender, BMI, ASA class, preoperative opioid dependence, day of surgery, sagittal alignment parameters, rate of revision surgery, three-column osteotomies, and interbody fusions were comparable between the cohorts (p>.05). In the ER cohort, there was reduced EBL (920±640 vs. 1437±555, p=.004) and no ER patient went to the ICU immediately following surgery, compared with 30% of H patients (p=.022). The ER cohort also had a greater number of patients ambulating by POD1 compared to the H cohort (100% vs. 55%, p=.010). ER patients had a shorter LOS (4.5±1.3 vs. 7.3±4.4 days, p=.010). A 90-day readmission and complications were comparable between the cohorts (p>.05). CONCLUSIONS: The creation of an ERAS pathway for patients undergoing thoracolumbar adult deformity surgery reduced length of stay without negatively affecting short-term morbidity and complications. Given the specificity of this pathway to a single surgeon and hospital, the resources and staffing changes that were instrumental in creating the pathway may not be generalizable to other centers.

Improving the taxonomy of fossil pollen using convolutional neural networks and superresolution microscopy.

Taxonomic resolution is a major challenge in palynology, largely limiting the ecological and evolutionary interpretations possible with deep-time fossil pollen data. We present an approach for fossil pollen analysis that uses optical superresolution microscopy and machine learning to create a quantitative and higher throughput workflow for producing palynological identifications and hypotheses of biological affinity. We developed three convolutional neural network (CNN) classification models: maximum projection (MPM), multislice (MSM), and fused (FM). We trained the models on the pollen of 16 genera of the legume tribe Amherstieae, and then used these models to constrain the biological classifications of 48 fossil Striatopollis specimens from the Paleocene, Eocene, and Miocene of western Africa and northern South America. All models achieved average accuracies of 83 to 90% in the classification of the extant genera, and the majority of fossil identifications (86%) showed consensus among at least two of the three models. Our fossil identifications support the paleobiogeographic hypothesis that Amherstieae originated in Paleocene Africa and dispersed to South America during the Paleocene-Eocene Thermal Maximum (56 Ma). They also raise the possibility that at least three Amherstieae genera (Crudia, Berlinia, and Anthonotha) may have diverged earlier in the Cenozoic than predicted by molecular phylogenies.

Glial Activation in the Thalamus Contributes to Vestibulomotor Deficits Following Blast-Induced Neurotrauma.

Vestibular impairment has become a frequent consequence following blast-related traumatic brain injury (bTBI) in military personnel and Veterans. Behavioral outcomes such as depression, fear and anxiety are also common comorbidities of bTBI. To accelerate pre-clinical research and therapy developments, there is a need to study the link between behavioral patterns and neuropathology. The transmission of neurosensory information often involves a pathway from the cerebral cortex to the thalamus, and the thalamus serves crucial integrative functions within vestibular processing. Pathways from the thalamus also connect with the amygdala, suggesting thalamic and amygdalar contributions to anxiolytic behavior. Here we used behavioral assays and immunohistochemistry to determine the sub-acute and early chronic effects of repeated blast exposure on the thalamic and amygdala nuclei. Behavioral results indicated vestibulomotor deficits at 1 and 3 weeks following repeated blast events. Anxiety-like behavior assessments depicted trending increases in the blast group. Astrogliosis and microglia activation were observed upon post-mortem pathological examination in the thalamic region, along with a limited glia response in the amygdala at 4 weeks. These findings are consistent with a diffuse glia response associated with bTBI and support the premise that dysfunction within the thalamic nuclei following repeated blast exposures contribute to vestibulomotor impairment.

Hyperphosphatasia with mental retardation syndrome type 4 in three unrelated South African patients.

Hyperphosphatasia with mental retardation syndrome (HPMRS) is a rare autosomal recessive disorder caused by pathogenic variants in genes involved in glycosylphosphatidylinositol metabolism that result in a similar phenotype. We describe the first three patients with HPMRS from sub-Saharan Africa. Detection was assisted by Face2Gene phenotype matching and confirmed by the presence of elevated serum alkaline phosphatase. All three patients had severe intellectual disability, absent speech, hypotonia and palatal abnormality (cleft palate in two, very high-arched palate in one), no or minimal brachytelephalangy, and high serum alkaline phosphatase levels. Additional findings included seizures in two, and brain imaging abnormalities in two. In all three patients HPMRS was a top-20 gestalt match using Face2Gene. The overall phenotype is consistent with descriptions in the literature of HPMRS type 4, although not specific to it. Whole exome sequencing in the index patient and his mother detected a candidate variant in a homozygous state in the index patient (PGAP3:c.557G>C, p.Arg186Thr) and heterozygous in the mother. Further variant interpretation indicated pathogenicity. Sanger sequencing of another two patients identified the same homozygous, pathogenic variant, confirming a diagnosis of HPMRS type 4. The shared homozygous variant in apparently unrelated families, and in the absence of consanguinity, suggests the possibility of genetic drift due to a population bottleneck effect, and further research is recommended.

Identification of a novel WAS mutation in a South African patient presenting with atypical Wiskott-Aldrich syndrome: a case report.

BACKGROUND: The X-linked recessive primary immunodeficiency disease (PIDD) Wiskott-Aldrich syndrome (WAS) is identified by an extreme susceptibility to infections, eczema and thrombocytopenia with microplatelets. The syndrome, the result of mutations in the WAS gene which encodes the Wiskott-Aldrich protein (WASp), has wide clinical phenotype variation, ranging from classical WAS to X-linked thrombocytopaenia and X-linked neutropaenia. In many cases, the diagnosis of WAS in first affected males is delayed, because patients may not present with the classic signs and symptoms, which may intersect with other thrombocytopenia causes. CASE PRESENTATION: Here, we describe a three-year-old HIV negative boy presenting with recurrent infections, skin rashes, features of autoimmunity and atopy. However, platelets were initially reported as normal in numbers and morphology as were baseline immune investigations. An older male sibling had died in infancy from suspected immunodeficiency. Uncertainty of diagnosis and suspected severe PIDD prompted urgent further molecular investigation. Whole exome sequencing identified c. 397 G > A as a novel hemizygous missense mutation located in exon 4 of WAS. CONCLUSION: With definitive molecular diagnosis, we could target treatment and offer genetic counselling and prenatal diagnostic testing to the family. The identification of novel variants is important to confirm phenotype variations of a syndrome.

Enhanced Recovery after Lumbar Spine Fusion: A Randomized Controlled Trial to Assess the Quality of Patient Recovery.

BACKGROUND: Prospective trials of enhanced recovery after spine surgery are lacking. We tested the hypothesis that an enhanced recovery pathway improves quality of recovery after one- to two-level lumbar fusion. METHODS: A patient- and assessor-blinded trial of 56 patients randomized to enhanced recovery (17 evidence-based pre-, intra-, and postoperative care elements) or usual care was performed. The primary outcome was Quality of Recovery-40 score (40 to 200 points) at postoperative day 3. Twelve points defined the clinically important difference. Secondary outcomes included Quality of Recovery-40 at days 0 to 2, 14, and 56; time to oral intake and discharge from physical therapy; length of stay; numeric pain scores (0 to 10); opioid consumption (morphine equivalents); duration of intravenous patient-controlled analgesia use; complications; and markers of surgical stress (interleukin 6, cortisol, and C-reactive protein). RESULTS: The analysis included 25 enhanced recovery patients and 26 usual care patients. Significantly higher Quality of Recovery-40 scores were found in the enhanced recovery group at postoperative day 3 (179 ± 14 vs. 170 ± 16; P = 0.041) without reaching the clinically important difference. There were no significant differences in recovery scores at days 0 (175 ± 16 vs. 162 ± 22; P = 0.059), 1 (174 ± 18 vs. 164 ± 15; P = 0.050), 2 (174 ± 18 vs. 167 ± 17; P = 0.289), 14 (184 ± 13 vs. 180 ± 12; P = 0.500), and 56 (187 ± 14 vs. 190 ± 8; P = 0.801). In the enhanced recovery group, subscores on the Quality of Recovery-40 comfort dimension were higher (longitudinal mean score difference, 4; 95% CI, 1, 7; P = 0.008); time to oral intake (-3 h; 95% CI, -6, -0.5; P = 0.010); and duration of intravenous patient-controlled analgesia (-11 h; 95% CI, -19, -6; P < 0.001) were shorter; opioid consumption was lower at day 1 (-57 mg; 95% CI, -130, -5; P = 0.030) without adversely affecting pain scores (-2; 95% CI, -3, 0; P = 0.005); and C-reactive protein was lower at day 3 (6.1; 95% CI, 3.8, 15.7 vs. 15.9; 95% CI, 6.6, 19.7; P = 0.037). CONCLUSIONS: Statistically significant gains in early recovery were achieved by an enhanced recovery pathway. However, significant clinical impact was not demonstrated.

Postoperative delirium after major orthopedic surgery.

BACKGROUND: Postoperative delirium (POD) is one of the most common complications in older adult patients undergoing elective surgery. Few studies have compared, within the same institution, the type of surgery, risk factors and type of anesthesia and analgesia associated with the development of POD. AIM: To investigate the following three questions: (1) What is the incidence of POD after non-ambulatory orthopedic surgery at a high-volume orthopedic specialty hospital? (2) Does surgical procedure influence incidence of POD after non-ambulatory orthopedic surgery? And (3) For POD after non-ambulatory orthopedic surgery, what are modifiable risk factors? METHODS: A retrospective cohort study was conducted of all non-ambulatory orthopedic surgeries at a single orthopedic specialty hospital between 2009 and 2014. Patients under 18 years were excluded from the cohort. Patient characteristics and medical history were obtained from electronic medical records. Patients with POD were identified using International Classification of Diseases, 9th Revision (ICD-9) codes that were not present on admission. For incidence analyses, the cohort was grouped into total hip arthroplasty (THA), bilateral THA, total knee arthroplasty (TKA), bilateral TKA, spine fusion, other spine procedures, femur/pelvic fracture, and other procedures using ICD-9 codes. For descriptive and regression analyses, the cohort was grouped, using ICD-9 codes, into THA, TKA, spinal fusions, and all procedures. RESULTS: Of 78492 surgical inpatient surgeries, the incidence from 2009 to 2014 was 1.2% with 959 diagnosed with POD. The incidence of POD was higher in patients undergoing spinal fusions (3.3%) than for patients undergoing THA (0.8%); THA patients had the lowest incidence. Also, urgent and/or emergent procedures, defined by femoral and pelvic fractures, had the highest incidence of POD (7.2%) than all other procedures. General anesthesia was not seen as a significant risk factor for POD for any procedure type; however, IV patient-controlled analgesia was a significant risk factor for patients undergoing THA [Odds ratio (OR) = 1.98, 95% confidence interval (CI): 1.19 to 3.28, P = 0.008]. Significant risk factors for POD included advanced age (for THA, OR = 4.9, 95%CI: 3.0-7.9, P < 0.001; for TKA, OR = 2.16, 95%CI: 1.58-2.94, P < 0.001), American Society of Anesthesiologists score of 3 or higher (for THA, OR = 2.01, 95%CI: 1.33-3.05, P < 0.001), multiple medical comorbidities, hyponatremia (for THA, OR = 2.36, 95%CI: 1.54 to 3.64, P < 0.001), parenteral diazepam (for THA, OR = 5.05, 95%CI: 1.5-16.97, P = 0.009; for TKA, OR = 4.40, 95%CI: 1.52-12.75, P = 0.007; for spine fusion, OR = 2.17, 95%CI: 1.19-3.97, P = 0.01), chronic opioid dependence (for THA, OR = 7.11, 95%CI: 3.26-15.51, P < 0.001; for TKA, OR = 2.98, 95%CI: 1.38-6.41, P = 0.005) and alcohol dependence (for THA, OR = 5.05, 95%CI: 2.72-9.37, P < 0.001; for TKA, OR = 6.40, 95%CI: 4.00-10.26, P < 0.001; for spine fusion, OR = 6.64, 95%CI: 3.72-11.85, P < 0.001). CONCLUSION: POD is lower (1.2%) than previously reported; likely due to the use of multi-modal regional anesthesia and early ambulation. Both fixed and modifiable factors are identified.