Association of Clinical Characteristics With Familial Hypercholesterolaemia Variants in a Lipid Clinic Setting: A Case-Control Study.

Objective: Familial hypercholesterolaemia (FH) variant positive subjects have over double the cardiovascular risk of low-density-lipoprotein-cholesterol (LDL-C) matched controls. It is desirable to optimise FH variant detection. Methods: We identified 213 subjects with FH gene panel reports (LDLR, APOB, PCSK9, and APOE) based on total cholesterol >310 mg/dL; excluding triglycerides >400 mg/dL, cascade screening, and patients without pre-treatment LDL-C recorded. Demographic, clinical and lipid parameters were recorded. Results: A 31/213 (14.6%) patients had pathogenic or likely pathogenic FH variants. 10/213 (4.7%) had variants of uncertain significance. Compared with patients without FH variants, patients with FH variants were younger (median age, 39 years vs. 48 years), had more tendon xanthomata (25.0% vs. 11.4%), greater proportion of first degree relatives with total cholesterol >95th percentile (40.6% vs. 16.5%), higher LDL-C (median, 271 mg/dL vs. 236 mg/dL), and lower triglycerides (median, 115 mg/dL vs. 159 mg/dL). The Besseling et al. model (c-statistic 0.798) improved FH variant discrimination over Friedewald LDL-C (c-statistic 0.724), however, Dutch Lipid Clinic Network Score (DLCNS) did not (c-statistic 0.665). Sampson LDL-C (c-statistic 0.734) had similar discrimination to Friedewald. Conclusion: Although tendon xanthomata and first degree relatives with high total cholesterol >95th percentile were associated with FH variants, DLCNS or Simon Broome criteria did not improve FH detection over LDL-C. Sampson LDL-C did not significantly improve discrimination over Friedewald. Although lower triglycerides and younger age of presentation are positively associated with presence of FH variants, this information is not commonly used in FH detection algorithms apart from Besseling et al.

Stakeholder-driven transformative adaptation is needed for climate-smart nutrition security in sub-Saharan Africa.

Improving nutrition security in sub-Saharan Africa under increasing climate risks and population growth requires a strong and contextualized evidence base. Yet, to date, few studies have assessed climate-smart agriculture and nutrition security simultaneously. Here we use an integrated assessment framework (iFEED) to explore stakeholder-driven scenarios of food system transformation towards climate-smart nutrition security in Malawi, South Africa, Tanzania and Zambia. iFEED translates climate-food-emissions modelling into policy-relevant information using model output implication statements. Results show that diversifying agricultural production towards more micronutrient-rich foods is necessary to achieve an adequate population-level nutrient supply by mid-century. Agricultural areas must expand unless unprecedented rapid yield improvements are achieved. While these transformations are challenging to accomplish and often associated with increased greenhouse gas emissions, the alternative for a nutrition-secure future is to rely increasingly on imports, which would outsource emissions and be economically and politically challenging given the large import increases required.

Evaluating computed bony range of motion (BROM) by registering in-vitro cadaver-based functional range of motion (FROM) to a hip motion simulation.

BACKGROUND: While modern hip replacement planning relies on hip motion simulation (HMS), it lacks the capability to include soft-tissues and ligaments restraints on computed bony range of motion (BROM), often leading to an overestimation of the in-vivo functional range of motion (FROM). Furthermore, there is a lack of literature on BROM assessment in relation to FROM. Therefore, the study aimed to assess computed BROM using in-vitro cadaver-derived FROM measurements, registered to a CT-based in-house HMS, and to further investigate the effect of functional and anatomical hip joint centres (FHJC and AHJC) on BROM. METHOD: Seven limiting and three non-limiting circumducted passive FROM of four cadaver hips were measured using optical coordinate measuring machine with reference spheres (RSs) affixed to the pelvis and the femur, following CT-scan of the specimen. The RSs' centres were used to register the measured FROM in HMS, enabling its virtual recreation to compute corresponding BROM by detecting nearest bony impingement. FHJC, estimated from non-limiting FROM, was compared with AHJC to examine their positional differences and effect on BROM. RESULTS: Differences in BROM and FROM were minimal in deep flexion (3.0° ± 4.1°) and maximum internal rotation (IR) at deep flexion (3.0° ± 2.9°), but substantially greater in extension (53.2° ± 9.5°). Bony impingement was observed during flexion, and IR at deep flexion for two hips. The average positional difference between FHJC and AHJC was 3.1 ± 1.2 mm, resulting in BROM differences of 1°-13° across four motions. CONCLUSIONS: The study provided greater insight into the applicability and reliability of computed BROM in pre-surgical planning.

Reference intervals for deconjugated urine metanephrines by Bhattacharya analysis.

BACKGROUND: Urine metanephrines are used to screen for phaeochromocytoma or paraganglioma (PPGL). Current reference intervals (RI) derived in healthy individuals are not age or sex-stratified, and lower than in hypertensive patients, leading to high false positive rates. This study aims to determine age and sex-stratified RI from a contingent screening population. METHODS: Patients with 24-h deconjugated urine metanephrines from 3/6/2010 to 27/8/2022 were included (2936 males, 5285 females), initially by liquid chromatography-electrochemical detection (LC-ECD) then liquid chromatography-tandem mass spectrometry (LC-MS/MS). Bhattacharya analysis was used after log transformation to determine age and sex-stratified RI for metanephrine excretion, normetanephrine excretion, metanephrine/creatinine and normetanephrine/creatinine ratios. RESULTS: Normetanephrine excretion increases with age (RI: males: 18-<30 years: <3.4 µmol/24 h, 30-<40 years: <3.7 µmol/24 h, 40+ years: <5.3 µmol/24 h; females: 18-<30 years: <2.7 µmol/24 h, 30-<40 years: <3.1 µmol/24 h, 40+ years: <3.7 µmol/24 h), while metanephrine excretion was consistent across adulthood (RI: males: 18+ years: <1.8 µmol/24 h; females: 18+ years: <1.2 µmol/24 h). However, normetanephrine/creatinine and metanephrine/creatinine increase steadily with age after early adulthood, likely due to a decrease in muscle mass, with females having higher normetanephrine/creatinine and metanephrine/creatinine ratios. CONCLUSIONS: Age and sex-stratified RI were derived for metanephrine excretion, normetanephrine excretion, metanephrine/creatinine and normetanephrine/creatinine ratios. This is expected to reduce false positives while flagging most PPGL.

Artefactually low creatinine by Beckman Coulter enzymatic method due to immunoglobulin M paraprotein interference.

An 81-year-old man was admitted to hospital with symptomatic coronavirus disease (COVID-19) infection. He had a background of progressive chronic inflammatory demyelinating polyneuropathy associated with Waldenstrom's macroglobulinaemia. His plasma creatinine on four separate samples was inconceivably low (all ≤13 µmol/L), as measured by a Beckman Coulter enzymatic assay) after being 72 µmol/L 3 months earlier. On further investigation, his serum immunoglobulin M (IgM) was 15.4 g/L and his plasma creatinine measured by Roche enzymatic and Roche Jaffe methods was 62 µmol/L and 64 µmol/L, respectively. This was consistent with results post dilution studies and polyethylene glycol (PEG) precipitation on the Beckman Coulter assay. There was no evidence of similar interference when reviewing creatinine results from 10 other patients with IgM paraproteinaemia who had been tested in our laboratory. Clinicians and laboratorians are reminded that enzymatic creatinine is not free from interferences. IgM paraprotein negative interference of enzymatic creatinine is rare and specific to a patient's IgM and assay combination, but should be considered in patients with an unexplained low enzymatic creatinine result. Useful investigations to identify an interference include dilution studies, PEG precipitation and measuring creatinine on an alternative method such as Jaffe, mass spectrometry or an enzymatic method from a different platform.

Habitat fragmentation reduces survival and drives source-sink dynamics for a large carnivore.

Rigorous understanding of how environmental conditions impact population dynamics is essential for species conservation, especially in mixed-use landscapes where source-sink dynamics may be at play. Conservation of large carnivore populations in fragmented, human-dominated landscapes is critical for their long-term persistence. However, living in human-dominated landscapes comes with myriad costs, including direct anthropogenic mortality and sublethal energetic costs. How these costs impact individual fitness and population dynamics are not fully understood, partly due to the difficulty in collecting long-term demographic data for these species. Here, we analyzed an 11-year dataset on puma (Puma concolor) space use, mortality, and reproduction in the Santa Cruz Mountains, California, USA, to quantify how living in a fragmented landscape impacts individual survival and population dynamics. Long-term exposure to housing density drove mortality risk for female pumas, resulting in an 18-percentage-point reduction in annual survival for females in exurban versus remote areas. While the overall population growth rate appeared stable, reduced female survival in more developed areas resulted in source-sink dynamics across the study area, with 42.1% of the Santa Cruz Mountains exhibiting estimated population growth rates <1. Since habitat selection is often used as a proxy for habitat quality, we also assessed whether puma habitat selection predicted source and sink areas. Patterns of daytime puma habitat selection predicted source areas, while time-of-day-independent habitat selection performed less well as a proxy. These results illuminate the individual- and population-level consequences of habitat fragmentation for large carnivores, illustrating that habitat fragmentation can produce source-sink dynamics that may not be apparent from other metrics of habitat quality. Locally, conserving high-quality source habitat within the Santa Cruz Mountains is necessary to support long-term puma population persistence. More broadly, source-sink dynamics may at play for other carnivore populations in similar fragmented systems, and linking landscape conditions to population dynamics is essential for effective conservation. Caution should be used in inferring habitat quality from habitat selection alone, but these results shed light on metrics of selection that may be better or worse proxies to identify source areas for large carnivores.

COVID-19: Acing the Treatment.

Angiotensin converting enzyme 2 is the functional receptor that the SARS-Cov-2 virus requires to enter cells and cause dysregulated inflammatory conditions that contribute towards acute lung injuries. The renin-angiotensin-aldosterone system with its physiological surveillance and regulation system can be implicated in both harm and therapeutic benefit. The initial observational studies suggesting the discontinuation of angiotensin converting enzyme inhibitors and angiotensin receptor blockers have been firmly rebutted by international societies. On the contrary, these therapeutics may confer a survival benefit in COVID-19 infections. Understanding the biological plausibility of this pathway alongside the emerging therapeutic evidence may yield new modes of treatment. Such developments appear fundamentally important in the battle against the inevitable emergence of new variants and their potential to drive future waves of COVID-19 pandemics.

Fabrication methods for high reflectance dielectric-metal point contact rear mirror for optoelectronic devices.

The patterned dielectric back contact (PDBC) structure can be used to form a point-contact architecture that features a dielectric spacer with spatially distributed, reduced-area metal point contacts between the semiconductor back not recognized contact layer and the metal back contact. In this structure, the dielectric-metal region provides higher reflectance and is electrically insulating. Reduced-area metal point contacts provide electrical conduction for the back contact but typically have lower reflectance. The fabrication methods discussed in this article were developed for thermophotovoltaic cells, but they apply to any III-V optoelectronic device requiring the use of a conductive and highly reflective back contact. Patterned dielectric back contacts may be used for enhanced sub-bandgap reflectance, for enhanced photon recycling near the bandgap energy, or both depending on the optoelectronic application. The following fabrication methods are discussed in the article•PDBC fabrication procedures for spin-on dielectrics and commonly evaporated dielectrics to form the spacer layer.•Methods to selectively etch a parasitically absorbing back contact layer using metal point contacts as an etch mask.•Methods incorporating a dielectric etch through different process techniques such as reactive ion and wet etching.

Does functional planning, 3D templating and patient-specific instrumentation improve accuracy in total hip replacement?- a randomized controlled trial.

AIMS: Debate continues as to the optimal orientation of the acetabular component in total hip arthroplasty (THA) and how to reliably achieve this. The primary objective of this study was to compare functional CT-based planning and patient-specific instruments with conventional THA using 2D templating. METHODS: A pragmatic single-center, patient-assessor blinded, randomized control trial of patients undergoing THA was performed. 54 patients (aged 18-70) were recruited to either Corin Optimized Positioning System (OPS) or conventional THA. All patients received a cementless acetabular component. All patients underwent pre- and postoperative CT scans, and four functional X-rays. Patients in the OPS group had a 3D surgical plan and bespoke guides made. Patients in the conventional group had a surgical plan based on 2D templating X-rays. The primary outcome measure was the mean error in acetabular anteversion as determined by postoperative CT scan. RESULTS: There was no statistically significant difference in the mean error in angle of acetabular anteversion when comparing OPS and conventional THA. In the OPS group, the achieved acetabular anteversion was within 10° of the planned anteversion in 96% of cases, compared with only 76% in the conventional group. The clinical outcomes were comparable between the groups. CONCLUSION: Large errors in acetabular orientation appear to be reduced when CT-based planning and patient-specific instruments are used compared to the standard technique but no significant differences were seen in the mean error.

Retrospective Cohort Analysis of Aspirin Use and Venous Thromboembolism in Patients with Pancreatic Cancer and an Indwelling Central Venous Catheter.

Background Patients with pancreatic cancer are at high risk of developing venous thromboembolism (VTE). It is unknown if aspirin reduces the risk of VTE in this setting. Objectives We sought to determine whether there is an association between aspirin use and VTE risk in patients with pancreatic cancer receiving chemotherapy with a central venous catheter (CVC). Patients/Methods We conducted a single-center, retrospective cohort study of adult patients diagnosed with pancreatic cancer and treated with chemotherapy using a CVC. Subjects were excluded if they were on anticoagulation at the time of CVC placement. The probability of VTE was analyzed using a time-to-event analysis framework for the development of VTE using the product-limit method of Kaplan and Meier (univariate) and adjusting for important confounding covariates using Cox proportional hazards regression (cause-specific hazard) and again using Fine and Gray regression (subdistributional hazard) with death prior to VTE considered a competing event. Results The final analysis included 314 cases (125 with any aspirin use and 189 without). Patients with any aspirin use had fewer VTE events (34.4%) compared with those without aspirin use (42.3%; p = 0.021) by log-rank test and after adjustment for multiple covariates using a Cox proportional hazards model (hazard ratio [HR] = 0.60; 95% confidence interval [CI]: 0.40-0.92; p = 0.019). Using Fine and Gray regression to account for death as a competing event, the effect of aspirin remained in the direction of benefit, but was not statistically significant (HR = 0.70; 95% CI: 0.47-1.05, p = 0.083). Higher body mass index, active smoking, and metastatic stage of cancer were associated with VTE events in the Cox proportional hazards model. Rates of major bleeding or clinically relevant minor bleeding were similar between treatment groups. Conclusions Aspirin may reduce the risk of VTE in patients with pancreatic cancer with a CVC. We did not observe a significant increase in the rates of major bleeding or clinically relevant nonmajor bleeding.

Development of bony range of motion (B-ROM) boundary for total hip replacement planning.

BACKGROUND AND OBJECTIVE: Pre-operative surgical planning using computer simulation is increasingly standard practice before Total Hip Arthroplasty (THA), in order to determine the optimal implant positions, and thereby minimise post-operative complications such as dislocation, wear and leg length discrepancy. One of the limitations of current methods, however, is the lack of information on the subject-specific reference range of motion (ROM) that could be used as targets for surgical planning. Only a limited number of hip motions are considered, which are neither subject-specific, nor representative of all the hip motions associated with all the activities of daily livings (ADLs). In this paper, therefore, a method was developed to calculate subject-specific representative bony range of motion (B-ROM) that would cover all the possible joint motions and presented in terms of pure joint motions. METHODS: Only 3D bone geometries of femur and pelvis, constructed from personalised CT scan, were used as inputs for healthy hip joint whereas implant geometries and their positions on native bone geometries were required for planned treatment side or replaced side. Hip joint motion simulation was carried out using six different Tait-Bryan intrinsic rotation sequences of three pure joint motions - flexion-extension, abduction-adduction and internal-external rotation, and B-ROM was then identified for any of these six different sequences which caused earliest feasible impingement. The B-ROM could be used as a list of ROM data points or visualised as multiple 2D surface plots or a 3D envelop. Using the developed method, the B-ROM of a contralateral healthy hip joint of a patient can be used to define the subject-specific target ROM values to inform the surgical planning of the arthritic hip side so that the patient's natural ROM could be restored as closely as possible by the planned implant placements. This was demonstrated with a clinical verification study using 'non-dislocating' and 'dislocating' THA patients. RESULTS: The results supported the study hypothesis that the percentage of intersected volume of the healthy and replaced side B-ROM was higher for the 'Non-Dislocator' patient (95%) compared to 'Dislocator' (78%). Also, the results showed that the only one sequence (first flexion-extension, then abduction-adduction and finally internal-external rotation) was not adequate to identify all the possible limiting B-ROM, and therefore, all the six rotation sequences should be considered. CONCLUSIONS: The method encompasses every potential ADL, and as a result, more comprehensive surgical planning is possible, as the implant positions can be optimised in order to maximise impingement-free ROM, and consequently minimise clinical complications.

Hb Westport [ß121 (GH4) Glu>Asp; HBB:c.366A>C]: A novel ß-globin variant interfering with HbA1c measurement.

OBJECTIVES: To describe a novel ß-globin variant that interferes with HbA1c analysis by cation exchange HPLC. DESIGN AND METHODS: Diabetes screening by HbA1c measurement was assessed using cation exchange HPLC and an immunoassay point-of-care analyzer. Routine hemoglobinopathy screening was performed including CBC, HbF and HbA2 measurement by cation exchange HPLC and capillary electrophoresis (CE). Further variant characterization was undertaken by ESI TOF mass spectrometry and DNA sequencing. RESULTS: Discordant HbA1c results were obtained for our subject, with elevated HbA1c of 52 mmol/mol measured by cation exchange HPLC and a normal level of 34 mmol/mol by immunoassay. Abnormal HbA1c peak shape prompted hemoglobinopathy screening to investigate potential variant interference. Cation exchange HPLC (using ß-thalassemia program) and CE results were apparently normal, with HbF and HbA2 detected within reference intervals. ESI TOF mass spectrometry revealed the presence of a variant ß-globin chain. A novel missense variant was confirmed at codon 121 of the ß-globin gene [ß121 (GH4) Glu>Asp; HBB: c.366A>C], which we have named Hb Westport. CONCLUSIONS: Hb Westport is a novel ß-globin variant that interferes with HbA1c measurement by Bio-Rad D-100 cation exchange HPLC, giving a falsely elevated result. This was clinically significant for our subject because the erroneously elevated HbA1c value was above the diabetes diagnostic threshold. Alternative methods for diabetes assessment should be considered in subjects with Hb Westport.

A loss-of-function IFNAR1 allele in Polynesia underlies severe viral diseases in homozygotes.

Globally, autosomal recessive IFNAR1 deficiency is a rare inborn error of immunity underlying susceptibility to live attenuated vaccine and wild-type viruses. We report seven children from five unrelated kindreds of western Polynesian ancestry who suffered from severe viral diseases. All the patients are homozygous for the same nonsense IFNAR1 variant (p.Glu386*). This allele encodes a truncated protein that is absent from the cell surface and is loss-of-function. The fibroblasts of the patients do not respond to type I IFNs (IFN-α2, IFN-ω, or IFN-ß). Remarkably, this IFNAR1 variant has a minor allele frequency >1% in Samoa and is also observed in the Cook, Society, Marquesas, and Austral islands, as well as Fiji, whereas it is extremely rare or absent in the other populations tested, including those of the Pacific region. Inherited IFNAR1 deficiency should be considered in individuals of Polynesian ancestry with severe viral illnesses.

The congenital dyserythropoieitic anemias: genetics and pathophysiology.

PURPOSE OF REVIEW: The congenital dyserythropoietic anemias (CDA) are hereditary disorders characterized by ineffective erythropoiesis. This review evaluates newly developed CDA disease models, the latest advances in understanding the pathogenesis of the CDAs, and recently identified CDA genes. RECENT FINDINGS: Mice exhibiting features of CDAI were recently generated, demonstrating that Codanin-1 (encoded by Cdan1) is essential for primitive erythropoiesis. Additionally, Codanin-1 was found to physically interact with CDIN1, suggesting that mutations in CDAN1 and CDIN1 result in CDAI via a common mechanism. Recent advances in CDAII (which results from SEC23B mutations) have also been made. SEC23B was found to functionally overlap with its paralogous protein, SEC23A, likely explaining the absence of CDAII in SEC23B-deficient mice. In contrast, mice with erythroid-specific deletion of 3 or 4 of the Sec23 alleles exhibited features of CDAII. Increased SEC23A expression rescued the CDAII erythroid defect, suggesting a novel therapeutic strategy for the disease. Additional recent advances included the identification of new CDA genes, RACGAP1 and VPS4A, in CDAIII and a syndromic CDA type, respectively. SUMMARY: Establishing cellular and animal models of CDA is expected to result in improved understanding of the pathogenesis of these disorders, which may ultimately lead to the development of new therapies.

Temperature-induced multi-species cohort effects in sympatric snakes.

In reptiles, reproductive maturity is often determined by size rather than age. Consequently, growth early in life may influence population dynamics through effects on generation time and survival to reproduction. Because reproductive phenology and pre- and post-natal growth are temperature dependent, environmental conditions may induce multi-species cohort effects on body size in sympatric reptiles. I present evidence of this using 10 years of neonatal size data for three sympatric viviparous snakes, Dekay's Brown snakes (Storeria dekayi), Red-bellied Snakes (S. occipitomaculata), and Common Garter snakes (Thamnophis sirtalis). End-of-season neonatal size varied in parallel across species such that snout-vent length was 36%-61% greater and mass was 65%-223% greater in years when gestating females could achieve higher April-May (vs. June-July or August-September) operative temperatures. Thus, temperature had a larger impact during follicular enlargement and ovulation than during gestation or post-natal growth. Multi-species cohort effects like these may affect population dynamics and the magnitude of these effects may increase with climate change.

Repeatability of Inertial Measurement Units for Measuring Pelvic Mobility in Patients Undergoing Total Hip Arthroplasty.

Consideration of pelvic mobility when positioning implants for total hip arthroplasty (THA) has been shown to reduce the risk of complications such as dislocation, squeaking and excessive wear. We aim to test the repeatability of pelvic tilt measurements taken between three positions (standing, flexed-seated and step-up) by an inertial measurement unit (IMU) and hence, evaluate their reliability in screening for high pelvic mobility in patients undergoing THA. The repeated IMU measurements of pelvic tilt were analysed for consistency and compared with measures taken by x-ray analysis. Our study showed greater variation in measures taken by the IMU particularly in the flexed-seated position. The patient's pelvic tilt in this position negatively correlated with their mid-back angle, suggesting the posture of the patient is a source of variation in the flexed-seated position if not kept consistent during assessments. IMUs were overall able to produce accurate and reliable measurements of pelvic tilt; however, protocols will need to be adjusted to factor in a patient's mid-back angle when taking future readings.

Coxiella burnetii in 3 Species of Turtles in the Upper Midwest, United States.

Coxiella burnetii, the causative bacterium of the zoonotic disease Q fever, has been documented in many different species. We describe documented turtles that were PCR positive for C. burnetii from multiple locations in Illinois and Wisconsin, USA. Assessing the conservation implications, reservoir potential, and zoonotic risk requires further research.