Medial Closing Wedge High Tibial Osteotomy Accurately Corrects Genu Valgum without Iatrogenic Deformity or Complications: A Consecutive Series of Thirty-one Procedures.

Introduction: Angular deformities of the tibia and femur lead to mechanical axis deviation (MAD) of the lower limb and malorientation of the joints adjacent to the deformity. The current study analyses the outcomes of using a medial closing wedge high tibial osteotomy (MCWHTO) for the management of genu valgum with high medial proximal tibial angle (MPTA), and combined MCWHTO with lateral opening-wedge distal femoral osteotomy (LOWDFO) in the setting of concomitant genu varum with low lateral distal femoral angle (LDFA). Methods: There were 18 high tibial osteotomy (HTO)-only and 13 combined HTO + distal femoral osteotomy (DFO) procedures performed. The primary radiographic outcome variables included postoperative MPTA and MAD (in mm). The accuracy of MAD correction was expressed as a percentage. The postoperative posterior proximal tibial angle (PPTA) and limb length discrepancy (LLD) were also measured as secondary radiographic outcome variables. The clinical outcome variables included intraoperative surgical complications (e.g., hinge fracture), all-causes for revision, union rate, time to union, and postoperative knee range of motion. Functional outcomes used included the LDSRS, PROMIS, and EuroQOL scores. Results: The mean preoperative MPTA was 92.9° (SD = 1.81, range: 88-96). After surgical correction, the mean MPTA was 86.0° (SD = 1.80, range: 83-90) (p < 0.0001). The mean preoperative MAD was 32.5 mm (SD = 20.16, range: 10-77) lateral to the centre of the knee joint. The mean postoperative MAD was 2.44 mm medial to the centre of the joint (SD = 7.13, range: 13 medial - 15 lateral) (p < 0.0001). The mean change in MAD achieved through surgical correction was 38.16 mm (SD = 17.94, range: 13-77). The accuracy of MAD correction was 96.1% (SD = 0.06%, range: 81.25-100%). The time to unassisted WB was a mean of 75 days (SD = 44.5, range: 44-242).There was a single stable hinge fracture and one case of chronic regional pain syndrome diagnosed. There were no cases of non-union and no indications for revision surgery in any case. Conclusion: Medial closing wedge high tibial osteotomy is an effective surgical procedure for the management of genu valgum deformity. The MPTA, LDFA, and MAD can be accurately corrected without significantly altering PPTA or limb length. It may be combined with open lateral distal femoral osteotomy for cases with femoral and tibial contributions to deformity without significantly impacting clinical outcomes. Functional outcomes, specifically relating to self-image are significantly improved after the MCWHTO has been performed. How to cite this article: Sheridan GA, Page BJ, Greenstein MD, et al. Medial Closing Wedge High Tibial Osteotomy Accurately Corrects Genu Valgum without Iatrogenic Deformity or Complications: A Consecutive Series of Thirty-one Procedures. Strategies Trauma Limb Reconstr 2024;19(2):82-86.

Neuronal parts list and wiring diagram for a visual system.

A catalogue of neuronal cell types has often been called a 'parts list' of the brain1, and regarded as a prerequisite for understanding brain function2,3. In the optic lobe of Drosophila, rules of connectivity between cell types have already proven to be essential for understanding fly vision4,5. Here we analyse the fly connectome to complete the list of cell types intrinsic to the optic lobe, as well as the rules governing their connectivity. Most new cell types contain 10 to 100 cells, and integrate information over medium distances in the visual field. Some existing type families (Tm, Li, and LPi)6-10 at least double in number of types. A new serpentine medulla (Sm) interneuron family contains more types than any other. Three families of cross-neuropil types are revealed. The consistency of types is demonstrated by analysing the distances in high-dimensional feature space, and is further validated by algorithms that select small subsets of discriminative features. We use connectivity to hypothesize about the functional roles of cell types in motion, object and colour vision. Connectivity with 'boundary types' that straddle the optic lobe and central brain is also quantified. We showcase the advantages of connectomic cell typing: complete and unbiased sampling, a rich array of features based on connectivity and reduction of the connectome to a substantially simpler wiring diagram of cell types, with immediate relevance for brain function and development.

Rare variant contribution to the heritability of coronary artery disease.

Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

Protection efforts have resulted in ~10% of existing fish biomass on coral reefs.

The amount of ocean protected from fishing and other human impacts has often been used as a metric of conservation progress. However, protection efforts have highly variable outcomes that depend on local conditions, which makes it difficult to quantify what coral reef protection efforts to date have actually achieved at a global scale. Here, we develop a predictive model of how local conditions influence conservation outcomes on ~2,600 coral reef sites across 44 ecoregions, which we used to quantify how much more fish biomass there is on coral reefs compared to a modeled scenario with no protection. Under the assumptions of our model, our study reveals that without existing protection efforts there would be ~10% less fish biomass on coral reefs. Thus, we estimate that coral reef protection efforts have led to approximately 1 in every 10 kg of existing fish biomass.

Hypertrophic nonunion management with distraction osteogenesis: a scoping review of the literature.

Introduction: Traditionally, stiff hypertrophic nonunions have been managed with open preparation of the nonunion site, which is then secured with internal fixation. Alternative surgical options are available including distraction osteogenesis with an external fixator. There is currently a limited amount of literature pertaining to the use of distraction osteogenesis in the management of hypertrophic nonunion. The aim of this systematic review was to collate and assess the effectiveness of distraction osteogenesis (DO) in the management of hypertrophic nonunions and to evaluate the complications that are commonly reported in the literature. Methods: We searched for articles pertaining to the treatment of hypertrophic nonunion using distraction osteogenesis. Several electronic bibliographic databases and clinical trial registries were searched using the MeSH terms "hypertrophic non-union," "distraction osteogenesis," "stiff non-union," and "External Fixation" in various combinations to return the maximal number of studies for review. We performed a systematic review and identified a total of 11 studies eligible for review. Results: The review of the literature demonstrated that this technique is highly effective in achieving bony union with minimal complications. The most common complication is mild superficial pin site infections, usually managed with oral antibiotics and effective wound hygiene. Other complications reported were deep pin tract infections, broken hardware, and deformity recurrence due to collapse of regenerate bone. Conclusion: The use of distraction osteogenesis with external fixator devices is an effective and safe method for producing bony union in hypertrophic nonunions. There were minimal associated complications.

Plasma proteomic signatures for type 2 diabetes mellitus and related traits in the UK Biobank cohort.

Aims/hypothesis: The plasma proteome holds promise as a diagnostic and prognostic tool that can accurately reflect complex human traits and disease processes. We assessed the ability of plasma proteins to predict type 2 diabetes mellitus (T2DM) and related traits. Methods: Clinical, genetic, and high-throughput proteomic data from three subcohorts of UK Biobank participants were analyzed for association with dual-energy x-ray absorptiometry (DXA) derived truncal fat (in the adiposity subcohort), estimated maximum oxygen consumption (VO2max) (in the fitness subcohort), and incident T2DM (in the T2DM subcohort). We used least absolute shrinkage and selection operator (LASSO) regression to assess the relative ability of non-proteomic and proteomic variables to associate with each trait by comparing variance explained (R2) and area under the curve (AUC) statistics between data types. Stability selection with randomized LASSO regression identified the most robustly associated proteins for each trait. The benefit of proteomic signatures (PSs) over QDiabetes, a T2DM clinical risk score, was evaluated through the derivation of delta (Δ) AUC values. We also assessed the incremental gain in model performance metrics using proteomic datasets with varying numbers of proteins. A series of two-sample Mendelian randomization (MR) analyses were conducted to identify potentially causal proteins for adiposity, fitness, and T2DM. Results: Across all three subcohorts, the mean age was 56.7 years and 54.9% were female. In the T2DM subcohort, 5.8% developed incident T2DM over a median follow-up of 7.6 years. LASSO-derived PSs increased the R2 of truncal fat and VO2max over clinical and genetic factors by 0.074 and 0.057, respectively. We observed a similar improvement in T2DM prediction over the QDiabetes score [Δ AUC: 0.016 (95% CI 0.008, 0.024)] when using a robust PS derived strictly from the T2DM outcome versus a model further augmented with non-overlapping proteins associated with adiposity and fitness. A small number of proteins (29 for truncal adiposity, 18 for VO2max, and 26 for T2DM) identified by stability selection algorithms offered most of the improvement in prediction of each outcome. Filtered and clustered versions of the full proteomic dataset supplied by the UK Biobank (ranging between 600-1,500 proteins) performed comparably to the full dataset for T2DM prediction. Using MR, we identified 4 proteins as potentially causal for adiposity, 1 as potentially causal for fitness, and 4 as potentially causal for T2DM. Conclusions/Interpretation: Plasma PSs modestly improve the prediction of incident T2DM over that possible with clinical and genetic factors. Further studies are warranted to better elucidate the clinical utility of these signatures in predicting the risk of T2DM over the standard practice of using the QDiabetes score. Candidate causally associated proteins identified through MR deserve further study as potential novel therapeutic targets for T2DM.

Management of rotational malalignment following operative treatment of fractures of the lower extremities. A scoping review.

BACKGROUND: Rotational malalignment after operative fracture treatment of the lower extremity may be associated with increased pain and functional impairment. Despite its clinical relevance, there are no uniform management guidelines. The aim of this scoping review is to provide an overview of all available evidence to diagnose and treat rotational deformities of the lower extremity following operative fracture treatment. METHODS: This scoping review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A literature search was carried out on 22 August 2023 by two independent reviewers in the Pubmed (MEDLINE), Embase, Web of Science, and Cochrane library databases. The search strategy was developed with the assistance of a biomedical information specialist. The main search terms were tibial and femoral malrotations. Disagreements were resolved through discussion with a third reviewer. RESULTS: After screening and quality assessment of 3929 unique identified records, 50 articles were included for qualitative synthesis. Most studies were retrospective case reports or case series. Thirty studies focused on the femur, 11 on the tibia and nine included both femur and tibia. Most of the included studies presented cases where malrotation was associated with other limb deformities. Only 18 studies focused solely on the treatment of malrotation of the lower extremities after operative fracture treatment. Regarding diagnosis, bilateral CT-scans were used in 34 studies. Regarding treatment, external fixation was used in two studies, internal fixation (either intramedullary nail or plate) in 45 studies, and in three studies the authors used both. Overall, revision surgery resulted in good clinical outcomes with low complication rates. CONCLUSION: This scoping review reveals that rotational malalignment following operative treatment of lower extremity fractures remains an important complication. Although it occurs frequently and is associated with severe disability for the patient, standardized guidelines regarding the terminology, diagnosis, indications for intervention and treatment are lacking. CT-scan is the most used diagnostic modality in daily clinical practice. Revision surgery, using diverse operative techniques, demonstrated positive results, significantly alleviating patient complaints with few complications. Nevertheless, an international consensus regarding the optimal management pathway is needed, and future prospective clinical studies seem therefore necessary.

A plasma proteomic signature for atherosclerotic cardiovascular disease risk prediction in the UK Biobank cohort.

Background: While risk stratification for atherosclerotic cardiovascular disease (ASCVD) is essential for primary prevention, current clinical risk algorithms demonstrate variability and leave room for further improvement. The plasma proteome holds promise as a future diagnostic and prognostic tool that can accurately reflect complex human traits and disease processes. We assessed the ability of plasma proteins to predict ASCVD. Method: Clinical, genetic, and high-throughput plasma proteomic data were analyzed for association with ASCVD in a cohort of 41,650 UK Biobank participants. Selected features for analysis included clinical variables such as a UK-based cardiovascular clinical risk score (QRISK3) and lipid levels, 36 polygenic risk scores (PRSs), and Olink protein expression data of 2,920 proteins. We used least absolute shrinkage and selection operator (LASSO) regression to select features and compared area under the curve (AUC) statistics between data types. Randomized LASSO regression with a stability selection algorithm identified a smaller set of more robustly associated proteins. The benefit of plasma proteins over standard clinical variables, the QRISK3 score, and PRSs was evaluated through the derivation of Δ AUC values. We also assessed the incremental gain in model performance using proteomic datasets with varying numbers of proteins. To identify potential causal proteins for ASCVD, we conducted a two-sample Mendelian randomization (MR) analysis. Result: The mean age of our cohort was 56.0 years, 60.3% were female, and 9.8% developed incident ASCVD over a median follow-up of 6.9 years. A protein-only LASSO model selected 294 proteins and returned an AUC of 0.723 (95% CI 0.708-0.737). A clinical variable and PRS-only LASSO model selected 4 clinical variables and 20 PRSs and achieved an AUC of 0.726 (95% CI 0.712-0.741). The addition of the full proteomic dataset to clinical variables and PRSs resulted in a Δ AUC of 0.010 (95% CI 0.003-0.018). Fifteen proteins selected by a stability selection algorithm offered improvement in ASCVD prediction over the QRISK3 risk score [Δ AUC: 0.013 (95% CI 0.005-0.021)]. Filtered and clustered versions of the full proteomic dataset (consisting of 600-1,500 proteins) performed comparably to the full dataset for ASCVD prediction. Using MR, we identified 11 proteins as potentially causal for ASCVD. Conclusion: A plasma proteomic signature performs well for incident ASCVD prediction but only modestly improves prediction over clinical and genetic factors. Further studies are warranted to better elucidate the clinical utility of this signature in predicting the risk of ASCVD over the standard practice of using the QRISK3 score.

Acute Cardiovascular Responses to the 100-Mile Western States Endurance Run.

Ultramarathon participation is growing in popularity and exposes runners to unique stressors including extreme temperatures, high altitude, and exceedingly long exercise duration. However, the acute effects of ultramarathon participation on the cardiovascular system are not well understood. PURPOSE: To determine the acute effects of trail ultramarathon participation on central artery stiffness and hemodynamics. METHODS: Forty-one participants (9F, 32M) participating in the 2023 Western States Endurance Run underwent measures of carotid-femoral pulse wave velocity (cf-PWV) and pulse wave analysis pre- and <1h post-race. Subendocardial viability ratio (SEVR) was calculated from central blood pressure (BP) waveforms. Serum was analyzed for creatine kinase (CK) activity as a measure of muscle damage. Normally distributed data are presented as mean±SD and non-normally distributed data are presented as median (interquartile range). RESULTS: Runners were middle-aged and generally lean (age=44±9 y, BMI=22.7±1.8 kg●m-2). There was no difference in cf-PWV from pre- to post-race (pre=6.4±1.0, post=6.2±0.85 m/s, p=0.104), a finding that persisted after adjusting for mean arterial pressure (p=0.563). Systolic and diastolic BP were lower post-race (pre=129/77±9/7, post=122/74±10/8 mmHg, ps<0.001). Augmentation index (AIx; pre=17.3±12.2, post=6.0±13.7%, p<0.001), AIx normalized to a heart rate of 75bpm (p=0.043), reflection magnitude (pre=55.5(49.0-60.8), post=45.5(41.8-48.8) %, p<0.001), and SEVR (pre=173.0(158.0-190.0), post=127.5(116.5-145.8) %, p<0.001) were reduced post-race. CK increased markedly from pre- to post-race (pre=111(85-162), post=11,973(5,049-17,954) U/L, p<0.001). CONCLUSIONS: Completing a 161-km trail ultramarathon does not affect central arterial stiffness and acutely reduces BP despite eliciting profound muscle damage. However, the reduced post-race SEVR suggests a short-term mismatch between myocardial work and coronary artery perfusion.

Genetically predicted lipoprotein(a) associates with coronary artery plaque severity independent of low-density lipoprotein cholesterol.

AIMS: Elevated Lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular disease, but the mechanisms of risk are debated. Studies have found inconsistent associations between Lp(a) and measurements of atherosclerosis. We aimed to assess the relationship between Lp(a), low-density lipoprotein cholesterol (LDL-C) and coronary artery plaque severity. METHODS: The study population consisted of participants of the Million Veteran Program who have undergone an invasive angiogram. The primary exposure was genetically predicted Lp(a), estimated by a polygenic score. Genetically predicted LDL-C was also assessed for comparison. The primary outcome was coronary artery plaque severity, categorized as normal, non-obstructive disease, 1-vessel disease, 2-vessel disease, and 3-vessel or left main disease. RESULTS: Among 18,927 adults of genetically inferred European ancestry and 4,039 adults of genetically inferred African ancestry, we observed consistent associations between genetically predicted Lp(a) and obstructive coronary plaque, with effect sizes trending upward for increasingly severe categories of disease. Associations were independent of risk factors, clinically measured LDL-C and genetically predicted LDL-C. However, we did not find strong or consistent evidence for an association between genetically predicted Lp(a) and risk for non-obstructive plaque. CONCLUSIONS: Genetically predicted Lp(a) is positively associated with coronary plaque severity independent of LDL-C, consistent with Lp(a) promoting atherogenesis. However, the effects of Lp(a) may be greater for progression of plaque to obstructive disease than for the initial development of non-obstructive plaque. A limitation of this study is that Lp(a) was estimated using genetic markers and could not be directly assayed, nor could apo(a) isoform size.

This study assessed the association between genetic propensity towards higher lipoprotein(a) [Lp(a)] in the blood and the severity of coronary artery plaque seen on clinical angiograms, independent of other factors, including low-density lipoprotein cholesterol (LDL-C). The study was conducted in a large U.S. population using data from the Million Veteran Program. Genetically predicted high Lp(a) was associated with obstructive coronary plaque, but it was not associated with non-obstructive coronary plaque. This association was independent of LDL-C, and the association was greater for more severe forms of disease.The mechanisms of association between Lp(a) and cardiovascular events are debated. Prior studies have shown that Lp(a) does not associate with early markers of atherosclerosis. Our analyses support the idea that Lp(a) plays less of a role in early plaque initiation but plays a significant role in the progression of plaque towards more severe disease, independent of LDL-C.

Intramedullary Nail Fixation for Metacarpal Fracture: A Case Report and Review of the Clinical and Biomechanical Evidence.

We present two cases of complex metacarpal fractures treated with an intramedullary locking nail. This is an emerging fixation method that minimizes tissue insult, provides sufficient stability, and allows early mobilization. Locking nails accommodate the capture of fractured fragments in complex unstable patterns and provide longitudinal and rotational stability. The described intrafocal technique is intended to improve coaxial placement of the wire into the medullary canal.

Structure-driven development of a biomimetic rare earth artificial metalloprotein.

The 2011 discovery of the first rare earth-dependent enzyme in methylotrophic Methylobacterium extorquens AM1 prompted intensive research toward understanding the unique chemistry at play in these systems. This enzyme, an alcohol dehydrogenase (ADH), features a La3+ ion closely associated with redox-active coenzyme pyrroloquinoline quinone (PQQ) and is structurally homologous to the Ca2+-dependent ADH from the same organism. AM1 also produces a periplasmic PQQ-binding protein, PqqT, which we have now structurally characterized to 1.46-Å resolution by X-ray diffraction. This crystal structure reveals a Lys residue hydrogen-bonded to PQQ at the site analogously occupied by a Lewis acidic cation in ADH. Accordingly, we prepared K142A- and K142D-PqqT variants to assess the relevance of this site toward metal binding. Isothermal titration calorimetry experiments and titrations monitored by UV-Vis absorption and emission spectroscopies support that K142D-PqqT binds tightly (Kd = 0.6 ± 0.2 µM) to La3+ in the presence of bound PQQ and produces spectral signatures consistent with those of ADH enzymes. These spectral signatures are not observed for WT- or K142A-variants or upon addition of Ca2+ to PQQ ⸦ K142D-PqqT. Addition of benzyl alcohol to La3+-bound PQQ ⸦ K142D-PqqT (but not Ca2+-bound PQQ ⸦ K142D-PqqT, or La3+-bound PQQ ⸦ WT-PqqT) produces spectroscopic changes associated with PQQ reduction, and chemical trapping experiments reveal the production of benzaldehyde, supporting ADH activity. By creating a metal binding site that mimics native ADH enzymes, we present a rare earth-dependent artificial metalloenzyme primed for future mechanistic, biocatalytic, and biosensing applications.

Percutaneous removal of hardware after orthopedic surgery: Is it safe? and What are patients saying?

OBJECTIVES: To analyze our patient's complication profile and rate after removal of hardware (ROH) surgery, and survey our patients to ask their overall status and improvement in symptomatology post-operatively. DESIGN: Retrospective chart review and survey. SETTING: Academic, tertiary referral center. PATIENTS/PARTICIPANTS: 173 patients with 314 pieces of hardware. Seventy-six patients (43.9%) responded to our survey. INTERVENTION: ROH surgery. MAIN OUTCOME MEASUREMENTS: Patient demographics and complications were recorded. All patients were sent a brief 3-question survey which asked: (1) Why did you get your hardware removed? (2) How did your overall status change after ROH? (3) How did the ROH affect your stiffness, pain, swelling, and mobility? RESULTS: There were 10 complications (5.5%): 5 infections, 2 with unresolved pain, 1 hematoma, 1 chronic regional pain syndrome exacerbation, and 1 recurrent deformity. All infections were treated with oral antibiotics and improved. All other complications resolved with treatment except for the patient who developed recurrent deformity. Patients underwent ROH surgery because their doctor suggested it (76.3%) and to improve mobility (39.5%). 86.9% reported their overall status improved after ROH. They improved regarding stiffness (73.7%), pain (73.6%), swelling (61.8%), and mobility (76.3%). Similar results were seen among different implants removed. CONCLUSIONS: The majority of patients who underwent percutaneous ROH were satisfied. They reported improvement in stiffness, pain, swelling and mobility (greatest improvement). The complication rate was low (5.5%). ROH can be a meaningful operation to patients allowing them to improve their quality of life with a low complication rate. LEVEL OF EVIDENCE: Level IV.

Hypertension and Ventilatory Responses During Exercise in the Fitness Registry and the Importance of Exercise National Database (FRIEND).

BACKGROUND: A high minute ventilation/rate of carbon dioxide production (V̇E/V̇co2) slope during exercise is prognostic for cardiovascular death. Recent data indicate that adults with either controlled or untreated primary hypertension, but not those with uncontrolled hypertension, exhibit a higher V̇E/V̇co2 slope during exercise. However, the sample sizes were modest. Therefore, we used the Fitness Registry and the Importance of Exercise National Database to determine whether adults with hypertension, particularly those with controlled or untreated hypertension, exhibit higher V̇E/V̇co2 slopes compared with adults without hypertension. METHODS AND RESULTS: Using the Fitness Registry and the Importance of Exercise National Database, we isolated primary hypertension by excluding those with any disease other than hypertension or taking any medications other than antihypertension medications. We also excluded current smokers and those with obesity. The V̇E/V̇co2 slope was determined during a peak cycling exercise test. All data are presented as median [interquartile range]. We compared groups using linear regression adjusted for age, male/female, and body mass index. The characteristics of the entire sample (n=4109) were age, 42 [18] years; 48% women; body mass index, 26 [4] kg/m2. The V̇E/V̇co2 slope did not differ between adults with hypertension (n=1940; 24.7 [3.7]) compared with those without hypertension (n=2169; 24.9 [3.8]) (hypertension versus no hypertension, P=0.31; overall model: R2=0.07, F4,4104=73.0; P<0.001). Further, the V̇E/V̇co2 slope did not differ between adults with medication-controlled hypertension (n=107; 24.4 [3.0]), untreated hypertension (n=1626; 24.8 [3.9]), uncontrolled hypertension (n=207; 24.8 [3.0]), or those without hypertension (n=2169; 24.9 [3.8]) (hypertension subgroup versus no hypertension, P≥0.06; overall model: R2=0.07, F6,4102=49.6, P<0.001). CONCLUSIONS: Primary hypertension is not associated with V̇E/V̇co2 slope in the Fitness Registry and the Importance of Exercise National Database.

Cryopreservation of Stem Cell-Derived ß-Like Cells Enriches for Insulin-Producing Cells With Improved Function.

The generation of stem cell-derived ß-like cells (sBCs) holds promise as not only an abundant insulin-producing cell source for replacement therapy of type 1 diabetes (T1D) but also as an invaluable model system for investigating human ß-cell development, immunogenicity, and function. Several groups have developed methodology to direct differentiate human pluripotent stem cells into pancreatic cell populations that include glucose-responsive sBCs. Nevertheless, the process of generating sBCs poses substantial experimental challenges. It involves lengthy differentiation periods, there is substantial variability in efficiency, and there are inconsistencies in obtaining functional sBCs. Here, we describe a simple and effective cryopreservation approach for sBC cultures that yields homogeneous sBC clusters that are enriched for insulin-expressing cells while simultaneously depleting proliferative progenitors. Thawed sBCs have enhanced glucose-stimulated insulin release compared with controls in vitro and can effectively engraft and function in vivo. Collectively, this approach alleviates current challenges with inefficient and variable sBC generation while improving their functional state. We anticipate that these findings can inform ongoing clinical application of sBCs for the treatment of patients with T1D and serve as an important resource for the wider diabetes field that will allow for accelerated research discoveries.

Interplay of race and neighborhood deprivation on resting and ambulatory blood pressure in young adults.

Nighttime blood pressure (BP) and BP dipping (daytime-nighttime BP) are prognostic for cardiovascular disease. When compared with other racial/ethnic groups, Black Americans exhibit elevated nighttime BP and attenuated BP dipping. Neighborhood deprivation may contribute to disparities in cardiovascular health, but its effects on resting and ambulatory BP patterns in young adults are unclear. Therefore, we examined associations between neighborhood deprivation with resting and nighttime BP and BP dipping in young Black and White adults. We recruited 19 Black and 28 White participants (23 males/24 females, 21 ± 1 yr, body mass index: 26 ± 4 kg/m2) for 24-h ambulatory BP monitoring. We assessed resting BP, nighttime BP, and BP dipping (absolute dip and nighttime:daytime BP ratio). We used the area deprivation index (ADI) to assess average neighborhood deprivation during early and mid-childhood and adolescence. When compared with White participants, Black participants exhibited higher resting systolic and diastolic BP (Ps ≤ 0.029), nighttime systolic BP (114 ± 9 vs. 108 ± 9 mmHg, P = 0.049), diastolic BP (63 ± 8 vs. 57 ± 7 mmHg, P = 0.010), and attenuated absolute systolic BP dipping (12 ± 5 vs. 9 ± 7 mmHg, P = 0.050). Black participants experienced greater average ADI scores compared with White participants [110 (10) vs. 97 (22), P = 0.002], and select ADI scores correlated with resting BP and some ambulatory BP measures. Within each race, select ADI scores correlated with some BP measures for Black participants, but there were no ADI and BP correlations for White participants. In conclusion, our findings suggest that neighborhood deprivation may contribute to higher resting BP and impaired ambulatory BP patterns in young adults warranting further investigation in larger cohorts.NEW & NOTEWORTHY We demonstrate that young Black adults exhibit higher resting blood pressure, nighttime blood pressure, and attenuated systolic blood pressure dipping compared with young White adults. Black adults were exposed to greater neighborhood deprivation, which demonstrated some associations with resting and ambulatory blood pressure. Our findings add to a growing body of literature indicating that neighborhood deprivation may contribute to increased blood pressure.

Extra-articular Osteotomy for the Management of Intra-articular Tibial Plateau Valgus Malunion.

OBJECTIVES: To report a case series of extra-articular osteotomies for the management of intra-articular tibial plateau malunions and to assess the ability to correct deformity and improve knee range of motion (ROM). METHODS: . DESIGN: Retrospective case series. SETTING: Academic, tertiary, referral center. PATIENT SELECTION CRITERIA: Adult patients with tibial plateau fracture malunion treated with extra-articular osteotomy of the femur and/or tibia between 2014 and 2023. OUTCOME MEASURES AND COMPARISON: Mechanical axis deviation (MAD), medial proximal tibia angle (MPTA), lateral distal femoral angle (LDFA), and posterior proximal tibia angle (PPTA) correction; knee ROM; and time to weight bearing. RESULTS: There were 7 patients included, 6 (85.7%) were female and 1 (14.3%) were male. The median age was 43.5 years (IQR 38.5-51, range 32-62). Four (57.1%) patients were treated with a high tibial osteotomy (HTO), and 3 (42.9%) patients were treated with an HTO and distal femoral osteotomy. One patient had concomitant supramalleolar osteotomy with HTO to address distal tibia procurvatum and valgus. Four were treated with hexapod frames, and 3 were treated with plates and screws. Median follow-up was 22.5 months (IQR 10.5-107 months, range 7-148 months). Surgical intervention corrected median radiographic measures of valgus malalignment preoperatively relative to postoperative values. This included MAD (42.5 mm-0 mm), valgus angle (12.5 degrees-1.5 degrees), MPTA (95 degrees-88.0°), and LDFA (86.0°-87.3 degrees). Surgical intervention increased maximal knee range of motion preoperatively to postoperatively. Median time to full weight bearing was 81.5 days (IQR 46-57 days, range 41-184 days). Two patients were converted to total knee arthroplasty after 5 and 10 years following HTO with hexapod frame. CONCLUSIONS: Extra-articular osteotomy is an effective treatment for addressing intra-articular malunion after tibia plateau fractures. It is effective in correcting the MAD, valgus deformity, MPTA, LDFA, PPTA, and improving knee ROM (measured through knee extension and flexion). LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Efficacy and Safety of Long-term Ketogenic Diet Therapy in a Patient With Type 1 Diabetes.

Fewer than 1% of patients with type 1 diabetes achieve normal glycemic control (glycated hemoglobin [HbA1c] < 5.7%/ < 39 mmol/mol). Additionally, exogenous insulin administration often causes "iatrogenic hyperinsulinemia," leading to whole-body insulin resistance and increased risk of cardiovascular complications. We present data on the clinical efficacy and safety of a long-term (10-year) ketogenic diet (≤50 g carbohydrates/day) therapy in a patient with type 1 diabetes. The use of a ketogenic diet resulted in successful glycemic control, assessed by HbA1c (5.5%; 36.6 mmol/mol), continuous glucose monitoring median glucose (98 mg/dL; 5.4 mmol/L), and glucose time-in-range of 70 to 180 mg/dL (90%) without acute glycemic complications. In conjunction, there was a 43% decrease in daily insulin requirements. Low-density lipoprotein cholesterol increased, whereas small-dense low-density lipoprotein was in the normal range (<90 nmol/L). No adverse effects were observed on thyroid function, kidney function, or bone mineral density. This case report demonstrates that a long-term ketogenic diet in a person with type 1 diabetes has considerable therapeutic benefits.

Deep mutational scanning reveals sequence to function constraints for SWEET family transporters.

Protein science is entering a transformative phase enabled by deep mutational scans that provide an unbiased view of the residue level interactions that mediate function. However, it has yet to be extensively used to characterize the mutational and evolutionary landscapes of plant proteins. Here, we apply the method to explore sequence-function relationships within the sugar transporter AtSWEET13. DMS results describe how mutational interrogation throughout different regions of the protein affects AtSWEET13 abundance and transport function. Our results identify novel transport-enhancing mutations that are validated using the FRET sensor assays. Extending DMS results to phylogenetic analyses reveal the role of transmembrane helix 4 (TM4) which makes the SWEET family transporters distinct from prokaryotic SemiSWEETs. We show that transmembrane helix 4 is intolerant to motif swapping with other clade-specific SWEET TM4 compositions, despite accommodating single point-mutations towards aromatic and charged polar amino acids. We further show that the transfer learning approaches based on physics and ML based In silico variant prediction tools have limited utility for engineering plant proteins as they were unable to reproduce our experimental results. We conclude that DMS can produce datasets which, when combined with the right predictive computational frameworks, can direct plant engineering efforts through derivative phenotype selection and evolutionary insights.