In Vitro and In Vivo Studies on a Mononuclear Ruthenium Complex Reveals It is a Highly Effective, Fast-Acting, Broad-Spectrum Antimicrobial in Physiologically Relevant Conditions.

The crystal structure of a previously reported antimicrobial RuII complex that targets bacterial DNA is presented. Studies utilizing clinical isolates of Gram-negative bacteria that cause catheter-associated urinary tract infection, (CA)UTI, in media that model urine and plasma reveal that good antimicrobial activity is maintained in all conditions tested. Experiments with a series of Staphylococcus aureus clinical isolates show that, unlike the majority of previously reported RuII-based antimicrobial leads, the compound retains its potent activity even in MRSA strains. Furthermore, experiments using bacteria in early exponential growth and at different pHs reveal that the compound also retains its activity across a range of conditions that are relevant to those encountered in clinical settings. Combinatorial studies involving cotreatment with conventional antibiotics or a previously reported analogous dinuclear RuII complex showed no antagonistic effects. In fact, although all combinations show distinct additive antibacterial activity, in one case, this effect approaches synergy. It was found that the Galleria Mellonella model organism infected with a multidrug resistant strain of the ESKAPE pathogen Acinetobacter baumannii could be successfully treated and totally cleared within 48 h after a single dose of the lead complex with no detectable deleterious effect to the host.

Gingival mesenchymal stem cells: Biological properties and therapeutic applications.

Our understanding of mesenchymal stem cells (MSCs) and their biological properties is steadily increasing, with more studies focusing on their therapeutic effects in the domains of immunology, tissue engineering and regenerative medicine. MSCs may be derived from tissues such as bone marrow, adipose, the umbilical cord, as well as from dental tissues (e.g., tooth germ, dental follicle, pulp tissue of exfoliated deciduous and permanent teeth, apical papilla, periodontal ligament, gingiva, and alveolar bone). Gingival mesenchymal stem cells (GMSCs) are non-hematopoietic adult stem cells isolated from the gingival lamina propria. When compared to MSCs purified from various dental and non-dental tissues, GMSCs are more abundant in source, relatively non-invasive to obtain, and genetically stable. In recent years, many studies have found that GMSCs possess the ability of self-renewal, multi-directional differentiation, and chemotaxis to inflammatory sites for immunity regulation. Their molecular and stem-cell properties make them highly suitable for both preclinical and clinical research. Extracellular vesicles (EVs) secreted by GMSCs are of key interest due to their ability to emulate the biological and therapeutic activity of GMSCs themselves. This paper will therefore review the current consensus on GMSCs, surveying their sources and isolation methods, their biological properties, and their therapeutic applications on inflammatory and immune-related diseases.

Experience of the first adult-focussed undiagnosed disease program in Australia (AHA-UDP): solving rare and puzzling genetic disorders is ageless.

BACKGROUND: Significant recent efforts have facilitated increased access to clinical genetics assessment and genomic sequencing for children with rare diseases in many centres, but there remains a service gap for adults. The Austin Health Adult Undiagnosed Disease Program (AHA-UDP) was designed to complement existing UDP programs that focus on paediatric rare diseases and address an area of unmet diagnostic need for adults with undiagnosed rare conditions in Victoria, Australia. It was conducted at a large Victorian hospital to demonstrate the benefits of bringing genomic techniques currently used predominantly in a research setting into hospital clinical practice, and identify the benefits of enrolling adults with undiagnosed rare diseases into a UDP program. The main objectives were to identify the causal mutation for a variety of diseases of individuals and families enrolled, and to discover novel disease genes. METHODS: Unsolved patients in whom standard genomic diagnostic techniques such as targeted gene panel, exome-wide next generation sequencing, and/or chromosomal microarray, had already been performed were recruited. Genome sequencing and enhanced genomic analysis from the research setting were applied to aid novel gene discovery. RESULTS: In total, 16/50 (32%) families/cases were solved. One or more candidate variants of uncertain significance were detected in 18/50 (36%) families. No candidate variants were identified in 16/50 (32%) families. Two novel disease genes (TOP3B, PRKACB) and two novel genotype-phenotype correlations (NARS, and KMT2C genes) were identified. Three out of eight patients with suspected mosaic tuberous sclerosis complex had their diagnosis confirmed which provided reproductive options for two patients. The utility of confirming diagnoses for patients with mosaic conditions (using high read depth sequencing and ddPCR) was not specifically envisaged at the onset of the project, but the flexibility to offer recruitment and analyses on an as-needed basis proved to be a strength of the AHA-UDP. CONCLUSION: AHA-UDP demonstrates the utility of a UDP approach applying genome sequencing approaches in diagnosing adults with rare diseases who have had uninformative conventional genetic analysis, informing clinical management, recurrence risk, and recommendations for relatives.

Femoral head decentration on hip MRI: comparison between imaging planes, methods of contrast administration, and hip deformities.

OBJECTIVES: To compare the prevalence of femoral head decentration (FHD) on different MR imaging planes in patients undergoing direct/indirect hip MR arthrography (MRA) with asymptomatic controls and to evaluate its association with osseous deformities. METHODS: IRB-approved retrospective single-center study of symptomatic hips undergoing direct or indirect hip MRA at 3 T. Asymptomatic participants underwent non-contrast hip MRI at 3 T. FHD was defined as a continuous fluid layer between the acetabulum and femoral head and assessed on axial, sagittal and radial images. The association of intra-articular/intra-venous contrast agents and the prevalence of FHD was evaluated. The association of FHD with osseous deformities and joint damage was assessed using multiple logistic regression analysis. RESULTS: Three-hundred ninety-four patients (447 hips, mean age 31 ± 9 years, 247 females) were included and compared to 43 asymptomatic controls (43 hips, mean age 31 ± 6 years, 26 females). FHD was most prevalent on radial images and more frequent in symptomatic hips (30% versus 2%, p < 0.001). FHD prevalence was not associated with the presence/absence of intra-articular contrast agents (30% versus 22%, OR = 1.5 (95% CI 0.9-2.5), p = 0.125). FHD was associated with hip dysplasia (OR = 6.1 (3.3-11.1), p < 0.001), excessive femoral torsion (OR = 3.0 (1.3-6.8), p = 0.010), and severe cartilage damage (OR = 3.6 (2.0-6.7), p < 0.001). CONCLUSION: While rare in asymptomatic patients, femoral head decentration in symptomatic patients is associated with osseous deformities predisposing to hip instability, as well as with extensive cartilage damage. CRITICAL RELEVANCE STATEMENT: Decentration of the femoral head on radial MRA may be interpreted as a sign of hip instability in symptomatic hips without extensive cartilage defects. Its presence could unmask hip instability and yield promise in surgical decision-making. KEY POINTS: The best method of identifying femoral head decentration is radial MRI. The presence/absence of intra-articular contrast is not associated with femoral head decentration. Femoral head decentration is associated with hip deformities predisposing to hip instability.

Analytical and behavioral characterization of 1-hexanoyl-LSD (1H-LSD).

The development of lysergic acid diethylamide (LSD) derivatives and analogs continues to inform the design of novel receptor probes and potentially new medicines. On the other hand, a number of newly developed LSD derivatives have also emerged as recreational drugs, leading to reports of their detection in some countries. One position in the ergoline scaffold of LSD that is frequently targeted is the N1-position; numerous N1-alkylcarbonyl LSD derivatives have been reported where the acyl chain is attached to the indole nitrogen, for example, in the form of linear n-alkane substituents, which represent higher homologs of the prototypical 1-acetyl-N,N-diethyllysergamide (1A-LSD, ALD-52). In this study, 1-hexanoyl-LSD (1H-LSD, SYN-L-027), a novel N1-acyl LSD derivative, was characterized analytically using standard techniques, followed by evaluation of its in vivo behavioral effects using the mouse head-twitch response (HTR) assay in C57BL/6J mice. 1H-LSD induced the HTR, with a median effective dose (ED50) of 192.4 µg/kg (equivalent to 387 nmol/kg), making it roughly equipotent to ALD-52 when tested previously under similar conditions. Similar to other N1-acylated analogs, 1H-LSD is anticipated to by hydrolyzed to LSD in vivo and acts as a prodrug. It is currently unknown whether 1H-LSD has appeared as on the research chemical market or is being used recreationally.

Accelerating Formulation Design via Machine Learning: Generating a High-throughput Shampoo Formulations Dataset.

Liquid formulations are ubiquitous yet have lengthy product development cycles owing to the complex physical interactions between ingredients making it difficult to tune formulations to customer-defined property targets. Interpolative ML models can accelerate liquid formulations design but are typically trained on limited sets of ingredients and without any structural information, which limits their out-of-training predictive capacity. To address this challenge, we selected eighteen formulation ingredients covering a diverse chemical space to prepare an open experimental dataset for training ML models for rinse-off formulations development. The resulting design space has an over 50-fold increase in dimensionality compared to our previous work. Here, we present a dataset of 812 formulations, including 294 stable samples, which cover the entire design space, with phase stability, turbidity, and high-fidelity rheology measurements generated on our semi-automated, ML-driven liquid formulations workflow. Our dataset has the unique attribute of sample-specific uncertainty measurements to train predictive surrogate models.

Rotational femoral osteotomies and cam resection improve hip function and internal rotation for patients with anterior hip impingement and decreased femoral version.

Femoroacetabular impingement (FAI) patients with reduced femoral version (FV) are poorly understood. The aim of this study is to assess (i) hip pain and range of motion, (ii) subjective satisfaction and (iii) subsequent surgeries of symptomatic patients who underwent rotational femoral osteotomies. A retrospective case series involving 18 patients (23 hips, 2014-2018) with anterior hip pain that underwent rotational femoral osteotomies for treatment of decreased FV was performed. The mean preoperative age was 25 ± 6 years (57% male), and all patients had decreased FV < 10° and minimum 1-year follow-up (mean follow-up 2 ± 1 years). Surgical indication was the positive anterior impingement test, limited internal rotation (IR) in 90° of flexion (mean 10 ± 8°) and IR in extension (mean 24 ± 11°), anterosuperior chondrolabral damage in Magnet resonance (MR) arthrography, CT-based measurement of decreased FV (mean 5 ± 3°, Murphy method) and no osteoarthritis (Tönnis Grade 0). Most patients had intra- and extra-articular subspine FAI (patient-specific 3D impingement simulation). Subtrochanteric rotational femoral osteotomies to increase FV (correction 20 ± 4°) were combined with cam resection (78%) and surgical hip dislocation (91%). (i) The positive anterior impingement test decreased significantly (P < 0.001) from pre- to postoperatively (100% to 9%). IR in 90° of flexion increased significantly (P < 0.001, 10 ± 8° to 31 ± 10°). (ii) Subjective satisfaction increased significantly (P < 0.001) from pre- to postoperatively (33% 77%). The mean Merle d'Aubigné and Postel score increased significantly (P < 0.001) from 14 ± 2 (8-15) points to 17 ± 1 (13-18, P < 0.001) points. Most patients (85%) reported at follow-up that they would undergo surgery again. (iii) At follow-up, all 23 hips were preserved (no conversion to total hip arthroplasty). One hip (4%) underwent revision osteosynthesis. Proximal rotational femoral osteotomies combined with cam resection improve hip pain and IR in most FAI patients with decreased FV at short-term follow-up. Rotational femoral osteotomies to increase FV are safe and effective.

SARS-CoV-2 Variants and COVID-19 in Bangladesh-Lessons Learned.

The coronavirus infectious disease-2019 (COVID-19) in Bangladesh is a paradigm for how one of the most densely populated countries in the world, with 1270 people per square kilometer, managed to cope with the COVID-19 pandemic under extraordinary circumstances. This review highlights the SARS-CoV-2 variants in Bangladesh and the timeline of their detection in the context of the global experience with the management of vaccination and natural SARS-CoV-2 infection. The motivation to overcome the COVID-19 vaccine dilemma and track Bangladeshi SARS-CoV-2 sub-variants underscores the potential for a low-income country to excel in international medical science, despite having stressed health care services and limited availability of resources for SARS-CoV-2 testing and gene sequencing.

The Role of Reactive Oxygen Species in Age-Related Macular Degeneration: A Comprehensive Review of Antioxidant Therapies.

This review article delves into the intricate roles of reactive oxygen species (ROS) in the pathogenesis of age-related macular degeneration (AMD). It presents a detailed analysis of the oxidative stress mechanisms that contribute to the development and progression of these diseases. The review systematically explores the dual nature of ROS in ocular physiology and pathology, underscoring their essential roles in cellular signaling and detrimental effects when in excess. In the context of AMD, the focus is on the oxidative impairment in the retinal pigment epithelium and Bruch's membrane, culminating in the deterioration of macular health. Central to this review is the evaluation of various antioxidant strategies in the prevention and management of AMD. It encompasses a wide spectrum of antioxidants, ranging from dietary nutrients like vitamins C and E, lutein, and zeaxanthin to pharmacological agents with antioxidative properties. The review also addresses novel therapeutic approaches, including gene therapy and nanotechnology-based delivery systems, aiming to enhance antioxidant defense mechanisms in ocular tissues. The article concludes by synthesizing current research findings, clinical trial data, and meta-analyses to provide evidence-based recommendations. It underscores the need for further research to optimize antioxidant therapies, considering individual patient factors and disease stages. This comprehensive review thus serves as a valuable resource for clinicians, researchers, and healthcare professionals in ophthalmology, offering insights into the potential of antioxidants in mitigating the burden of AMD.

Smart Contact Lenses in Ophthalmology: Innovations, Applications, and Future Prospects.

Smart contact lenses represent a breakthrough in the intersection of medical science and innovative technology, offering transformative potential in ophthalmology. This review article delves into the technological underpinnings of smart contact lenses, emphasizing the current landscape and advancements in biosensors, power supply, biomaterials, and the transmission of ocular information. This review further applies new innovations to their emerging role in the diagnosis, monitoring, and management of various ocular conditions. Moreover, we explore the impact of technical innovations on the application of smart contact lenses in monitoring glaucoma, managing postoperative care, and dry eye syndrome, further elucidating the non-invasive nature of these devices in continuous ocular health monitoring. The therapeutic potential of smart contact lenses such as treatment through targeted drug delivery and the monitoring of inflammatory biomarkers is also highlighted. Despite promising advancements, the implementation of smart contact lenses faces technical, regulatory, and patient compliance challenges. This review synthesizes the recent advances to provide an outlook on the state of smart contact lens technology. Furthermore, we discuss future directions, focusing on potential technological enhancements and new applications within ophthalmology.

Evidence for a transfer-to-trap mechanism of fluorophore concentration quenching in lipid bilayers.

It is important to understand the behaviours of fluorescent molecules because, firstly, they are often utilized as probes in biophysical experiments and, secondly, they are crucial cofactors in biological processes such as photosynthesis. A phenomenon called "fluorescence quenching" occurs when fluorophores are present at high concentrations but the mechanisms for quenching are debated. Here, we used a technique called "in-membrane electrophoresis" to generate concentration gradients of fluorophores within a supported lipid bilayer (SLB), across which quenching was expected to occur. Fluorescence lifetime imaging microscopy (FLIM) provides images where the fluorescence intensity in each pixel is correlated to fluorescence lifetime: the intensity provides information about the location and concentration of fluorophores and the lifetime reveals the occurrence of energy-dissipative processes. FLIM was used to compare the quenching behaviour of three commonly-used fluorophores: Texas Red (TR), nitrobenzoaxadiazole (NBD) and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY). FLIM images provided evidence of quenching in regions where the fluorophores accumulated but the degree of quenching varied between the different fluorophores. The relationship between quenching and concentration was quantified and the "critical radius for trap formation", representing the relative quenching strength, was calculated as 2.70, 2.02 and 1.14 nm, for BODIPY, TR and NBD, respectively. The experimental data supports the theory that quenching takes place via a "transfer-to-trap" mechanism which proposes, firstly, that excitation energy is transferred between fluorophores and may reach a "trap site" resulting in immediate energy dissipation and, secondly, that trap sites are formed in a concentration-dependent manner. Some previous work suggested that quenching occurs only when fluorophores aggregate, or form long-lived dimers, but our data and this theory argues that traps may be "statistical pairs" of fluorophores that exist only transiently. Our findings should inspire future work to assess whether these traps can be charge-transfer states, excited state dimers or something else.

Bioengineering from the laboratory to clinical translation in oral and maxillofacial reconstruction.

Background: Conventional techniques used in oral and maxillofacial reconstruction focus mainly on utilizing autologous tissues that have unquestionably improved function and esthetics for many patients, worldwide. However, the success depends on countless factors such as: donor and recipient sites conditions, patient's medical history, surgeon's experience, restricted availability of high-quality autogenous tissues or stem cells, and increased surgical cost and time. Materials and Methods: Lately, teaming researchers, scientists, surgeons, and engineers, to address these limitations, have allowed tremendous progress in recombinant protein therapy, cell-based therapy, and gene therapy. Results: Over the past few years, biomedical engineering has been evolving from the laboratory to clinical applications, for replacement of damaged body tissues due to trauma, cancer, congenital or acquired disorders. Conclusions: This review provides an outlook on the content, benefits, recent advances, limitations, and future expectations of biomedical engineering for salivary glands, oral mucosa, dental structures, and maxillofacial reconstruction.

Respiratory infection- and asthma-prone, low vaccine responder children demonstrate distinct mononuclear cell DNA methylation pathways.

BACKGROUND: Infants with frequent viral and bacterial respiratory infections exhibit compromised immunity to routine immunizations. They are also more likely to develop chronic respiratory diseases in later childhood. This study investigated the feasibility of epigenetic profiling to reveal endotype-specific molecular pathways with potential for early identification and immuno-modulation. Peripheral blood mononuclear cells from respiratory infection allergy/asthma-prone (IAP) infants and non-infection allergy/asthma prone (NIAP) were retrospectively selected for genome-wide DNA methylation and single nucleotide polymorphism analysis. The IAP infants were enriched for the low vaccine responsiveness (LVR) phenotype (Fisher's exact p-value = 0.02). RESULTS: An endotype signature of 813 differentially methylated regions (DMRs) comprising 238 lead CpG associations (FDR < 0.05) emerged, implicating pathways related to asthma, mucin production, antigen presentation and inflammasome activation. Allelic variation explained only a minor portion of this signature. Stimulation of mononuclear cells with monophosphoryl lipid A (MPL), a TLR agonist, partially reversed this signature at a subset of CpGs, suggesting the potential for epigenetic remodeling. CONCLUSIONS: This proof-of-concept study establishes a foundation for precision endotyping of IAP children and highlights the potential for immune modulation strategies using adjuvants for future investigation.

The drainome: longitudinal metagenomic characterisation of wastewater from hospital ward sinks to characterize the microbiome and resistome and assess the effects of decontamination interventions.

BACKGROUND: Hospital drains and water interfaces are implicated in nosocomial transmission of pathogens. Metagenomics can assess the microbial composition and presence of antimicrobial resistance genes in drains ('the drainome') but studies applying these methods longitudinally and to assess infection control interventions are lacking. AIM: Apply long-read metagenomics coupled with microbiological measurements to investigate the drainome and assess the effects of a peracetic acid-containing decontamination product. METHODS: 12-week study in three phases: a baseline phase, an intervention phase of enhanced decontamination with peracetic acid, and a post-intervention phase. Five hospital sink drains on an intensive care unit were sampled twice weekly. Each sample had 1) measurement of total viable count (TVC), 2) metagenomic analyses including i) taxonomic classification of bacteria and fungi ii) antibiotic resistance gene detection iii) plasmid identification, and 3) immunochromatographic detection of antimicrobial residues. FINDINGS: Overall TVCs remain unchanged in the intervention phase (+386 CFU/mL, SE 705, p=0.59). There was a small but significant increase in the microbial diversity in the intervention phase (-0.07 in Simpson's index, SE 0.03, p=0.007), which was not sustained post-intervention (-0.05, SE 0.03, p=0.08). The intervention was associated with increased relative abundance of the Pseudomonas genus (18.3% to 40.5% [+22.2%], SE 5.7%, p<0.001). Extended spectrum beta-lactamases were found in all samples, with NDM-carbapenemase found in 3 drains in 6 samples. Antimicrobial residues were detected in a large proportion of samples (31/115, 27%), suggesting use of sinks for non-handwashing activities. CONCLUSIONS: Metagenomics and other measurements can measure the composition of the drainome and assess the effectiveness of decontamination interventions.

N - acetyl-transferases required for iron uptake and aminoglycoside resistance promote virulence lipid production in M. marinum.

Phagosomal lysis is a key aspect of mycobacterial infection of host macrophages. Acetylation is a protein modification mediated enzymatically by N-acetyltransferases (NATs) that impacts bacterial pathogenesis and physiology. To identify NATs required for lytic activity, we leveraged Mycobacterium marinum, a nontubercular pathogen and an established model for M. tuberculosis. M. marinum hemolysis is a proxy for phagolytic activity. We generated M. marinum strains with deletions in conserved NAT genes and screened for hemolytic activity. Several conserved lysine acetyltransferases (KATs) contributed to hemolysis. Hemolysis is mediated by the ESX-1 secretion system and by phthiocerol dimycocerosate (PDIM), a virulence lipid. For several strains, the hemolytic activity was restored by the addition of second copy of the ESX-1 locus. Using thin-layer chromatography (TLC), we found a single NAT required for PDIM and phenolic glycolipid (PGL) production. MbtK is a conserved KAT required for mycobactin siderophore synthesis and virulence. Mycobactin J exogenously complemented PDIM/PGL production in the Δ mbtK strain. The Δ mbtK M. marinum strain was attenuated in macrophage and Galleria mellonella infection models. Constitutive expression of either eis or papA5, which encode a KAT required for aminoglycoside resistance and a PDIM/PGL biosynthetic enzyme, rescued PDIM/PGL production and virulence of the Δ mbtK strain. Eis N-terminally acetylated PapA5 in vitro , supporting a mechanism for restored lipid production. Overall, our study establishes connections between the MbtK and Eis NATs, and between iron uptake and PDIM and PGL synthesis in M. marinum . Our findings underscore the multifunctional nature of mycobacterial NATs and their connection to key virulence pathways. Significance Statement: Acetylation is a modification of protein N-termini, lysine residues, antibiotics and lipids. Many of the enzymes that promote acetylation belong to the GNAT family of proteins. M. marinum is a well-established as a model to understand how M. tuberculosis causes tuberculosis. In this study we sought to identify conserved GNAT proteins required for early stages of mycobacterial infection. Using M. marinum, we determined that several GNAT proteins are required for the lytic activity of M. marinum. We uncovered previously unknown connections between acetyl-transferases required for iron uptake and antimicrobial resistance, and the production of the unique mycobacterial lipids, PDIM and PGLOur data support that acetyl-transferases from the GNAT family are interconnected, and have activities beyond those previously reported.

Modified Dunn Procedure for Open Reduction of Chronic Slipped Capital Femoral Epiphysis.

Background: Abnormal femoral head anatomy following moderate-to-severe slipped capital femoral epiphysis (SCFE) can lead to femoroacetabular impingement and premature osteoarthritis4-10. Surgical correction at the deformity site through capital reorientation has the potential to fully ameliorate this but has traditionally been associated with high rates of osteonecrosis11-15. The modified Dunn procedure has the potential to restore anatomy in hips with SCFE while protecting the blood supply to the femoral head. Description: A surgical dislocation of the hip is performed according to the technique described by Ganz et al.16. The remaining posterosuperior portion of the greater trochanter is trimmed to the level of the femoral neck by subperiosteal bone removal performed in an inside-out manner. The periosteum of the femoral neck is gradually elevated. The resulting soft-tissue flap, consisting of the retinaculum and external rotators, holds the blood vessels supplying the epiphysis. The femoral epiphysis is pinned in situ (in unstable cases) with threaded Kirschner wires, the ligamentum teres is transected, and the femoral head is dislocated. With the femoral neck exposed, the epiphysis is gradually mobilized from the metaphysis, allowing exposure of the residual femoral neck and inspection of any posteroinferior callus. To avoid tension on the retinacular vessels during reduction of the epiphysis, the posterior neck callus is completely excised. The remaining physis is removed with use of a burr while holding the epiphysis stable. The epiphysis is gently reduced onto the femoral neck, avoiding tension on the retinacular vessels. If tension is noted, the femoral neck is rechecked for residual callus, which is excised. If no callus is found, the neck may be carefully shortened in order to minimize tension. Epiphyseal fixation is achieved with use of a 3-mm fully threaded wire inserted antegrade through the fovea to the lateral cortex below the greater trochanter. A second wire is inserted retrograde under fluoroscopy. After reducing the hip, the capsule is closed and the greater trochanter is reattached with use of 3.5-mm cortical screws. Alternatives: Alternatives include nonoperative treatment, in situ fixation (e.g., pinning or screw fixation), gentle closed reduction with pinning, and triplanar trochanteric osteotomy (e.g., Imhauser or Southwick osteotomies). Rationale: In situ pinning of mild-to-moderate, stable SCFE yields good long-term results with low rates of osteonecrosis9. Treatment of higher-grade SCFE without reduction aims to avoid osteonecrosis and assumes that the proximal femoral deformity will remodel; however, the head-neck offset will remain abnormal, risking impingement and early-onset osteoarthritis5,8. The procedure described in the present article allows anatomic reduction of the epiphysis with a low risk of osteonecrosis. Surgical dislocation of the hip16 with development of an extended retinacular soft-tissue flap17 provides extensive subperiosteal exposure of the circumferential femoral neck and preserves the vulnerable blood supply to the epiphysis18. The Dunn subcapital realignment procedure15 with callus removal and slip angle correction allows anatomic restoration of the proximal femur. Expected Outcomes: Reported results of various centers performing the procedure vary greatly with regard to the number of hips treated and the follow-up time. Most studies have been retrospective and have lacked a control group. The reported risk of osteonecrosis ranges from 0% to 25.9%19, with the wide range most likely because of the challenging nature of the technique, the low number of cases per surgeon, and the long learning curve associated with the procedure. In centers with extensive experience in pediatric hip-preserving surgery, the reported rate of osteonecrosis is low3. Studies with mid to long-term follow-up have shown no conversion to total hip arthroplasty3,20,21, but residual deformities can persist, and subsequent surgery is possible. Important Tips: Extensive experience in surgical hip dislocation and retinacular flap development is a prerequisite for successful outcomes and low rates of osteonecrosis.Sufficient callus and physeal remnant resections are needed to avoid tension on the retinacular vessels during epiphyseal reduction.The skin incision should be centered over the greater trochanterThe Gibson interval must be carefully prepared for adequate release and to avoid injury.Tension on the periosteal flap should be avoided to prevent stress on the retinacular vessels. Acronyms and Abbreviations: AP = anteroposteriorAVN = avascular necrosis (i.e., osteonecrosis)CI = confidence intervalCT = computed tomographyK-wire = Kirschner wireMRI = magnetic resonance imagingOA = osteoarthritisSHD = surgical hip dislocationTHA = total hip arthroplastyVTE = venous thromboembolism.

Moisture availability and groundwater recharge paced by orbital forcing over the past 750,000 years in the southwestern USA.

Quaternary climate changes are driven in part by variations in the distribution and strength of insolation due to orbital parameters. Continental climate variability is well documented for the most recent glacial-interglacial cycles, yet few records extend further back in time. Such records are critically needed to comprehensively assess the entire spectrum of natural climate variability against the backdrop of anthropogenic warming. Here, we apply uranium isotope geochronology to calcite deposits to date groundwater-table changes in Devils Hole cave, Nevada. The deposits record multi-meter groundwater-table fluctuations over the last 750,000 years, reflecting the long-term evolution of hydroclimate in this presently arid region. During periods between glacial or interglacial extremes, the water table responded sensitively to variations in 65°N summer insolation, likely caused by the increasing extent of North American ice sheets during cold period, which steered moisture-laden trajectories towards the southwestern USA. These orbitally-driven hydroclimatic changes are superimposed on a tectonically-driven long-term decline in the regional groundwater table observed prior to 438,000 ± 14,000 years ago.

Aptis Distal Radioulnar Joint Arthroplasty: A Multicenter Evaluation of Functional Outcomes, Complications, and Patient Satisfaction.

Background The Aptis distal radioulnar joint (DRUJ) implant has been commonly used to replace the DRUJ and restore wrist function in patients with a severely destroyed DRUJ. Objective Promising results have been described in the literature. However, the clinical results in a multicenter setting are sparse and variable. This study evaluates the short- to midterm clinical results of 53 patients with a (mean) follow-up of 51 months. Patients and Methods Fifty-three patients (59 implants) treated between 2011 and 2020 in three different institutions were retrospectively identified in a prospectively collected database. The main indication for Aptis DRUJ arthroplasty was a destroyed DRUJ and gross distal radioulnar instability and isolated DRUJ osteoarthritis. Functional outcome, complications, and patient satisfaction were evaluated. Patients completed the Patient-Rated Wrist Evaluation (PRWE) questionnaire and an additional questionnaire about patient satisfaction and return to hobby/work. Results Implant survival was 92%, the surgical follow-up showed many complications (64,4%), and revision surgery was needed frequently (40.7%). In 13 cases, the follow-up was longer than 5 years. Three reimplantations had to be performed and two implants were permanently explanted. In spite of this all, wrist and forearm motion as well as pain reduction was adequate and patient satisfaction was reasonable (72.2%). Conclusion The Aptis DRUJ arthroplasty is a viable option that can provide adequate wrist and forearm function after secure patient selection and surgical placement of the implant in the wrist with a good bone stock of the radius. The complication rate was found to be high, yet patient satisfaction was reasonable. In the case of secondary surgery, additional surgery seems to be needed. For primary surgery, the implant seems to be successful without complications. Different complications have been described, but further analysis is warranted to find the causes of complications and to objectify the performance of the Aptis DRUJ implant. Level of Evidence IV.