Wearable Devices in Cardiovascular Medicine.

Wearable devices, such as smartwatches and activity trackers, are commonly used by patients in their everyday lives to manage their health and well-being. These devices collect and analyze long-term continuous data on measures of behavioral or physiologic function, which may provide clinicians with a more comprehensive view of a patients' health compared with the traditional sporadic measures captured by office visits and hospitalizations. Wearable devices have a wide range of potential clinical applications ranging from arrhythmia screening of high-risk individuals to remote management of chronic conditions such as heart failure or peripheral artery disease. As the use of wearable devices continues to grow, we must adopt a multifaceted approach with collaboration among all key stakeholders to effectively and safely integrate these technologies into routine clinical practice. In this Review, we summarize the features of wearable devices and associated machine learning techniques. We describe key research studies that illustrate the role of wearable devices in the screening and management of cardiovascular conditions and identify directions for future research. Last, we highlight the challenges that are currently hindering the widespread use of wearable devices in cardiovascular medicine and provide short- and long-term solutions to promote increased use of wearable devices in clinical care.

Genome Sequencing as an Alternative to Cytogenetic Analysis in Myeloid Cancers.

BACKGROUND: Genomic analysis is essential for risk stratification in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). Whole-genome sequencing is a potential replacement for conventional cytogenetic and sequencing approaches, but its accuracy, feasibility, and clinical utility have not been demonstrated. METHODS: We used a streamlined whole-genome sequencing approach to obtain genomic profiles for 263 patients with myeloid cancers, including 235 patients who had undergone successful cytogenetic analysis. We adapted sample preparation, sequencing, and analysis to detect mutations for risk stratification using existing European Leukemia Network (ELN) guidelines and to minimize turnaround time. We analyzed the performance of whole-genome sequencing by comparing our results with findings from cytogenetic analysis and targeted sequencing. RESULTS: Whole-genome sequencing detected all 40 recurrent translocations and 91 copy-number alterations that had been identified by cytogenetic analysis. In addition, we identified new clinically reportable genomic events in 40 of 235 patients (17.0%). Prospective sequencing of samples obtained from 117 consecutive patients was performed in a median of 5 days and provided new genetic information in 29 patients (24.8%), which changed the risk category for 19 patients (16.2%). Standard AML risk groups, as defined by sequencing results instead of cytogenetic analysis, correlated with clinical outcomes. Whole-genome sequencing was also used to stratify patients who had inconclusive results by cytogenetic analysis into risk groups in which clinical outcomes were measurably different. CONCLUSIONS: In our study, we found that whole-genome sequencing provided rapid and accurate genomic profiling in patients with AML or MDS. Such sequencing also provided a greater diagnostic yield than conventional cytogenetic analysis and more efficient risk stratification on the basis of standard risk categories. (Funded by the Siteman Cancer Research Fund and others.).

Comparable Clinical and Functional Outcomes Between Osteochondral Allograft Transplantation and Autologous Chondrocyte Implantation for Articular Cartilage Lesions in the Patellofemoral Joint at a Mean Follow-up of 5 Years.

PURPOSE: To assess clinical outcomes and return to sport (RTS) rates among patients that undergo osteochondral allograft (OCA) transplantation and autologous chondrocyte implantation (ACI) or matrix-induced autologous chondrocyte implantation (MACI), for patellofemoral articular cartilage defects. METHODS: A retrospective review of patients who underwent an OCA or ACI/MACI from 2010-2020 was conducted. Patient-reported outcomes (PROs) collected included: Visual Analog Scale for pain/satisfaction, Knee Injury and Osteoarthritis Outcome Score (KOOS), and RTS. The percentage of patients that met the Patient Acceptable Symptom State (PASS) for KOOS was recorded. Logistic regression was used to identify predictors of worse outcomes. RESULTS: A total of 95 patients were included (78% follow-up) with ACI or MACI performed in 55 cases (57.9%) and OCA in 40 (42.1%). A tibial tubercle osteotomy was the most common concomitant procedure for OCA (66%) and ACI/MACI (98%). Overall, KOOS pain was significantly poorer in OCA than ACI/MACI (74.7, 95% CI [68.1, 81.1] vs 83.6, 95% CI [81.3, 88.4], p= 0.012), while the remaining KOOS subscores were non-significantly different (all p>0.05). Overall, RTS rate was 54%, with no significant difference in return between OCA or ACI/MACI (52% vs 58%, p= 0.738). There were 26 (27%) reoperations and 5 (5%) graft failures in the entire group. Increasing age was associated with lower satisfaction in OCA and poorer outcomes in ACI/MACI, while larger lesion area was associated with lower satisfaction and poorer outcomes in ACI/MACI. CONCLUSION: Clinical and functional outcomes were similar in patients that underwent OCA or ACI/MACI for patellofemoral articular cartilage defects at a mean follow-up of 5 years. Patients who received OCA had a higher proportion of degenerative cartilage lesions and, among those with trochlear lesions, reported higher pain at final follow-up than their ACI/MACI counterparts. Overall, increasing age and a larger lesion size were associated with worse patient-reported outcomes.

Patients who undergo tibial tubercle anteromedialization with medial patellofemoral ligament reconstruction demonstrate similar rates of return to sport compared to isolated MPFL reconstruction.

PURPOSE: To investigate the rate of return to sports and sport psychological readiness between patients who underwent isolated MPFLR (iMPFLR) compared to a matched cohort of patients who underwent MPFLR with anteromedializing tibial tubercle osteotomy (MPFLR/TTO). METHODS: Patients who underwent primary MPFLR with or without TTO for recurrent patellar instability were retrospectively reviewed from 2012 to 2020 at a single institution. Preinjury sport and work information, Kujala, Tegner, Visual Analogue Score for pain, satisfaction and MPFL-Return to Sport after Injury (MPFL-RSI) score were collected. Two readers independently measured the tibial tuberosity-trochlear groove distance, Caton-Deschamps index and Dejour classification for trochlear dysplasia. Patients in iMPFLR and MPFLR/TTO groups were matched 1:1 on age, sex, body mass index and follow-up length. Multivariate regression analysis was performed to determine whether the MPFL-RSI was associated with a return to sport. RESULTS: This study included 74 patients at mean follow-up of 52.5 months (range: 24-117). These groups returned to sport at similar rates (iMPFLR: 67.6%, MPFLR/TTO: 73.0%, not significant [ns]), though iMPFLR patients returned more quickly (8.4 vs. 12.8 months, p = 0.019). Rates of return to preinjury sport level were also similar (45.9% vs. 40.5%, ns). Patients with Dejour B/C took more time to return to sport compared to patients with mild/no trochlear pathology (13.8 vs. 7.9 months, p = 0.003). Increasing MPFL-RSI score was significantly predictive of the overall return to sport (odds ratio [OR]: 1.08, 95% confidence interval [CI] [1.03, 1.13], p < 0.001) and return to preinjury level (OR: 1.07, 95% CI [1.04, 1.13], p < 0.001). Most patients in iMPFLR and MPFLR/TTO groups resumed work (95.7% vs. 88.5%, ns), though iMPFLR patients who returned to preinjury work levels did so more quickly (1.7 vs. 4.6 months, p = 0.005). CONCLUSION: Patients who underwent MPFLR with anteromedializing TTO demonstrated similar rates of return to sport and psychological readiness compared to an isolated MPFLR matched comparison group, though iMPFLRs returned more quickly. Patients with more severe trochlear pathology required more time to return to sports. LEVEL OF EVIDENCE: Level III.

Decreased "Polar Axis Angle" is Associated with Instability after Total Hip Arthroplasty: A New Method to Assess Functional Component Position on Lateral Seated Radiographs.

BACKGROUND: Research on hip instability has focused on establishing "safe" ranges of combined component position in supine posture or functional placement of the acetabular component based on the hip-spine relationship. A new angle, the polar axis angle (PAA), of the total hip arthroplasty (THA) components describes the concentricity of both components and can be evaluated in functional positions that confer a greater risk of instability (i.e., sitting). The goal of this study was to compare the polar axis angle in functional positions between patients who experienced a postoperative dislocation, and a matched control group who did not have a dislocation. METHODS: An institutional database was searched for patients experiencing a dislocation after primary THA. Patients who had postoperative full-length standing and seated lateral radiographs were included in the dislocator group. A control group of non-dislocator patients was matched 2:1 by age, body mass index (BMI), sex, and hip-spine classification. Radiographic measurements of the neck angle, acetabular ante-inclination, and polar axis angle (PAA) were performed by two separate blinded, trained reviewers. RESULTS: The lateral seated neck angle and lateral seated polar axis angle measurements were significantly lower in the dislocator groups (n = 37) when compared with the control group (n = 74) (23 versus 33 degrees, P < 0.001; 74 versus 83 degrees, P = 0.012, respectively). Significant differences were also observed in changes in the polar axes and neck angles between standing and seated positions (P < 0.001 and P < 0.001, respectively). When comparing patients who have mobile spines versus stiff spines within the dislocator group, there were no differences in the acetabular, neck, or polar axis angles. The effect of neck angle on the polar axis angle showed a linear trend across cohorts. CONCLUSIONS: Patients who experience postoperative instability have a significantly lower polar axis angle on lateral seated radiographs when matched for age, sex, BMI, and hip-spine classification. In addition, the lower seated polar axis angle is driven more strongly by decreased functional femoral anteversion, which emphasizes the role of functional femoral version on stability in THA.

Enhancer transcription identifies cis-regulatory elements for photoreceptor cell types.

Identification of cell type-specific cis-regulatory elements (CREs) is crucial for understanding development and disease, although identification of functional regulatory elements remains challenging. We hypothesized that context-specific CREs could be identified by context-specific non-coding RNA (ncRNA) profiling, based on the observation that active CREs produce ncRNAs. We applied ncRNA profiling to identify rod and cone photoreceptor CREs from wild-type and mutant mouse retinas, defined by presence or absence, respectively, of the rod-specific transcription factor (TF) NrlNrl-dependent ncRNA expression strongly correlated with epigenetic profiles of rod and cone photoreceptors, identified thousands of candidate rod- and cone-specific CREs, and identified motifs for rod- and cone-specific TFs. Colocalization of NRL and the retinal TF CRX correlated with rod-specific ncRNA expression, whereas CRX alone favored cone-specific ncRNA expression, providing quantitative evidence that heterotypic TF interactions distinguish cell type-specific CRE activity. We validated the activity of novel Nrl-dependent ncRNA-defined CREs in developing cones. This work supports differential ncRNA profiling as a platform for the identification of cell type-specific CREs and the discovery of molecular mechanisms underlying TF-dependent CRE activity.

Adjusting expected deaths for mortality displacement during the COVID-19 pandemic: a model based counterfactual approach at the level of individuals.

BACKGROUND: Near-real time surveillance of excess mortality has been an essential tool during the COVID-19 pandemic. It remains critical for monitoring mortality as the pandemic wanes, to detect fluctuations in the death rate associated both with the longer-term impact of the pandemic (e.g. infection, containment measures and reduced service provision by the health and other systems) and the responses that followed (e.g. curtailment of containment measures, vaccination and the response of health and other systems to backlogs). Following the relaxing of social distancing regimes and reduction in the availability of testing, across many countries, it becomes critical to measure the impact of COVID-19 infection. However, prolonged periods of mortality in excess of the expected across entire populations has raised doubts over the validity of using unadjusted historic estimates of mortality to calculate the expected numbers of deaths that form the baseline for computing numbers of excess deaths because many individuals died earlier than they would otherwise have done: i.e. their mortality was displaced earlier in time to occur during the pandemic rather than when historic rates predicted. This is also often termed "harvesting" in the literature. METHODS: We present a novel Cox-regression-based methodology using time-dependent covariates to estimate the profile of the increased risk of death across time in individuals who contracted COVID-19 among a population of hip fracture patients in England (N = 98,365). We use these hazards to simulate a distribution of survival times, in the presence of a COVID-19 positive test, and then calculate survival times based on hazard rates without a positive test and use the difference between the medians of these distributions to estimate the number of days a death has been displaced. This methodology is applied at the individual level, rather than the population level to provide a better understanding of the impact of a positive COVID-19 test on the mortality of groups with different vulnerabilities conferred by sociodemographic and health characteristics. Finally, we apply the mortality displacement estimates to adjust estimates of excess mortality using a "ball and urn" model. RESULTS: Among the exemplar population we present an end-to-end application of our methodology to estimate the extent of mortality displacement. A greater proportion of older, male and frailer individuals were subject to significant displacement while the magnitude of displacement was higher in younger females and in individuals with lower frailty: groups who, in the absence of COVID-19, should have had a substantial life expectancy. CONCLUSION: Our results indicate that calculating the expected number of deaths following the first wave of the pandemic in England based solely on historical trends results in an overestimate, and excess mortality will therefore be underestimated. Our findings, using this exemplar dataset are conditional on having experienced a hip fracture, which is not generalisable to the general population. Fractures that impede mobility in the weeks that follow the accident/surgery considerably shorten life expectancy and are in themselves markers of significant frailty. It is therefore important to apply these novel methods to the general population, among whom we anticipate strong patterns in mortality displacement - both in its length and prevalence - by age, sex, frailty and types of comorbidities. This counterfactual method may also be used to investigate a wider range of disruptive population health events. This has important implications for public health monitoring and the interpretation of public health data in England and globally.

The impact of the COVID-19 pandemic on cardiovascular disease prevention and corresponding geographical inequalities in England: interrupted time series analysis.

BACKGROUND: There has been disruption to the detection and management of those with hypertension and atrial fibrillation (AF) during the COVID-19 pandemic. This is likely to vary geographically and could have implications for future mortality and morbidity. We aimed to estimate the change in diagnosed prevalence, treatment and prescription indicators for AF and hypertension and assess corresponding geographical inequalities. METHODS: Using the Quality and Outcomes Framework (2016/17 to 2021/22) and the English Prescribing Datasets (2018 to 2022), we described age standardised prevalence, treatment and prescription item rates for hypertension and AF by geography and over time. Using an interrupted time-series (ITS) analysis, we estimated the impact of the pandemic (from April 2020) on missed diagnoses and on the percentage change in medicines prescribed for these conditions. Finally, we described changes in treatment indicators against Public Health England 2029 cardiovascular risk targets. RESULTS: We observed 143,822 fewer (-143,822, 95%CI:-226,144, -61,500, p = 0.001) diagnoses of hypertension, 60,330 fewer (-60,330, 95%CI: -83,216, -37,444, p = 0.001) diagnoses of AF and 1.79% fewer (-1.79%, 95%CI: -2.37%, -1.22%), p < 0.0001) prescriptions for these conditions over the COVID-19 impact period. There was substantial variation across geography in England in terms of the indirect impact of the COVID-19 pandemic on the diagnosis, prescription, and treatment rates of hypertension and AF. 20% of Sub Integrated Care Boards account for approximately 62% of all missed diagnoses of hypertension. The percentage of individuals who had their hypertension controlled fell from 75.8% in 2019/20 to 64.1% in 2021/22 and the percentage of individuals with AF who were risk assessed fell from 97.2% to 90.7%. CONCLUSIONS: Hypertension and AF detection and management were disrupted during the COVID-19 pandemic. The disruption varied considerably across diseases and geography. This highlights the utility of administrative and geographically granular datasets to inform targeted efforts to mitigate the indirect impacts of the pandemic through applied secondary prevention measures.

Thyroid hormone receptors mediate two distinct mechanisms of long-wavelength vision.

Thyroid hormone (TH) signaling plays an important role in the regulation of long-wavelength vision in vertebrates. In the retina, thyroid hormone receptor ß (thrb) is required for expression of long-wavelength-sensitive opsin (lws) in red cone photoreceptors, while in retinal pigment epithelium (RPE), TH regulates expression of a cytochrome P450 enzyme, cyp27c1, that converts vitamin A1 into vitamin A2 to produce a red-shifted chromophore. To better understand how TH controls these processes, we analyzed the phenotype of zebrafish with mutations in the three known TH nuclear receptor transcription factors (thraa, thrab, and thrb). We found that no single TH nuclear receptor is required for TH-mediated induction of cyp27c1 but that deletion of all three (thraa-/-;thrab-/-;thrb-/- ) completely abrogates its induction and the resulting conversion of A1- to A2-based retinoids. In the retina, loss of thrb resulted in an absence of red cones at both larval and adult stages without disruption of the underlying cone mosaic. RNA-sequencing analysis revealed significant down-regulation of only five genes in adult thrb-/- retina, of which three (lws1, lws2, and miR-726) occur in a single syntenic cluster. In the thrb-/- retina, retinal progenitors destined to become red cones were transfated into ultraviolet (UV) cones and horizontal cells. Taken together, our findings demonstrate cooperative regulation of cyp27c1 by TH receptors and a requirement for thrb in red cone fate determination. Thus, TH signaling coordinately regulates both spectral sensitivity and sensory plasticity.

Mortality and Complications Following Early Conversion Arthroplasty for Failed Hip Fracture Surgery.

BACKGROUND: Hip fracture in older patients leads to high morbidity and mortality. Patients who are treated surgically but fail acutely face a more complex operation with conversion total hip arthroplasty (THA). This study investigated mortalities and complications in patients who experienced failure within one year following hip fracture surgery requiring conversion THA. METHODS: Patients aged 60 years or more undergoing conversion THA within one year following intertrochanteric or femoral neck fracture were identified and propensity-matched to patients sustaining hip fractures treated surgically but not requiring conversion within the first year. Patients who had two-year follow-up (91 conversions; 247 comparisons) were analyzed for 6-month, 12-month, and 24-month mortalities, 90-day readmissions, surgical complications, and medical complications. RESULTS: Nonunion and screw cutout were the most common indications for conversion THA. Mortalities were similar between groups at 6 months (7.7% conversion versus 6.1% nonconversion, P = .774), 12 months (11% conversion versus 12% nonconversion, P = .999), and 24 months (14% conversion versus 22% nonconversion, P = .163). Survivorships were similar between groups for the entire cohort and by fracture type. Conversion THA had a higher rate of 90-day readmissions (14% versus 3.2%, P = .001), and medical complications (17% versus 6.1%, P = .006). Inpatient and 90-day orthopaedic complications were similar. CONCLUSION: Conversion THA for failed hip fracture surgery had comparable mortality rates to hip fracture surgery, with higher rates of perioperative medical complications and readmissions. Conversion THA following hip fracture represents a potential "second hit" that both surgeons and patients should be aware of with initial decision-making.

The impact of clonal diversity and mosaicism on haematopoietic function in Fanconi anaemia.

Recent advances have facilitated studies of the clonal architecture of the aging haematopoietic system, and provided clues to the mechanisms underlying the origins of hematopoietic malignancy. Much less is known about the clonal composition of haematopoiesis and its impact in bone marrow failure (BMF) disorders, including Fanconi anaemia (FA). Understanding clonality in FA is likely to inform both the marked predisposition to cancer and the rapid erosion of regenerative reserve seen with this disease. This may also hold broader lessons for haematopoietic stem cell biology in other diseases with a clonal restriction. In this review, we focus on the conceptual basis and available tools to study clonality, and highlight insights in somatic mosaicism and malignant evolution in FA in the context of haematopoietic failure and gene therapy.

Early SARS-CoV-2-associated acute transverse myelitis: A case for neurotropism?

There are increasing reports of immune-mediated and para-infectious syndromes beyond the well-known respiratory manifestations of severe-acute-respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the spectrum of severe neurological sequelae of SARS-CoV-2 remains undefined. We present the case of a 66-year-old female with rapidly progressive lower limb neurology 3 days post SARS-CoV-2 infection. Clinical and radiological findings were in keeping with transverse myelitis and treatment success was achieved with methylprednisolone and remdesivir. This report will discuss the associations between SARS-CoV-2 and acute transverse myelitis. We believe this is one of few described cases of early SARS-CoV-2-associated transverse myelitis secondary to neurotropism and the first successfully treated with the inclusion of remdesivir in the therapeutic regimen.

Clinical Decision Support for Laboratory Testing.

BACKGROUND: As technology enables new and increasingly complex laboratory tests, test utilization presents a growing challenge for healthcare systems. Clinical decision support (CDS) refers to digital tools that present providers with clinically relevant information and recommendations, which have been shown to improve test utilization. Nevertheless, individual CDS applications often fail, and implementation remains challenging. CONTENT: We review common classes of CDS tools grounded in examples from the literature as well as our own institutional experience. In addition, we present a practical framework and specific recommendations for effective CDS implementation. SUMMARY: CDS encompasses a rich set of tools that have the potential to drive significant improvements in laboratory testing, especially with respect to test utilization. Deploying CDS effectively requires thoughtful design and careful maintenance, and structured processes focused on quality improvement and change management play an important role in achieving these goals.

Clinical impact of whole-genome sequencing in patients with early-onset dementia.

BACKGROUND: In the clinical setting, identification of the genetic cause in patients with early-onset dementia (EOD) is challenging due to multiple types of genetic tests required to arrive at a diagnosis. Whole-genome sequencing (WGS) has the potential to serve as a single diagnostic platform, due to its superior ability to detect common, rare and structural genetic variation. METHODS: WGS analysis was performed in 50 patients with EOD. Point mutations, small insertions/deletions, as well as structural variants (SVs) and short tandem repeats (STRs), were analysed. An Alzheimer's disease (AD)-related polygenic risk score (PRS) was calculated in patients with AD. RESULTS: Clinical genetic diagnosis was achieved in 7 of 50 (14%) of the patients, with a further 8 patients (16%) found to have established risk factors which may have contributed to their EOD. Two pathogenic variants were identified through SV analysis. No expanded STRs were found in this study cohort, but a blinded analysis with a positive control identified a C9orf72 expansion accurately. Approximately 37% (7 of 19) of patients with AD had a PRS equivalent to >90th percentile risk. DISCUSSION: WGS acts as a single genetic test to identify different types of clinically relevant genetic variations in patients with EOD. WGS, if used as a first-line clinical diagnostic test, has the potential to increase the diagnostic yield and reduce time to diagnosis for EOD.

Trends in Irish hip fracture surgery over a 7-year period and international registry comparison.

BACKGROUND: Hip fractures are a significant cause of morbidity and mortality in elderly patients. Timely surgical fixation and early mobilisation are the cornerstone to successful outcomes. The Irish Hip Fracture Database (IHFD) was established in 2012 and publishes annual reports on hip fracture care. This paper describes the trends in surgical fixation in Ireland during a 7-year period (2013-2019), assesses for compliance with guidelines and compares the most recent published reports from ten international hip fracture registries. METHODS: All published IHFD reports were systematically reviewed and tabulated. Data corresponding to demographics, fracture type, surgical fixation and post-operative management was plotted and analysed. Ten international hip fracture registries were identified and reviewed. Data was extracted corresponding to the IHFD dataset. RESULTS: A total of 21,684 hip fractures were recorded during this period. The majority of patients were female (70.16%), >80 years old (58.26%), admitted from their own home (82.13%) and ASA grade 3 (53%). The majority of undisplaced and displaced intracapsular fractures were treated with hemiarthroplasty, 62% and 88% respectively. There has been a decline in the use of dynamic hip screw (DHS) for intertrochanteric fractures with intramedullary nails being favoured. CONCLUSION: Despite greater awareness of hip fracture care through the IHFD and the introduction of Best Practice Tariffs (BPT), further improvements are needed. Ireland compares well to international standards but has low rates of compliance to NICE guidelines for surgical fixation.

Conditional targeting in mice reveals that hepatic homogentisate 1,2-dioxygenase activity is essential in reducing circulating homogentisic acid and for effective therapy in the genetic disease alkaptonuria.

Alkaptonuria is an inherited disease caused by homogentisate 1,2-dioxygenase (HGD) deficiency. Circulating homogentisic acid (HGA) is elevated and deposits in connective tissues as ochronotic pigment. In this study, we aimed to define developmental and adult HGD tissue expression and determine the location and amount of gene activity required to lower circulating HGA and rescue the alkaptonuria phenotype. We generated an alkaptonuria mouse model using a knockout-first design for the disruption of the HGD gene. Hgd tm1a -/- mice showed elevated HGA and ochronosis in adulthood. LacZ staining driven by the endogenous HGD promoter was localised to only liver parenchymal cells and kidney proximal tubules in adulthood, commencing at E12.5 and E15.5 respectively. Following removal of the gene trap cassette to obtain a normal mouse with a floxed 6th HGD exon, a double transgenic was then created with Mx1-Cre which conditionally deleted HGD in liver in a dose dependent manner. 20% of HGD mRNA remaining in liver did not rescue the disease, suggesting that we need more than 20% of liver HGD to correct the disease in gene therapy. Kidney HGD activity which remained intact reduced urinary HGA, most likely by increased absorption, but did not reduce plasma HGA nor did it prevent ochronosis. In addition, downstream metabolites of exogenous 13C6-HGA, were detected in heterozygous plasma, revealing that hepatocytes take up and metabolise HGA. This novel alkaptonuria mouse model demonstrated the importance of targeting liver for therapeutic intervention, supported by our observation that hepatocytes take up and metabolise HGA.

A massively parallel reporter assay reveals context-dependent activity of homeodomain binding sites in vivo.

Cone-rod homeobox (CRX) is a paired-like homeodomain transcription factor (TF) and a master regulator of photoreceptor development in vertebrates. The in vitro DNA binding preferences of CRX have been described in detail, but the degree to which in vitro binding affinity is correlated with in vivo enhancer activity is not known. In addition, paired-class homeodomain TFs can bind DNA cooperatively as both homodimers and heterodimers at inverted TAAT half-sites separated by 2 or 3 nucleotides. This dimeric configuration is thought to mediate target specificity, but whether monomeric and dimeric sites encode distinct levels of activity is not known. Here, we used a massively parallel reporter assay to determine how local sequence context shapes the regulatory activity of CRX binding sites in mouse photoreceptors. We assayed inactivating mutations in more than 1700 TF binding sites and found that dimeric CRX binding sites act as stronger enhancers than monomeric CRX binding sites. Furthermore, the activity of dimeric half-sites is cooperative, dependent on a strict 3-bp spacing, and tuned by the identity of the spacer nucleotides. Saturating single-nucleotide mutagenesis of 195 CRX binding sites showed that, on average, changes in TF binding site affinity are correlated with changes in regulatory activity, but this relationship is obscured when considering mutations across multiple cis-regulatory elements (CREs). Taken together, these results demonstrate that the activity of CRX binding sites is highly dependent on sequence context, providing insight into photoreceptor gene regulation and illustrating functional principles of homeodomain binding sites that may be conserved in other cell types.

Management of bile duct stones at cholecystectomy: an Australian single-centre experience over 2 years.

BACKGROUND: Bile duct stones with an intact gallbladder can be treated with either bile duct exploration at cholecystectomy or endoscopic retrograde cholangiopancreatography (ERCP) before or after cholecystectomy. The aim of this study was to evaluate the management of bile duct stones at cholecystectomy at our institution. We also aimed to identify risk factors for failure of ductal clearance in our series. METHODS: A retrospective review of 690 laparoscopic cholecystectomies over a 2-year period was performed. Patients who underwent laparoscopic bile duct exploration formed the study population. RESULTS: Of 69 patients with suspected bile duct stones at cholecystectomy 67 (97%) patients underwent laparoscopic bile duct exploration upfront. Complete ductal clearance was achieved in 52 (78%) patients. Postoperative complications (10/67, 15%) included postoperative bleeding (2/67, 3%), bile leak (1/67, 1%), and superficial wound infection (1/67, 1%). There was no mortality. The mean operative time was 126 min and the median length of stay was 2 (1-4) days. A wider common bile duct (CBD) (≥ 8 mm) increased the risk of failed ductal clearance (OR 4.50; 95% confidence interval (CI) 1.15-19.23). CONCLUSION: This study found that laparoscopic bile duct exploration can effectively and safely treat bile duct stones suspected at cholecystectomy.

The increasing impact of length of stay "outliers" on length of stay at an urban academic hospital.

BACKGROUND: As healthcare systems strive for efficiency, hospital "length of stay outliers" have the potential to significantly impact a hospital's overall utilization. There is a tendency to exclude such "outlier" stays in local quality improvement and data reporting due to their assumed rare occurrence and disproportionate ability to skew mean and other summary data. This study sought to assess the influence of length of stay (LOS) outliers on inpatient length of stay and hospital capacity over a 5-year period at a large urban academic medical center. METHODS: From January 2014 through December 2019, 169,645 consecutive inpatient cases were analyzed and assigned an expected LOS based on national academic center benchmarks. Cases in the top 1% of national sample LOS by diagnosis were flagged as length of stay outliers. RESULTS: From 2014 to 2019, mean outlier LOS increased (40.98 to 45.11 days), as did inpatient LOS with outliers excluded (5.63 to 6.19 days). Outlier cases increased both in number (from 297 to 412) and as a percent of total discharges (0.98 to 1.56%), and outlier patient days increased from 6.7 to 9.8% of total inpatient plus observation days over the study period. CONCLUSIONS: Outlier cases utilize a disproportionate and increasing share of hospital resources and available beds. The current tendency to exclude such outlier stays in data reporting due to assumed rare occurrence may need to be revisited. Outlier stays require distinct and targeted interventions to appropriately reduce length of stay to both improve patient care and maintain hospital capacity.

The majority of athletes fail to return to play following anterior cruciate ligament reconstruction due to reasons other than the operated knee.

PURPOSE: The purpose of this study is to evaluate the reasons why athletes do not return to play (RTP) following anterior cruciate ligament (ACL) reconstruction from a large single-centre database. METHODS: The institutional ACL registry was screened for patients that had undergone a primary ACLR and had RTP status reported at 24-month follow-up. The reasons that patients were unable to RTP at 24 months were evaluated. The ACL-Return to Sport Index (ACL-RSI) was evaluated at baseline and 24-month follow-up to evaluate psychological ability to RTP. RESULTS: At 2 years, 1140 patients returned to play, and 222 had not returned to play. The most common reasons athletes were unable to return was fear of reinjury (27.5%), lack of confidence in performance on return (19.4%) and external life factors (16.6%), i.e. work commitments and family reasons. Other reasons for athletes not returning to play were residual knee pain (10%) and subsequent injury (5%). The ACL-RSI score was significantly lower at diagnosis (40.3 vs. 49.3; p = 0.003) and 2 years (41.8 vs. 78.7; p < 0.0001) in athletes who did not return to play vs. those that did RTP. CONCLUSION: The majority of patients that report they have not returned to play do so due to external life and psychological factors associated with their injury, including fear of reinjury and lack of confidence in performance. A small minority of patients were unable to return due to residual knee symptoms or reinjury. Pre-operative psychological assessment and intervention may identify those less likely to RTP and provide an opportunity for targeted interventions to further improve RTP outcomes. LEVEL OF EVIDENCE: III.