Roles for actin assembly in endocytosis.

Endocytosis includes a number of processes by which cells internalize segments of their plasma membrane, enclosing a wide variety of material from outside the cell. Endocytosis can contribute to uptake of nutrients, regulation of signaling molecules, control of osmotic pressure, and function of synapses. The actin cytoskeleton plays an essential role in several of these processes. Actin assembly can create protrusions that encompass extracellular materials. Actin can also support the processes of invagination of a membrane segment into the cytoplasm, elongation of the invagination, scission of the new vesicle from the plasma membrane, and movement of the vesicle away from the membrane. We briefly discuss various types of endocytosis, including phagocytosis, macropinocytosis, and clathrin-independent endocytosis. We focus mainly on new findings on the relative importance of actin in clathrin-mediated endocytosis (CME) in yeast versus mammalian cells.

Capping protein regulators fine-tune actin assembly dynamics.

Capping protein (CP) binds the fast growing barbed end of the actin filament and regulates actin assembly by blocking the addition and loss of actin subunits. Recent studies provide new insights into how CP and barbed-end capping are regulated. Filament elongation factors, such as formins and ENA/VASP (enabled/vasodilator-stimulated phosphoprotein), indirectly regulate CP by competing with CP for binding to the barbed end, whereas other molecules, including V-1 and phospholipids, directly bind to CP and sterically block its interaction with the filament. In addition, a diverse and unrelated group of proteins interact with CP through a conserved 'capping protein interaction' (CPI) motif. These proteins, including CARMIL (capping protein, ARP2/3 and myosin I linker), CD2AP (CD2-associated protein) and the WASH (WASP and SCAR homologue) complex subunit FAM21, recruit CP to specific subcellular locations and modulate its actin-capping activity via allosteric effects.

Do Phosphodiesterase Type 5 Inhibitors Increase the Risk of Biochemical Recurrence After Radical Prostatectomy?

PURPOSE: There have been conflicting studies on the association between phosphodiesterase type 5 inhibitor (PDE5i) use and biochemical recurrence (BCR) following radical prostatectomy (RP). Our aim was to determine whether PDE5i drug exposure after RP increases the risk of BCR in patients undergoing RP. MATERIALS AND METHODS: An institutional database of prostate cancer patients treated between January 2009 and December 2020 was reviewed. BCR was defined as 2 PSA measurements greater than 0.1 ng/mL. PDE5i exposure was defined using a 0 to 3 scale, with 0 representing never use, 1 sometimes use, 2 regularly use, and 3 routinely use. The risk of BCR with any PDE5i exposure, the quantity of exposure, and the duration of PDE5i exposure were assessed by multivariable Cox proportional hazards models. RESULTS: The sample size included 4630 patients to be analyzed, with 776 patients having BCR. The median follow-up for patients without BCR was 27 (IQR 12, 49) months. Eighty-nine percent reported taking a PDE5i at any time during the first 12 months after RP, and 60% reported doing so for 6 or more months during the year after RP. There was no evidence of an increase in the risk of BCR associated with any PDE5i use (HR 1.05, 95% CI 0.84, 1.31, P = .7) or duration of PDE5i use in the first year (HR 0.98 per 1 month duration, 95% CI 0.96, 1.00, P = .055). Baseline oncologic risk was lower in patients using PDE5i, but differences between groups were small, suggesting that residual confounding is unlikely to obscure any causal association with BCR. CONCLUSIONS: Prescription of PDE5i to men after RP can be based exclusively on quality of life considerations. Patients receiving PDE5is can be reassured that their use does not increase the risk of BCR.

A register-based study describing time trends in risk factor control and serious hypoglycaemia together with the effects of starting continuous glucose monitoring in people with type 1 diabetes in Norway.

AIMS: To describe trends in risk factor control and serious hypoglycaemia in people with type 1 diabetes and to assess the effect of starting continuous glucose monitoring (CGM) in the real-world setting. METHODS: Two cross-sectional surveys including 5746 individuals in 2012 and 18,984 individuals in 2020 based on data recorded in the Norwegian Diabetes Register for Adults (NDR-A) and an analysis of a longitudinal cohort of 2057 individuals where data on CGM and HbA1c were available in the NDR-A in 2012 and 2020. RESULTS: In the cross-sectional surveys mean HbA1c decreased from 66 mmol/mol (99% CI 65, 66) (8.2%) in 2012 to 61 mmol/mol (99% CI 61, 61) (7.7%) in 2020 (p < 0.0001). The proportion reporting serious hypoglycaemia decreased from 16.9 to 6.2% in 2020 (p < 0.0001). Mean LDL-cholesterol decreased from 2.80 (99% CI 2.78, 2.83) to 2.63 (99% CI 2.61, 2.65) mmol/l in 2020 (p < 0.0001). Mean blood pressure increased slightly. In the CGM cohort, we found a 3 mmol/mol (0.3%) greater improvement in mean HbA1c and a greater reduction in serious hypoglycaemia (-12.3% vs. -6.2%) among individuals that had started using CGM between 2013 and 2020 when compared with individuals that had not started using CGM. CONCLUSIONS: Between 2012 and 2020, we found marked improvements in glycaemic control and a considerable decrease in the proportion of individuals reporting serious hypoglycaemia. The proportion of individuals using CGM increased substantially and individuals that had started using CGM by 2020 showed greater improvement in glycaemic control and less serious hypoglycaemia.

Insulin initiation in patients with type 2 diabetes is often delayed, but access to a diabetes nurse may help-insights from Norwegian general practice.

Objective: We opted to study how support staff operational capacity and diabetes competences may impact the timeliness of basal insulin-initiation in general practice patients with type 2 diabetes (T2D).Design/Setting/Outcomes: This was an observational and retrospective study on Norwegian primary care patients with T2D included from the ROSA4-dataset. Exposures were (1) support staff size, (2) staff size relative to number of GPs, (3) clinic access to a diabetes nurse and (4) share of staff with diabetes course (1 and 2 both relate to staff operational capacity, whereas 3 and 4 are both indicatory of staff diabetes competences). Outcomes were 'timely basal insulin-initiation' (primary) and 'attainment of HbA1c<7%' after insulin start-up (secondary). Associations were analyzed using multiple linear regression, and directed acyclic graphs guided statistical adjustments.Subjects: Insulin naïve patients with 'timely' (N = 294), 'postponed' (N = 219) or 'no need of' (N = 3,781) basal insulin-initiation, respectively.Results: HbA1c [median (IQR)] increased to 8.8% (IQR, 8.0, 10.2) prior to basal insulin-initiation, which reduced HbA1c to 7.3 (6.8-8.1) % by which only 35% of the subjects reached HbA1c <7%. Adjusted risk of 'timely basal insulin-initiation' was more than twofold higher if access to a diabetes nurse (OR = 2.40, [95%CI, 1.68, 3.43]), but related only vaguely to staff size (OR = 1.01, [95%CI, 1.00, 1.03]). No other staff factors related significantly to neither the primary nor the secondary outcome.Conclusion: In Norwegian general practice, insulin initiation in people with T2D may be affected by therapeutic inertia but access to a diabetes nurse may help facilitating more timely insulin start-up.

In patients with type 2 diabetes (T2D) cared for by their general practice physician (GP), insulin therapy was susceptible to therapeutic inertia.In Norwegian general practice, chance of timely basal insulin-initiation was found more than two-fold higher if the GP had access to a diabetes nurse.In contrast, the timeliness of basal insulin-initiation in general practice patients with T2D seemed unaffected by share of support staff with diabetes course and by factors indicatory of support staff overall operational capacity.In Norwegian general practice, a diabetes nurse seems to offer unique clinical benefits to the care of insulin treated patients with T2D.

CARMIL3 is important for cell migration and morphogenesis during early development in zebrafish.

Cell migration is important during early animal embryogenesis. Cell migration and cell shape are controlled by actin assembly and dynamics, which depend on capping proteins, including the barbed-end heterodimeric actin capping protein (CP). CP activity can be regulated by capping-protein-interacting (CPI) motif proteins, including CARMIL (capping protein Arp2/3 myosin-I linker) family proteins. Previous studies of CARMIL3, one of the three highly conserved CARMIL genes in vertebrates, have largely been limited to cells in culture. Towards understanding CARMIL function during embryogenesis in vivo, we analyzed zebrafish lines carrying mutations of carmil3. Maternal-zygotic mutants showed impaired endodermal migration during gastrulation, along with defects in dorsal forerunner cell (DFC) cluster formation, which affected the morphogenesis of Kupffer's vesicle (KV). Mutant KVs were smaller, contained fewer cells and displayed decreased numbers of cilia, leading to defects in left/right (L/R) patterning with variable penetrance and expressivity. The penetrance and expressivity of the KV phenotype in carmil3 mutants correlated well with the L/R heart positioning defect at the end of embryogenesis. This in vivo animal study of CARMIL3 reveals its new role during morphogenesis of the vertebrate embryo. This role involves migration of endodermal cells and DFCs, along with subsequent morphogenesis of the KV and L/R asymmetry.

Targeting primary and metastatic uveal melanoma with a G protein inhibitor.

Uveal melanoma (UM) is the most common intraocular tumor in adults. Nearly half of UM patients develop metastatic disease and often succumb within months because effective therapy is lacking. A novel therapeutic approach has been suggested by the discovery that UM cell lines driven by mutant constitutively active Gq or G11 can be targeted by FR900359 (FR) or YM-254890, which are bioavailable, selective inhibitors of the Gq/11/14 subfamily of heterotrimeric G proteins. Here, we have addressed the therapeutic potential of FR for UM. We found that FR inhibited all oncogenic Gq/11 mutants reported in UM. FR arrested growth of all Gq/11-driven UM cell lines tested, but induced apoptosis only in a few. Similarly, FR inhibited growth of, but did not efficiently kill, UM tumor cells from biopsies of primary or metastatic tumors. FR evoked melanocytic redifferentiation of UM tumor cells with low (class 1), but not high (class 2), metastatic potential. FR administered systemically below its LD50 strongly inhibited growth of PDX-derived class 1 and class 2 UM tumors in mouse xenograft models and reduced blood pressure transiently. FR did not regress xenografted UM tumors or significantly affect heart rate, liver function, hematopoiesis, or behavior. These results indicated the existence of a therapeutic window in which FR can be explored for treating UM and potentially other diseases caused by constitutively active Gq/11.

Altered Capicua expression drives regional Purkinje neuron vulnerability through ion channel gene dysregulation in spinocerebellar ataxia type 1.

Selective neuronal vulnerability in neurodegenerative disease is poorly understood. Using the ATXN1[82Q] model of spinocerebellar ataxia type 1 (SCA1), we explored the hypothesis that regional differences in Purkinje neuron degeneration could provide novel insights into selective vulnerability. ATXN1[82Q] Purkinje neurons from the anterior cerebellum were found to degenerate earlier than those from the nodular zone, and this early degeneration was associated with selective dysregulation of ion channel transcripts and altered Purkinje neuron spiking. Efforts to understand the basis for selective dysregulation of channel transcripts revealed modestly increased expression of the ATXN1 co-repressor Capicua (Cic) in anterior cerebellar Purkinje neurons. Importantly, disrupting the association between ATXN1 and Cic rescued the levels of these ion channel transcripts, and lentiviral overexpression of Cic in the nodular zone accelerated both aberrant Purkinje neuron spiking and neurodegeneration. These findings reinforce the central role for Cic in SCA1 cerebellar pathophysiology and suggest that only modest reductions in Cic are needed to have profound therapeutic impact in SCA1.

International comparison of glycaemic control in people with type 1 diabetes: an update and extension.

AIMS: To update and extend a previous cross-sectional international comparison of glycaemic control in people with type 1 diabetes. METHODS: Data were obtained for 520,392 children and adults with type 1 diabetes from 17 population and five clinic-based data sources in countries or regions between 2016 and 2020. Median HbA1c (IQR) and proportions of individuals with HbA1c < 58 mmol/mol (<7.5%), 58-74 mmol/mol (7.5-8.9%) and ≥75 mmol/mol (≥9.0%) were compared between populations for individuals aged <15, 15-24 and ≥25 years. Logistic regression was used to estimate the odds ratio (OR) of HbA1c < 58 mmol/mol (<7.5%) relative to ≥58 mmol/mol (≥7.5%), stratified and adjusted for sex, age and data source. Where possible, changes in the proportion of individuals in each HbA1c category compared to previous estimates were calculated. RESULTS: Median HbA1c varied from 55 to 79 mmol/mol (7.2 to 9.4%) across data sources and age groups so a pooled estimate was deemed inappropriate. OR (95% CI) for HbA1c < 58 mmol/mol (<7.5%) were 0.91 (0.90-0.92) for women compared to men, 1.68 (1.65-1.71) for people aged <15 years and 0.81 (0.79-0.82) aged15-24 years compared to those aged ≥25 years. Differences between populations persisted after adjusting for sex, age and data source. In general, compared to our previous analysis, the proportion of people with an HbA1c  < 58 mmol/l (<7.5%) increased and proportions of people with HbA1c ≥ 75 mmol/mol (≥9.0%) decreased. CONCLUSIONS: Glycaemic control of type 1 diabetes continues to vary substantially between age groups and data sources. While some improvement over time has been observed, glycaemic control remains sub-optimal for most people with Type 1 diabetes.

Junctional Localization of Septin 2 Is Required for Organization of Junctional Proteins in Static Endothelial Monolayers.

OBJECTIVE: Septin 2 is localized at junctions in human microvascular endothelial monolayers. The junctional localization of septin 2 is necessary for organization of cell-cell adhesion proteins of endothelial cells. Approach and Results: Septin 2 was depleted at junctions by suppression of expression using shRNA, treatment with inflammatory cytokine, TNF (tumor necrosis factor)-α, and ectopic overexpression of septin 2 phosphatidylinositol 4,5-bisphosphate binding mutant defect in interaction with plasma membrane. Under those conditions, organizations and expression levels of various junctional proteins were analyzed. Confocal images of immunofluorescence staining showed substantial disorganization of adherens junctional proteins, nectin-2 and afadin, TJP (tight junction protein), ZO (zonula occludens)-1, and intercellular adhesion protein, PECAM-1 (platelet-endothelial cell adhesion molecule-1). Immunoblots for those proteins did not show significant changes in expression except for nectin-2 that highly increased in expression. Significant differential gene expression profiles and biological pathway analysis by septin 2 suppression and by TNF-α treatment using RNA-seq showed common overlapping pathways. The commonalities in expression may be consistent with the similar effects on the overall organization of cell-cell adhesion proteins. CONCLUSIONS: Localization of septin 2 at cell junctions are required for the arrangement of junctional proteins and the integrity of the barrier formed by endothelial monolayers.

The total prevalence of diagnosed diabetes and the quality of diabetes care for the adult population in Salten, Norway.

Objective: To assess the total prevalence of types 1 and 2 diabetes and to describe and compare cardiovascular risk factors, vascular complications and the quality of diabetes care in adults with types 1 and 2 diabetes in Salten, Norway. Research design and methods: Cross-sectional study including all patients with diagnosed diabetes in primary and specialist care in Salten, 2014 (population 80,338). Differences in cardiovascular risk factors, prevalence of vascular complications and attained treatment targets between diabetes types were assessed using regression analyses. Results: We identified 3091 cases of diabetes, giving a total prevalence in all age groups of 3.8%, 3.4% and 0.45% for types 2 and 1 diabetes, respectively. In the age group 30-89 years the prevalence of type 2 diabetes was 5.3%. Among 3027 adults aged 18 years and older with diabetes, 2713 (89.6%) had type 2 and 304 (10.0%) type 1 diabetes. The treatment target for haemoglobin A1c (⩽7.0%/53 mmol/mol) was reached in 61.1% and 22.5% of types 2 and 1 diabetes patients, respectively. After adjusting for age, sex and diabetes duration we found differences between patients with types 2 and 1 diabetes in mean haemoglobin A1c (7.1% vs. 7.5%, P<0.001), blood pressure (136/78 mmHg vs. 131/74 mmHg, P<0.001) and prevalence of coronary heart disease (23.1% vs. 15.8%, P<0.001). Conclusions: The prevalence of diagnosed type 2 diabetes was slightly lower than anticipated. Glycaemic control was not satisfactory in the majority of patients with type 1 diabetes. Coronary heart disease was more prevalent in patients with type 2 diabetes.

Australian guidelines for the prevention and treatment of posttraumatic stress disorder: Updates in the third edition.

OBJECTIVE: This paper describes the development of the third edition of the National Health and Medical Research Australian Guidelines for the Prevention and Treatment of Acute Stress Disorder, posttraumatic stress disorder and Complex posttraumatic stress disorder, highlighting key changes in scope, methodology, format and treatment recommendations from the previous 2013 edition of the Guidelines. METHOD: Systematic review of the international research was undertaken, with GRADE methodology used to assess the certainty of the evidence, and evidence to decision frameworks used to generate recommendations. The Guidelines are presented in an online format using MAGICApp. RESULTS: Key changes since the publication of the 2013 Guidelines include a new conditional recommendation for Child and Family Traumatic Stress Intervention for children and adolescents with symptoms within the first 3 months of trauma, and a strong recommendation for trauma-focused cognitive behaviour therapy for the child alone or with a caregiver, for those with diagnosed posttraumatic stress disorder. For adults with posttraumatic stress disorder, strong recommendations are made for specific types of trauma-focused cognitive behaviour therapy and conditional recommendations are made for five additional psychological interventions. Where medication is indicated for adults with posttraumatic stress disorder, venlafaxine is now conditionally recommended alongside sertraline, paroxetine or fluoxetine. CONCLUSION: These Guidelines, based on systematic review of the international literature, are intended to guide decision making for practitioners, service planners, funders and those seeking treatment for trauma related mental health concerns. For an Australian Guideline, a critical limitation is the absence of research on the treatment of Australian Aboriginal and Torres Strait Islander peoples. The new online format of the Australian posttraumatic stress disorder Guidelines means that they can be updated as sufficient new evidence becomes available.

Intravenous Immunomodulatory Nanoparticle Treatment for Traumatic Brain Injury.

OBJECTIVE: There are currently no definitive disease-modifying therapies for traumatic brain injury (TBI). In this study, we present a strong therapeutic candidate for TBI, immunomodulatory nanoparticles (IMPs), which ablate a specific subset of hematogenous monocytes (hMos). We hypothesized that prevention of infiltration of these cells into brain acutely after TBI would attenuate secondary damage and preserve anatomic and neurologic function. METHODS: IMPs, composed of US Food and Drug Administration-approved 500nm carboxylated-poly(lactic-co-glycolic) acid, were infused intravenously into wild-type C57BL/6 mice following 2 different models of experimental TBI, controlled cortical impact (CCI), and closed head injury (CHI). RESULTS: IMP administration resulted in remarkable preservation of both tissue and neurological function in both CCI and CHI TBI models in mice. After acute treatment, there was a reduction in the number of immune cells infiltrating into the brain, mitigation of the inflammatory status of the infiltrating cells, improved electrophysiologic visual function, improved long-term motor behavior, reduced edema formation as assessed by magnetic resonance imaging, and reduced lesion volumes on anatomic examination. INTERPRETATION: Our findings suggest that IMPs are a clinically translatable acute intervention for TBI with a well-defined mechanism of action and beneficial anatomic and physiologic preservation and recovery. Ann Neurol 2020;87:442-455.

Factors associated with potential over- and undertreatment of hyperglycaemia and annual measurement of HbA1c in type 2 diabetes in norwegian general practice.

AIMS: To identify individual and general practitioner (GP) characteristics associated with potential over- and undertreatment of hyperglycaemia in type 2 diabetes and with HbA1c not being measured. METHODS: A cross-sectional study that included 10233 individuals with type 2 diabetes attending 282 GPs. Individuals with an HbA1c measurement during the last 15 months were categorized as potentially overtreated if they were prescribed a sulphonylurea and/or insulin when the HbA1c was less than 53 mmol/mol (7%) when aged over 75 years or less than 48 mmol/mol (6.5%) when aged between 65 and 75 years. Potential undertreatment was defined as age less than 60 years and HbA1c > 64 mmol/mol (8.0%) or HbA1c > 69 mmol/mol (8.5%) and treated with lifestyle modification and/or monotherapy. We used multilevel binary and multinominal logistic regression models to examine associations. RESULTS: Overall, 4.1% were potentially overtreated, 7.8% were potentially undertreated and 11% did not have HbA1c measured. Characteristics associated with potential overtreatment were as follows: long diabetes duration, prescribed antihypertensive medication, cardiovascular disease and renal failure. Potential undertreatment was associated with male gender, non-western origin and low educational level. Characteristics associated with not having an HbA1c measurement performed were male gender, age < 50 years and cardiovascular diseases. GP specialist status and GPs' use of a Noklus diabetes application reduced the risk of not having an HbA1c measurement performed. CONCLUSION: Potential overtreatment in elderly individuals with type 2 diabetes was relatively low. Nevertheless, appropriate de-intensification or intensification of treatment and regular HbA1c measurement in identified subgroups is warranted.

High adherence to recommended diabetes follow-up procedures by general practitioners is associated with lower estimated cardiovascular risk.

AIMS: To explore whether the general practitioners' (GPs') performance of recommended processes of care was associated with estimated risk of cardiovascular disease (CVD) and poor glycaemic control in patients with type 2 diabetes. METHODS: A cross-sectional study from Norwegian general practice including 6015 people with type 2 diabetes <75 years old, without CVD and their 275 GPs. The GPs were split into quintiles based on each GP's average performance of six recommended processes of care. The quintiles were the exposure variable in multilevel regression models with 10-year risk of cardiovascular events estimated by NORRISK 2 (total and modifiable fraction) and poor glycaemic control (HbA1c >69 mmol/mol (>8.5%)) as outcome variables. RESULTS: The mean total and modifiable estimated 10-year CVD risk was 12.3% and 3.3%, respectively. Compared with patients of GPs in the highest-performing quintile, patients treated by GPs in the lowest quintile had an adjusted total and modifiable CVD risk that was 1.88 (95% CI 1.17-2.60) and 1.78 (1.14-2.41) percent point higher. This represents a relative mean difference of 16.6% higher total and 74.8% higher modifiable risk among patients of GPs in the lowest compared with the highest quintile. For patients with GPs in the lowest-performing quintile, the adjusted odds of poor glycaemic control was 1.77 (1.27-2.46) times higher than that for patients with a GP in the highest quintile. CONCLUSIONS: We found a pattern of lower CVD risk and better glycaemic control in patients of GPs performing more recommended diabetes processes of care.

Factors associated with treatment in primary versus specialist care: A population-based study of people with type 2 and type 1 diabetes.

AIMS: The objectives of this study are to identify the proportion and characteristics of people with type 1 and 2 diabetes treated in primary, specialist and shared care and to identify the proportion of persons with type 2 diabetes reaching HbA1c treatment targets and the clinical risk factors and general practitioner and practice characteristics associated with treatment in specialist care. METHODS: Population-based cross-sectional study including all adults ≥18 years diagnosed with diabetes in primary and specialist care in Salten, Norway. We used multivariable mixed-effects logistic regression models with level of care as outcome variable and population, general practitioner, and practice characteristics as exposure variables. RESULTS: Of 2704 people with type 2 diabetes, 13.5% were treated in shared care and 2.1% in specialist care only. Of 305 people with type 1 diabetes, 14.4% received treatment in primary care only. The HbA1c treatment target of 53 mmol/mol (7.0%) was reached by 67.3% of people with type 2 diabetes in primary care versus 30.4% in specialist care. HbA1c , use of insulin, coronary heart disease, retinopathy and urban practice location were positively associated with treatment in specialist care. General practitioners' use of a structured form and a diabetes nurse were negatively associated with specialist care. CONCLUSIONS: Of people with type 2 diabetes, 16% were treated in specialist care. They had higher HbA1c and more vascular complications, as expected from priority guidelines. The use of a structured diabetes form and diabetes nurses seem to support type 2 diabetes follow-up in primary care.

Chest radiograph at admission predicts early intubation among inpatient COVID-19 patients.

OBJECTIVE: The 2019 Coronavirus (COVID-19) results in a wide range of clinical severity and there remains a need for prognostic tools which identify patients at risk of rapid deterioration and who require critical care. Chest radiography (CXR) is routinely obtained at admission of COVID-19 patients. However, little is known regarding correlates between CXR severity and time to intubation. We hypothesize that the degree of opacification on CXR at time of admission independently predicts need and time to intubation. METHODS: In this retrospective cohort study, we reviewed COVID-19 patients who were admitted to an urban medical center during March 2020 that had a CXR performed on the day of admission. CXRs were divided into 12 lung zones and were assessed by two blinded thoracic radiologists. A COVID-19 opacification rating score (CORS) was generated by assigning one point for each lung zone in which an opacity was observed. Underlying comorbidities were abstracted and assessed for association. RESULTS: One hundred forty patients were included in this study and 47 (34%) patients required intubation during the admission. Patients with CORS ≥ 6 demonstrated significantly higher rates of early intubation within 48 h of admission and during the hospital stay (ORs 24 h, 19.8, p < 0.001; 48 h, 28.1, p < 0.001; intubation during hospital stay, 6.1, p < 0.0001). There was no significant correlation between CORS ≥ 6 and age, sex, BMI, or any underlying cardiac or pulmonary comorbidities. CONCLUSIONS: CORS ≥ 6 at the time of admission predicts need for intubation, with significant increases in intubation at 24 and 48 h, independent of comorbidities. KEY POINTS: • Chest radiography at the time of admission independently predicts time to intubation within 48 h and during the hospital stay in COVID-19 patients. • More opacities on chest radiography are associated with several fold increases in early mechanical ventilation among COVID-19 patients. • Chest radiography is useful in identifying COVID-19 patients whom may rapidly deteriorate and help inform clinical management as well as hospital bed and ventilation allocation.

Femoral Neck Notching in Dual Mobility Implants: Is This a Reason for Concern?

BACKGROUND: Dual mobility (DM) total hip arthroplasty (THA) implants have been advocated for patients at risk for impingement due to abnormal spinopelvic mobility. Impingement against cobalt-chromium acetabular bearings, however, can result in notching of titanium femoral stems. This study investigated the incidence of femoral stem notching associated with DM implants and sought to identify risk factors. METHODS: A multicenter retrospective study reviewed 256 modular and 32 monoblock DM components with minimum 1-year clinical and radiographic follow-up, including 112 revisions, 4 conversion THAs, and 172 primary THAs. Radiographs were inspected for evidence of femoral notching and to calculate acetabular inclination and anteversion. Revisions and dislocations were recorded. RESULTS: Ten cases of femoral notching were discovered (3.5%), all associated with modular cylindrospheric cobalt-chromium DM implants (P = .049). Notches were first observed radiographically at mean 1.3 years after surgery (range 0.5-2.7 years). Notch location was anterior (20%), superior (60%), or posterior (20%) on the prosthetic femoral neck. Notch depth ranged from 1.7% to 20% of the prosthetic neck diameter. Eight cases with notching had lumbar pathology that can affect spinopelvic mobility. None of these notches resulted in stem fracture, at mean 2.7-year follow-up (range 1-7.6 years). There were no dislocations or revisions in patients with notching. CONCLUSION: Femoral notching was identified in 3.5% of DM cases, slightly surpassing the dislocation rate in a cohort selected for risk of impingement and instability. Although these cases of notching have not resulted in catastrophic failures thus far, further study of clinical sequelae is warranted. Component position, spinopelvic mobility, and implant design may influence risk.

Introducing an ANP-led temporal artery biopsy service for patients with suspected giant cell arteritis.

Giant cell arteritis (GCA) is an uncommon autoimmune inflammatory vasculopathy that can lead to the destruction and occlusion of various arteries that consequently can cause serious complications such as stroke or sight loss. It is seen as a medical emergency. The most commonly affected vessel in GCA is the temporal artery in the side of the head, hence the condition is sometimes also referred to as 'temporal arteritis'. This article discusses the introduction of an advanced nurse practitioner-led temporal artery biopsy service.

Comparative Analysis of CPI-Motif Regulation of Biochemical Functions of Actin Capping Protein.

The heterodimeric actin capping protein (CP) is regulated by a set of proteins that contain CP-interacting (CPI) motifs. Outside of the CPI motif, the sequences of these proteins are unrelated and distinct. The CPI motif and surrounding sequences are conserved within a given protein family, when compared to those of other CPI-motif protein families. Using biochemical assays with purified proteins, we compared the ability of CPI-motif-containing peptides from different protein families (a) to bind to CP, (b) to allosterically inhibit barbed-end capping by CP, and (c) to allosterically inhibit interaction of CP with V-1, another regulator of CP. We found large differences in potency among the different CPI-motif-containing peptides, and the different functional assays showed different orders of potency. These biochemical differences among the CPI-motif peptides presumably reflect interactions between CP and CPI-motif peptides involving amino acid residues that are conserved but are not part of the strictly defined consensus, as it was originally identified in comparisons of sequences of CPI motifs across all protein families [Hernandez-Valladares, M., et al. (2010) Structural characterization of a capping protein interaction motif defines a family of actin filament regulators. Nat. Struct. Mol. Biol. 17, 497-503; Bruck, S., et al. (2006) Identification of a Novel Inhibitory Actin-capping Protein Binding Motif in CD2-associated Protein. J. Biol. Chem. 281, 19196-19203]. These biochemical differences may be important for conserved distinct functions of CPI-motif protein families in cells with respect to the regulation of CP activity and actin assembly near membranes.