Cranial bone imaging using ultrashort echo-time bone-selective MRI as an alternative to gradient-echo based "black-bone" techniques.

OBJECTIVES: CT is the clinical standard for surgical planning of craniofacial abnormalities in pediatric patients. This study evaluated three MRI cranial bone imaging techniques for their strengths and limitations as a radiation-free alternative to CT. METHODS: Ten healthy adults were scanned at 3 T with three MRI sequences: dual-radiofrequency and dual-echo ultrashort echo time sequence (DURANDE), zero echo time (ZTE), and gradient-echo (GRE). DURANDE bright-bone images were generated by exploiting bone signal intensity dependence on RF pulse duration and echo time, while ZTE bright-bone images were obtained via logarithmic inversion. Three skull segmentations were derived, and the overlap of the binary masks was quantified using dice similarity coefficient. Craniometric distances were measured, and their agreement was quantified. RESULTS: There was good overlap of the three masks and excellent agreement among craniometric distances. DURANDE and ZTE showed superior air-bone contrast (i.e., sinuses) and soft-tissue suppression compared to GRE. DISCUSSIONS: ZTE has low levels of acoustic noise, however, ZTE images had lower contrast near facial bones (e.g., zygomatic) and require effective bias-field correction to separate bone from air and soft-tissue. DURANDE utilizes a dual-echo subtraction post-processing approach to yield bone-specific images, but the sequence is not currently manufacturer-supported and requires scanner-specific gradient-delay corrections.

Outcomes of transcatheter aortic valve replacement in patients with cardiogenic shock.

AIMS: The safety and efficacy of transcatheter aortic valve replacement (TAVR) with contemporary balloon expandable transcatheter valves in patients with cardiogenic shock (CS) remain largely unknown. In this study, the TAVRs performed for CS between June 2015 and September 2022 using SAPIEN 3 and SAPIEN 3 Ultra bioprosthesis from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry were analysed. METHODS AND RESULTS: CS was defined as: (i) coding of CS within 24 h on Transcatheter Valve Therapy Registry form; and/or (ii) pre-procedural use of inotropes or mechanical circulatory support devices and/or (iii) cardiac arrest within 24 h prior to TAVR. The control group was comprised of all the other patients undergoing TAVR. Baseline characteristics, all-cause mortality, and major complications at 30-day and 1-year outcomes were reported. Landmark analysis was performed at 30 days post-TAVR. Cox-proportional multivariable analysis was performed to determine the predictors of all-cause mortality at 1 year. A total of 309 505 patients underwent TAVR with balloon-expandable valves during the study period. Of these, 5006 patients presented with CS prior to TAVR (1.6%). The mean Society of Thoracic Surgeons score was 10.76 ± 10.4. The valve was successfully implanted in 97.9% of patients. Technical success according to Valve Academic Research Consortium-3 criteria was 94.5%. In a propensity-matched analysis, CS was associated with higher in-hospital (9.9% vs. 2.7%), 30-day (12.9% vs. 4.9%), and 1-year (29.7% vs. 22.6%) mortality compared to the patients undergoing TAVR without CS. In the landmark analysis after 30 days, the risk of 1-year mortality was similar between the two groups [hazard ratio (HR) 1.07, 95% confidence interval (CI) 0.95-1.21]. Patients who were alive at 1 year noted significant improvements in functional class (Class I/II 89%) and quality of life (ΔKCCQ score +50). In the multivariable analysis, older age (HR 1.02, 95% CI 1.02-1.03), peripheral artery disease (HR 1.25, 95% CI 1.06-1.47), prior implantation of an implantable cardioverter-defibrillator (HR 1.37, 95% CI 1.07-1.77), patients on dialysis (HR 2.07, 95% CI 1.69-2.53), immunocompromised status (HR 1.33, 95% CI 1.05-1.69), New York Heart Association class III/IV symptoms (HR 1.50, 95% CI 1.06-2.12), lower aortic valve mean gradient, lower albumin levels, lower haemoglobin levels, and lower Kansas City Cardiomyopathy Questionnaire scores were independently associated with 1-year mortality. CONCLUSION: This large observational real-world study demonstrates that the TAVR is a safe and effective treatment for aortic stenosis patients presenting with CS. Patients who survived the first 30 days after TAVR had similar mortality rates to those who were not in CS.

Transitions in Video Laryngoscope Technology to Improve First-Pass Success.

Prehospital intubation is a high-risk, relatively low frequency procedure. Provider experience plays a key role in first-pass success rates, especially in the setting of a difficult airway. While strong foundational knowledge is necessary to equip providers with an adequate understanding of intubation procedures and the skill set needed to manage a difficult airway, effective equipment may provide an extra boost in first-pass success for novice airway providers. First-pass success is correlated with decreased adverse events and should be maximized in the prehospital setting. After evaluating overall first-pass success of 66% to 83% from 2016 to 2020, AHN LifeFlight enacted changes in education, training, and video laryngoscopy equipment to successfully increase first-pass success to over 90%.

Treatment against glucose-dependent cancers through metabolic PFKFB3 targeting of glycolytic flux.

Reprogrammed metabolism and high energy demand are well-established properties of cancer cells that enable tumor growth. Glycolysis is a primary metabolic pathway that supplies this increased energy demand, leading to a high rate of glycolytic flux and a greater dependence on glucose in tumor cells. Finding safe and effective means to control glycolytic flux and curb cancer cell proliferation has gained increasing interest in recent years. A critical step in glycolysis is controlled by the enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), which converts fructose 6-phosphate (F6P) to fructose 2,6-bisphosphate (F2,6BP). F2,6BP allosterically activates the rate-limiting step of glycolysis catalyzed by PFK1 enzyme. PFKFB3 is often overexpressed in many human cancers including pancreatic, colon, prostate, and breast cancer. Hence, PFKFB3 has gained increased interest as a compelling therapeutic target. In this review, we summarize and discuss the current knowledge of PFKFB3 functions, its role in cellular pathways and cancer development, its transcriptional and post-translational activity regulation, and the multiple pharmacologic inhibitors that have been used to block PFKFB3 activity in cancer cells. While much remains to be learned, PFKFB3 continues to hold great promise as an important therapeutic target either as a single agent or in combination with current interventions for breast and other cancers.

MRI Quantification of Cortical Bone Porosity, Mineralization, and Morphologic Structure in Postmenopausal Osteoporosis.

Background Preclinical studies have suggested that solid-state MRI markers of cortical bone porosity, morphologic structure, mineralization, and osteoid density are useful measures of bone health. Purpose To explore whether MRI markers of cortical bone porosity, morphologic structure, mineralization, and osteoid density are affected in postmenopausal osteoporosis (OP) and to examine associations between MRI markers and bone mineral density (BMD) in postmenopausal women. Materials and Methods In this single-center study, postmenopausal women were prospectively recruited from January 2019 to October 2020 into two groups: participants with OP who had not undergone treatment, defined as having any dual-energy x-ray absorptiometry (DXA) T-score of -2.5 or less, and age-matched control participants without OP (hereafter, non-OP). Participants underwent MRI in the midtibia, along with DXA in the hip and spine, and peripheral quantitative CT in the midtibia. Specifically, MRI measures of cortical bone porosity (pore water and total water), osteoid density (bound water [BW]), morphologic structure (cortical bone thickness), and mineralization (phosphorous [P] density [31P] and 31P-to-BW concentration ratio) were quantified at 3.0 T. MRI measures were compared between OP and non-OP groups and correlations with BMD were assessed. Results Fifteen participants with OP (mean age, 63 years ± 5 [SD]) and 19 participants without OP (mean age, 65 years ± 6) were evaluated. The OP group had elevated pore water (11.6 mol/L vs 9.5 mol/L; P = .007) and total water densities (21.2 mol/L vs 19.7 mol/L; P = .03), and had lower cortical bone thickness (4.8 mm vs 5.6 mm; P < .001) and 31P density (6.4 mol/L vs 7.5 mol/L; P = .01) than the non-OP group, respectively, although there was no evidence of a difference in BW or 31P-to-BW concentration ratio. Pore and total water densities were inversely associated with DXA and peripheral quantitative CT BMD (P < .001), whereas cortical bone thickness and 31P density were positively associated with DXA and peripheral quantitative CT BMD (P = .01). BW, 31P density, and 31P-to-BW concentration ratio were positively associated with DXA (P < .05), but not with peripheral quantitative CT. Conclusion Solid-state MRI of cortical bone was able to help detect potential impairments in parameters reflecting porosity, morphologic structure, and mineralization in postmenopausal osteoporosis. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Bae in this issue.

Phosphatidylinositol 3,5-bisphosphate regulates Ca2+ transport during yeast vacuolar fusion through the Ca2+ ATPase Pmc1.

The transport of Ca2+ across membranes precedes the fusion and fission of various lipid bilayers. Yeast vacuoles under hyperosmotic stress become fragmented through fission events that requires the release of Ca2+ stores through the TRP channel Yvc1. This requires the phosphorylation of phosphatidylinositol-3-phosphate (PI3P) by the PI3P-5-kinase Fab1 to produce transient PI(3,5)P2 pools. Ca2+ is also released during vacuole fusion upon trans-SNARE complex assembly, however, its role remains unclear. The effect of PI(3,5)P2 on Ca2+ flux during fusion was independent of Yvc1. Here, we show that while low levels of PI(3,5)P2 were required for Ca2+ uptake into the vacuole, increased concentrations abolished Ca2+ efflux. This was as shown by the addition of exogenous dioctanoyl PI(3,5)P2 or increased endogenous production of by the hyperactive fab1T2250A mutant. In contrast, the lack of PI(3,5)P2 on vacuoles from the kinase dead fab1EEE mutant showed delayed and decreased Ca2+ uptake. The effects of PI(3,5)P2 were linked to the Ca2+ pump Pmc1, as its deletion rendered vacuoles resistant to the effects of excess PI(3,5)P2 . Experiments with Verapamil inhibited Ca2+ uptake when added at the start of the assay, while adding it after Ca2+ had been taken up resulted in the rapid expulsion of Ca2+ . Vacuoles lacking both Pmc1 and the H+ /Ca2+ exchanger Vcx1 lacked the ability to take up Ca2+ and instead expelled it upon the addition of ATP. Together these data suggest that a balance of efflux and uptake compete during the fusion pathway and that the levels of PI(3,5)P2 can modulate which path predominates.

Copper blocks V-ATPase activity and SNARE complex formation to inhibit yeast vacuole fusion.

The accumulation of copper in organisms can lead to altered functions of various pathways and become cytotoxic through the generation of reactive oxygen species. In yeast, cytotoxic metals such as Hg+ , Cd2+ and Cu2+ are transported into the lumen of the vacuole through various pumps. Copper ions are initially transported into the cell by the copper transporter Ctr1 at the plasma membrane and sequestered by chaperones and other factors to prevent cellular damage by free cations. Excess copper ions can subsequently be transported into the vacuole lumen by an unknown mechanism. Transport across membranes requires the reduction of Cu2+ to Cu+ . Labile copper ions can interact with membranes to alter fluidity, lateral phase separation and fusion. Here we found that CuCl2 potently inhibited vacuole fusion by blocking SNARE pairing. This was accompanied by the inhibition of V-ATPase H+ pumping. Deletion of the vacuolar reductase Fre6 had no effect on the inhibition of fusion by copper. This suggests that Cu2+ is responsible for the inhibition of vacuole fusion and V-ATPase function. This notion is supported by the differential effects of chelators. The Cu2+ -specific chelator triethylenetetramine rescued fusion, whereas the Cu+ -specific chelator bathocuproine disulfonate had no effect on the inhibited fusion.

A systems biology approach to discovering pathway signaling dysregulation in metastasis.

Total metastatic burden is the primary cause of death for many cancer patients. While the process of metastasis has been studied widely, much remains to be understood. Moreover, few agents have been developed that specifically target the major steps of the metastatic cascade. Many individual genes and pathways have been implicated in metastasis but a holistic view of how these interact and cooperate to regulate and execute the process remains somewhat rudimentary. It is unclear whether all of the signaling features that regulate and execute metastasis are yet fully understood. Novel features of a complex system such as metastasis can often be discovered by taking a systems-based approach. We introduce the concepts of systems modeling and define some of the central challenges facing the application of a multidisciplinary systems-based approach to understanding metastasis and finding actionable targets therein. These challenges include appreciating the unique properties of the high-dimensional omics data often used for modeling, limitations in knowledge of the system (metastasis), tumor heterogeneity and sampling bias, and some of the issues key to understanding critical features of molecular signaling in the context of metastasis. We also provide a brief introduction to integrative modeling that focuses on both the nodes and edges of molecular signaling networks. Finally, we offer some observations on future directions as they relate to developing a systems-based model of the metastatic cascade.

Cardiovascular procedural deferral and outcomes over COVID-19 pandemic phases: A multi-center study.

BACKGROUND: The COVID-19 pandemic has disrupted routine cardiovascular care, with unclear impact on procedural deferrals and associated outcomes across diverse patient populations. METHODS: Cardiovascular procedures performed at 30 hospitals across 6 Western states in 2 large, non-profit healthcare systems (Providence St. Joseph Health and Stanford Healthcare) from December 2018-June 2020 were analyzed for changes over time. Risk-adjusted in-hospital mortality was compared across pandemic phases with multivariate logistic regression. RESULTS: Among 36,125 procedures (69% percutaneous coronary intervention, 13% coronary artery bypass graft surgery, 10% transcatheter aortic valve replacement, and 8% surgical aortic valve replacement), weekly volumes changed in 2 distinct phases after the initial inflection point on February 23, 2020: an initial period of significant deferral (COVID I: March 15-April 11) followed by recovery (COVID II: April 12 onwards). Compared to pre-COVID, COVID I patients were less likely to be female (P = .0003), older (P < .0001), Asian or Black (P = .02), or Medicare insured (P < .0001), and COVID I procedures were higher acuity (P < .0001), but not higher complexity. In COVID II, there was a trend toward more procedural deferral in regions with a higher COVID-19 burden (P = .05). Compared to pre-COVID, there were no differences in risk-adjusted in-hospital mortality during both COVID phases. CONCLUSIONS: Significant decreases in cardiovascular procedural volumes occurred early in the COVID-19 pandemic, with disproportionate impacts by race, gender, and age. These findings should inform our approach to future healthcare disruptions.

Hospital Survival After Surgical Repair of Truncus Arteriosus with Interrupted Aortic Arch: Results from a Multi-institutional Database.

Truncus arteriosus (TA) is a major congenital cardiac malformation that requires surgical repair in the first few weeks of life. Interrupted aortic arch (IAA) is an associated malformation that significantly impacts the complexity of the TA operation. The aim of this study was to (1) define the comorbid conditions associated with TA and (2) determine the hospital survival and morbidity of patients with TA with and without an IAA. Data was collected from the Vizient Clinical Database/Resource Manager, formerly University HealthSystem Consortium, which encompasses more than 160 academic medical centers in the United States. The database was queried for patients admitted from 2002 to 2016 who were ≤ 4 months of age at initial admission, diagnosed with TA, and underwent complete surgical repair during that hospitalization. Of the 645 patients with TA who underwent surgery, 98 (15%) had TA with an interrupted aortic arch (TA-IAA). Both TA and TA-IAA were associated with a high prevalence of comorbidities, including DiGeorge syndrome, prematurity, and other congenital malformations. There was no difference in mortality between TA and TA-IAA (13.7-18.4%, p value = 0.227). No comorbid conditions were associated with an increased mortality in either group. However, patients with TA-IAA had a longer post-operative length of stay (LOS) compared to those without IAA (30 versus 40.3 days, p value = 0.001) and this effect was additive with each additional comorbid condition. In conclusion, the addition of IAA to TA is associated with an increased post-operative LOS, but does not increase in-hospital mortality.

Quantitative imaging of the spine in adolescent idiopathic scoliosis: shifting the paradigm from diagnostic to comprehensive prognostic evaluation.

PURPOSE: We aimed to provide a perspective review of the available quantitative imaging modalities of the spine for prognostic evaluation of the adolescent idiopathic scoliosis (AIS). METHODS: A technical description of the current imaging technologies for quantitative assessment of the pediatric spine with scoliosis was provided, and the pros and cons of each method were discussed. Imaging modalities that quantify the overall 3D alignment of the spine as well as the structural specification of the spinal bone, intervertebral disc, endplates, and ligaments as it pertains to development and progression of the idiopathic spinal deformities in adolescents were discussed. RESULTS: Low-dose and microdose stereoradiography, ultrasound, and rasterstereography provide quantitative imaging of the 3D spinal alignment with low or no radiation in standing posture which allows repetitive imaging for early detection of the curve development. Quantitative magnetic resonance imaging, including ultrashort dual-echo time and T1-rho can provide quantitative assessment of the spinal tissues relevant to development of idiopathic spinal deformity in pediatric population. New computed tomography scans that uses dual-energy can provides high-resolution measure of the current-state of the bone quality and morphology as well as the osteogenic properties of the bone by quantitative evaluation of the bone marrow. CONCLUSION: The presented imaging modalities can provide a wide spectrum of quantifiable information relevant to development and progression of the spinal deformity. Clinical application of these technologies can change the paradigm in clinical assessment of the pediatric scoliosis by improving our understanding of the pathogenesis of the idiopathic scoliosis.

Autophagy efficacy and vitamin D status: Population effects.

Toll-like receptor (TLR) 2/1 signalling is linked to autophagy through transcriptional actions of the 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)-vitamin D receptor (VDR) complex. Population-specific effects have been reported for TLR2/1-VDR signalling. We hypothesized that population effects extend to autophagy and are influenced by vitamin D status. Serum 25(OH)D3 of healthy South Africans (Black individuals n = 10, White individuals n = 10) was quantified by LC-MS/MS. Primary monocytes-macrophages were supplemented in vitro with 1,25(OH)2D3 and stimulated with the lipoprotein Pam3CysSerLys4. TLR2, VDR, hCAP18, Beclin1, LC3-IIB, cytokines and CYP24A1 mRNA were quantified by flow cytometry and RT-qPCR, respectively. Black individuals showed significantly lower overall cumulative LC3-IIB (P < 0.010), but higher Beclin1, VDR, IL6 and TNFA (P < 0.050) than White individuals. 1,25(OH)2D3 enhanced autophagic flux in monocytes-macrophages from Black individuals upon TLR2/1 stimulation and strengthened autophagy in 25(OH)D3 deficient individuals (independent cohort, n = 20). These findings support population-directed vitamin D supplementation.

Rapid ventricular pacing during transcatheter valve procedures using an internal device and programmer: A demonstration of feasibility.

OBJECTIVES: To develop a protocol for using a pre-existing, permanent pacemaker or defibrillator device for rapid ventricular pacing during transcatheter valve procedures and demonstrate feasibility. BACKGROUND: Placement of a passive fixation, temporary pacemaker wire is considered routine during most transcatheter valve procedures to facilitate controlled or rapid ventricular pacing at the time of balloon expansion or valve deployment. Many patients presenting for such procedures have a pre-existing, permanent pacemaker or defibrillator device which could be used for the same function, obviating the need for temporary pacemaker wire placement. METHODS: We developed a strategy for rapid pacing from the pre-existing device using a programmer during transcatheter valve procedures in consecutive patients over a 3-month period. Complications and clinical outcomes were recorded. RESULTS: There were 135 transcatheter valve procedures performed during the study. Of these, 28 (20.7%) had pre-existing devices (17 transcatheter aortic valve replacement, 3 aortic valve-in-valve, 2 mitral valve-in-valve, and 6 balloon aortic valvuloplasty). All patients underwent rapid ventricular pacing using a commercially available device programmer. There were no adverse events related to device pacing and no patients required placement of a temporary pacemaker wire during the procedure. At 30-days follow-up, there were no deaths, one major vascular complication related to arterial access, and one patient with renal failure requiring dialysis. CONCLUSION: Pacing from a commercially available device programmer is safe, feasible, and may reduce both procedural cost and complications such as cardiac tamponade by avoiding placement of a temporary pacemaker lead during transcatheter valve procedures.

Iodine-mediated hydration of alkynes on keto-functionalized scaffolds: mechanistic insight and the regiospecific hydration of internal alkynes.

An iodine-mediated hydration reaction of alkynes serves as a green alternative to metal-catalyzed procedures. Previous work has shown that this method works well with terminal alkynes on keto-functionalized scaffolds, including 1,3-dicarbonyls and their heteroatom analogues. It was hypothesized that the reaction proceeds through a 5-exo-dig neighboring group participation (NGP) cyclization and an α-iodo intermediate. The work described herein probes the existence of the intermediate through NMR investigations and explores the scope of the hydration process with internal alkynes. The NMR experiments confirm the existence of the α-iodo intermediate, and methodology studies demonstrate that alkyl-capped, asymmetric, internal alkynes undergo a regiospecific hydration, also via the 5-exo-dig NGP pathway.

A mouse model of DEPDC5-related epilepsy: Neuronal loss of Depdc5 causes dysplastic and ectopic neurons, increased mTOR signaling, and seizure susceptibility.

DEPDC5 is a newly identified epilepsy-related gene implicated in focal epilepsy, brain malformations, and Sudden Unexplained Death in Epilepsy (SUDEP). In vitro, DEPDC5 negatively regulates amino acid sensing by the mTOR complex 1 (mTORC1) pathway, but the role of DEPDC5 in neurodevelopment and epilepsy has not been described. No animal model of DEPDC5-related epilepsy has recapitulated the neurological phenotypes seen in patients, and germline knockout rodent models are embryonic lethal. Here, we establish a neuron-specific Depdc5 conditional knockout mouse by cre-recombination under the Synapsin1 promotor. Depdc5flox/flox-Syn1Cre (Depdc5cc+) mice survive to adulthood with a progressive neurologic phenotype that includes motor abnormalities (i.e., hind limb clasping) and reduced survival compared to littermate control mice. Depdc5cc+ mice have larger brains with increased cortical neuron size and dysplastic neurons throughout the cortex, comparable to the abnormal neurons seen in human focal cortical dysplasia specimens. Depdc5 results in constitutive mTORC1 hyperactivation exclusively in neurons as measured by the increased phosphorylation of the downstream ribosomal protein S6. Despite a lack of increased mTORC1 signaling within astrocytes, Depdc5cc+ brains show reactive astrogliosis. We observed two Depdc5cc+ mice to have spontaneous seizures, including a terminal seizure. We demonstrate that as a group Depdc5cc+ mice have lowered seizure thresholds, as evidenced by decreased latency to seizures after chemoconvulsant injection and increased mortality from pentylenetetrazole-induced seizures. In summary, our neuron-specific Depdc5 knockout mouse model recapitulates clinical, pathological, and biochemical features of human DEPDC5-related epilepsy and brain malformations. We thereby present an important model in which to study targeted therapeutic strategies for DEPDC5-related conditions.

Fighting fungus with a laser and a hose: Management of a giant Candida albicans implantable cardioverter-defibrillator lead vegetation with simultaneous AngioVac aspiration and laser sheath lead extraction.

Infections involving internal cardiac devices can be very challenging to treat, and almost universally require complete device extraction for successful management. Of the pathogens that cause device-related endocarditis, fungi such as Candida albicans are notoriously difficult to manage because of their propensity to produce large vegetations and the need for long-term treatment with potentially toxic medications. Furthermore, individuals who develop fungal, device-associated endocarditis are typically among the most complex patients, with significant comorbidities that place them at high risk for open heart procedures such as surgical device extraction. We present a case of one such patient in whom treatment of Candida albicans device-related endocarditis was managed using AngioVac® aspiration of a large right atrial vegetation with simultaneous laser sheath extraction of the implantable cardioverter-defibrillator lead.

Pushing with the pigtail: a novel approach to placing the MitraClip in a patient with a severely restricted posterior mitral leaflet.

The MitraClip is an US Food and Drug Administration-approved device for inoperable patients with severe degenerative mitral regurgitation (MR) and is under investigation for use in patients with severe functional MR. Simultaneously grasping both leaflets of the mitral valve can be technically challenging, however, in patients with a restricted posterior leaflet. We present one such case in which a pigtail catheter, placed retrograde into the left ventricle, was able to push the ventricular surface of the posterior leaflet into closer approximation with the anterior leaflet, and facilitate successful clip placement. We provide this report in hopes that it will provide a useful strategy for interventionalists faced with this challenging situation.

Genetic Consequences of Pleistocene Sea-Level Change on Hawaiian Megalagrion Damselflies.

The Hawaiian Islands have long been an important laboratory for evolutionary research because their geological histories offer many natural experiments. For example, the Maui Nui complex, 4 islands that have been repeatedly connected and separated by fluctuating sea levels, lie near Hawaii Island, which has never been connected to another island. Here, we examine the genetic consequences of fluctuating island areas and connectivity using microsatellite analysis of 2 widespread, endemic Hawaiian damselflies. We screened 152 Megalagrion xanthomelas individuals from 5 islands at 14 loci and 34 Megalagrion pacificum from 3 islands at 11 loci to explore dispersal patterns and genetic diversity. Our data suggest that Pleistocene fluctuations in sea level alternated between creating land bridges that facilitated gene flow between once and future islands, and ocean channels that inhibited dispersal. Furthermore, interglacial periods of high sea stands likely reduced suitable habitat availability, causing the loss of genetic diversity on Maui Nui due to bottlenecks and founder events. Finally, we propose that gene flow from Molokai to Lanai may be enhanced by assisted dispersal from the trade winds that are channeled between volcanoes on western Maui and eastern Molokai. Our results emphasize the importance of variable microevolutionary processes in Hawaiian biogeography.

Nonsurgical Management of Knee Pain in Adults.

The role of the family physician in managing knee pain is expanding as recent literature supports nonsurgical management for many patients. Effective treatment depends on the etiology of knee pain. Oral analgesics-most commonly nonsteroidal anti-inflammatory drugs and acetaminophen-are used initially in combination with physical therapy to manage the most typical causes of chronic knee pain. The American Academy of Orthopaedic Surgeons recommends against glucosamine/chondroitin supplementation for osteoarthritis. In patients who are not candidates for surgery, opioid analgesics should be used only if conservative pharmacotherapy is ineffective. Exercise-based therapy is the foundation for treating knee osteoarthritis and patellofemoral pain syndrome. Weight loss should be encouraged for all patients with osteoarthritis and a body mass index greater than 25 kg per m2. Aside from stabilizing traumatic knee ligament and tendon tears, the effectiveness of knee braces for chronic knee pain is uncertain, and the use of braces should not replace physical therapy. Foot orthoses can be helpful for anterior knee pain. Corticosteroid injections are effective for short-term pain relief in patients with osteoarthritis. The benefit of hyaluronic acid injections is controversial, and recommendations vary; recent systematic reviews do not support a clinically significant benefit. Small studies suggest that regenerative injections can improve pain and function in patients with chronic knee tendinopathies and osteoarthritis.