A marine heatwave drives significant shifts in pelagic microbiology.

Marine heatwaves (MHWs) cause disruption to marine ecosystems, deleteriously impacting macroflora and fauna. However, effects on microorganisms are relatively unknown despite ocean temperature being a major determinant of assemblage structure. Using data from thousands of Southern Hemisphere samples, we reveal that during an "unprecedented" 2015/16 Tasman Sea MHW, temperatures approached or surpassed the upper thermal boundary of many endemic taxa. Temperate microbial assemblages underwent a profound transition to niche states aligned with sites over 1000 km equatorward, adapting to higher temperatures and lower nutrient conditions bought on by the MHW. MHW conditions also modulate seasonal patterns of microbial diversity and support novel assemblage compositions. The most significant affects of MHWs on microbial assemblages occurred during warmer months, when temperatures exceeded the upper climatological bounds. Trends in microbial response across several MHWs in different locations suggest these are emergent properties of temperate ocean warming, which may facilitate monitoring, prediction and adaptation efforts.

A new synthesis method for complex electric field patterning using a multichannel dense array system with applications in low-intensity noninvasive neuromodulation.

Multichannel coil array systems offer precise spatiotemporal electronic steering and patterning of electric and magnetic fields without the physical movement of coils or magnets. This capability could potentially benefit a wide range of biomagnetic applications such as low-intensity noninvasive neuromodulation or magnetic drug delivery. In this regard, the objective of this work is to develop a unique synthesis method, that enabled by a multichannel dense array system, generates complex current pattern distributions not previously reported in the literature. Simulations and experimental results verify that highly curved or irregular (e.g., zig-zag) patterns at singular and multiple sites can be efficiently formed using this method. The synthesis method is composed of three primary components; a pixel cell (basic unit of pattern formation), a template array ("virtual array": code that disseminates the coil current weights to the "physical" dense array), and a hexagonal coordinate system. Low-intensity or low-field magnetic stimulation is identified as a potential application that could benefit from this work in the future and as such is used as an example to frame the research.

Comparative Hydrophobic Core Dynamics Between Wild-Type Amyloid-ß Fibrils, Glutamate-3 Truncation, and Serine-8 Phosphorylation.

Post-translational modifications (PTMs) of amyloid-ß (Aß) species are implicated in the modulation of overall toxicities and aggregation propensities. We investigated the internal dynamics in the hydrophobic core of the truncated ΔE3 mutant fibrils of Aß1-40 and compared them with prior and new data for wild-type fibrils as well as with phosphorylated S8 fibrils. Deuteron static solid-state NMR techniques, spanning line-shape analysis, longitudinal relaxation, and chemical exchange saturation transfer methods, were employed to assess the rotameric jumps of several methyl-bearing and aromatic groups in the core of the fibrils. Taken together, the results indicate the rather significant influence of the PTMs on the hydrophobic core dynamics, which propagates far beyond the local site of the chemical modification. The phosphorylated S8 fibrils display an overall rigidifying of the core based on the higher activation barriers of motions than the wild-type fibrils, whereas the ΔE3 fibrils induce a broader variety of changes, some of which are thermodynamic in nature rather than the kinetic ones.

Component Microenvironments and System Biogeography Structure Microorganism Distributions in Recirculating Aquaculture and Aquaponic Systems.

Flowthrough and pond aquaculture system microbiome management practices aim to mitigate fish disease and stress. However, the operational success of recirculating aquaculture systems (RAS) depends directly on system microbial community activities. In RAS, each component environment is engineered for a specific microbial niche for waste management, as the water continuously flowing through the system must be processed before returning to the rearing tank. In this study, we compared waste management component microbiomes (rearing tank water, pH correction tank, solid-waste clarifier, biofilter, and degassing tower) within a commercial-scale freshwater RAS by high-throughput 16S rRNA gene sequencing. To assess consistency among freshwater RAS microbiomes, we also compared the microbial community compositions of six aquaculture and aquaponic farms. Community assemblages reflected site and source water relationships, and the presence of a hydroponic subsystem was a major community determinant. In contrast to the facility-specific community composition, some sequence variants, mainly classified into Flavobacterium, Cetobacterium, the family Sphingomonadaceae, and nitrifying guilds of ammonia-oxidizing archaea and Nitrospira, were common across all facilities. The findings of this study suggest that, independently of system design, core taxa exist across RAS rearing similar fish species but that system design informs the individual aquatic microbiome assemblages. Future RAS design would benefit from understanding the roles of these core taxa and then capitalizing on their activities to further reduce system waste/added operational controls.IMPORTANCE Recirculating aquaculture systems (RAS) are agroecosystems for intensive on-land cultivation of products of fisheries. Practitioners that incorporate edible plant production into RAS refer to these facilities as aquaponic systems (AP). RAS have the potential to offset declining production levels of wild global fisheries while reducing waste and product distance to market, but system optimization is needed to reduce costs. Both RAS and AP rely on microbial consortia for maintaining water quality and promoting fish/plant health, but little is known about the microorganisms actually present. This lack of knowledge prevents optimization of designs and operational controls to target the growth of beneficial microbial species or consortia. The significance of our research is in identifying the common microorganisms that inhabit production RAS and AP and the operational factors that influence which microorganisms colonize and become abundant. Identifying these organisms is a first step toward advanced control of microbial activities that improve reproducibility and reduce costs.

Transradial interventions in contemporary vascular surgery practice.

OBJECTIVES: Upper extremity arterial access is often required for endovascular procedures, especially for antegrade access to the visceral aortic branches. Radial arterial access has been shown previously to have low complication rates, and patients tolerate the procedure well and are able to recover quickly. However, transradial access remains relatively uncommon amongst vascular surgeons. METHODS: The radial artery was evaluated by ultrasound to evaluate for adequate caliber, and to identify any aberrant anatomy or arterial loops. A modified Barbeau test was performed to ensure sufficient collateral circulation. A cocktail of nitroglycerin, verapamil and heparin was administered intra-arterially to combat vasospasm. Sheaths up to 6 French were utilized for interventions. On completion of the procedure, a compression band was used for hemostasis in all cases. RESULTS: Twenty-five interventions were performed in 24 patients. The left radial artery was used in 23/25 cases (92.0%). Procedures included visceral and renal artery interventions; stent graft repair of a renal artery aneurysm; embolization of splenic, pancreaticoduodenal and internal mammary aneurysms; embolization of bilateral hypogastric arteries following blunt pelvic trauma; interventions for peripheral arterial disease; delivery of a renal snorkel graft during endovascular aortic aneurysm repair, and access for diagnostic catheters during thoracic endovascular aortic aneurysm repair. Technical success was 92.0%. There was one post-operative radial artery occlusion (4.3%) which led to paresthesias but resolved with anticoagulation. There were no instances of arterial rupture, hematoma, or hand ischemia requiring intervention. CONCLUSIONS: Using the transradial approach, we have demonstrated a high technical success rate over a range of clinical contexts with minimal morbidity and no significant complications such as bleeding or hand ischemia. The safety profile compares favorably to historical complication rates from brachial access. Radial access is a safe and useful skill for vascular surgeons to master.

Path to Impact for Autonomous Field Deployable Chemical Sensors: A Case Study of in Situ Nitrite Sensors.

Natural freshwater systems have been severely affected by excess loading of macronutrients (e.g., nitrogen and phosphorus) from fertilizers, fossil fuels, and human and livestock waste. In the USA, impacts to drinking water quality, biogeochemical cycles, and aquatic ecosystems are estimated to cost US$210 billion annually. Field-deployable nutrient sensors (FDS) offer potential to support research and resource management efforts by acquiring higher resolution data than are currently supported by expensive conventional sampling methods. Following nearly 40 years of research and development, FDS instruments are now starting to penetrate commercial markets. However, instrument uncertainty factors (high cost, reliability, accuracy, and precision) are key drivers impeding the uptake of FDS by the majority of users. Using nitrite sensors as a case study, we review the trends, opportunities, and challenges in producing and implementing FDS from a perspective of innovation and impact. We characterize the user community and consumer needs, identify trends in research approaches, tabulate state-of-the-art examples and specifications, and discuss data life cycle considerations. With further development of FDS through prototyping and testing in real-world applications, these tools can deliver information for protecting and restoring natural waters, enhancing process control for industrial operations and water treatment, and providing novel research insights.

RNA-Seq of the Caribbean reef-building coral Orbicella faveolata (Scleractinia-Merulinidae) under bleaching and disease stress expands models of coral innate immunity.

Climate change-driven coral disease outbreaks have led to widespread declines in coral populations. Early work on coral genomics established that corals have a complex innate immune system, and whole-transcriptome gene expression studies have revealed mechanisms by which the coral immune system responds to stress and disease. The present investigation expands bioinformatic data available to study coral molecular physiology through the assembly and annotation of a reference transcriptome of the Caribbean reef-building coral, Orbicella faveolata. Samples were collected during a warm water thermal anomaly, coral bleaching event and Caribbean yellow band disease outbreak in 2010 in Puerto Rico. Multiplex sequencing of RNA on the Illumina GAIIx platform and de novo transcriptome assembly by Trinity produced 70,745,177 raw short-sequence reads and 32,463 O. faveolata transcripts, respectively. The reference transcriptome was annotated with gene ontologies, mapped to KEGG pathways, and a predicted proteome of 20,488 sequences was generated. Protein families and signaling pathways that are essential in the regulation of innate immunity across Phyla were investigated in-depth. Results were used to develop models of evolutionarily conserved Wnt, Notch, Rig-like receptor, Nod-like receptor, and Dicer signaling. O. faveolata is a coral species that has been studied widely under climate-driven stress and disease, and the present investigation provides new data on the genes that putatively regulate its immune system.

Variability in length of stay after uncomplicated pulmonary lobectomy: is length of stay a quality metric or a patient metric?†.

OBJECTIVES: Previous studies have identified predictors of prolonged length of stay (LOS) following pulmonary lobectomy. LOS is typically described to have a direct relationship to postoperative complications. We sought to determine the LOS and factors associated with variability after uncomplicated pulmonary lobectomy. METHODS: Analysing the State Inpatient Databases, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality database, we reviewed lobectomies performed (2009-11) on patients in California, Florida and New York. LOS and comorbidities were identified. Multivariable regression analysis (MVA) was used to determine factors associated with LOS greater than the median. Patients with postoperative complications or death were excluded. RESULTS: Among 22 647 lobectomies performed, we identified 13 099 patients (58%) with uncomplicated postoperative courses (mean age = 66 years; 56% female; 76% white, 57% Medicare; median DEYO comorbidity score = 3, 55% thoracotomy, 45% thoracoscopy/robotic). There was a wide distribution in LOS [median LOS = 5 days; interquartile range (IQR) 4-7]. By MVA, predictors of prolonged LOS included, age ≥ 75 years [odds ratio (OR) 1.7, 95% confidence interval (CI) 1.4-2.0], male gender (OR 1.2, 95% CI 1.1-1.2), chronic obstructive pulmonary disease (OR 1.6, 95% CI 1.5-1.7) and other comorbidities, Medicaid payer (OR 1.7, 95% CI 1.4-2.1) versus private insurance, thoracotomy (OR 3.0, 95% CI 2.8-3.3) versus video-assisted thoracoscopic surgery/robotic approach and low hospital volume (OR 2.4, 95% CI 2.1-2.6). CONCLUSIONS: Variability exists in LOS following even uncomplicated pulmonary lobectomy. Variability is driven by clinical factors such as age, gender, payer and comorbidities, but also by surgical approach and volume. All of these factors should be taken into account when designing clinical care pathways or when allocating payment resources. Attempts to define an optimal LOS depend heavily upon the patient population studied.

Integration of genetic and physical maps of the Primula vulgaris S locus and localization by chromosome in situ hybridization.

Heteromorphic flower development in Primula is controlled by the S locus. The S locus genes, which control anther position, pistil length and pollen size in pin and thrum flowers, have not yet been characterized. We have integrated S-linked genes, marker sequences and mutant phenotypes to create a map of the P. vulgaris S locus region that will facilitate the identification of key S locus genes. We have generated, sequenced and annotated BAC sequences spanning the S locus, and identified its chromosomal location. We have employed a combination of classical genetics and three-point crosses with molecular genetic analysis of recombinants to generate the map. We have characterized this region by Illumina sequencing and bioinformatic analysis, together with chromosome in situ hybridization. We present an integrated genetic and physical map across the P. vulgaris S locus flanked by phenotypic and DNA sequence markers. BAC contigs encompass a 1.5-Mb genomic region with 1 Mb of sequence containing 82 S-linked genes anchored to overlapping BACs. The S locus is located close to the centromere of the largest metacentric chromosome pair. These data will facilitate the identification of the genes that orchestrate heterostyly in Primula and enable evolutionary analyses of the S locus.

Comparison of Pain Score Reduction Using Triamcinolone vs. Betamethasone in Transforaminal Epidural Steroid Injections for Lumbosacral Radicular Pain.

OBJECTIVE: Although the comparative efficacy of particulate vs. nonparticulate steroids for the treatment of radicular pain with transforaminal epidural steroid injection has been investigated, there is minimal literature comparing particulate steroids. The authors aimed to determine whether transforaminal epidural steroid injection with triamcinolone or betamethasone, two particulate corticosteroids, more effectively reduces lumbosacral radicular pain. DESIGN: This is a longitudinal cohort study of 1021 patients (1568 transforaminal epidural steroid injections) who received betamethasone or triamcinolone between January 2006 and October 2007 in an academic spine center. The frequency of greater than 50% pain reduction was compared between groups. RESULTS: This study included 42.4% (433) male and 57.6% (588) female patients, with a mean (SD) age of 54.1 (16.7) yrs. Betamethasone and triamcinolone were used in 78.8% (1235) and 21.2% (333) of subjects, respectively. Significantly more patients who received triamcinolone (44.4% [95% confidence interval, 36.2%-52.8%]) experienced greater than 50% pain reduction at short-term follow-up (1-4 wks) compared with patients who received betamethasone (26.8% [95% confidence interval, 22.7%-31.4%]). CONCLUSIONS: Patients who received transforaminal epidural steroid injection with triamcinolone reported more frequent pain relief of greater than 50% at short-term follow-up compared with those who received betamethasone. These findings further develop the literature on comparative effectiveness in epidural steroid injections. However, given the exploratory and retrospective nature of this investigation, further study is needed.

Concordant pain provocation during transforaminal epidural steroid injection for lumbosacral radiculopathy: effect on pain outcome and predictive factors.

BACKGROUND: Anecdotal report suggests that provocation of pain during epidural steroid injection (ESI) that is concordant with typical radicular symptoms predicts pain outcome following injection. However, limited evidence exists that substantiates this theory. Additionally, there is a paucity of literature investigating factors associated with the provocation of pain during ESI. OBJECTIVES: The goal of this study was to determine whether provocation of concordant radicular pain during transforaminal ESI predicts pain relief immediately after injection and at short-term follow-up. Demographic, radiologic, and procedural factors associated with the pain provocation and pain outcomes at immediate and short-term follow-up were also investigated. STUDY DESIGN: Longitudinal cohort study. SETTING: Urban academic outpatient interventional spine clinics. METHODS: Adults who underwent a fluoroscopically guided transforaminal ESI without sedation between January 1, 2006, and October 29, 2007, for the treatment of lumbosacral radicular pain were included in this study. The relationships between provocation of concordant pain, immediate post-injection, and follow-up visual analogue scale (VAS) pain scores, as well as with demographic, radiologic, and procedural factors were determined using chi-square/Fisher's exact tests for categorical variables and t-tests or ANOVA for numerical variables. RESULTS: One thousand twenty one patients, 42.4% (433) male/57.6% (588) female, with a mean (SD) age of 54.1 (16.7) years were included in the study. Concordant pain provocation did not predict the magnitude of pain reduction (P = 0.9255) or the frequency of achieving > 50% pain relief (P = 0.7449) at short-term follow-up. Radiologic evidence of foraminal stenosis or nerve root impingement (P < 0.0001) and the lack of a medial-superior contrast flow pattern (P = 0.0199) were associated with a greater frequency of pain provocation during transforaminal ESI. LIMITATIONS: This study is primarily limited by possible selection bias given that patients who did not follow-up in the clinic could not be studied, and an incomplete follow-up rate (66%). Conclusions regarding subacute and long-term pain outcomes cannot be determined from this study as only short-term data were available. CONCLUSIONS: Provocation of concordant radicular pain does not predict pain relief at short-term follow-up after a transforaminal ESI. Foraminal stenosis, nerve root impingement, and lack of a medial-superior contrast flow pattern are associated with pain during the transforaminal ESI. Thus, clinicians should be aware of these radiologic and procedural risk factors for inciting pain during transforaminal ESI.

Proteasome function is required for platelet production.

The proteasome inhibiter bortezomib has been successfully used to treat patients with relapsed multiple myeloma; however, many of these patients become thrombocytopenic, and it is not clear how the proteasome influences platelet production. Here we determined that pharmacologic inhibition of proteasome activity blocks proplatelet formation in human and mouse megakaryocytes. We also found that megakaryocytes isolated from mice deficient for PSMC1, an essential subunit of the 26S proteasome, fail to produce proplatelets. Consistent with decreased proplatelet formation, mice lacking PSMC1 in platelets (Psmc1(fl/fl) Pf4-Cre mice) exhibited severe thrombocytopenia and died shortly after birth. The failure to produce proplatelets in proteasome-inhibited megakaryocytes was due to upregulation and hyperactivation of the small GTPase, RhoA, rather than NF-κB, as has been previously suggested. Inhibition of RhoA or its downstream target, Rho-associated protein kinase (ROCK), restored megakaryocyte proplatelet formation in the setting of proteasome inhibition in vitro. Similarly, fasudil, a ROCK inhibitor used clinically to treat cerebral vasospasm, restored platelet counts in adult mice that were made thrombocytopenic by tamoxifen-induced suppression of proteasome activity in megakaryocytes and platelets (Psmc1(fl/fl) Pdgf-Cre-ER mice). These results indicate that proteasome function is critical for thrombopoiesis, and suggest inhibition of RhoA signaling as a potential strategy to treat thrombocytopenia in bortezomib-treated multiple myeloma patients.

High-throughput screen of natural product extracts in a yeast model of polyglutamine proteotoxicity.

Proteins with expanded polyglutamine (polyQ) segments cause a number of fatal neurodegenerative disorders, including Huntington's disease (HD). Previous high-throughput screens in cellular and biochemical models of HD have revealed compounds that mitigate polyQ aggregation and proteotoxicity, providing insight into the mechanisms of disease and leads for potential therapeutics. However, the structural diversity of natural products has not yet been fully mobilized toward these goals. Here, we have screened a collection of ~11 000 natural product extracts for the ability to recover the slow growth of ΔProQ103-expressing yeast cells in 384-well plates (Z' ~ 0.7, CV ~ 8%). This screen identified actinomycin D as a strong inhibitor of polyQ aggregation and proteotoxicity at nanomolar concentrations (~50-500 ng/mL). We found that a low dose of actinomycin D increased the levels of the heat-shock proteins Hsp104, Hsp70 and Hsp26 and enhanced binding of Hsp70 to the polyQ in yeast. Actinomycin also suppressed aggregation of polyQ in mammalian cells, suggesting a conserved mechanism. These results establish natural products as a rich source of compounds with interesting mechanisms of action against polyQ disorders.

Chemoproteomic discovery of AADACL1 as a regulator of human platelet activation.

A comprehensive knowledge of the platelet proteome is necessary for understanding thrombosis and for envisioning antiplatelet therapies. To discover other biochemical pathways in human platelets, we screened platelets with a carbamate library designed to interrogate the serine hydrolase subproteome and used competitive activity-based protein profiling to map the targets of active carbamates. We identified an inhibitor that targets arylacetamide deacetylase-like 1 (AADACL1), a lipid deacetylase originally identified in invasive cancers. Using this compound, along with highly selective second-generation inhibitors of AADACL1, metabolomics, and RNA interference, we show that AADACL1 regulates platelet aggregation, thrombus growth, RAP1 and PKC activation, lipid metabolism, and fibrinogen binding to platelets and megakaryocytes. These data provide evidence that AADACL1 regulates platelet and megakaryocyte activation and highlight the value of this chemoproteomic strategy for target discovery in platelets.

The E3 ubiquitin ligase CHIP and the molecular chaperone Hsc70 form a dynamic, tethered complex.

The E3 ubiquitin ligase CHIP (C-terminus of Hsc70 Interacting Protein, a 70 kDa homodimer) binds to the molecular chaperone Hsc70 (a 70 kDa monomer), and this complex is important in both the ubiquitination of Hsc70 and the turnover of Hsc70-bound clients. Here we used NMR spectroscopy, biolayer interferometry, and fluorescence polarization to characterize the Hsc70-CHIP interaction. We found that CHIP binds tightly to two molecules of Hsc70 forming a 210 kDa complex, with a Kd of approximately 60 nM, and that the IEEVD motif at the C-terminus of Hsc70 (residues 642-646) is both necessary and sufficient for binding. Moreover, the same motif is required for CHIP-mediated ubiquitination of Hsc70 in vitro, highlighting its functional importance. Relaxation-based NMR experiments on the Hsc70-CHIP complex determined that the two partners move independently in solution, similar to "beads on a string". These results suggest that a dynamic C-terminal region of Hsc70 provides for flexibility between CHIP and the chaperone, allowing the ligase to "search" a large space and engage in productive interactions with a wide range of clients. In support of this suggestion, we find that deleting residues 623-641 of the C-terminal region, while retaining the IEEVD motif, caused a significant decrease in the efficiency of Hsc70 ubiquitination by CHIP.

Arteriovenous malformations and other vascular malformation syndromes.

Vascular malformations are a disruption of the normal vascular pattern in which it is expected that a capillary network of microscopic vessels lies interposed between high-pressure arteries that deliver blood and thin-walled veins that collect low-pressure blood for return to the heart. In the case of arteriovenous malformations, arteries or arterioles connect directly to the venous collection system, bypassing any capillary bed. Clinical consequences result from rupture and hemorrhage, from dramatically increased blood flow, or from the loss of capillary functions such as nutrient exchange and filtering function. These malformations can occur sporadically or as a component of inherited vascular malformation syndromes. In these and other hereditary vascular malformation syndromes, genetic studies have identified proteins and pathways involved in vascular morphogenesis and development. A common theme observed is that vascular malformations result from disruption in pathways involved in vascular stability. Here we review the vascular malformations and pathways involved in hereditary hemorrhagic telangiectasia, capillary malformation-arteriovenous malformation, cerebral cavernous malformations, and mucocutaneous venous malformations.

Interleukin receptor activates a MYD88-ARNO-ARF6 cascade to disrupt vascular stability.

The innate immune response is essential for combating infectious disease. Macrophages and other cells respond to infection by releasing cytokines, such as interleukin-1ß (IL-1ß), which in turn activate a well-described, myeloid-differentiation factor 88 (MYD88)-mediated, nuclear factor-κB (NF-κB)-dependent transcriptional pathway that results in inflammatory-cell activation and recruitment. Endothelial cells, which usually serve as a barrier to the movement of inflammatory cells out of the blood and into tissue, are also critical mediators of the inflammatory response. Paradoxically, the cytokines vital to a successful immune defence also have disruptive effects on endothelial cell-cell interactions and can trigger degradation of barrier function and dissociation of tissue architecture. The mechanism of this barrier dissolution and its relationship to the canonical NF-κB pathway remain poorly defined. Here we show that the direct, immediate and disruptive effects of IL-1ß on endothelial stability in a human in vitro cell model are NF-κB independent and are instead the result of signalling through the small GTPase ADP-ribosylation factor 6 (ARF6) and its activator ARF nucleotide binding site opener (ARNO; also known as CYTH2). Moreover, we show that ARNO binds directly to the adaptor protein MYD88, and thus propose MYD88-ARNO-ARF6 as a proximal IL-1ß signalling pathway distinct from that mediated by NF-κB. Finally, we show that SecinH3, an inhibitor of ARF guanine nucleotide-exchange factors such as ARNO, enhances vascular stability and significantly improves outcomes in animal models of inflammatory arthritis and acute inflammation.

Features of protein-protein interactions that translate into potent inhibitors: topology, surface area and affinity.

Protein-protein interactions (PPIs) control the assembly of multi-protein complexes and, thus, these contacts have enormous potential as drug targets. However, the field has produced a mix of both exciting success stories and frustrating challenges. Here, we review known examples and explore how the physical features of a PPI, such as its affinity, hotspots, off-rates, buried surface area and topology, might influence the chances of success in finding inhibitors. This analysis suggests that concise, tight binding PPIs are most amenable to inhibition. However, it is also clear that emerging technical methods are expanding the repertoire of 'druggable' protein contacts and increasing the odds against difficult targets. In particular, natural product-like compound libraries, high throughput screens specifically designed for PPIs and approaches that favour discovery of allosteric inhibitors appear to be attractive routes. The first group of PPI inhibitors has entered clinical trials, further motivating the need to understand the challenges and opportunities in pursuing these types of targets.

Stable fixation of short-stem femoral implants in patients 70 years and older.

BACKGROUND: Limitations of conventional uncemented femoral stems persist, including proximal-distal mismatch, nonideal load transfer, loss of bone, and difficulties with minimally invasive surgery. Metaphyseal-engaging short-stem implants have been designed to address these issues in THA. While these devices have been studied in younger patients, it is unclear whether they offer advantages in older patients. QUESTIONS/PURPOSES: We asked whether the stability and bony ingrowth of an off-the-shelf short stem in patients 70 years and older were similar to those achieved in patients younger than 70 years at 2-year followup. Furthermore, we asked whether pain and function scores were affected by age, bone quality, or varus alignment. PATIENTS AND METHODS: We retrospectively reviewed 60 patients (65 hips) 70 years and older (mean, 75 years; range, 70-86 years) treated with an uncemented short stem (range, 90-105 mm). We compared radiographic alignment, stability, and bony ingrowth, as well as Harris hip scores and WOMAC pain scores, to a cohort of 89 patients (91 hips) younger than 70 years. Minimum followup was 24 months (mean, 35 months; range, 24-60 months). RESULTS: Radiographs showed proximal bony ingrowth and stable fixation of all implants. Average Harris hip score at last followup was 88 (range, 70-100) for the 70 years and older cohort and 93 (range, 70-100) for younger than 70 years cohort; no patients reported thigh pain. Postoperative WOMAC scores averaged 6 (range, 0-43) and 5 (range, 0-25), respectively. CONCLUSIONS: Short-stem implants provide solid, dependable fixation in osteoporotic bone at minimum 2-year followup, while meeting some of the limitations in conventional primary THA. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.