Humanistic and Economic Burden of Geographic Atrophy: A Systematic Literature Review.

PURPOSE: Geographic atrophy (GA), the advanced form of dry age-related macular degeneration, can result in irreversible blindness over time. We performed a systematic literature review to assess the humanistic and economic burden of GA. METHODS: Predefined search terms were used to identify studies in PubMed, Embase, and Cochrane Library; conference abstracts also were searched. RESULTS: Of 1111 unique studies identified, 25 studies on humanistic burden, 4 on economic burden, and 3 on both humanistic and economic burden of GA were included. Vision-related functioning and health-related quality of life (HRQOL) are poor in patients with GA. HRQOL is commonly measured using the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25); patients with GA have significantly lower composite and subscale scores for near activities, distance activities, dependency, driving, social functioning, mental health, role difficulties, color vision, and peripheral vision than individuals without GA. Driving is a particular concern, and inability to drive affects dependency. Vision-related quality of life (VRQOL) declines as GA progresses. While we identified only 7 reports describing the economic burden of GA, its direct costs may be substantial. In a US study, mean cost to the payer per patient with GA was $11,533 in the year after diagnosis. A multinational study estimated annualized total direct costs of €1772 per patient with GA, mainly driven by diagnostic tests and procedures (€1071). Patients with GA are at increased risk of falls and fractures, potentially increasing direct costs. Only one study evaluated indirect costs, estimating ~$24.4 billion in yearly lost wages among people with severe vision loss due to GA or drusen ≥125 µm. CONCLUSION: GA represents a significant humanistic burden. Evidence on the economic impact of GA is limited; characterizing the economic burden of GA requires further research. Interventions that reduce GA-related disability may improve HRQOL and reduce indirect costs.

Transtendinous Rotator Cuff Tear Repair with Bone Marrow Aspirate Concentrate Dermal Allograft Augmentation.

Rotator cuff tears involving the musculotendinous junction with a significant amount of tendon still attached to the footprint laterally represent a challenging scenario for shoulder arthroscopists. Because of these challenges, adjunctive techniques to bridge tissue gaps may be required, and biologic augmentation may be considered to improve the healing environment. The following technique presents a stepwise approach to accomplishing the dual goals of a stable anatomic repair and biologic augmentation of this difficult pattern of rotator cuff pathology.

Subgroup analysis of clinical and MRI outcomes in participants with a first clinical demyelinating event at risk of multiple sclerosis in the ORACLE-MS study.

BACKGROUND: In the Phase 3, 96-week ORACLE-MS study, cladribine 10 mg tablets (3.5 mg/kg or 5.25 mg/kg cumulative dose over 2 years) significantly reduced the rate of conversion to clinically definite multiple sclerosis (CDMS) per the Poser criteria (henceforth referred to as CDMS), multiple sclerosis (MS) per the 2005 McDonald criteria, and the number of new or persisting T1 gadolinium-enhancing (Gd+), new or enlarging T2, and combined unique active (CUA) lesions versus placebo in participants with a first clinical demyelinating event (FCDE). Patient demographic and disease characteristics may be predictors of disease progression. The current study analyzed the effect of cladribine tablets in subgroups of participants in the ORACLE-MS study by baseline demographics and disease characteristics. METHODS: This analysis retrospectively examined data collected from 616 participants enrolled in the ORACLE-MS study (placebo, n=206; cladribine tablets 3.5 mg/kg, n=206; cladribine tablets 5.25 mg/kg, n=204). Five subgroups were predetermined by baseline demographics, including sex, age (<30 or ≥30 years), classification of FCDE, and lesion characteristics, including absence or presence of T1 Gd+ lesions and number of T2 lesions (<9 or ≥9). Selected endpoints of the ORACLE-MS study were re-analyzed for these subgroups. The primary and main secondary endpoints were time to conversion to CDMS and MS (2005 McDonald criteria), respectively. Secondary magnetic resonance imaging (MRI) endpoints included cumulative T1 Gd+ and new or enlarging T2 lesions. Cox proportional hazards models were used to evaluate time to conversion to CDMS and MS (2005 McDonald criteria). This analysis focused primarily on the results for the cladribine tablets 3.5 mg/kg group because this dosage is approved for relapsing forms of MS. RESULTS: In the overall intent-to-treat (ITT) population, cladribine tablets 3.5 mg/kg significantly reduced the risk of conversion to CDMS (hazard ratio [HR]=0.326; P<0.0001) and MS (2005 McDonald criteria; HR=0.485; P<0.0001) versus placebo. Similar effects of cladribine tablets on risk of conversion were observed in post hoc analyses of subgroups defined by various baseline characteristics. In both the ITT population and across subgroups, cladribine tablets 3.5 mg/kg reduced the numbers of cumulative T1 Gd+ (range of rate ratios: 0.106-0.399), new or enlarging T2 (range of rate ratios: 0.178-0.485), and CUA (range of rate ratios: 0.154-0.384) lesions versus placebo (all nominal P<0.03). Multivariate Cox proportional hazards models revealed that age (HR=0.577, nominal P<0.0001), FCDE classification (HR=0.738, nominal P=0.0043), presence of T1 Gd+ lesions (HR=0.554, nominal P<0.0001), and number of T2 lesions (HR=0.417, nominal P<0.0001) at baseline were factors associated with risk of conversion to MS (2005 McDonald criteria), whereas no baseline factors examined were associated with risk of conversion to CDMS. CONCLUSION: In this post hoc analysis of the ORACLE-MS study, cladribine tablets reduced the risk of conversion to multiple sclerosis and lesion burden in participants with an FCDE in the overall ITT population and multiple subgroups defined by baseline demographics and lesion characteristics.

Arthroscopic Posterior Capsular Release for Loss of Knee Extension.

Arthrofibrosis, as a result of osteoarthritis, after trauma, or after knee surgery, can have significant implications for patient function, satisfaction, and outcomes. When extensive conservative management fails to achieve satisfactory results, surgical intervention may be necessary. Arthroscopic techniques to release anterior adhesions are often viewed as easier and safer than posterior releases required for flexion contractures. We present our technique of a safe, effective, and reproducible arthroscopic complete posterior capsulotomy.

Underdosing of Prophylactic Enoxaparin Is Common in Orthopaedic Trauma and Predicts 90-Day Venous Thromboembolism.

OBJECTIVES: To determine the feasibility and impact of real-time anti-factor Xa (aFXa) level monitoring and enoxaparin dose adjustment in orthopaedic trauma. To examine the adequacy of standard fixed-dose enoxaparin chemoprophylaxis and to examine whether patient-specific factors influence enoxaparin metabolism. DESIGN: Prospective cohort. SETTING: Academic Level-I trauma center. PATIENTS: Postoperative adult orthopaedic trauma patients undergoing acute fracture or nonunion surgery of the pelvis, acetabulum, or lower extremity placed on 30 mg of enoxaparin twice daily. INTERVENTION: Peak steady-state aFXa levels were drawn with a goal range of 0.2-0.4 IU/mL. Patients with out-of-range levels underwent a 10-mg dose adjustment followed by repeat aFXa draws. MAIN OUTCOME MEASURES: Peak and trough aFXa levels, 90-day venous thromboembolism, and bleed events. RESULTS: Of 109 enrolled patients, 43% had inadequate initial peak aFXa levels (aFXa < 0.2 IU/mL) with standard dosing. Higher gross weight, acetabular surgery, and operation length predicted low aFXa levels (P < 0.001, 0.006, 0.004, respectively). Dose adjustment increased the proportion of patients with in-range aFXa levels from 53.2% to 87.8% (P < 0.001). Patients with low aFXa levels during hospitalization or at discharge had significantly higher 90-day deep vein thrombosis and pulmonary embolism rates compared to those with adequate aFXa levels (deep vein thrombosis 12% vs. 1.36%; P = 0.023, pulmonary embolism 8% vs. 0%; P = 0.027). There were no major bleed events. CONCLUSIONS: Patients receiving inadequate enoxaparin chemoprophylaxis were at significantly increased risk of 90-day venous thromboembolism. Standard fixed-dose enoxaparin provided inadequate chemoprophylaxis in 43% of postoperative orthopaedic trauma patients, which significantly improved with dose adjustment. Weight, acetabular surgery, and operation length predicted inadequate enoxaparin prophylaxis. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Recurrent natural killer/T-cell lymphoma of the lacrimal sac and nasolacrimal duct in a 59-year-old Caucasian woman.

A 59-year-old Caucasian woman with past medical history significant for Natural Killer (NK)/T-cell lymphoma of the right nasal septum in remission for nine months presented after surveillance PET-CT imaging revealed increased metabolic activity in the right nasolacrimal duct. She also reported ipsilateral epiphora starting around this time. The lacrimal sac and nasolacrimal ductal mucosa were biopsied via an external approach. Pathologic evaluation revealed a proliferation of lymphoid cells with necrotic tissue. Immunohistochemical staining demonstrated predominantly CD3+, EBER+, and CD56+ cells indicating recurrent NK/T-cell lymphoma. This case describes an unusual presentation of recurrent NK/T-cell lymphoma involving the lacrimal excretory system in a Caucasian adult. Recurrent malignancy should be considered in the differential of any patient with a history of a lymphoproliferative disorder near the lacrimal drainage system who presents with new onset epiphora.

Patient- and Procedure-Specific Variables Driving Total Direct Costs of Outpatient Anterior Cruciate Ligament Reconstruction.

BACKGROUND: Few studies have investigated the influence of patient-specific variables or procedure-specific factors on the overall cost of anterior cruciate ligament reconstruction (ACLR) in an ambulatory surgery setting. PURPOSE: To determine patient- and procedure-specific factors influencing the overall direct cost of outpatient arthroscopic ACLR utilizing a unique value-driven outcomes (VDO) tool. STUDY DESIGN: Cohort study (economic and decision analysis); Level of evidence, 3. METHODS: All ACLRs performed by 4 surgeons over 2 years were retrospectively reviewed. Cost data were derived from the VDO tool. Patient-specific variables included age, body mass index, comorbidities, American Society of Anesthesiologists (ASA) classification, smoking status, preoperative Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Computerized Adaptive Testing (PF-CAT) score, and preoperative Single Assessment Numeric Evaluation (SANE) score. Procedure-specific variables included graft type, revision status, associated injuries and procedures, time from injury to ACLR, surgeon, and operating room (OR) time. Multivariate analysis determined patient- and procedure-related predictors of total direct costs. RESULTS: There were 293 autograft reconstructions, 110 allograft reconstructions, and 31 hybrid reconstructions analyzed. Patient-specific factors did not significantly influence the ACLR cost. The mean OR time was shorter for allograft reconstruction (P < .001). Predictors of an increased direct cost included the use of an allograft or hybrid graft (44.5% and 33.1% increase, respectively; P < .001), increased OR time (0.3% increase per minute; P < .001), surgeon 3 or 4 (9.1% or 5.9% increase, respectively; P < .001 or P = .001, respectively), and concomitant meniscus repair (24.4% increase; P < .001). Within the meniscus repair cohort, all-inside, root, and combined repairs correlated with a 15.5%, 31.4%, and 53.2% increased mean direct cost, respectively, compared with inside-out repairs (P < .001). CONCLUSION: This study failed to identify modifiable patient-specific factors influencing direct costs of ACLR. Allografts and hybrid grafts were associated with an increased total direct cost. Meniscus repair independently predicted an increased direct cost, with all-inside, root, and combined repairs being costlier than inside-out repairs. The time-saving potential of all-inside meniscus repair was not realized in this study, making implant use a significant factor in the overall cost of ACLR with meniscus repair.

Treatment satisfaction significantly improves in patients with multiple sclerosis switching from interferon beta therapy to peginterferon beta-1a every 2 weeks.

OBJECTIVES: Posthoc analysis of treatment satisfaction in patients switching to subcutaneous (SC) peginterferon beta-1a in the ALLOW study. PATIENTS AND METHODS: Patients with relapsing multiple sclerosis treated with intramuscular interferon (IFN) beta-1a or SC IFN beta-1a or beta-1b remained on their current therapy for a 4-week run-in period, followed by a switch to SC peginterferon beta-1a 125 mcg every 2 weeks for 48 weeks. Treatment satisfaction was measured using the Treatment Satisfaction Questionnaire for Medication (TSQM), which covers effectiveness, side effects, convenience, and global satisfaction. Patients completed the TSQM at baseline (prior to starting the 4-week run-in period) and 4, 12, 24, 36, and 48 weeks after switching, and scores were analyzed for the overall population and compared to baseline. Patients reported the severity of flu-like symptoms (FLS) at baseline and with each peginterferon beta-1a injection; clinicians evaluated the occurrence of injection-site reactions (ISRs) after the first dose of peginterferon beta-1a and every 12 weeks thereafter. TSQM scores were stratified by the presence of FLS or ISRs during the study period and by prior IFN therapy use. RESULTS: For the overall population (n=194), convenience and global satisfaction scores significantly improved from baseline at all time points, and side effect satisfaction scores significantly improved up to week 36. Convenience scores significantly improved regardless of FLS, ISRs, or prior IFN therapy. Patients without FLS during the study period showed significant improvements in global satisfaction, but not side effect satisfaction, versus those with FLS. Patients switching from SC IFN therapies achieved greater improvements in treatment satisfaction than patients who switched from intramuscular IFN beta-1a. CONCLUSIONS: Switching relapsing multiple sclerosis patients to SC peginterferon beta-1a from other IFN therapies significantly improved treatment satisfaction and convenience.

Systematic approach for dissecting the molecular mechanisms of transcriptional regulation in bacteria.

Gene regulation is one of the most ubiquitous processes in biology. However, while the catalog of bacterial genomes continues to expand rapidly, we remain ignorant about how almost all of the genes in these genomes are regulated. At present, characterizing the molecular mechanisms by which individual regulatory sequences operate requires focused efforts using low-throughput methods. Here, we take a first step toward multipromoter dissection and show how a combination of massively parallel reporter assays, mass spectrometry, and information-theoretic modeling can be used to dissect multiple bacterial promoters in a systematic way. We show this approach on both well-studied and previously uncharacterized promoters in the enteric bacterium Escherichia coli In all cases, we recover nucleotide-resolution models of promoter mechanism. For some promoters, including previously unannotated ones, the approach allowed us to further extract quantitative biophysical models describing input-output relationships. Given the generality of the approach presented here, it opens up the possibility of quantitatively dissecting the mechanisms of promoter function in E. coli and a wide range of other bacteria.

DNA Repair and Photoprotection: Mechanisms of Overcoming Environmental Ultraviolet Radiation Exposure in Halophilic Archaea.

Halophilic archaea push the limits of life at several extremes. In particular, they are noted for their biochemical strategies in dealing with osmotic stress, low water activity and cycles of desiccation in their hypersaline environments. Another feature common to their habitats is intense ultraviolet (UV) radiation, which is a challenge that microorganisms must overcome. The consequences of high UV exposure include DNA lesions arising directly from bond rearrangement of adjacent bipyrimidines, or indirectly from oxidative damage, which may ultimately result in mutation and cell death. As such, these microorganisms have evolved a number of strategies to navigate the threat of DNA damage, which we differentiate into two categories: DNA repair and photoprotection. Photoprotection encompasses damage avoidance strategies that serve as a "first line of defense," and in halophilic archaea include pigmentation by carotenoids, mechanisms of oxidative damage avoidance, polyploidy, and genomic signatures that make DNA less susceptible to photodamage. Photolesions that do arise are addressed by a number of DNA repair mechanisms that halophilic archaea efficiently utilize, which include photoreactivation, nucleotide excision repair, base excision repair, and homologous recombination. This review seeks to place DNA damage, repair, and photoprotection in the context of halophilic archaea and the solar radiation of their hypersaline environments. We also provide new insight into the breadth of strategies and how they may work together to produce remarkable UV-resistance for these microorganisms.

Bipyrimidine Signatures as a Photoprotective Genome Strategy in G + C-rich Halophilic Archaea.

Halophilic archaea experience high levels of ultraviolet (UV) light in their environments and demonstrate resistance to UV irradiation. DNA repair systems and carotenoids provide UV protection but do not account for the high resistance observed. Herein, we consider genomic signatures as an additional photoprotective strategy. The predominant forms of UV-induced DNA damage are cyclobutane pyrimidine dimers, most notoriously thymine dimers (T^Ts), which form at adjacent Ts. We tested whether the high G + C content seen in halophilic archaea serves a photoprotective function through limiting T nucleotides, and thus T^T lesions. However, this speculation overlooks the other bipyrimidine sequences, all of which capable of forming photolesions to varying degrees. Therefore, we designed a program to determine the frequencies of the four bipyrimidine pairs (5' to 3': TT, TC, CT, and CC) within genomes of halophilic archaea and four other randomized sample groups for comparison. The outputs for each sampled genome were weighted by the intrinsic photoreactivities of each dinucleotide pair. Statistical methods were employed to investigate intergroup differences. Our findings indicate that the UV-resistance seen in halophilic archaea can be attributed in part to a genomic strategy: high G + C content and the resulting bipyrimidine signature reduces the genomic photoreactivity.

Distal Femoral Osteotomy for the Valgus Knee: Medial Closing Wedge Versus Lateral Opening Wedge: A Systematic Review.

PURPOSE: (1) To determine the radiographic correction/healing rate, patient-reported outcomes, reoperation rate, and complication rate after distal femoral osteotomy (DFO) for the valgus knee with lateral compartment pathology. (2) To summarize the reported results of medial closing wedge and lateral opening wedge DFO. METHODS: We conducted a systematic review of PubMed, MEDLINE, and CINAHL to identify studies reporting outcomes of DFOs for the valgus knee. Keywords included "distal femoral osteotomy," "chondral," "cartilage," "valgus," "joint restoration," "joint preservation," "arthritis," and "gonarthrosis." Two authors first reviewed the articles; our study exclusion criteria were then applied, and the articles were included on the basis relevance defined by the aforementioned criteria. The Methodological Index for Nonrandomized Studies scale judged the quality of the literature. Sixteen studies were relevant to the research questions out of 191 studies identified by the original search. RESULTS: Sixteen studies were identified reporting on 372 osteotomies with mean follow-up of 45 to 180 months. All studies reported mean radiographic correction to a near neutral mechanical axis, with 3.2% nonunion and 3.8% delayed union rates. There was a 9% complication rate and a 34% reoperation rate, of which 15% were converted to arthroplasty. There were similar results reported for medial closing wedge and lateral opening wedge techniques, with a higher conversion to arthroplasty in the medial closing wedge that was confounded by longer mean follow-up in this group (mean follow-up 100 v 58 months). CONCLUSIONS: DFOs for the valgus knee with lateral compartment disease provide improvements in patient-reported knee health-related quality of life at midterm follow-up but have high rates of reoperation. No evidence exists proving better results of either the lateral opening wedge or medial closing wedge techniques. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies.

Practice Location Characteristics of Non-Traditional Dental Practices.

Current and future dental school graduates are increasingly likely to choose a non-traditional dental practice-a group practice managed by a dental service organization or a corporate practice with employed dentists-for their initial practice experience. In addition, the growth of non-traditional practices, which are located primarily in major urban areas, could accelerate the movement of dentists to those areas and contribute to geographic disparities in the distribution of dental services. To help the profession understand the implications of these developments, the aim of this study was to compare the location characteristics of non-traditional practices and traditional dental practices. After identifying non-traditional practices across the United States, the authors located those practices and traditional dental practices geographically by zip code. Non-traditional dental practices were found to represent about 3.1% of all dental practices, but they had a greater impact on the marketplace with almost twice the average number of staff and annual revenue. Virtually all non-traditional dental practices were located in zip codes that also had a traditional dental practice. Zip codes with non-traditional practices had significant differences from zip codes with only a traditional dental practice: the populations in areas with non-traditional practices had higher income levels and higher education and were slightly younger and proportionally more Hispanic; those practices also had a much higher likelihood of being located in a major metropolitan area. Dental educators and leaders need to understand the impact of these trends in the practice environment in order to both prepare graduates for practice and make decisions about planning for the workforce of the future.

Can AST/ALT ratio indicate recovery after acute paracetamol poisoning?

CONTEXT: Paracetamol (acetaminophen or APAP) is the most common pharmaceutical exposure in the US. Elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels indicate hepatic toxicity. AST and ALT levels rise in similar proportions but later decline at different rates, with AST falling more rapidly than ALT. OBJECTIVE: To determine whether the AST/ALT ratio can indicate that a patient has passed the time of peak AST concentration. METHODS: We retrospectively identified cases of patients hospitalized for acute APAP poisoning by querying the pharmacy database of all patients treated with acetylcysteine (NAC) from January 1, 2001 to March 19, 2013. We included all patients with severe APAP poisoning, defined as AST or ALT greater than 1000 IU/L. Patients who were given NAC for other indications, those without APAP poisoning, and those receiving liver transplantation were excluded. We then recorded paired AST and ALT concentrations from each patient's hospital course. We classified each pair as clearly post-peak or not, and calculated the AST/ALT ratio for each pair of values. We compared different thresholds of AST/ALT ratio in increments of 0.1 to find the optimal value that reliably indicated resolving transaminases. RESULTS: We identified 1820 patients who received NAC during the study period. Of these, 333 received NAC for suspected poisoning by APAP. After excluding patients without severe APAP poisoning, other diagnoses explaining transaminase elevations, and patients who underwent liver transplantation, we had 37 evaluable patients with 343 evaluable pairs of AST and ALT concentrations. An AST/ALT ratio less than or equal to 0.4 was 99% sensitive for identifying patients with resolving transaminases. CONCLUSION: An AST/ALT ratio less than or equal to 0.4 following severe hepatoxicity from paracetamol poisoning appears to be highly predictive of recovery in patients treated with NAC. This has potential to be an indicator of safe discontinuation of NAC treatment.

Promoter architecture dictates cell-to-cell variability in gene expression.

Variability in gene expression among genetically identical cells has emerged as a central preoccupation in the study of gene regulation; however, a divide exists between the predictions of molecular models of prokaryotic transcriptional regulation and genome-wide experimental studies suggesting that this variability is indifferent to the underlying regulatory architecture. We constructed a set of promoters in Escherichia coli in which promoter strength, transcription factor binding strength, and transcription factor copy numbers are systematically varied, and used messenger RNA (mRNA) fluorescence in situ hybridization to observe how these changes affected variability in gene expression. Our parameter-free models predicted the observed variability; hence, the molecular details of transcription dictate variability in mRNA expression, and transcriptional noise is specifically tunable and thus represents an evolutionarily accessible phenotypic parameter.

Oral cancer: FAQ.

The efficacy of clinical examination in detecting intraoral malignances has recently been called into question, as it does not accurately predict the histological diagnosis. A brief reexamination of one study provides some insights into what this means to the clinician. Making a diagnosis on the basis of a clinical examination may result in a false-positive finding and unnecessary treatment. However, a more significant concern would be a false-negative finding, in which disease is present but not detected and therefore not treated. The most effective preventive strategy is to help patients reduce or eliminate dangerous habits, and to remain alert for signs of potentially malignant or early-stage lesions, and perform routine visual and tactile examinations of all patients. A working knowledge of the clinical epidemiology of oral cancer, familiarity with the risk factors, signs and symptoms, together with continued vigilance in the form of regular, systematic and thorough clinical examination remains the most basic means of ensuring early detection of oral cancer and providing the best care possible.