Primary anterior cruciate ligament reconstruction: perioperative considerations and complications

Anterior cruciate ligament (ACL) injuries are among the most commonly studied orthopaedic injuries. Despite having an excellent prognosis, complications do occur. The timely recognition and management of complications is imperative to ensure the success of reconstruction. Avoiding such complications requires thorough preoperative planning, proficient technical skills to properly manage intraoperative complications, and an extensive knowledge of possible postoperative complications.     

Exposure–response analyses of blood pressure and heart rate changes for methylphenidate in healthy adults

The aim of the study was to evaluate the exposure–response (E–R) relationships of blood pressure (BP) and heart rate (HR) changes in healthy adults taking methylphenidate (MPH). Intensive time profiles of BP and HR from healthy adults in placebo and MPH treatment arms of seven clinical trials from the FDA internal database were utilized for this analysis. The analysis model contains a circadian component for placebo effect and an E–R component to describe drug effect. Internal validation was performed using goodness-of-fit plots and visual predictive check. A meta-database based on a systemic literature search was constructed and used for external validation of the developed models. We found that circadian models could quantify the time profiles of BP/HR in placebo arms. Linear models could describe the correlations between MPH concentrations, and BP/HR changes. The BP and HR changes were highly dependent on the shapes of MPH pharmacokinetic (PK) profiles without an apparent time delay. MPH has the greatest effect on HR, followed by systolic BP, and diastolic BP. Internal validation revealed that the developed models could adequately describe the circadian rhythms of HR and BP in placebo arms and the E–R relationships of MPH. External validation showed the models had good predictive capability of the literature data. In conclusion, the developed models adequately characterized the circadian rhythm and the MPH induced effects on BP and HR. The changes in BP and HR were highly correlated with MPH blood levels with no apparent delay. The time courses of BP and HR are similar to the MPH PK profiles. As a result, the immediate-release formulation may yield larger maximum BP and HR effect than the extended-release formulation under similar dose.     

Achieve control: a pragmatic clinical trial of insulin glargine 300 U/mL versus other basal insulins in insulin-naïve patients with type 2 diabetes

Objective: This study aims to compare the effectiveness of insulin glargine 300 U/mL (Gla-300) with its accompanying patient support program with that of other basal insulin and available patient support programs in patients with type 2 diabetes (T2D) in a real-world setting in terms of achieving HEDIS (Healthcare Effectiveness Data and Information Set) individualized glycemic targets without documented symptomatic hypoglycemia.

Methods: Achieve Control is a US-based, multicenter, randomized, open-label, active-controlled, parallel group pragmatic Phase IV trial in insulin-naïve patients with T2D uncontrolled on ≥2 oral antidiabetes drugs (OAD) and/or glucagon-like peptide-1 receptor antagonists (GLP-1 RA). Inclusion criteria include a diagnosis of T2D, age ≥18 years, and glycated hemoglobin (HbA1c) between 8.0% and 11.0%. Patients will be assigned to either the Gla-300 or other basal insulin group. The primary end point is the proportion of patients achieving HEDIS HbA1c targets (<8.0% [64 mmol/mol] in patients with comorbidities or aged ≥65 years; <7.0% [58 mmol/mol] in all other patients) without occurrence of symptomatic hypoglycemia (blood glucose ≤70 mg/dL) from baseline to 6 months. Secondary end points include rates of documented symptomatic nocturnal hypoglycemia and severe hypoglycemia; change from baseline in HbA1c, fasting glucose, and body weight; treatment persistence; patient-reported outcomes; and healthcare resource utilization. Planned enrollment is 3270 patients across approximately 400 clinical sites.

Conclusion: Pragmatic clinical trials offer the potential to assess comparative effectiveness in broadly based patient populations receiving care (with or without a corresponding educational support program) in real-world clinical settings. The results of Achieve Control should elucidate the benefits of management of T2D with Gla-300 versus other basal insulins in terms of patient outcomes, experiences, and perceptions, and its impact on healthcare resource utilization and cost.

Clinical trial registration: www.clinicaltrials.gov identifier is NCT02451137.     

Negative regulators of the RIG‐I‐like receptor signaling pathway

Upon recognition of specific molecular patterns on microbes, host cells trigger an innate immune response, which culminates in the production of type I interferons, proinflammatory cytokines and chemokines, and restricts pathogen replication and spread within the host. At each stage of this response, there are stimulatory and inhibitory signals that regulate the magnitude, quality, and character of the response. Positive regulation promotes an antiviral state to control and eventually clear infection, whereas negative regulation dampens inflammation and prevents immune‐mediated tissue damage. An overexuberant innate response can lead to cell and tissue destruction, and the development of spontaneous autoimmunity. The retinoic acid‐inducible gene I (RIG‐I)‐like receptors (RLRs), RIG‐I and melanoma differentiation‐associated gene 5 (MDA5), belong to a family of cytosolic host RNA helicases that recognize distinct nonself RNA signatures and trigger innate immune responses against several RNA viruses by signaling through the essential adaptor protein mitochondrial antiviral signaling (MAVS). The RLR signaling pathway is tightly regulated to maximize antiviral immunity and minimize immune‐mediated pathology. This review highlights contemporary findings on negative regulators of the RLR signaling pathway, with specific focus on the proteins and biological processes that directly regulate RIG‐I, MDA5 and MAVS signaling function.     

An inexpensive,simple technique to improve the safety of femoral arterial puncture

We describe a safe and inexpensive technique of avoiding femoral access site complications. Initial fluoroscopic screening of a fully inserted local anesthetic needle helps localize the anticipated arterial puncture site. Repeating fluoroscopy after guide wire insertion through the puncture needle confirms the exact puncture site in the artery.A 40-year-old obese male presented with a history of acute anterior wall myocardial infarction with ongoing chest pain. His ECG showed persistent ST elevation despite receiving tenecteplase 3 h ago. Rescue PTCA was planned. After the femoral artery was punctured, as per our protocol, a check fluoroscopy was performed after insertion of the guide wire, but before removing the puncture needle. This revealed an inappropriately high femoral arterial puncture (Fig. 1). Recognition of this high puncture prompted removal of the needle and wire before administration of heparin or insertion of the arterial sheath, followed by an ‘ideal’ puncture at a lower level, thereby avoiding potential local access site complications, which could have been severe in this obese and recently thrombolysed patient.Open in a separate windowFig. 1Femoral access in an obese individual with the aid of fluoroscopy. The position of guide wire where it exits the puncture needle indicates the unduly high punctured site in femoral artery (arrow).The femoral approach is still used in a majority of interventions. Access site complications including bleeding, hematomas, pseudoaneurysms, arteriovenous fistulas, and retroperitoneal bleeding can occur in 1–10% of procedures and are commoner when the artery is inappropriately punctured1. Most of these complications can be avoided by ensuring a correct femoral puncture technique and ‘ideal’ placement of the femoral sheath in the common femoral artery (CFA), which is ideally punctured before its bifurcation. This site is conveniently located above the head of the femur2 (Fig. 2), which aids in the compression of the artery after sheath removal.Open in a separate windowFig. 2Optimal location for femoral artery access. The outlined dot marks the sheath entry site into the CFA at the medial aspect of the femoral head in the midline. (A) Inferior border of the femoral head. (B) Center of the femoral head. (C) Line demarcating inguinal ligament running from the anterior superior iliac spine to the pubic symphysis. (D) Bifurcation of CFA into superficial femoral artery and profunda.Reproduced from Rashid MN, Baily SR.2In most individuals, the ideal puncture site is located 2–3 cm below the inguinal skin crease. Hence most operators puncture the femoral artery using the inguinal crease as a landmark. However, the inguinal crease does not necessarily maintain a constant relationship with the head of the femur, especially in obese patients. This often results in ‘low’ punctures, where the superficial femoral artery (SFA) may be punctured instead of the CFA. Hemostasis after ‘low’ punctures may be inadequate since the artery cannot be compressed against the femoral head. Other operators utilize an anatomical approach, locating the bony landmarks of the anterior superior iliac spine and pubic symphysis to identify the level of the inguinal ligament and then puncturing approximately 2–3 cm below this, which represents the level of the CFA.Since the central theme of a good femoral puncture lies in puncturing the CFA at the junction of the medial 1/3 and lateral 2/3 of the femoral head, it is intuitively and logically obvious that this landmark should be located as the primary target (Fig. 2)2 and not its whereabouts, as anticipated by the femoral crease or inguinal ligament. The femoral head can be visualized quickly and easily with negligible amounts of additional radiation. The use of fluoroscopy to visualize the femoral head in locating the femoral access site was first described by Grossman in 1974.3 Garrett et al.4 attempted to promote the use of routine fluoroscopy during femoral puncture. Chadwick et al.5 refined the procedure by using an artery forceps to better localize the femoral head.In our endeavor to reduce access site complications, we describe a simple technique to aid puncture at the ideal site. Once the operator has decided the location to perform the femoral puncture (using his preferred technique), local anesthesia (LA) is administered in the usual way. This is the stage at which the first step of our modified technique occurs. With the LA needle still inserted to a depth of 2–3 cm, fluoroscopy is performed to ascertain the relationship of the needle tip relative to the head of the femur (Fig. 3). The femoral artery is usually located a few millimeters above this site.Open in a separate windowFig. 3Femoral artery access in an obese individual with the aid of fluoroscopy. The fluoroscopy of the needle used to administer local anesthetic, introduced 2 cm.Once the artery is punctured and the guide-wire is inserted, the exact site where the artery has been punctured can be verified. Fluoroscopy without removing the puncture needle clearly demonstrates where the guide wire exits the needle (Fig. 4). This 2nd step of our modified technique demarcates the exact site of the arterial access relative to the femoral head.Open in a separate windowFig. 4Femoral artery access in an obese individual with the aid of fluoroscopy. The position of the guide wire where it exits the puncture needle indicates the properly punctured site in femoral artery (arrow).Using this disciplined arterial puncture protocol, we have often been able to identify “low” or “high” punctures (as in the case described earlier) prior to insertion of the sheath or administration of heparin, which are easily addressed by re-puncturing at an appropriate level. This has resulted in a dramatic reduction of access site complications in those operators who have chosen to adopt this simple technique.This technique costs nothing, takes only a few seconds, but contributes immensely to reducing femoral access-site complications. Its routine use in every patient should be standard protocol in every catheterization laboratory. Obtaining a cine run documenting the anticipated puncture site with the local anesthetic needle in place and another cine run after passing the guide wire through the puncture needle, is a good way of ensuring that all operators including trainees employ this simple technique. This will allow every patient to enjoy the advantages of an ideal femoral puncture and lower access site complications.     

School-based approaches to the correction of refractive error in children

The World Health Organization estimates that 13 million children aged 5-15 years worldwide are visually impaired from uncorrected refractive error. School vision screening programs can identify and treat or refer children with refractive error. We concentrate on the findings of various screening studies and attempt to identify key factors in the success and sustainability of such programs in the developing world. We reviewed original and review articles describing children's vision and refractive error screening programs published in English and listed in PubMed, Medline OVID, Google Scholar, and Oxford University Electronic Resources databases. Data were abstracted on study objective, design, setting, participants, and outcomes, including accuracy of screening, quality of refractive services, barriers to uptake, impact on quality of life, and cost-effectiveness of programs. Inadequately corrected refractive error is an important global cause of visual impairment in childhood. School-based vision screening carried out by teachers and other ancillary personnel may be an effective means of detecting affected children and improving their visual function with spectacles. The need for services and potential impact of school-based programs varies widely between areas, depending on prevalence of refractive error and competing conditions and rates of school attendance. Barriers to acceptance of services include the cost and quality of available refractive care and mistaken beliefs that glasses will harm children's eyes. Further research is needed in areas such as the cost-effectiveness of different screening approaches and impact of education to promote acceptance of spectacle-wear. School vision programs should be integrated into comprehensive efforts to promote healthy children and their families.