Because penicillin agents are implicated in granulopoiesis inhibition, healthcare professionals frequently consider discontinuation of such therapy in patients with decreasing white blood cell counts. No systematic review to date has described piperacillin and the patient population at risk for this adverse drug reaction (ADR). This review sought to assess the occurrence of piperacillin-induced neutropenia, describe characteristics of affected patients and assess the reporting modalities that most accurately classify this ADR. Case reports, cohort studies and clinical trials identified by comprehensive searches of PubMed and the US FDA Adverse Event Reporting System (AERS) database were reviewed for patient demographics, duration and dose of piperacillin or piperacillin-tazobactam treatment and the occurrence of neutropenia. Causality assessments were performed. Six published case reports, three cohort studies, 178 clinical trials and two compilations of phase I-III trials were reviewed. Review of case reports was notable in that the duration of beta-lactam therapy prior to the noting of leukopenia always exceeded 15 days. No deaths were recorded in this group. Among 13,816 patients enrolled in non-neutropenic fever studies, the occurrence of piperacillin-induced neutropenia was rare: five patients (0.04%) developed neutropenia; none died. The demographics for this group were poorly documented. Through the AERS database, we identified 366 unique cases of piperacillin or piperacillin-tazobactam-induced haematological abnormalities, including neutropenia (n = 183, 50.0%), leukopenia, (n = 99, 27%), agranulocytosis (n = 58, 15.8%) and others. In 62 cases, patients received between 1 and 14 days of therapy (mean 7.7 + 4.1 days). Overall, there were 82 (22.4%) deaths. Reports of haematological ADRs among patients receiving piperacillin or piperacillin-tazobactam are rare. Report of neutropenia associated with piperacillin usage prior to 15 days of therapy is a novel finding that requires further evaluation. Current reporting methods poorly characterise patient groups at risk.

Endoscopic management has become an effective method to repair proximal hamstring injuries. However, due to the complexity of such a procedure, the dissemination of the technique of endoscopic hamstring repair has occurred slowly among orthopaedic surgeons. This Technical Note with a video modifies previously described techniques and provides safer and more simplified endoscopic management of proximal hamstring injuries.

Identification of serious adverse drug reactions (sADRS) associated with commonly used drugs can elude detection for years. Reye’s syndrome (RS), nephrogenic systemic fibrosis (NSF), and pure red cell aplasia (PRCA) among chronic kidney disease (CKD) patients were recognized in 1951, 2000, and 1998, respectively. Reports associating these syndromes with aspirin, gadodiamide, and epoetin, were published 29, 6, and 4 years later, respectively. We obtained primary information from clinicians who identified causes of these sADRs and reviewed factors contributing to delayed identification of these toxicities. Overall, 3,500 aspirin-associated RS cases in the United States, 1,605 gadolinium-associated NSF cases, and 181 epoetin-associated PRCA cases were reported. Delays in FDA regulation of over-the- counter medications and administration of aspirin to children contributed to development of RS. For NSF, in 1996, the Danish Medicine Agency approved high-dose gadodiamide administration to chronic kidney disease (CKD) patients undergoing MR scans. Overall, 88 % of Danish NSF cases were from two hospitals and 97 % of United States’ NSF cases were from 60 hospitals. These hospitals frequently administered high-doses of gadodiamide to CKD patients. Another factor was the decision to administer linear chelated contrast agents versus lower risk macrocyclic chelated agents. For PRCA, increased use of subcutaneous epoetin formulations to CKD patients, in part due to convenience and cost-savings considerations, and a European regulatory requirement requiring removal of albumin as a stabilizer, led to toxicity. Overall, 81, 13, and 17 years elapsed between drug introduction into practice and identification of a causal relationship for aspirin, erythropoietin, and gadodiamide, respectively. A substantial decline in new cases of these sADRs occurred within two years of identification of the offending drug. Clinicians should be vigilant for sADRs, even for frequently-prescribed pharmaceuticals, particularly in settings where formulation or regulatory changes have occurred, or when over-the-counter, off-label, or pediatric use is common

The purpose of this study was to define the diagnostic value of magnetic resonance imaging (MRI) and plain radiographs (X-ray [XR]) in identifying an osteochondral defect or loose body in patients undergoing operative treatment for patellar instability. A total of 87 patients treated operatively for patellar instability with medial patellofemoral ligament (MPFL) reconstruction between 2015 and 2019 were identified. Inclusion criteria were evidence of clinical patellar instability, preoperative XR and MRI studies, and concomitant diagnostic knee arthroscopy and MPFL reconstruction performed to address patellar instability. Patients were excluded if they had a history of prior procedure for patellar instability on the surgical knee, underwent MPFL reconstruction without concomitant diagnostic knee arthroscopy, or had an anterior cruciate ligament or posterior cruciate ligament deficient knee. Operative notes and arthroscopic images were reviewed to identify osteochondral or chondral injuries and loose bodies noted during diagnostic arthroscopy. The primary outcome was the identification of intra-articular loose bodies, chondral injury, or osteochondral defect on preoperative plain radiographs and MRI in patients with patellar instability. All MRIs were performed on a 3T MRI. The sensitivity and specificity of identifying loose bodies on MRI were 0.52 and 0.92 and on XR were 0.23 and 0.98, respectively. The sensitivity and specificity of identifying osteochondral lesions on MRI were 0.43 and 0.81 and on XR were 0.08 and 0.97, respectively. Of the 87 available reports, 45 (51%) described performing chondroplasty for Outerbridge grade II/III chondral lesions on diagnostic arthroscopy. In conclusion, MRI and XR are poorly sensitive at identifying loose bodies or osteochondral defects after patellar dislocations. The poor sensitivity of imaging studies must be considered when determining whether or not to recommend operative management to a patient with patellar instability. This is a Level IV, diagnostic study.

Purpose: Pharmaceutical safety is a public health issue. In 2005, the Connecticut Attorney General (AG) raised concerns over adverse drug reactions in off-label settings, noting that thalidomide was approved to treat a rare illness, but more than 90% of its use was off label. A hematologist had reported thalidomide with doxorubicin or dexamethasone was associated with venous thromboembolism (VTE) rates of 25%. We review US Food and Drug Administration (FDA) and manufacturer responses to a citizen petition filed to address these thalidomide safety issues.Methods: Case study. Results:The AG petitioned the FDA requesting thalidomiderelated safety actions. Coincidentally, the manufacturer submitted a supplemental New Drug Approval (sNDA), requesting approval to treat multiple myeloma with thalidomide-dexamethasone. FDA safety officers reviewed the petition and the literature and noted that VTE risks with thalidomide were not appropriately addressed in the existing package insert. In the sNDA application, the manufacturer reported thalidomide-associated toxicities for multiple myeloma were primarily somnolence and neurotoxicity, and a proposed package insert did not focus on VTE risks. In October, the FDA informed the Oncology Drug Division that VTE risks with thalidomide were poorly addressed in the existing label. After reviewing this memorandum, an Oncology Drug Division reviewer informed the manufacturer that approval of the sNDA would be delayed until several thalidomide-associated VTE safety actions, including revisions of the package insert, were implemented. The manufacturer and FDA agreed on these actions, and the sNDA was approved. Conclusion:New approaches addressing off-label safety are needed. The conditions that facilitated the successful response to this citizen petition are uncommon.