Lopinavir-Ritonavir in SARS-CoV-2 Infection and Drug-Drug Interactions with Cardioactive Medications.

Lopinavir-ritonavir combination is being used for the treatment of SARS-CoV-2 infection. A low dose of ritonavir is added to other protease inhibitors to take advantage of potent inhibition of cytochrome (CYP) P450 3A4, thereby significantly increasing the plasma concentration of coadministered lopinavir. Ritonavir also inhibits CYP2D6 and induces CYP2B6, CYP2C19, CYP2C9, and CYP1A2. This potent, time-dependent interference of major hepatic drug-metabolizing enzymes by ritonavir leads to several clinically important drug-drug interactions. A number of patients presenting with acute coronary syndrome and acute heart failure may have SARS-CoV-2 infection simultaneously. Lopinavir-ritonavir is added to their prescription of multiple cardiac medications leading to potential drug-drug interactions. Many cardiology, pulmonology, and intensivist physicians have never been exposed to clinical scenarios requiring co-prescription of cardiac and antiviral therapies. Therefore, it is essential to enumerate these drug-drug interactions, to avoid any serious drug toxicity, to consider alternate and safer drugs, and to ensure better patient care.

Revision Total Knee Arthroplasty Using an Uncemented Metaphyseal Sleeve, Rotating Hinge Prosthesis: A Case Series of 99 Patients.

BACKGROUND: Hinge knee replacement is a salvage procedure with historically high failure and complication rates. We aim to analyze the use of an uncemented metaphyseal sleeve revision knee replacement in our unit-a third-generation rotating hinge knee prosthesis. This is the largest reported series of this implant with longest follow up. METHODS: We retrospectively identified 99 revision cases performed (2002-2018). In total, 67 of 99 (68%) cases were performed for aseptic etiology, whereas 32 of 99 (32%) cases were performed for infection. Clinical outcomes were assessed using the Oxford Knee Score, survivorship analysis, and incidence of revision/reoperations. Mean follow-up was 7 years (range 1.5-18). RESULTS: At follow-up, the mean Oxford Knee Score had improved from 10 points to 25 points. At mean 7 years of follow up, 18 of 99 cases had undergone revision giving a survivorship of 81% (90% aseptic). In total, 10 of 18 cases were performed for infection (10%) and 9 of 18 cases were performed for aseptic reasons (9%), of which 5 were for patella resurfacing (2 revision), 2 for failure of bony ingrowth, and 1 for fracture. Twenty-six patients (26%) had complications postoperatively, with patella disorders and reduced range of movement the most common. Patients who did not undergo patella resurfacing were significantly more likely to need revision of any cause (P = .01). CONCLUSION: This is the largest study of this prosthesis with longest follow-up. It demonstrates good survivorship and improvement in knee pain. Those with infection are at greatest risk of revision. Significant numbers have patella dysfunction/anterior knee symptoms therefore patella resurfacing should be considered when using this implant. LEVEL OF EVIDENCE: IV.

Extra-articular tibial deformity management in total knee replacement.

BACKGROUND: Presence of an extra-articular deformity in the femur or tibia poses a challenge to the surgeon undertaking knee replacement procedure. The conundrum is whether to correct the deformity beforehand, or accept the deformity and compensate for this through placement of the implant. MATERIAL AND METHODS: This is a retro-spective study comprising six patients who had a knee replacement in the presence of an extra-articular deformity of the tibia treated at our centre. All six had the knee replacement without correction of deformity. The data evaluated included clinical outcome, mechanical axis correction, type of implant, and the use of any software / computer guidance.The deformity was managed through planning of tibial resection without the need for pre-operative deformity correction. RESULTS: Mean age was 66.5 years. Mean coronal plane deformity in the tibia was 8.6 degrees. The hip- knee-ankle improved from a mean 12.6 degrees to 4 degrees. Mean Oxford knee score improved from a mean of 19 to 33.6. CONCLUSION: Planning the tibial resection on the basis of mechanical axis of tibia allows correction of alignment without the need for preoperative correction.Correction of the deformity may not be needed if the maximum tibial resection is less than 15 mm.

Endocrine changes in SARS-CoV-2 patients and lessons from SARS-CoV.

Coronavirus infection outbreaks have occurred frequently in the last two decades and have led to significant mortality. Despite the focus on reducing mortality by preventing the spread of the virus, patients have died due to several other complications of the illness. The understanding of pathological mechanisms and their implications is continuously evolving. A number of symptoms occur in these patients due to the involvement of various endocrine glands. These clinical presentations went largely unnoticed during the first outbreak of severe acute respiratory syndrome (SARS) in 2002-2003. A few of these derangements continued during the convalescence phase and sometimes occurred after recovery. Similar pathological and biochemical changes are being reported with the novel coronavirus disease outbreak in 2020. In this review, we focus on these endocrine changes that have been reported in both SARS coronavirus and SARS coronavirus-2. As we battle the pandemic, it becomes imperative to address these underlying endocrine disturbances that are contributing towards or predicting mortality of these patients.

The biplanar open wedge high tibial osteotomy preserving the tibial tubercle.

BACKGROUND: High tibial osteotomy (HTO) is a treatment option for relatively young patients with isolated medial compartment arthritis of the knee. Medial open wedge osteotomies allow easier control of correction, but can lead to patella infera as a result of distalization of the tibial tubercle. This retrospective study reports results of a biplanar tibial tubercle preserving HTO, designed to preserve patellar height. METHODS: The study is a retrospective analysis of 12 consecutive patients (11 men, 1 woman) average age 39.6 years who underwent the procedure between 2009 and 2012. A biplanar open wedge tibial osteotomy was performed and stabilised with a medial locking plate. Patients were allowed full weight bearing at 6 weeks. Preoperative and postoperative function was recorded on the Oxford knee score, Lysholm score and Tegner activity scale. Minimum follow up was 26 months. RESULTS: All patients had healing of the osteotomy with no delayed union. Eleven patients reported improvement in symptoms with an average preoperative Oxford score of 26 and postoperative score of 39 out of 48. The Lysholm score improved from 58 to 72 out of 100. There was one point improvement in Tegner activity scale. There was no statistical difference in patellar height before and one year after surgery. The correction in varus averaged 8.3°. CONCLUSION: The biplanar High tibial Osteotomy allows preservation of patellar height, while achieving desired varus correction.

Knee arthrodesis with a long intramedullary nail as limb salvage for complex periprosthetic infections.

BACKGROUND: Periprosthetic infection following total knee arthroplasty is a devastating complication, which is not always satisfactorily resolved by revision surgery. Arthrodesis is a salvage alternative to above-knee amputation or permanent resection arthroplasty. Fixation options include internal compression plating, external fixation, and intramedullary nails. METHODS: We retrospectively reviewed twelve consecutive cases (9 males, 3 females; mean age, 67 years) of knee arthrodesis with a long intramedullary nail, performed at a single institution between 2003 and 2014. Desired outcomes were the ability to mobilize without pain, solid radiographic fusion, and the eradication of infection. RESULTS: Mean follow-up was 48.5 months (range, 9-120 months). Eleven patients (92 %) demonstrated stable fusion, ten patients (83 %) were ambulatory without pain, and ten patients (83 %) remained without infection at most recent follow-up. Eight patients (67 %) achieved union at an average of 12 months; three required repeat procedures, achieving union at an average of 9 months. There was a significant difference (P < 0.01) between the numbers of previous operations amongst the eight patients who initially achieved union (mean, 3.25) and three who subsequently required repeat procedures (mean, 8.33). CONCLUSIONS: In contrast to similar studies, we performed a single-stage exchange where possible, while comparable ambulatory and fusion rates were observed. Numerous previous attempts at revision arthroplasty, co-morbidities, and infections with highly resistant organisms have been associated with further complications. Although technically challenging, knee arthrodesis with a long intramedullary nail offers an acceptable limb salvage procedure for carefully selected patients with complex periprosthetic infections.

Longer term follow up of outcomes following implantation of a modular rotating hinge knee prosthesis: 53 implants at mean 7.6 year follow up.

BACKGROUND: Rotating hinge knee replacements are becoming more common but have historically had high complication and failure rates. This study is one of the largest to assess the implant survival and patient outcomes of a third-generation rotating hinge knee replacement at a single tertiary orthopaedic centre. METHODS: Data for consecutive operations at our tertiary unit between 2006 to 2020 were assessed with review of electronic patient and radiology records. The Oxford Knee Score was used to assess outcomes and the Kaplan Meier method used to estimate survivorship. RESULTS: 53 rotating hinge knees were implanted in 46 patients (13 male, 33 female) at a mean age of 67.8 years. 21 were primary and 32 were revision procedures. Indications for use of this implant included instability, loosening, fracture and infection. Survivorship was 77.8% at the mean follow up of 7.6 years. A total of 29 complications were noted with ongoing pain, stiffness, infection and patellofemoral symptoms being the most common. 8% of unresurfaced patellas required a subsequent secondary resurfacing. The Oxford Knee Score demonstrated a significant improvement from 14.6 preoperatively to 27.5 at one year postoperatively, which was maintained in the longer term. CONCLUSION: The third-generation rotating hinge knee implant in use at our unit has improved outcomes for patients. The survivorship of the implant is comparable to the published literature, although there is a paucity of data. The complication rates remain relatively high and patients should be counselled appropriately. We advise resurfacing the patella to avoid the need for secondary procedures.

An evaluation of physical medicine and rehabilitation accredited sports medicine fellowship websites.

BACKGROUND: Due to the virtual format of fellowship applications, prospective physical medicine and rehabilitation (PM&R) sports medicine fellowship applicants commonly rely upon fellowship website content to make decisions about applications. Studies have shown that information available to fellowship applicants on program websites is inadequate, and there is no standard for important components of sports medicine fellowship websites. OBJECTIVE: To determine what sports medicine fellowship program features PM&R residents, fellows, and attending physicians consider the most important to be listed on fellowship websites, as well as to assess the scope of information available on fellowship websites. DESIGN: We developed a 30-item list of criteria that fell into categories of general information, fellowship education, recruitment, experience, and academic research. Survey participants were asked to rank the importance of those various items. We then assessed the 21 PM&R accredited sports medicine fellowship websites for the presence of these criteria. PARTICIPANTS: Ninety-six survey respondents composed of PM&R residents, current sports medicine fellows, and attendings. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE(S): Not applicable. RESULTS: Items ranked as most important were those in the categories of general information, fellowship experience, and fellowship recruitment. The most valued items were program location, program coordinator contact information, program length, specific requirements for applying, number of positions, types of procedures taught, and specific sites covered. Academic research items were ranked as least important. CONCLUSIONS: Survey respondents identified many fellowship website items as important factors when applying to programs. Many of these items were not listed on fellowship websites, suggesting that adding these criteria to fellowship sites might benefit applicants. Our findings can be used to develop standardized criteria for important components of sports medicine fellowship websites to improve the application and recruitment process.

Parameters of Spinal Cord Stimulation in Complex Regional Pain Syndrome: Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Complex Regional Pain Syndrome (CRPS) is a chronic debilitating neuropathic pain condition characterized by autonomic and inflammatory features that typically occurs after a traumatic event. Spinal cord stimulation (SCS) has been shown to be effective in the treatment of chronic CRPS refractory to conventional treatment modalities. The collective evidence of novel parameters of SCS for treating CRPS has not been characterized extensively. OBJECTIVE: To provide evidence for the use of SCS to treat CRPS and characterize the additional benefits of various SCS waveforms. STUDY DESIGN: Systematic Review and Meta-analysis. METHODS: PubMed, Embase and CINHLA were screened for all randomized controlled trials (RCT) comparing SCS parameters for the treatment of CRPS. RESULTS: Four RCTs were identified that included SCS as a treatment arm for CRPS. Of these, one study compared low frequency tonic SCS (LF-SCS) versus conventional physical therapy, 2 studies compared placebo/sham SCS with LF-SCS and a multitude of waveforms, and one study compared LF-SCS with high-frequency SCS (HF-SCS). Two of the studies were rated as having a low risk of bias, one study was rated as having some concerns for bias, while the final study was rated as having a high risk of bias. A meta-analysis of 4 studies comparing conventional therapy/placebo SCS stimulation against LF-SCS revealed increased benefit of LF-SCS in pain reduction up to a month (mean difference [MD] = -1.17 points; 95% CI = -1.61 to -0.73; P < 0.001, I2 = 42%). Another meta-analysis of 2 studies showed that LF-SCS results in higher global perceived effect scores relative to conventional therapy/placebo SCS stimulation (MD = 1.58; 95% CI = 1.00 to 2.15; P < 0.001, I2 = 0%). LIMITATIONS: A pooled analysis using different designs for RCTs was conducted. Some studies folded in multiple neuropathic pain pathologies in addition to CRPS. One study was at a high risk for bias in at least one domain. CONCLUSION: LF-SCS is superior to conventional therapy/placebo SCS stimulation. However, more evidence is required to demonstrate that novel SCS parameters are superior to LF-SCS in improving pain scores and functional outcomes.

Pharmacoinvasive therapy for acute myocardial infarction.

Thrombus remains the bane of interventional cardiology. The use of thrombus extraction devices and distal protection devices has been controversial. Pharmacological modulation using intracoronary (IC) thrombolytic therapy during percutaneous coronary intervention (PCI) is also not an established choice although intravenous thrombolytic therapy is widely accepted and applied treatment of choice for acute ST-elevation myocardial infarction (STEMI). This case report shows successful management of a patient of STEMI using a combination of IC thrombolytic therapy, thrombectomy device, and PCI.

STEMI with flush occlusion of a coronary artery: An interventional dilemma.

Flush occlusions of coronary arteries present with multiple challenges during primary percutaneous coronary intervention (PPCI). We describe a case of anterior ST-elevation myocardial infarction in cardiogenic shock, where it was not possible to identify the origin of left anterior descending artery (LAD) as it was flush occluded and initial attempts to place a coronary guidewire in the LAD during PPCI were unsuccessful. After failed attempts with multiple guidewires, a combined pharmacological-mechanical approach resulted in successful timely revascularization and subsequent recovery of the patient. .

Metaphyseal Sleeve Failure in Revision Total Knee Arthroplasty.

Introduction A significant percentage of patients require re-revision surgery regardless of the demonstrated durable short- and mid-term clinical results using metaphyseal sleeves in revision total knee arthroplasty (TKA). The aim of this study was to identify the association between sleeve alignment and contact zones, with loosening in patients with revision TKA. Materials & Methods Of a series of 103 patients who underwent revision TKA, at a mean follow-up of eight years, six patients were re-revised for tibial loosening. These patients were compared with 19 unrevised control subjects in a 1:3 ratio. We calculated and compared the cumulative number of contact zones between the porous-coated part of the sleeve and bone on immediate postoperative X-rays between re-revised and unrevised patients. The main hypothesis was that neutral positioning and absolute circumferential contact between trabecular metaphyseal bone and porous-coated part of the sleeve would lead to a better outcome. Results The use of a conservative (nonparametric) approach indeed revealed better circumferential contact between trabecular metaphyseal bone and porous-coated part of the sleeve among the survivors, i.e., survivors: median (interquartile range [IQR]): 3 (2-4); failures: 3 (1-3), p = 0.003 (Mann-Whitney [MW] test). The difference was borderline significant for coronal alignment, i.e., survivors: median (IQR): -1 (-4 to 2); failures: 0 (-1 to 3), p = 0.0569 (MW test). Conclusion A circumferential bony contact of the metaphyseal sleeve would lead to better survival of the revision implant, whereas the degree of varus fixation did not seem to influence the longevity of the implant.

Results of revision knee replacement for patients with isolated fixed flexion deformity after primary or revision knee replacement.

BACKGROUND: Postoperative fixed flexion deformity is a known complication of knee replacement surgery. We present our results of revision surgery for treatment of isolated fixed flexion deformity after knee replacement. METHODS: 32 patients had revision knee replacement for fixed flexion deformity and were included in this retrospective study. Minimum follow up period was 28 months. RESULTS: Two different surgical interventions had been done in these patients. Group 1 (15 patients) had revision of the femoral component, posterior capsular release and tibial component was not revised. Group 2 (18 Patients) had revision of both femoral and tibial components. One patient was included in both groups as she had both interventions. The extent of preoperative flexion deformity in group 1 was from 15 to 40 deg (mean 20.6 deg). Postoperative range of extension was 0 to 20 deg (mean 8.2 deg). In group 2, preoperative flexion deformity was 10 to 25 deg (mean 16.9 deg) and postoperative flexion deformity was 0 to 20 deg (mean 4.2 deg). The difference in improvement between the two groups was not statistically significant on Mann Whitney U test (two tailed p value 0.181) for non normal distribution. Improvement in Oxford knee score following surgery was only 1 point in both groups. CONCLUSION: Revision for isolated fixed flexion deformity leads to improvement in range of extension, but improvement in clinical score is marginal. The choice of preservation or revision of the tibial component did not make a significant difference to the outcome.

Mechanism of Thimerosal-Induced Structural Destabilization of a Recombinant Rotavirus P[4] Protein Antigen Formulated as a Multi-Dose Vaccine.

In a companion paper, a two-step developability assessment is presented to rapidly evaluate low-cost formulations (multi-dose, aluminum-adjuvanted) for new subunit vaccine candidates. As a case study, a non-replicating rotavirus (NRRV) recombinant protein antigen P[4] was found to be destabilized by the vaccine preservative thimerosal, and this effect was mitigated by modification of the free cysteine (C173S). In this work, the mechanism(s) of thimerosal-P[4] protein interactions, along with subsequent effects on the P[4] protein's structural integrity, are determined. Reversible complexation of ethylmercury, a thimerosal degradation byproduct, with the single cysteine residue of P[4] protein is demonstrated by intact protein mass analysis and biophysical studies. A working mechanism involving a reversible S-Hg coordinate bond is presented based on the literature. This reaction increased the local backbone flexibility of P[4] within the helical region surrounding the cysteine residue and then caused more global destabilization, both as detected by HX-MS. These effects correlate with changes in antibody-P[4] binding parameters and alterations in P[4] conformational stability due to C173S modification. Epitope mapping by HX-MS demonstrated involvement of the same cysteine-containing helical region of P[4] in antibody-antigen binding. Future formulation challenges to develop low-cost, multi-dose formulations for new recombinant protein vaccine candidates are discussed.

Rapid Developability Assessments to Formulate Recombinant Protein Antigens as Stable, Low-Cost, Multi-Dose Vaccine Candidates: Case-Study With Non-Replicating Rotavirus (NRRV) Vaccine Antigens.

A two-step developability assessment workflow is described to screen variants of recombinant protein antigens under various formulation conditions to rapidly identify stable, aluminum-adjuvanted, multi-dose vaccine candidates. For proof-of-concept, a series of sequence variants of the recombinant non-replicating rotavirus (NRRV) P[8] protein antigen (produced in Komagataella phaffii) were compared in terms of primary structure, post-translational modifications, antibody binding, conformational stability, relative solubility and preservative compatibility. Based on these results, promising P[8] variants were down-selected and the impact of key formulation conditions on storage stability was examined (e.g., presence or absence of the aluminum-adjuvant Alhydrogel and the preservative thimerosal) as measured by differential scanning calorimetry (DSC) and antibody binding assays. Good correlations between rapidly-generated developability screening data and storage stability profiles (12 weeks at various temperatures) were observed for aluminum-adsorbed P[8] antigens. These findings were extended and confirmed using variants of a second NRRV antigen, P[4]. These case-study results with P[8] and P[4] NRRV variants are discussed in terms of using this vaccine formulation developability workflow to better inform and optimize formulation design with a wide variety of recombinant protein antigens, with the long-term goal of rapidly and cost-efficiently identifying low-cost vaccine formulations for use in low and middle income countries.