Enhancing the Efficiency of the Individual Case Safety Report (ICSR) Quality and Compliance through Automation.

BACKGROUND: Over the past few years, major inspection findings have been identified in the "management of adverse reactions" that may be due to increasing workload in pharmaceutical organizations impacting the correctness of information in individual case safety reports (ICSRs). Although retrospective quality check (Retro-QC) and late submission analyses are important steps in ensuring ICSR quality, their manual application poses several challenges that can be overcome through automation. OBJECTIVES: To improve the efficiency of the Retro-QC analysis and late submission analysis using a computer-operated tool called Compliance and Metrics Management (CMM) tool, and to measure the tool's effectiveness in terms of productivity, time, and cost savings by comparing against the manual process. METHODS: Time savings were calculated by measuring the difference in time taken during the manual process versus the automated process. Cost savings were measured in terms of hourly remuneration for the time saved. Productivity was calculated as the difference between the number of cases handled in the manual versus automated process. Thus, the overall efficiency was measured in terms of time and cost savings along with increased productivity. RESULTS: Automation resulted in time savings of 49% and cost savings of 43% for Retro-QC analysis, and the productivity level increased by 67%. For late submission analysis, the CMM tool resulted in time savings of 88% and cost savings of 87%. CONCLUSION: CMM tool enhanced the efficiency of both Retro-QC and late submission analyses by increasing productivity along with time and cost savings. It also reduced the number of errors, thereby enhancing the accuracy of the process and overall compliance.

Utility of Panoramic Radiographs in the Screening of Individuals with Edentulous Arches: A Need-Analysis Study

Abstract Objective: To evaluate the utility of panoramic radiographs in pre-prosthetic screening of edentulous arches. Material and Methods: Panoramic radiographs taken for three years were retrospectively analyzed. Observations from the radiographs shall be categorized and classified into either of the two categories, namely: 'findings with minimal impact on denture fabrication' and 'findings which affect denture fabrication and require further evaluation.' Anatomic variations, jaw pathologies, and residual ridge resorption patterns were assessed. Results: This study included the initial screening of 23,020 panoramic radiographs, out of which 505 (showing either one or both edentulous arches) were included for the study purpose. The age range of the subjects was from 21 to 94 years. 52.6% of the radiographs showed positive findings. More than half of the radiographs belonged to the males (52.5%). Hyperpneumatization of the maxillary sinus, crestal position of the mental foramen, and retained root fragments were the most common entities noted in the radiographs. Changes in the mental foramen were significantly higher in males than females (p=0.002). Conclusion: Observations from this study showed that panoramic radiographs have high utility for screening edentulous arches, and they should be used in routine clinical practice before denture fabrication.

Prosthodontic rehabilitation of a patient with nintedanib-induced osteonecrosis of the jaw: A clinical report.

Medication-related osteonecrosis of the jaw results in extensive excision and proves challenging to rehabilitate prosthetically. This article describes the prosthodontic rehabilitation of medication-related osteonecrosis of the jaw induced by nintedanib. A custom-made subperiosteal implant was designed to adapt to the bone, remaining after the excision of the jaw necrosis. The implant followed the anatomic contour of the residual bone and was milled in titanium alloy, allowing the rehabilitation of a patient with a fixed dental prosthesis.

Evaluating the impact of a Risk Evaluation and Mitigation Strategy with tolvaptan to monitor liver safety in patients with autosomal dominant polycystic kidney disease.

Background: On approval of JYNARQUE (tolvaptan) for use in patients with autosomal dominant polycystic kidney disease (ADPKD) at risk for rapid progression, the US Food and Drug Administration required a Risk Evaluation and Mitigation Strategy (REMS) from the sponsor, which includes collection of post marketing liver safety data. Methods: This is a retrospective interim analysis of the ongoing REMS. The period evaluated was from REMS implementation (14 May 2018) at tolvaptan commercialization to the analysis cutoff date (23 February 2021). Patients were previously tolvaptan-naïve and initiated tolvaptan in the post marketing setting. Reports of possible severe drug-induced liver injury (DILI) were evaluated for severity based on the evidence obtained (e.g. liver enzyme levels, symptoms, diagnostic tests and event outcomes). The incidence of DILI was compared between the REMS and tolvaptan clinical trials in ADPKD. Results: Among 6711 REMS patients, 60 (0.9%) cases of possible severe DILI were reported, 4 of which were confirmed as serious and potentially fatal by the sponsor. One of these four patients met Hy's law criteria. In all four patients, liver enzymes normalized after tolvaptan discontinuation. The duration of tolvaptan exposure in the REMS is currently shorter than in completed clinical trials, but within this limitation, the incidence of possible severe DILI was lower in the REMS than in clinical trials (incidence rate ratio 0.587; P = .000411). Conclusions: In interim data on >6000 tolvaptan REMS patients, <1% experienced possible severe DILI. Monthly monitoring, as described in the tolvaptan prescribing information, enables the prompt detection of liver enzyme abnormalities and appropriate drug discontinuation.

Using an Automated Algorithm to Identify Potential Drug-Induced Liver Injury Cases in a Pharmacovigilance Database.

INTRODUCTION: Drug-induced liver injury (DILI) is the most frequent cause of acute liver failure in North America and Europe, but it is often missed because of unstandardized diagnostic methods and criteria. This study aimed to develop and validate an automated algorithm to identify potential DILI cases in routine pharmacovigilance (PV) activities. METHODS: Post-marketing hepatic adverse events reported for a potentially hepatotoxic drug in a global PV database from 19 March 2017 to 18 June 2018 were assessed manually and with the automated algorithm. The algorithm provided case assessments by applying pre-specified criteria to all case data and narratives simultaneously. RESULTS: A total of 1456 cases were included for analysis and assessed manually. Sufficient data for algorithm assessment were available for 476 cases (32.7%). Of these cases, manual assessment identified 312 (65.5%) potential DILI cases while algorithm assessment identified 305 (64.1%) potential DILI cases. Comparison of manual and algorithm assessments demonstrated a sensitivity of 97.8% and a specificity of 79.3% for the algorithm. Given the prevalence of potential DILI cases in the population studied, the algorithm was calculated to have positive predictive value 56.3% and negative predictive value 99.2%. The time required for manual review compared to algorithm review suggested that application of the algorithm prior to manual screening would have resulted in a time savings of 42.2%. CONCLUSION: An automated algorithm to identify potential DILI cases was developed and successfully implemented. The algorithm demonstrated a high sensitivity, a high negative predictive value, along with significant efficiency and utility in a real-time PV database.

Effect of Brexpiprazole on Prolactin and Sexual Functioning: An Analysis of Short- and Long-Term Study Data in Major Depressive Disorder.

PURPOSE/BACKGROUND: Evidence supports use of adjunctive atypical antipsychotics in major depressive disorder (MDD). Impaired sexual functioning is common in MDD and may be worsened by antipsychotic adverse effects. We evaluated the effect of brexpiprazole on prolactin and sexual functioning in patients with MDD. METHODS/PROCEDURES: In short-term studies, patients received adjunctive brexpiprazole 1, 2, or 3 mg or placebo. The long-term study was a flexible-dose (0.5-3 mg/d) open-label extension (OLE). Change from baseline and shifts in prolactin status and prolactin-related treatment-emergent adverse events (TEAEs) were assessed. Sexual functioning was assessed by the Massachusetts General Hospital Sexual Functioning Questionnaire. FINDINGS/RESULTS: Median changes in prolactin levels from baseline to week 6 in short-term studies were as follows: brexpiprazole, 5.99 ng/mL (females) and 1.61 ng/mL (males); placebo, -0.15 ng/mL (females) and -0.08 ng/mL (males).Median changes from baseline to week 52 in the OLE were as follows: 0.27 ng/mL (females) and 0.27 ng/mL (males). Prolactin levels in patients with baseline prolactin greater than 1× upper limit of normal values tended to decrease over time.The proportion of brexpiprazole-treated patients with greater than 3× upper limit of normal postbaseline prolactin values in short-term studies for both sexes was low (0%-0.3%) and did not differ from placebo: OLE, 0.5% (females) and 0.8% (males).In short-term studies, the incidence of prolactin-related TEAEs was 3.1% for brexpiprazole and 0.7% for placebo (OLE, 3.1%). There were overall numerical improvements from baseline in sexual functioning for females and males after short- and long-term brexpiprazole treatment, with statistically significant improvements for brexpiprazole versus placebo in females on the items 'interest in sex' (-0.19; 95% confidence interval [CI], -0.33 to -0.05; P = 0.0074), 'sexually aroused' (-0.17; 95% CI, -0.30 to -0.03; P = 0.0154), and 'overall sexual satisfaction' (-0.16; 95% CI, -0.30 to -0.03; P = 0.0184). IMPLICATIONS/CONCLUSIONS: There were small changes in prolactin levels, low proportions of patients with postbaseline elevated prolactin values, low incidences of prolactin-related TEAEs, and modest improvements in sexual functioning with adjunctive brexpiprazole in MDD.

Effects of nonaldehyde immersion disinfection on the mechanical properties of flexible denture materials.

STATEMENT OF PROBLEM: Variation in the baseline mechanical properties of polyamide thermoplastic polymers used in the fabrication of prosthetic dental appliances and the effects of nonaldehyde disinfectants on the mechanical properties of these polymers are unclear. PURPOSE: The purpose of this in vitro study was to compare the flexural and impact strengths of 2 flexible denture materials (Valplast and Sunflex) and evaluate the effect of 24-hour immersion in nonaldehyde disinfectant (Perform) on their flexural and impact strengths. MATERIAL AND METHODS: Of 48 specimens of Valplast and Sunflex, half were immersed in nonaldehyde disinfectant solution containing the active ingredient 2% peroxymonosulfate for 24 hours. Flexural and impact strengths were measured using a universal testing machine. The Student t test with Bonferroni correction was used (α=.008). RESULTS: For the Valplast group, the mean ±standard deviation flexural strength was 27.8 ±0.57 MPa, and the impact strength was 3.5 ±0.98 kJ/m2. For the Sunflex group, the mean flexural strength was 57.4 ±4.09 MPa, and the impact strength was 6.0 ±3.11 kJ/m2. Sunflex showed greater flexural strength (P≤.001) and impact strength (P=.001) than Valplast. A significant increase in the impact strength (P≤.001) but not in the flexural strength of Valplast was observed after exposure to the disinfectant solution. Immersion disinfection had no significant effect on the strength of Sunflex. CONCLUSIONS: The flexural and impact strengths of Sunflex were significantly greater than those of Valplast. Immersion disinfection with peroxymonosulfate had no significant effect on Sunflex but increased the impact strength of Valplast.

Effect of Brexpiprazole on Prolactin: An Analysis of Short- and Long-Term Studies in Schizophrenia.

BACKGROUND: Hyperprolactinemia is an undesirable effect of most antipsychotics because of D2-receptor blockade. We assessed the effect of the D2-receptor partial agonist brexpiprazole on prolactin, based on pooled data from three 6-week, randomized, placebo-controlled studies and two open-label extension studies in patients with schizophrenia. METHODS: In the short-term studies, patients received 0.25, 1, 2, 4 mg brexpiprazole or placebo; or flexible-dose brexpiprazole (2-4 mg/d), placebo, or active reference. The extension studies were 52-week, flexible-dose (1-4 mg/d) studies. We studied changes from baseline and shifts in prolactin status in patients with normal or elevated prolactin levels at baseline, and prolactin-related treatment-emergent adverse events (TEAEs). RESULTS: Median changes from baseline to week 6 in brexpiprazole-treated patients in short-term studies were as follows: 3.63 ng/mL (females), 0.26 ng/mL (males); placebo: -2.15 ng/mL (females), -1.08 ng/mL (males).Median changes from baseline to week 52 in long-term studies were 0.60 ng/mL (females) and 0.18 ng/mL (males). Prolactin levels in patients with baseline values greater than 1× upper limit of normal tended to decrease over time regardless of previous treatment.The proportions of brexpiprazole-treated patients with greater than 3× upper limit of normal postbaseline prolactin values in short-term studies were as follows: 1.5% (females), 1.6% (males); placebo: 3.6% (females), 3.4% (males). Corresponding figures in long-term studies were 5.3% (females) and 2.0% (males).In short-term studies, the incidence of prolactin-related TEAEs was 1.8% for brexpiprazole and 0.6% for placebo. In long-term studies, the incidence of prolactin-related TEAEs was 1.7%. CONCLUSIONS: Small changes in prolactin levels, low proportions of patients with postbaseline elevated prolactin values, and low incidence of prolactin-related TEAEs were observed after treatment with brexpiprazole.

Biomechanical assessment of an alternative method of staple fixation for anchoring the Bone Patellar Tendon Bone graft to the tibia.

INTRODUCTION: The Anterior cruciate ligament (ACL) is the most commonly injured ligament around the knee and is best reconstructed with a biological graft. For ideal graft fixation, there should be sufficient initial strength to avoid failure of fixation and sufficient stiffness to restore the stability of the knee and to avoid gradual loosening in the post-operative period.When considering fixation of Bone Patellar Tendon Bone (BPTB) grafts to the tibia, the interference screw is considered to be the gold standard. As an alternative, we have used of staples and stainless steel (SS) wire to anchor the BPTB graft to the tibia and femur. The aim of this study was to assess the biomechanical efficacy of this fixation technique for anchoring the BPTB graft to the proximal tibia. We used a bovine model to compare three fixation techniques -interference screw, braided polyester sutures tied to a screw post and SS wire tied to a staple. MATERIALS AND METHODS: Fifteen fresh bovine knees specimens were used for the study. The patella was fixed to a load cell and the construct was pre-tensioned to 40N to allow for creep of the tendon. The BPTB graft was fixed to the tibia using the three fixation techniques - the interference screw, polyester suture tied to a post, and SS wire anchored to a staple. After fixation, the graft was subjected to a single load to failure test, and the forces generated were recorded. The ultimate failure load (the pullout strength), stiffness, and mode of failure were noted. RESULTS: In the single load-to-failure biomechanical testing, the ultimate failure load and stiffness for Staple with SS wire were 726.40N and 61.9N/mm respectively. For the screw post and polyester suture, it was 733.20N and 53.22N/mm, and for Interference screw - 594.00N and 79.50 N/mm respectively. There was no statistically significant difference in the stiffness or ultimate failure load between the three fixation techniques. The graft fixation using interference screws failed at the bone- tunnel interface by slippage of the bone block from the tunnel in all 5 specimens. In all 5 of the specimens fixed with polyester suture and the screw post, the fixation failed when the polyester suture snapped. When the SS wire and staple construct was stressed, the graft failed as the SS wire cut through the graft in 4 specimens, and in the fifth construct, the knot over the staple unraveled as the load was applied. CONCLUSION: The biomechanical properties of BPTB graft fixation with SS wire tied to a staple is similar to that of other fixation devices like the interference screw and suture post. This technique provides a simple, yet effective fixation for the graft - but needs further clinical assessment.

A Case of Concomitant Pseudocyesis and Couvade Syndrome Variant.

Per DSM-V, pseudocyesis is included under the category "other specified somatic symptom and related disorder" and is defined as a false belief of being pregnant that is associated with objective signs and reported symptoms of pregnancy. The male counterpart of pseudocyesis is Couvade syndrome, also called "sympathetic pregnancy" where a man experiences symptoms of pregnancy when his female partner is pregnant. There are extensive reports on pseudocyesis and Couvade syndrome in psychiatric literature but none with features of both, in a single case. Here we present a unique case of a fifty-eight-year-old mother who presented with symptoms of concomitant pseudocyesis and Couvade syndrome concurrently when her daughter was pregnant. This case report discusses the epidemiology, course of symptoms and common comorbidities associated with this interesting diagnosis.

The inter-teres approach to glenoid neck fractures: an alternative approach to glenoid fixation.

BACKGROUND: Scapula fractures are rare injuries that are generally treated nonoperatively. When surgery is performed, it is commonly undertaken through the posterior approach, which can be invasive and unforgiving on the soft tissues. We describe an alternative safe approach between teres major and minor that remains deep to a fascial sling formed by the combined infraspinatus and teres minor fasciae and deep to the primary nerve to teres minor, which is a terminal branch of the axillary nerve. METHODS: Between January 2008 and June 2014, there were 22 patients who underwent scapula fixation with this approach who were retrospectively identified and prospectively invited for clinical review by the American Shoulder and Elbow Surgeons (ASES) evaluation form and Constant score. Postoperative external rotation (ER) power in both abduction and adduction was also assessed. RESULTS: Five patients were lost to follow-up. All of the remaining patients were male with a mean age of 44.5 years (28-66 years). Mean follow-up time was 34.7 months (3-72 months). The mean ASES score for the 17 patients was 86.6 (41.6-100); the mean Constant score was 89.3 (22-100). The only significant factor affecting the ASES score was an ipsilateral neurologic upper limb injury. ER power was improved or equivalent to the contralateral side in 8 of the 10 patients assessed for ER; it was weaker in 2 patients, both of whom had surgical fixation of the vertebral border of the scapula. CONCLUSION: The inter-teres approach may be a safe alternative approach in glenoid fixation, although the loss of ER strength needs further evaluation.

South Indian calcaneal talar facet configurations and osteoarthritic changes.

The purpose of this study was to determine the talar facet configuration of South Indian calcanei, measure the angle between the anterior and middle facet planes of these calcanei, and assess the relation between the above parameters and the degenerative changes in the subtalar joints. The angle between the anterior and middle talar facets was measured in 222 South Indian adult calcanei. The degree of sclerosis was measured on radiographs of the calcanei. Lipping and osteophytes around the joints were recorded by visual inspection. The facet patterns observed were fused anterior and middle facets (Type I), three separate facets (Type II), absence of the anterior facet (Type III), three merged facets (Type IV), and a new pattern of absent anterior and fused middle and posterior facets (Type V). An anterolateral impression was present in nine calcanei. Type I was the predominant pattern (72%). Type II configuration had the least mean angle (125 degrees) and had less number of calcanei with significant osteoarthritic changes. A wider angle was observed in Type I and Type III calcanei. Type IV and Type V were observed in only three and one calcanei, respectively. Lipping and osteophytes were observed in Type I to IV configurations. There was no correlation between the facet configuration and the radiological subchondral sclerosis in the posterior talar facet of the calcanei. This study reveals that the talar facet configuration of calcanei and the angle between the anterior and middle facets influence the stability of the subtalar joints and development of osteoarthritis.