Paediatric Septic Arthritis of the Hip and the Efficacy of Kocher's Criteria: A Literature Review.

Pediatric septic arthritis (SA), an intra-articular infection in children, is considered a surgical emergency. The most commonly affected joints are the lower limb joints. It is more common in children below five years old and in males. Several scoring systems aid in the prediction of the disease and help differentiate it from similar differential diagnoses (such as transient synovitis (TS)). The first and most famous scoring system is Kocher's Criteria (KC), which utilizes a mixture of clinical signs, symptoms, and laboratory markers to predict the likelihood of the diagnosis. This review aims to assess the current literature to look at primary papers comparing the predicted probability of KC to the original probability described therefore evaluating its efficacy and usefulness in today's pediatric population. PubMed was searched using the terms "septic arthritis AND hip AND (Kocher OR Kocher's criteria)," 27 studies resulted, and each study was screened by reading the abstracts. Six studies were included in this review. Inclusion criteria were any study that looked at SA of the hip in the pediatric population prospectively or retrospectively, using KC to help make a diagnosis and looking at the predicted probability of KC. Exclusion criteria included studies looking at adults, joints other than the hip, and papers not assessing the predicted probability. The efficacy of KC for diagnosing SA is not well-supported by current literature. Studies indicate that KC have low specificity for SA, suggesting it should not replace arthrocentesis as the diagnostic gold standard. Clinicians should use this model cautiously, and more extensive, prospective studies are needed to validate its effectiveness.

Outcomes of drug-coated balloon angioplasty in patients with dyslipidemia in the BIOLUX P-III registry: A subgroup analysis.

OBJECTIVES: The aim of this study was to assess the mid-term outcomes of the use of drug-coated balloons (DCBs) to treat infrainguinal peripheral arterial disease (PAD) in patients with dyslipidemia. METHODS: BIOLUX P-III is a prospective, international, multicenter, all-comers registry-based study that was conducted at 44 sites with follow-ups at 6, 12 and 24 months. The present study is a subgroup analysis comparing the outcomes associated with endovascular revascularization with those associated with Passeo-18 lux DCBs in patients with and without dyslipidemia. The proportions of patients free from major adverse events (defined as device- or procedure-related mortality within 30 days, clinically driven target lesion revascularization (CD-TLR) and major target limb amputation), target vessel revascularization, and patient-reported outcomes within 24 months postintervention were compared between the two groups. RESULTS: A total of 876 patients with symptomatic PAD who underwent peripheral revascularization with DCBs and had information on their dyslipidemia status were included; 588 of those patients had dyslipidemia. There was no difference in the proportion of patients free from MAEs between the groups. The percentages of patients who were 6, 12 and 24 months free from CD-TLR were significantly lower in the dyslipidemia group than in the nondyslipidemia group (86.3% vs 91.9% at 2 years, p = .0183). Similarly, the percentage of patients free from target vessel revascularization was lower in the dyslipidemia group at all timepoints (83.3% vs 89.3% at 2 years, p = .0203). There was no difference in mortality or major or minor limb amputation rates. Other secondary outcomes were similar between the groups. CONCLUSIONS: Compared to those without dyslipidemia, patients with symptomatic PAD and dyslipidemia who underwent revascularization with a Passeo-18 lux DCB had greater rates of CD-TLR and TVR. However, having dyslipidemia did not increase the risk of mortality or limb amputation. CLINICAL TRIAL REGISTRATION: NCT02276313.

Aspirin Compared to Other Thromboprophylactic Agents in Patients Following Total Hip Arthroplasty: A Literature Review.

Total hip arthroplasty (THA) is a common but major surgery performed in the United Kingdom and around the globe. THA is associated with several postoperative complications, with one of the most common being venous thromboembolism (VTE) in the form of deep venous thrombosis (DVT) or pulmonary embolism (PE). VTE following orthopaedic surgery can have major consequences in terms of patient morbidity and may even cause mortality. It carries a significant cost to the health service, and thromboprophylactic agents are used to decrease the risk. Several different options are available for chemical thromboprophylaxis, including aspirin, low-molecular-weight heparin (LMWH), direct oral anticoagulants (DOACs), and warfarin. This study aims to review the literature to determine if aspirin is less superior to the other available chemical thromboprophylaxis in postoperative patients following THA. The primary outcome assessed in this review is rates of symptomatic 90-day VTE in the form of PE or DVT. A literature review was conducted using PubMed, Scopus, and Google Scholar using the following terms: 'Aspirin AND (low molecular weight heparin OR LMWH OR Enoxaparin OR Apixaban OR DOAC OR direct oral anticoagulant OR warfarin) AND (orthopaedic OR orthopedic) AND (Total hip replacement OR THR OR THA OR total hip arthroplasty) AND ('venous thromboembolism' OR VTE).' Aspirin appears to have promising results as thromboprophylaxis in cases of THA. However, it is still up for debate as to whether it is non-inferior to other forms of thromboprophylaxis.

The Importance of Prion Research.

Over the past four decades, prion diseases have received considerable research attention owing to their potential to be transmitted within and across species as well as their consequences for human and animal health. The unprecedented nature of prions has led to the discovery of a paradigm of templated protein misfolding that underlies a diverse range of both disease-related and normal biological processes. Indeed, the "prion-like" misfolding and propagation of protein aggregates is now recognized as a common underlying disease mechanism in human neurodegenerative disorders such as Alzheimer's and Parkinson's disease and the prion principle has led to the development of novel diagnostic and therapeutic strategies for these illnesses. Despite these advances, research into the fundamental biology of prion diseases has declined, likely due to their rarity and the absence of an acute human health crisis. Given the past translational influence, continued research on the etiology, pathogenesis, and transmission of prion disease should remain a priority. In this review we highlight several important "unsolved mysteries" in the prion disease research field and how solving them may be crucial for the development of effective therapeutics, preventing future outbreaks of prion disease, and understanding the pathobiology of more common human neurodegenerative disorders.

Optimal surgical approach for mid-transverse colon cancer: a systematic review and meta-analysis.

BACKGROUND AND AIM: The incidence of cancer colon has increased dramatically. In addition, the database lacks a review to analyze the outcomes of surgeries for mid-transverse colon cancer with several recent controversial studies. We aimed to compare the outcomes of extended hemicolectomy versus transverse colectomy for mid-transverse colon cancer. METHOD: PubMed, Scopes, Web of Science and Cochrane Library were searched for eligible studies from inception to 1 December 2022 and a systematic review and meta-analysis were done to detect. RESULTS: According to eligibility criteria, 8 studies (2237 patients) were included in our study. The pooled results of the included studies showed no difference in the 5-year OS, 3-year DFS and 5-year DFS between the two types of surgery (5-year OS, RR = 1.15, 95% CI 0.94-1.39, P = 0.17), (3-year OS, RR = 0.96, 95% CI 0.88-1.06, P = 0.42) and (5-year DFS, RR = 1.21, 95% CI 0.91-1.62, P = 0.20). In addition to that, the recurrence rate and the incidence of complications were similar in the two groups (Recurrence rate, RR = 1.08, 95% CI 0.62-1.89, P = 0.79) and (Complications, RR = 1.07, 95% CI 0.74-1.54, P = 0.72). However, the number of LN harvest and the time of the operation were more in case of extended hemicolectomy. CONCLUSION: Despite harvesting less LN, transverse colectomy has similar oncological outcomes to extended hemicolectomy for mid-transverse colon cancer. In addition to that, there was no significant difference in the incidence of complications between the two surgeries.

Pten regulates endocytic trafficking of cell adhesion and Wnt signaling molecules to pattern the retina.

The retina is exquisitely patterned, with neuronal somata positioned at regular intervals to completely sample the visual field. Here, we show that phosphatase and tensin homolog (Pten) controls starburst amacrine cell spacing by modulating vesicular trafficking of cell adhesion molecules and Wnt proteins. Single-cell transcriptomics and double-mutant analyses revealed that Pten and Down syndrome cell adhesion molecule Dscam) are co-expressed and function additively to pattern starburst amacrine cell mosaics. Mechanistically, Pten loss accelerates the endocytic trafficking of DSCAM, FAT3, and MEGF10 off the cell membrane and into endocytic vesicles in amacrine cells. Accordingly, the vesicular proteome, a molecular signature of the cell of origin, is enriched in exocytosis, vesicle-mediated transport, and receptor internalization proteins in Pten conditional knockout (PtencKO) retinas. Wnt signaling molecules are also enriched in PtencKO retinal vesicles, and the genetic or pharmacological disruption of Wnt signaling phenocopies amacrine cell patterning defects. Pten thus controls vesicular trafficking of cell adhesion and signaling molecules to establish retinal amacrine cell mosaics.

Intraoperative Extravascular Ultrasound in the Identification of Flow-Limiting Dissections after Balloon Angioplasty in the Femoropopliteal Segment.

Background: The BIO REACT study is designed to investigate the incremental value of Extravascular UltraSound (EVUS) added to conventional angiography, compared to conventional angiography only for the identification of Flow-Limiting Dissections (FLD) and to evaluate the safety and efficacy of the REsponse Adapted Combination Therapy (REACT) for the treatment of femoropopliteal lesions. Methods: The primary endpoints were the specificity and sensitivity of EVUS added to angiography for the detection of FLD. Secondary endpoints were primary patency of the REACT therapy within 12 months, fCD-TLR, freedom from MAE, major target limb amputations (mTLA) and survival rates within 24 months. Results: A total of 150 patients were included. EVUS added to angiography had an overall sensitivity of 29% and specificity of 93% for the detection of FLD. There was no PSVR cut-off offering a clinically acceptable trade-off between meaningful sensitivity and specificity values for the detection of FLD. At 12 months, treatment with the REACT resulted in primary patency and fCD-TLR of 81.6% and 94.3%, respectively. In addition, freedom from MAE was 94.3% at 12 months. At 24 months, the survival rate was 94.0%. No mTLA was reported up to the 24-month follow-up. Conclusions: The addition of DUS to angiography showed limited value for detecting FLD in femoropopliteal artery disease.

Injury Severity is a Key Contributor to Coagulation Dysregulation and Fibrinogen Consumption.

Background: Traumatic injury is a leading cause of death for those under the age of 45, with 40% occurring due to hemorrhage. Severe tissue injury and hypoperfusion lead to marked changes in coagulation, thereby preventing formation of a stable blood clot and increasing hemorrhage associated mortality. Objectives: We aimed to quantify changes in clot formation and mechanics occurring after traumatic injury and the relationship to coagulation kinetics, and fibrinolysis. Methods: Plasma was isolated from injured patients upon arrival to the emergency department. Coagulation kinetics and mechanics of healthy donors and patient plasma were compared with rheological, turbidimetric and thrombin generation assays. ELISA's were performed to determine tissue plasminogen activator (tPA) and D-dimer concentration, as fibrinolytic markers. Results: Sixty-three patients were included in the study. The median injury severity score (ISS) was 17, median age was 37.5 years old, and mortality rate was 30%. Rheological, turbidimetric and thrombin generation assays indicated that trauma patients on average, and especially deceased patients, exhibited reduced clot stiffness, increased fibrinolysis and reduced thrombin generation compared to healthy donors. Fibrinogen concentration, clot stiffness, D-dimer and tPA all demonstrated significant direct correlation to increasing ISS. Machine learning algorithms identified and highlighted the importance of clinical factors on determining patient outcomes. Conclusions: Viscoelastic and biochemical assays indicate significant contributors and predictors of mortality for improved patient treatment and therapeutic target detection. ESSENTIALS: Traumatic injury may lead to alterations in a patient's ability to form stable blood clotsA study was performed to assess how trauma severity affects coagulation kineticsKey alterations were observed in trauma patients, who exhibit weaker and slower forming clotsPaired with machine learning methods, the results indicate key aspects contributing to mortality.

Efficacy of embolotherapy for the treatment of pelvic congestion syndrome: A systematic review.

Pelvic congestion syndrome (PCS) poses a significant health, diagnostic, and economic challenges. Transcatheter embolisation has emerged as a promising treatment for PCS. A systematic review was performed in order to assess the safety and efficacy of transcatheter embolisation in the treatment of PCS. A systematic search of electronic databases was performed using 'PubMed', 'Embase', 'Medline (OVID)', and 'Web of Science', for articles pertaining to efficacy of embolotherapy for the treatment of pelvic congestion syndrome. A total of 25 studies were included in this systematic review with a combined total of 2038 patients. All patients included were female with a mean average age of 37.65 (31-51). Of the 25 studies, 18/25 studies reported pre- and post-procedural pelvic pain outcomes using a visual analogue scale (VAS). All studies showed a reduction in VAS post-procedure. Transcatheter embolisation had a high technical success rate (94%) and an overall complication rate of 9.0%, of which 10.4% were major and 89.6% were minor. Fifteen out of 19 (78.9%) major complications required a subsequent intervention. Transcatheter embolisation using various techniques is effective and safe in treating PCS. A low quality of evidence limits the currently available literature; however, embolisation has shown to improve symptoms in the majority of patients with low complication rates and recurrence rates.

Adjuvant chemotherapy improves survival amongst octogenarians following resection of colorectal adenocarcinoma.

BACKGROUND: The Australian population is ageing, with an increasing number of patients diagnosed with colorectal cancer in their eighth decade. This group represents a challenging cohort to deliver multidisciplinary care, with increased morbidity and mortality related to surgical and oncological therapies. This project aimed to compare surgical and oncological outcomes in octogenarian and non-octogenarian patients with colorectal cancer. METHODS: A matched case-control retrospective review of a prospectively maintained institutional database of colorectal cancer patients treated between 2005 and 2021 was conducted. Patient demographics, treatment details, peri-operative complications, and long-term survival were reported. The primary outcome, cancer-specific survival, was investigated using time-to-event analysis and interrogated with multivariate regression. RESULTS: There were 747 patients included in the study. There was no difference in five-year cancer-specific survival and recurrence-free survival between cohorts. Multivariate analysis for octogenarians confirmed a significant hazard signal associated with worsening cancer stage and a survival benefit associated with the administration of adjuvant therapy. However, we noted that stage-matched octogenarian patients received less adjuvant treatment compared to non-octogenarians. CONCLUSION: Octogenarians undergoing treatment for colorectal cancer have similar cancer-specific survival and recurrence-free survival to non-octogenarians. Our study demonstrates a survival benefit when adjuvant therapy is provided to octogenarians, despite only half of this cohort receiving therapy compared to their younger peers. Further research into adjuvant therapy with surgical resection for CRC in older Australians is required.

A Systematic Review and Meta-Analysis: Do We Still Need Microscope Surgery in Hepatic Artery Anastomosis to Decrease the Incidence of Complications in Living Donor Liver Transplantation?

Hepatic artery thrombosis (HAT) is the most serious vascular complication after liver transplantation (LT). Moreover, in comparison to deceased donor liver transplantation (DDLT), hepatic artery (HA) anastomosis is more challenging in living donor liver transplantation (LDLT) with a lot of controversial topics about the use of microscopic surgery. We aimed to compare the use of microscopic and loupe surgery in HA anastomosis in adult and pediatric LDLT to decrease the incidence of vascular complications. We searched PubMed, Scopes, Web of Science, and Cochrane Library for eligible studies from inception to April 2023 and a systematic review and a meta-analysis were done. According to our eligibility criteria, 10 studies with a total of 1939 patients were included. In comparison to microscopic surgery, loupe anastomosis has a similar incidence of HAT (thrombosis, risk ratio (RR) = 0.96, 95% CI = 0.26-3.48, P = 0.95). In addition to that, no significant difference was detected between the two types in terms of stenosis, decreased blood flow and hospital stay (decreased blood flow, RR = 0.68, 95% CI = 0.01-86.65, P = 0.88), (stenosis, RR = 1.81, 95% CI = 0.19-17.21, P = 0.60), (hospital stay, mean deviation (MD) = 1.16, 95% CI = -3.79-6.11, P = 0.65). However, the anastomotic time was longer in the case of microscopic surgery (anastomotic time, MD = 24.09, 95% CI = 7.79-40.39, P = 0.004). With an equal incidence of complications and longer anastomotic time, there is no added benefit of the routine use of microscopic surgery in HA anastomosis in LDLT.

Duct-to-Duct Anastomosis Versus Bilioenteric Anastomosis for Pediatrics Living Donor Liver Transplantation: A Systematic Review and Meta-Analysis.

With an incidence exceeding 30%, biliary complications after pediatric liver transplantation remain a great challenge. In addition, the database includes numerous controversial papers about the safety of duct-to-duct anastomosis compared to Reux-en-Y hepaticojejunostomy for pediatric living donor liver transplantation (LDLT). We aim to compare the two techniques in pediatric LDLT by conducting a systematic review and meta-analysis. PUBMED, Web of Science, Scopus, and Cochrane Library were searched for eligible studies from 1989 to October 2022. According to our eligibility criteria, seven articles (561 pediatric LDLT) were included in our study. On one hand, DD anastomosis is associated with a higher rate of biliary stricture in comparison to RYHJ (OR: 2.47, 95% CI = 1.20-5.09, P = 0.01; I2 = 12%). On the other hand, the incidence of cholangitis was higher in RYHJ (OR: 0.10 95% CI = 0.01- 0.84, P = 0.03; I2 = 0%). However, there was no significant difference in the overall incidence of complications, leakage and mortality between the two groups (overall incidence of complication OR: 1.12, 95% CI = 0.34-3.68, P = 0.86; I2 = 62%), (Leakage OR: 2.22, 95% CI = 0.79-6.23, P = 0.13; I2 = 18%) and (Mortality OR: 2.53, 95% CI = 0.61-10.57, P = 0.30; I2 = 0%). In conclusion, with a lower incidence of cholangitis, an equal overall incidence of biliary complication, and the possibility of RY conversion in case of stricture, DD anastomosis offers a feasible, safe, and more physiological alternative to RYHJ for pediatric LDLT.

Delayed cardiac tamponade secondary to blast injury from gunshot wound.

Penetrating injuries are recognized for the direct tissue damage, which is typically evident on physical examination. Secondary injuries resulting from kinetic energy transfer in the case of gunshot wounds (GSWs), often referred to as "blast injuries", may affect tissues distant to the ballistic trajectory and are often occult. We present a case of delayed cardiac tamponade resulting from secondary blast injury. The patient sustained a thoraco-abdominal GSW with entry adjacent to the cardiac box. An Advanced Trauma Life Support (ATLS)-guided assessment revealed intra-abdominal injuries necessitating operative intervention without evidence of cardiac injury. On post-operative day four, the patient developed chest pain, tachycardia, and shortness of breath. Imaging revealed a large pericardial effusion with cardiac tamponade. Emergent exploration revealed hemopericardium secondary to a bleeding epicardial hematoma without evidence of pericardial violation. Clinicians must maintain a high clinical suspicion for occult, indirect blast injuries which may be life-threatening.

A sex-based analysis of 5-year outcomes following stenting for the treatment of aorto-iliac occlusive disease.

OBJECTIVES: The aim of this study was to evaluate the impact of sex on mid-term outcomes following stenting for aorto-iliac occlusive disease (AIOD). METHODS: The Covered versus Balloon Expandable Stent Trial (COBEST) compared the safety and efficacy of the covered stent (CS) with those of the bare metal stent (BMS) in the treatment of hemodynamically significant AIOD. It was identified that CS provided a significant benefit. The primary endpoint of our analysis was the rate of primary patency 5 years following stenting for AIOD (inclusive of both CS and BMS) in both sexes. RESULTS: Of the 168 lesions treated, 103 (61%) were present in men and 65 (39%) were present in women. Of the concomitant comorbidities, diabetes mellitus was significantly more common in women (17.5% vs 41.5%, p = .006). Although chronic limb threatening ischemia (CLTI) at the time of intervention was more common in women, the difference was not significant (16.5% vs 24.6%, p = .395). Sex was not associated with the primary patency rate (male; 0.70, 95% confidence interval [CI]: 0.23-2.19, p = .543). When considering both male sex and the utilization of BMS, no significant impact was found on the primary patency rate (hazard ratio [HR]: 3.43, 95% CI: 0.69-17.10, p = .133). All-cause mortality at 60 months was 22.6% in men compared to 19.4% in women (p = .695). CONCLUSIONS: No significant difference was identified in the primary patency rate between the sexes. Further investigation is warranted to ascertain whether sex-specific interventional guidelines are required in this regard.

Spontaneous retroperitoneal haemorrhage following re-perfusion of an ischaemic kidney leading to emergency trauma nephrectomy.

Here we present a rare case of life-threatening spontaneous renal haemorrhage following elective vascular surgery. A 73-year-old gentleman presents to the ED with acute onset right sided flank pain, 24 hours post bilateral renal artery stent insertion for renal artery stenosis. Subsequent angiography demonstrated bilateral renal artery stent occlusion with near complete bilateral kidney infarction. The patient urgently underwent bilateral renal artery thrombectomy. Post-operatively the patient developed severe unilateral flank pain and became haemodynamically unstable. Subsequent imaging revealed a large right sided retroperitoneal haematoma with active arterial bleeding. The patient ultimately underwent a right sided trauma nephrectomy for haemorrhage control.

Management Experiences of Post-Gastrectomy Severe Alkaline Reflux Esophagitis.

Alkaline reflux esophagitis is a recognized complication of procedures that compromise the lower esophageal sphincter (LES), including gastrectomy. Incidence of reflux is dependent on the reconstructive procedure, with Roux-en-Y (RY) esophagojejunostomy commonly accepted as the optimal method. The authors report their experience of 5 patients who underwent remedial intervention for severe alkaline reflux esophagitis following gastric cancer surgery, over a 6-year period (2014-2020). Primary diagnoses encompassed 4 gastric adenocarcinomas and 1 gastric neuroendocrine tumor. Four patients previously underwent total gastrectomy and 1 subtotal gastrectomy with RY reconstruction. Onset of postoperative reflux symptoms ranged from 2 weeks to 3 years. Failing medical management, all patients underwent jejunojejunal anastomosis and Roux limb length revision with surgical jejunostomy. At follow-up, 4 out of 5 patients had some degree of symptom resolution and one with unresolved symptoms. The authors report our experience of managing this complication following gastrectomy with jejunojejunal anastomosis and Roux limb length revision.

Management of secondary aorto-enteric fistulae: a multi-centre study.

BACKGROUND: Secondary aorto-enteric fistulae (SAEF) are a rare, complex and life-threatening complication following aortic repair. Traditional treatment strategy has been with open aortic repair (OAR), with emergence of endovascular repair (EVAR) as a potentially viable initial treatment option. Controversy exists over optimal immediate and long-term management. METHODS: This was a retrospective, observational, multi-institutional cohort study. Patients who had been treated for SAEF between 2003 and 2020 were identified using a standardized database. Baseline characteristics, presenting features, microbiological, operative, and post-operative variables were recorded. The primary outcomes were short and mid-term mortality. Descriptive statistics, binomial regression, Kaplan-Meier and Cox age-adjusted survival analyses were performed. RESULTS: Across 5 tertiary centres, a total of 47 patients treated for SAEF were included, 7 were female and the median (range) age at presentation was 74 years (48-93). In this cohort, 24 (51%) patients were treated with initially with OAR, 15 (32%) with EVAR-first and 8 (17%) non-operatively. The 30-day and 1-year mortality for all cases that underwent intervention was 21% and 46% respectively. Age-adjusted survival analysis revealed no statistically significant difference in mortality in the EVAR-first group compared to the OAR-first group, HR 0.99 (95% CI 0.94-1.03, P = 0.61). CONCLUSION: In this study there was no difference in all-cause mortality in patients who had OAR or EVAR as first line treatment for SAEF. In the acute setting, alongside broad-spectrum antimicrobial therapy, EVAR can be considered as an initial treatment for patients with SAEF, as a primary treatment or a bridge to definitive OAR.

Opportunistic optimization of inhaler technique in hospitalized adults with asthma: a two-phase educational study.

OBJECTIVE: To investigate effectiveness of two different educational methods to improve inhaler techniques in patients with prior diagnosis of asthma, hospitalized with a non-asthma-related diagnosis. METHODS: We undertook a real-world, opportunistic quality-improvement project. Inhaler technique in hospitalized patients with prior diagnosis of asthma was assessed in two cohorts over two 12-week cycles using a standardized device-specific proforma of seven-step inhaler technique, classed: "good" if 6/7 steps achieved; "fair" if 5/7 compliant; "poor" for others. Baseline data was collected in both cycles. Cycle one involved face-to-face education by a healthcare professional; cycle two involved additional use of an electronic device to show device-specific videos (asthma.org.uk). In both cycles, patients were reassessed within two days for improvements and the two methods compared for effectiveness. RESULTS: During cycle one 32/40 patients were reassessed within 48 h; eight lost to follow-up. During cycle two 38/40 patients were reassessed within 48 h; two lost to follow-up During cycle one, two and 12 had good/fair baseline technique respectively, and 26 poor. Most commonly missed steps were no expiry check/not rinsing mouth after steroid use. On reassessment 17% patients improved from poor to fair/good. During cycle two, initial technique assessment identified: 23 poor; 12 fair; five good. Post-videos, 35% of patients improved from poor to fair/good. Proportion of patients improving from poor to fair, or poor/fair to good increased in cycle two vs one (52.5% vs 33%). CONCLUSION: Visual instruction is associated with improved technique compared to verbal feedback. This is a user-friendly and cost-effective approach to patient education.

Transforming Evidence Generation for Drug Label Changes: A Case Study.

Computer Modeling and Simulation (CM&S) provides the opportunity to drastically reduce clinical trial patient burden and advance regulatory decision making. At the suggestion of the US Food and Drug Administration (FDA), MannKind Corporation and Nudge BG submitted an application to the FDA Model-Informed Drug Development (MIDD) pilot program to support a label change for the initial dose of Afrezza® (insulin human), a novel inhalable insulin with a rapid pharmacokinetic and pharmacodynamic profile. The MIDD pilot program demonstrates the FDA's commitment to advancing regulatory science through the adoption of evidence generated by CM&S. A simulation framework was developed based on empirical data. It was used to generate evidence to support the label change. Briefing packages and presentations were prepared for two meetings with the FDA, over a period of four months. The model was thoroughly characterized, determined to be low risk for the question of interest, and submitted along with additional clinical evidence for validation. The FDA found the simulation framework to be helpful in providing insights into the question of interest and provides reasonable glycemic outcome predictions. At the conclusion of the MIDD paired meetings, FDA personnel from the Center for Drug Evaluation and Research review team accepted the simulation and requested additional, traditional clinical evidence to support the proposed label change. In the post-meeting comments, the FDA invited MannKind to submit a proposal for a data package including the CM&S evidence in a Type C meeting for further discussion on the label change. This MIDD pilot experience suggests that CM&S is a credible method for evidence generation. Collaboration between sponsor organizations as well as all stakeholders in the FDA, including proponents of CM&S, can further support regulatory decision-making. The learnings from early participants will allow the program to reach its full potential and thereby ultimately benefit patients, sponsors, and FDA.