Current and evolving approaches for improving the oral permeability of BCS Class III or analogous molecules.

The Biopharmaceutics Classification System (BCS) classifies pharmaceutical compounds based on their aqueous solubility and intestinal permeability. The BCS Class III compounds are hydrophilic molecules (high aqueous solubility) with low permeability across the biological membranes. While these compounds are pharmacologically effective, poor absorption due to low permeability becomes the rate-limiting step in achieving adequate bioavailability. Several approaches have been explored and utilized for improving the permeability profiles of these compounds. The approaches include traditional methods such as prodrugs, permeation enhancers, ion-pairing, etc., as well as relatively modern approaches such as nanoencapsulation and nanosizing. The most recent approaches include a combination/hybridization of one or more traditional approaches to improve drug permeability. While some of these approaches have been extremely successful, i.e. drug products utilizing the approach have progressed through the USFDA approval for marketing; others require further investigation to be applicable. This article discusses the commonly studied approaches for improving the permeability of BCS Class III compounds.

Risk-based lung cancer screening performance in a universal healthcare setting.

Globally, lung cancer is the leading cause of cancer death. Previous trials demonstrated that low-dose computed tomography lung cancer screening of high-risk individuals can reduce lung cancer mortality by 20% or more. Lung cancer screening has been approved by major guidelines in the United States, and over 4,000 sites offer screening. Adoption of lung screening outside the United States has, until recently, been slow. Between June 2017 and May 2019, the Ontario Lung Cancer Screening Pilot successfully recruited 7,768 individuals at high risk identified by using the PLCOm2012noRace lung cancer risk prediction model. In total, 4,451 participants were successfully screened, retained and provided with high-quality follow-up, including appropriate treatment. In the Ontario Lung Cancer Screening Pilot, the lung cancer detection rate and the proportion of early-stage cancers were 2.4% and 79.2%, respectively; serious harms were infrequent; and sensitivity to detect lung cancers was 95.3% or more. With abnormal scans defined as ones leading to diagnostic investigation, specificity was 95.5% (positive predictive value, 35.1%), and adherence to annual recall and early surveillance scans and clinical investigations were high (>85%). The Ontario Lung Cancer Screening Pilot provides insights into how a risk-based organized lung screening program can be implemented in a large, diverse, populous geographic area within a universal healthcare system.

Predictive value of 3D imaging to guide implant selection in immediate breast reconstruction.

BACKGROUND: Pre-operative estimation of breast mound volume for immediate breast reconstruction is necessary for operative planning, especially in direct-to-implant reconstruction. Our purpose was to investigate the relationship between pre-operative predictions of breast mound weight from 3D imaging and actual mastectomy weight and implant size. METHODS: A retrospective chart review of all patients who had previously undergone nipple-sparing mastectomy (NSM) by a single surgeon was performed. Pre-operative 3D images were reviewed and calculations of breast mound weight were performed by three independent reviewers. Intra-operative mastectomy weight and final implant weight were collected from patient charts. A regression analysis between calculated and actual values was performed. RESULTS: There were 59 reconstructed breasts included. Pre-operative 3D imaging-guided breast weight calculations were similar across reviewers (R=0.96). Pre-operative calculations of breast weight were 49.4g (SD=134.0) smaller than actual mastectomy specimens. Mastectomy specimens were 41.0g (SD=130.2) smaller than final implant sizes. Thereby, the relationship was as follows: Pre-operative calculated breast weight < actual Mastectomy weight < implant weight. Mastectomy weight and final implant size had linear relationships with pre-operative calculations of breast weight. Formulas for predicting mastectomy weight [mastectomy weight = 63.2 + 0.95 (pre-operative calculated weight)] and implant size [Implant weight = 209.7+ 0.56 (pre-operative calculated weight)] from pre-operative calculations of breast weight were generated. CONCLUSIONS: Three-dimensional scanning technologies may be a useful tool to predict implant sizes for direct-to-implant breast reconstruction. Final implant size was heavier than intra-operative mastectomy weight and pre-operative calculated breast mound weight.

"Uninformed" Consent: Patient Recollection From Surgical Consent in Hand Surgery-A Quality Improvement Initiative.

Background: Informed surgical consent is necessary and routine; however, it can have significant inadequacies. Our purpose was to investigate patient recollection of the surgical consent process and evaluate adequacy from the patient's perspective. Methods: A quality improvement framework was used. Two patient surveys capturing information recall and satisfaction of the consent process were administered in 5 consecutive hand clinics. All patients who previously underwent elective hand surgery were included. Results: There was exceptionally low recall of the risks and benefits of surgery in 103 consecutive patients who underwent hand surgery. Patients under age 35 had slightly better recall of surgical risks. Unexpected postoperative events affected patient perceptions of the consent process. Conclusions: Patients who have undergone elective hand surgery have poor recollection of the information discussed during the surgical consent process, and therefore the process is lacking. Surgeons may falsely assume that the consent process is sound because it is erroneously perceived as being sufficient by most patients.

Wire Cerclage Versus Cable Closure After Sternotomy for Dehiscence and DSWI: A Systematic Review and Meta-Analysis.

OBJECTIVE: Cable closure has been introduced as a potential alternative to traditional wire cerclage (WC) for closure of median sternotomy. To evaluate whether cable closure improves patient outcomes, we conducted a systematic review and meta-analysis of the literature. METHODS: Ovid versions of Medline and Embase, and Google Scholar were used for the literature search. This yielded 7 studies (n = 2,758), which compared traditional WC to cable closure systems. Outcomes included deep sternal wound infection, sternal dehiscence, postoperative pain score, and sternal wound infection. RESULTS: We found significantly lower incidence of sternal dehiscence for cable closure compared to WC (risk ratio [RR] 0.14, 95% confidence interval [CI]: 0.03 to 0.59, P < 0.01, I 2 = 0%) but no difference in DSWI (RR 0.97, 95% CI: 0.39 to 2.42, P = 0.95, I 2 = 33%). Cable closure was also associated with lower pain when compared with the WC group (mean difference -1.04 points, 95% CI: -1.89 to -0.19, P = 0.02, I 2 = 87%). CONCLUSIONS: This study suggests that cable closure results in less incidence of sternal dehiscence and pain compared to WC. Nonetheless, there remains a limited number of studies on this topic and further high-quality studies are required to confirm the results of this meta-analysis.

Sleeping with Elevated Upper Body Does Not Attenuate Acute Mountain Sickness: Pragmatic Randomized Clinical Trial.

PURPOSE: Acute mountain sickness commonly occurs following ascent to high altitude and is aggravated following sleep. Cephalad fluid shifts have been implicated. We hypothesized that sleeping with the upper body elevated by 30º reduces the risk of acute mountain sickness. METHODS: In a pragmatic, randomized, observer-blinded field study at 4554 meters altitude, we investigated 134 adults aged 18-70 years with a Lake Louise score between 3 and 12 points on the evening of their arrival at the altitude. The individuals were exposed to sleeping on an inflatable cushion elevating the upper body by 30º or on a sham pillow in a horizontal position. The primary endpoint was the change in the Acute Mountain Sickness-Cerebral (AMS-C) score in the morning after sleeping at an altitude of 4554 meters compared with the evening before. Sleep efficiency was the secondary endpoint. RESULTS: Among 219 eligible mountaineers, 134 fulfilled the inclusion criteria and were randomized. The AMS-C score increased by 0.250 ± 0.575 in the control group and by 0.121 ± 0.679 in the intervention group (difference 0.105; 95% confidence interval, -0.098-0.308; P = .308). Oxygen saturation in the morning was 79% ± 6% in the intervention group and 78% ± 6% in the control group (P = .863). Sleep efficiency did not differ between groups (P = .115). CONCLUSIONS: Sleeping with the upper body elevated by 30° does not lead to relevant reductions in acute mountain sickness symptoms or hypoxemia at high altitude.

Rigid Plate Fixation Versus Wire Cerclage for Sternotomy After Cardiac Surgery: A Meta-Analysis.

BACKGROUND: Traditionally, wire cerclage has been used to reapproximate the sternum after sternotomy. Recent evidence suggests that rigid plate fixation for sternal closure may reduce the risk of sternal complications. METHODS: The Medline and Embase databases were searched from inception to February 2017 for studies that compared rigid plate fixation with wire cerclage for cardiac surgery patients undergoing sternotomy. Random effects meta-analysis compared rates of sternal complications (primary outcome, defined as deep or superficial sternal wound infection, or sternal instability), early mortality, and length of stay (secondary outcomes). RESULTS: Three randomized controlled trials (n = 427) and five unadjusted observational studies (n = 1,025) met inclusion criteria. There was no significant difference in sternal complications with rigid plate fixation at a median of 6 months' follow-up (incidence rate ratio 0.51, 95% confidence interval [CI]: 0.20 to 1.29, p = 0.15) overall, but a decrease when including only patients at high risk for sternal complications (incidence rate ratio 0.23, 95% CI: 0.06 to 0.89, p = 0.03; two observational studies). Perioperative mortality was reduced favoring rigid plate fixation (relative risk 0.40, 95% CI: 0.28 to 0.97, p = 0.04; four observational studies and one randomized controlled trial). Length of stay was similar overall (mean difference -0.77 days, 95% CI: -1.65 to +0.12, p = 0.09), but significantly reduced with rigid plate fixation in the observational studies (mean difference -1.34 days, 95% CI: -2.05 to -0.63, p = 0.0002). CONCLUSIONS: This meta-analysis, driven by the results of unmatched observational studies, suggests that rigid plate fixation may lead to reduced sternal complications in patients at high risk for such events, improved perioperative survival, and decreased hospital length of stay. More randomized controlled trials are required to confirm the potential benefits of rigid plate fixation for primary sternotomy closure.

Crib Mattress Investigation: A quality improvement study to assess mattress cover permeability and bacterial growth in crib mattresses.

PURPOSE: Any opening in a medical bed mattress cover may allow bodily fluids to enter the mattress, leading to contamination and potential nosocomial infection. This study's purpose was to assess permeability of crib mattress covers and measure bacterial growth within and on crib mattress surfaces. METHOD: Mattresses were selected randomly from hospital inventory. Bonney's blue dye was applied over mattress covers to assess permeability. Mattress cover surface swabs were acquired from standardized locations. Samples of mattress foam were acquired under sterile conditions. All samples were collected with the Eswab and eMRSA systems (Copan Diagnostics Inc, Brescia, Italy). Total aerobic bacteria count and colony types were assessed. Results are presented as mean ± standard error of the mean, independent t tests and analysis of variance were used to analyze data, and significance was achieved with P < .05. RESULTS: All mattresses (n = 7) had Bonney's blue dye visible on underlying mattress foam. There were 77 samples and 44 had bacterial growth. Total bacterial count ranged from 0.2-11.6 CFU/cm(2) with mean of 1.7 ± 0.38 CFU/cm(2). There was no relative differences between mattress sample location and colony type. All samples were negative for Staphylococcus aureus, including methicillin-resistant S aureus. CONCLUSIONS: Any crack in a mattress cover renders it permeable to fluid entering the mattress. Bacterial growth was present on mattress covers and within mattress foam. Mattresses support microbial viability from which nosocomial infection may occur.

Participation of women and sex analyses in late-phase clinical trials of new molecular entity drugs and biologics approved by the FDA in 2007-2009.

BACKGROUND: Biological sex differences may contribute to differential treatment outcomes for therapeutic products. This study tracks women's participation in late-phase clinical trials (LPCTs), where efficacy and safety of drugs and biologics are evaluated, of new molecular entity (NME) drugs and biologics approved by the U.S. Food and Drug Administration (FDA) in 2007-2009. Furthermore, presentations of sex-based analyses were assessed from the FDA reviews. METHODS: New drug applications (NDAs) and biologics license applications (BLAs) were accessed from the U.S. FDA database and evaluated for women's participation in LPCTs. Sex-based analyses for efficacy and safety contained in FDA reviews were surveyed. Ratios for women's LPCT participation (PROPORTION OF STUDY SUBJECTS) to their proportion in the disease population were calculated for each approved therapeutic product and grouped into therapeutic categories. RESULTS: Sex-specific (n=5) and pediatric (n=3) drug applications were excluded. Women's participation in LPCTs was 39%, 48%, and 42% in NDAs (n=50) and 49%, 62%, and 58% in BLAs (n=11) for 2007, 2008, and 2009, respectively. Sixty-four percent of NDAs and 91% of BLAs had participation to proportion ratios of ≥0.80. Seventy-four percent of NDA reviews and 64% of BLA reviews included safety and efficacy sex analysis. Ninety-six percent of NDA reviews and 100% of BLA reviews included efficacy sex analysis. CONCLUSION: Women's participation in LPCTs averaged 43% for NDAs and 57% for BLAs in 2007-2009 and varied widely by indication. As a comparison, the 2001 U.S. Government Accountability Office (GAO) reported 52% of women's participation for drug clinical trials in1998-2000 and an FDA study reported 45% for BLAs approved from 1995 to 1999. This study showed that sex-analysis of both safety and efficacy in NDA has increased to 74% since the GAO report of 72%, while those for BLAs increased to 64% from 37% reported for therapeutic biologics approved in 1995-1999. Knowledge of disease prevalence and participation in clinical trials provides an understanding of recruitment and retention patterns of patients in these trials.

HIV delays IFN-α production from human plasmacytoid dendritic cells and is associated with SYK phosphorylation.

Plasmacytoid dendritic cells (pDC) are the major producers of type I interferons (IFNs) in humans and rapidly produce IFN-α in response to virus exposure. Although HIV infection is associated with pDC activation, it is unclear why the innate immune response is unable to effectively control viral replication. We systematically compared the effect of HIV, Influenza, Sendai, and HSV-2 at similar target cell multiplicity of infection (M.O.I.) on human pDC function. We found that Influenza, Sendai, HSV-2 and imiquimod are able to rapidly induce IFN-α production within 4 hours to maximal levels, whereas HIV had a delayed induction that was maximal only after 24 hours. In addition, maximal IFN-α induction by HIV was at least 10 fold less than that of the other viruses in the panel. HIV also induced less TNF-α and MIP-1ß but similar levels of IP-10 compared to other viruses, which was also mirrored by delayed upregulation of pDC activation markers CD83 and CD86. BDCA-2 has been identified as an inhibitory receptor on pDC, signaling through a pathway that involves SYK phosphorylation. We find that compared to Influenza, HIV induces the activation of the SYK pathway. Thus, HIV delays pDC IFN-α production and pDC activation via SYK phosphorylation, allowing establishment of viral populations.