Perineural and lymphovascular invasion in squamous cell carcinoma of the tongue.

BACKGROUND: Perineural invasion (PNI) and lymphovascular invasion (LVI) may be adverse prognostic indicators in squamous cell carcinoma (SCC) of the tongue. METHODS: The percentages of histological PNI and LVI were determined in 335 patients with tongue SCC. Sixty tumours originally reported as negative for these features were tested to determine how many more were positive with "immunohistochemical enhancement." RESULTS: PNI was found in 141 (42.1%) and LVI in 51 (15.2%) patients. 79.4% of the 141 patients who had PNI and 72.6% of the 51 with LVI had a T3 or T4 tumour. Lymph node metastasis was identified in 145 (51.2%) of the 280 patients who had undergone neck dissection; 58.2% of the 141 patients with PNI and 80.4% of the 51 patients with LVI had lymph node metastasis. There was a highly statistically significant correlation between PNI with increasing pT (P < .00001) and pN (P < .0001) stage, and a statistically significant correlation between LVI and pT stage (P < .001), the association of LVI with pN status could not be reliably tested statistically. Immunohistochemistry for S100 identified five further cases of PNI, but review of the original H&E showed the feature was present in four and had been missed at original reporting. CD31 identified three further possible cases of LVI and D2-40 none. The endothelium of some vascular channels was positive for both CD31 and D2-40 and cross-reactivity with other cells compromised interpretation. CONCLUSIONS: Histological identification of PNI and LVI per se remains of uncertain prognostic significance. "Immunohistochemical enhancement" offered little benefit.

Challenges and opportunities to include patient-centric product design in industrial medicines development to improve therapeutic goals.

In the past, drug developers in industry chose approaches mainly focusing on the drug product's efficacy, safety and quality according to the level required by regulatory expectations stipulated in guidelines, pharmacopoeia and other regulatory provisions. By putting more focus on the patient perspective, regulatory authorities are currently raising their requirements regarding successful product submissions. The increasing involvement of patients in the product development process (e.g. conduction of human factor use tests, integration of feedback from patient and patient advisory groups into clinical programmes) requires adaptations to the existing and established industrial drug development processes without compromising fast patient access to innovative therapies. This review provides an expert opinion on the emerging challenges and opportunities to implement a patient-centric approach into new drug development programmes. The aim is to better understand the challenge of finding the right balance between bringing innovative drugs fast to the patients and to develop these in parallel in a patient-centric product form as well as why this is an opportunity and how stakeholder parties (e.g. patients, clinicians, pharmacists, caregivers, regulators) can provide support to achieve desired outcomes.

Pharmacokinetics and Abuse Potential of Asalhydromorphone, a Novel Prodrug of Hydromorphone, After Intranasal Administration in Recreational Drug Users.

OBJECTIVES: Hydromorphone (HM) is a potent µ-opioid receptor agonist with high susceptibility for abuse. A prodrug of hydromorphone, asalhydromorphone (ASAL-HM), has been designed to deter nonoral forms of abuse associated with hydromorphone. This study evaluated the intranasal (IN) pharmacokinetics and exploratory abuse potential of ASAL-HM compared with HM. DESIGN: Single-center, randomized, double-blind, crossover study. SETTING: Clinical research site. SUBJECTS: Healthy adult, nondependent recreational opioid users. METHODS: Subjects (N = 26) were randomized to receive IN administration of 16.1 mg of ASAL-HM and 8.0 mg of HM (molar-equivalent with respect to hydromorphone). Blood samples were taken through 24 hours postdose, and pharmacodynamic end points (Drug Liking, Feeling High, Take Drug Again, Overall Drug Liking) were assessed through eight hours postdose. Nasal irritation and safety were also assessed. RESULTS: Relative to IN HM, the rate (Cmax) and extent (area under the curve [AUC0-last, AUC0-inf]) of exposure to hydromorphone following IN ASAL-HM were reduced by ≥50%. Consistent with these findings, scores on "at-the-moment" (i.e., Drug Liking Emax, High Emax) and retrospective (i.e., Take Drug Again, Overall Drug Liking) end points were statistically significantly lower for IN ASAL-HM, with mean/median differences ranging from 11.4 to 25.0 points. ASAL-HM produced greater nasal-related effects, such as nasal burning and facial pain, and a lower incidence of typical opioid-related adverse events such as euphoria, pruritus, and somnolence. CONCLUSIONS: The novel hydromorphone prodrug ASAL-HM produced marked reductions in hydromorphone exposure and abuse-related effects following IN administration compared with HM. ASAL-HM has desirable molecular features for incorporation into putative abuse-deterrent immediate-release and extended-release hydromorphone products.

Total Knee Arthroplasty Has A Positive Effect on Patients With Low Mental Health Scores.

BACKGROUND: The purpose of this study is to determine the impact of total knee arthroplasty (TKA) on mental health. METHODS: A total of 205 patients who underwent primary TKA with baseline and 1-year postoperative Short Form-12 Mental Component Score (MCS) were included in this retrospective analysis. Eighty-five (41%) patients had a preoperative MCS less than 50 points, while 120 (59%) patients had a preoperative MCS over 50 points. Two groups were assigned to the patients based on their preoperative MCS: low MCS <50 and high MCS >50. RESULTS: A preoperative MCS less than 50 points was predictive of greater improvement in MCS at 1 year after TKA (P < .001). Patients with low MCS improved by a mean of 10.6 points from 39.1 ± 8.6 points preoperatively to mean of 49.7 ± 10.7 points 1 year after TKA (P < .001). Patients with a high MCS decreased by a mean of 3.5 points from 60.01 ± 6.0 points preoperatively to mean of 56.6 ± 6.8 points 1 year after TKA (P < .001). This remained higher than the postoperative MCS of the patients with a low MCS, 49.7 ± 10.7 (P < .001). The patients with a high MCS had greater improvement in the Short Form-12-Physical domain (14.8 points) than the patients with a low MCS (9.2 points, P < .001). CONCLUSION: Patients with lower baseline mental health had greater improvement in postoperative mental health following TKA than patients with higher baseline mental health. Low preoperative MCS was associated with less improvement in patient-reported outcome measures. Patients with lower baseline mental health scores before TKA benefit mentally and physically from the procedure.

Short-Term Safety of the Direct Superior Approach for Total Hip Arthroplasty.

INTRODUCTION: Minimally invasive surgery total hip arthroplasty (MIS-THA) is becoming increasingly popular. There are several approaches to MIS-THA that vary according to anatomical access to the hip joint. The direct superior (DS) approach is a recent modification of an MIS posterior approach that spares the iliotibial band and most of the short external rotators of the hip, particularly the quadratus femoris. While FDA approved, there is a lack of data in the current literature on DS outcomes and the safety of this approach is yet to be systematically evaluated. MATERIALS AND METHODS: The goal of this study is to provide a quantitative analysis of the safety and complications of primary DS-total hip arthroplasty at 90 days post-surgery through a retrospective multicenter case series of 301 patients. Special attention was given to intra- and postoperative complications, readmissions, mean operative time, hospital-stay length, and postoperative ambulation distance. RESULTS: Surgical complications included three (1%) intraoperative calcar fractures and four (1%) postoperative peri-prosthetic fractures. The postoperative medical complication rate was 3% with four (1%) patients requiring readmission. The mean operative time was 70 ± 19 minutes, hospital-stay length 41 ± 19 hours, and the estimated blood loss (EBL) was 213 ± 129 ml. There were no acute episodes of instability at 90-day follow up. The intra- and postoperative results are similar with those reported in the literature for both the anterior and posterior approaches. CONCLUSION: This study indicates that the DS approach appears to be safe with a low complication rate at 90 days that is comparable to more conventional approaches, such as the direct anterior and posterior techniques. This information is also valuable for the evaluation of reimbursements for DS-THA as current bundled-payment models heavily emphasize 90-day outcomes and complications. Long-term direct comparative studies with the anterior and posterior approaches is required to fully evaluate DS-THAs.

What is the optimal site and biopsy technique for the diagnosis of oral mucosal autoimmune blistering disease?

BACKGROUND: The aim of this study was to determine which biopsy method produces the best diagnostic yield in patients presenting with autoimmune blistering diseases (AIBDs) of the oral mucosa. METHODS: This was a retrospective audit of patients who were biopsied at least once for a suspected AIBD of the oral mucosa. The type (incisional or punch) and site of biopsies were recorded in conjunction with case notes, electronic records and histopathological reports in order to calculate sensitivity, specificity and the method of biopsy which produced the superior diagnostic yield. RESULTS: A total of 125 biopsy samples from 66 patients were identified and reviewed. A diagnosis of AIBD was established in 49 (74%) patients. The chi-square test showed there was a statistically significantly higher (P = 0.0016) diagnostic yield using the punch biopsy technique compared to the scalpel method. The gingiva was the best biopsy site in terms of achieving a definitive diagnosis (P = 0.0001) regardless of the biopsy method used. CONCLUSIONS: A punch biopsy is more likely than scalpel biopsy to obtain a definitive diagnosis in patients presenting with a suspected oral AIBD. The gingiva is the optimal site to sample.

Pharmacokinetics and Abuse Potential of Benzhydrocodone, a Novel Prodrug of Hydrocodone, After Intranasal Administration in Recreational Drug Users.

Objective: Developing an acetaminophen-free, immediate-release hydrocodone product remains an unmet medical need; however, new opioid analgesics should not introduce new abuse risks. Benzhydrocodone is a prodrug of hydrocodone that must be metabolized into hydrocodone by enzymes in the intestinal tract to optimally deliver its pharmacologic effects. This study evaluated the intranasal pharmacokinetics and abuse potential of benzhydrocodone active pharmaceutical ingredient (API) compared with hydrocodone bitartrate (HB) API. Design: Single-center, randomized, double-blind, crossover study. Setting: Clinical research site. Subjects: Healthy adult, nondependent, recreational opioid users. Methods: Subjects (N = 51 Completers) were randomized to receive 13.34 mg of intranasal benzhydrocodone API and 15.0 mg of intranasal HB API (molar-equivalent doses of hydrocodone). Blood samples were taken, and Drug Liking scores (assessed on a bipolar visual analog scale) were obtained throughout each dosing interval. Nasal irritation and safety were assessed. Results: Peak hydrocodone plasma concentration (Cmax) was 36.0% lower, and total hydrocodone exposures (AUClast and AUCinf) were 20.3% and 19.5% lower, respectively, for benzhydrocodone API compared with HB API (P < 0.0001). All partial AUC values were lower for benzhydrocodone API, with a ≥ 75% reduction in hydrocodone exposure at all time intervals up to one hour postdose (P < 0.0001). Median Tmax of hydrocodone following benzhydrocodone API was delayed by more than one hour compared with HB. Drug Liking score, as assessed by maximal liking (Emax), was significantly lower for benzhydrocodone API vs HB API (P = 0.004), with 45% of subjects showing a ≥ 30% reduction in Drug Liking Emax. Conclusion: Reductions in hydrocodone exposure and associated decreases in Drug Liking relative to HB suggest that the prodrug benzhydrocodone may deter intranasal abuse.

Relative Bioavailability, Intranasal Abuse Potential, and Safety of Benzhydrocodone/Acetaminophen Compared with Hydrocodone Bitartrate/Acetaminophen in Recreational Drug Abusers.

Objectives: Benzhydrocodone is a hydrocodone prodrug that has been combined with acetaminophen (APAP) in a novel immediate-release analgesic. This study evaluated the relative bioavailability, intranasal abuse potential, and safety of benzhydrocodone/APAP compared with commercially available hydrocodone bitartrate (HB)/APAP. Design: Single-center, randomized, double-blind, double-dummy, two-part study comprising a Dose Selection (Part A) phase and a Main Study (Part B) phase. Setting: Clinical research site. Subjects: Healthy adult, nondependent, recreational opioid users with a history of intranasal abuse. Methods: Subjects (N = 42) in Part B received five in-clinic treatments consisting of intranasal and oral benzhydrocodone/APAP (13.34/650 mg), intranasal and oral hydrocodone/APAP (15/650 mg), and placebo, with four or more days of washout between treatments. Pharmacodynamic assessments included subjective effects of Drug Liking, Overall Drug Liking, and Take Drug Again (assessed on visual analog scale [VAS]), as well as nasal irritation. Pharmacokinetics and safety were also assessed. Results: Hydrocodone Cmax was 11% lower for intranasal benzhydrocodone/APAP vs intranasal HB/APAP (P = 0.0027). Early cumulative hydrocodone exposures for intranasal benzhydrocodone/APAP through 0.5, 1, and 2 hours were reduced by approximately 50%, 29%, and 15%, respectively (P ≤ 0.0024). Correspondingly, Drug Liking VAS values up to two hours postdose were significantly lower for intranasal benzhydrocodone/APAP vs intranasal HB/APAP (P ≤ 0.0079), although peak Drug Liking VAS (Emax) scores were not different (P = 0.2814). Adverse nasal effects were more frequent for intranasal benzhydrocodone/APAP vs intranasal HB/APAP. Conclusions: Reduced hydrocodone exposure and drug liking at early time intervals, coupled with adverse nasal effects, can be expected to provide a level of deterrence to the intranasal route of abuse for benzhydrocodone/APAP.

Effects of Acute and Chronic Treatments with Dopamine D2 and D3 Receptor Ligands on Cocaine versus Food Choice in Rats.

Dopamine D3 receptor ligands are potential medications for psychostimulant addiction. Medication assessment may benefit from preclinical studies that evaluate chronic medication effects on choice between an abused drug and an alternative, nondrug reinforcer. This study compared acute and chronic effects of dopamine D2- and D3-preferring ligands on choice between intravenous cocaine and palatable food in rats. Under baseline conditions, cocaine maintained dose-dependent increases in cocaine choice and reciprocal decreases in food choice. Acutely, the D2 agonist R-(-)-norpropylapomorphine (NPA) and antagonist L-741,626 [3-[[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole] produced leftward and rightward shifts in cocaine dose-effect curves, respectively, whereas the partial agonist terguride had no effect. All three drugs dose-dependently decreased food-maintained responding. Chronically, the effects of R-(-)-norpropylapomorphine and L-741,626 on cocaine self-administration showed marked tolerance, whereas suppression of food-reinforced behavior persisted. Acute effects of the D3 ligands were less systematic and most consistent with nonselective decreases in cocaine- and food-maintained responding. Chronically, the D3 agonist PF-592,379 [5-[(2R,5S)-5-methyl-4-propylmorpholin-2-yl]pyridin-2-amine] increased cocaine choice, whereas an intermediate dose of the D3 antagonist PG01037 [N-[(E)-4-[4-(2,3-dichlorophenyl)piperazin-1-yl]but-2-enyl]-4-pyridin-2-ylbenzamide] produced a therapeutically desirable decrease in cocaine choice early in treatment; however, tolerance to this effect developed, and lower and higher doses were ineffective. D3 ligands failed to significantly modify total cocaine intake but caused persistent decreases in food intake. Thus, D2-and D3-preferring ligands showed distinct profiles, consistent with different pharmacological actions. In addition, these results highlight the role of acute versus chronic treatment as a determinant of test drug effects. With the possible exception of the D3 antagonist PG01037, no ligand was promising in terms of cocaine addiction treatment.

Budesonide foam induces remission in patients with mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis.

BACKGROUND & AIMS: Budesonide is a high-potency, second-generation corticosteroid designed to minimize systemic adverse consequences of conventional corticosteroids. We performed 2 randomized, phase 3 trials to evaluate the ability of budesonide rectal foam, formulated to optimize retention and provide uniform delivery of budesonide to the rectum and distal colon, to induce remission in patients with ulcerative proctitis or ulcerative proctosigmoiditis. METHODS: Two identically designed, randomized, double-blind, placebo-controlled trials evaluated the efficacy of budesonide foam for induction of remission in 546 patients with mild to moderate ulcerative proctitis or ulcerative proctosigmoiditis who received budesonide foam 2 mg/25 mL twice daily for 2 weeks, then once daily for 4 weeks, or placebo. RESULTS: Remission at week 6 occurred significantly more frequently among patients receiving budesonide foam than placebo (Study 1: 38.3% vs 25.8%; P = .0324; Study 2: 44.0% vs 22.4%; P < .0001). A significantly greater percentage of patients receiving budesonide foam vs placebo achieved rectal bleeding resolution (Study 1: 46.6% vs 28.0%; P = .0022; Study 2: 50.0% vs 28.6%; P = .0002) and endoscopic improvement (Study 1: 55.6% vs 43.2%; P = .0486; Study 2: 56.0% vs 36.7%; P = .0013) at week 6. Most adverse events occurred at similar frequencies between groups, although events related to changes in cortisol values were reported more frequently with budesonide foam. There were no cases of clinically symptomatic adrenal insufficiency. CONCLUSIONS: Budesonide rectal foam was well tolerated and more efficacious than placebo in inducing remission in patients with mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis. ClinicalTrials.gov ID: NCT01008410 and NCT01008423.

Once-daily Mesalamine Formulation for Maintenance of Remission in Ulcerative Colitis: A Randomized, Placebo-controlled Clinical Trial.

GOALS: To evaluate the efficacy and safety of mesalamine granules 1.5 g once daily for maintenance of ulcerative colitis (UC) remission. BACKGROUND: Mesalamine is a first-line treatment for induction and maintenance of UC remission. STUDY: A phase 3, randomized, double-blind, placebo-controlled trial of patients with a history of mild to moderate UC, currently in remission, who received mesalamine granules once daily for 6 months. The primary efficacy endpoint was percentage of patients maintaining UC remission at 6 months. RESULTS: A significantly greater percentage of patients receiving mesalamine granules versus placebo were in remission at 6 months (79.9% vs. 66.7%; P=0.03). A greater percentage of patients receiving mesalamine granules maintained a revised Sutherland Disease Activity Index (SDAI)≤2 with no individual component of revised SDAI>1 and rectal bleeding=0 at 6 months (72.0% vs. 58.1%; P=0.04). No significant differences between groups were observed for change from baseline to 6 months for total SDAI score or its components (ie, stool frequency, rectal bleeding, mucosal appearance, physician's rating of disease). Mesalamine granules treatment resulted in a significantly longer remission duration versus placebo (P=0.02) and decreased patients' risk of relapse by 43% (hazard ratio=0.57; 95% confidence interval, 0.35-0.93; P=0.02). Mesalamine granules were well tolerated, and adverse events related to hepatic, renal, and pancreatic function-potential concerns with long-term treatment-occurred at a rate similar to placebo. CONCLUSIONS: Once-daily mesalamine granules are efficacious and safe for the maintenance of UC remission.

Long-Term Benefit of Mesalamine Granules for Patients Who Achieved Corticosteroid-Induced Ulcerative Colitis Remission.

BACKGROUND: Patients with ulcerative colitis (UC) who achieve remission with corticosteroids often relapse after tapering or discontinuation; alternative treatments limiting steroid exposure and UC relapse would be beneficial. It remains uncertain whether patients with corticosteroid-induced remission experience benefit with mesalamine granules (MG), a locally acting aminosalicylate extended-release capsule formulation for maintenance of UC remission in adults. AIMS: Efficacy and safety of MG 1.5 g once daily was evaluated in patients with UC in corticosteroid-induced remission. METHODS: Data from patients with previous corticosteroid use to achieve baseline UC remission were analyzed from two 6-month randomized, double-blind, placebo-controlled trials and a 24-month open-label extension (OLE). Six-month relapse-free rates were assessed using the revised Sutherland Disease Activity Index. UC-related adverse events (AEs) were recorded during the 30 months. RESULTS: Included were 158 steroid-treated patients in UC remission (MG, n = 105; placebo, n = 53) and 74/105 MG-treated patients who continued MG in the OLE. A significantly larger percentage of patients remained relapse-free at 6 months with MG (77.1 %) versus placebo (54.7 %; P = 0.006), with a 55 % reduction in relapse risk (hazard ratio [HR] 0.45; 95 % CI 0.25-0.79). There was a similar (49.2 %) reduction in risk of UC-related AEs at 6 months (HR 0.51; 95 % CI 0.31-0.84; P = 0.009) that was sustained during the OLE. CONCLUSIONS: MG 1.5 g once daily administered for maintenance of corticosteroid-induced remission was associated with low risk of relapse and UC-related AEs. CLINICALTRIALS.GOV: NCT00744016, NCT00767728, and NCT00326209.

Budesonide Foam Has a Favorable Safety Profile for Inducing Remission in Mild-to-Moderate Ulcerative Proctitis or Proctosigmoiditis.

BACKGROUND: Budesonide foam, a rectally administered, second-generation corticosteroid with extensive hepatic first-pass metabolism, is efficacious for the treatment of mild-to-moderate ulcerative proctitis and ulcerative proctosigmoiditis. AIM: The aim of this study was to comprehensively assess the safety and pharmacokinetic profile of budesonide foam. METHODS: Data from five phase III studies were pooled to further evaluate safety, including an open-label study (once-daily treatment for 8 weeks), an active-comparator study (once-daily treatment for 4 weeks), and two placebo-controlled studies and an open-label extension study (twice-daily treatment for 2 weeks, then once daily for 4 weeks). Data from the placebo-controlled studies and two phase I studies (i.e., patients with mild-to-moderate ulcerative colitis and healthy volunteers) were pooled to evaluate the pharmacokinetics of budesonide foam. RESULTS: A similar percentage of patients reported adverse events in the budesonide foam and placebo groups, with the majority of adverse events being mild or moderate in intensity (93.3 vs 96.0%, respectively). Adverse events occurred in 41.4 and 36.3% of patients receiving budesonide foam and placebo, respectively. Mean morning cortisol concentrations remained within the normal range for up to 8 weeks of treatment; there were no clinically relevant effects of budesonide foam on the hypothalamic-pituitary-adrenal axis. Population pharmacokinetic analysis demonstrated low systemic exposure after budesonide foam administration. CONCLUSIONS: This integrated analysis demonstrated that budesonide foam for the induction of remission of distal ulcerative colitis is safe overall, with no clinically relevant effects on the hypothalamic-pituitary-adrenal axis.

The Post-Levator Aponeurosis Fat Pad.

PURPOSE: To examine the post-aponeurotic space and to confirm and define the presence of a post-aponeurosis fat-pad. METHODS: Experimental anatomic study. Nineteen-orbits from 10 freeze-preserved, unembalmed cadavers of caucasian subjects. In 12 orbits of 7 cadavers, a transconjunctival dissection of the everted upper eyelid was undertaken. Müller's muscle (MM) and conjunctiva were dissected as a composite flap exposing the posterior surface of the aponeurosis (LA) and the commencement of the levator palpebrae superioris (LPS) muscle. Anatomical localisation was agreed by 2 senior surgeons and an anatomist (VM). In the remaining 7 orbits a 1cm central upper eyelid wedge-excision was paraffin-embedded and studied histologically. RESULTS: Nineteen upper-eyelids from 10 freeze-preserved, unembalmed caucasian cadavers (5-male, 5-female, mean age 80.9; range 67-91 years) were studied. Of 12 eyelids of 7 cadavers, dissected and macroscopically evaluated, a fat-pad was identified in the post-aponeurotic space of all eyelids. Of these, 8 (66%) were predominantly diffuse. The remainder, mixed diffuse-discrete. All 4 of the latter category appeared multi-lobular. The fat-pad was seen to lie predominantly centro-medially, overlying MM, extending superiorly beyond the LA to lie posterior to LPS. Of the 7 upper eyelid wedge-excisions examined microscopically, a fat-pad was identified in all post-aponeurotic spaces, lying between 2 distinct tracts of smooth muscle. The anterior smooth muscle tract was intimately related to the posterior aspect of the LA, in keeping with the posterior smooth muscle layer of the aponeurosis. The posterior smooth muscle tract was in keeping with MM, thicker than the anterior layer, multi-layered and in 6 of 7 eyelids, interspersed with fat. CONCLUSIONS: We confirm and describe a distinct layer of fat in the post-aponeurotic space, consistently found between MM and the posterior smooth muscle layer of the aponeurosis. We refer to this as the post-aponeurosis fat-pad. These findings provide further anatomical detail for the surgeon undertaking blepharoptosis surgery, who may, in some cases, mistake the presence of fat in this space either for the pre-aponeurotic fat-pad, or for degenerative changes within MM that lies deep to it.

Efficacy and Tolerability of Subcutaneous Methylnaltrexone in Patients with Advanced Illness and Opioid-Induced Constipation: A Responder Analysis of 2 Randomized, Placebo-Controlled Trials.

BACKGROUND: Subcutaneous methylnaltrexone is efficacious and well tolerated in inducing bowel movements in patients with advanced illness and opioid-induced constipation (OIC); factors determining optimal responsiveness to OIC treatment, however, have not been elucidated. This post hoc responder analysis examined the influence of demographic and baseline characteristics on methylnaltrexone efficacy and tolerability in this population. METHODS: Data were pooled from 2 randomized, double-blind, placebo-controlled, phase 3 studies of subcutaneous methylnaltrexone (0.15 and 0.30 mg/kg) [ClinicalTrials.gov identifiers: Study 301 - NCT00401362; Study 302 - NCT00402038]. Subgroup analyses of the primary outcome, percentage of patients with rescue medication-free bowel movements (RFBM) within 4 hours of first dose, were conducted for age, sex, primary diagnosis, baseline constipation-related distress score, and baseline oral morphine equivalent dose. RESULTS: More than 50% of 165 patients treated with either methylnaltrexone dose experienced a RFBM within 4 hours vs. 14.6% of 123 placebo-treated patients (P < 0.0001 for both methylnaltrexone doses vs. placebo). Methylnaltrexone response was significantly greater than placebo response in all subgroups (P < 0.01). The largest differences vs. placebo were observed for patients taking methylnaltrexone 0.30 mg/kg with a noncancer primary diagnosis (70.0% [methylnaltrexone] vs. 12.8% [placebo]; P < 0.001) and for patients taking methylnaltrexone 0.30 mg/kg maintained on ≥ 150 mg/day baseline morphine equivalent doses (73.3% vs. 16.7%; P < 0.0001). Common adverse events were abdominal pain (pooled methylnaltrexone: 27.9%, placebo: 9.8%), flatulence (13.3%, 5.7%), and nausea (10.9%, 4.9%). Tolerability was comparable across subgroups. CONCLUSION: Subcutaneous methylnaltrexone provides a rapid, robust, and consistent RFBM response in patients with advanced illness and OIC. Methylnaltrexone 0.30 mg/kg may elicit particularly favorable responses in select patient populations.

Arthroplasty for femoral neck fractures is at risk for under restoration of lateral femoral offset.

PURPOSE: The aim of the study was to determine the restoration of hip biomechanics through lateral offset, leg length, and acetabular component position when comparing non-arthroplasty surgeons (NAS) to elective arthroplasty surgeons (EAS). METHODS: 131 patients, with a femoral neck fracture treated with a THA by 7 EAS and 20 NAS, were retrospectively reviewed. 2 blinded observers measured leg-length discrepancy, femoral offset, and acetabular component position. Multivariate logistic regression models examined the association between the surgeon groups and restoration of lateral femoral, acetabular offset, leg length discrepancy, acetabular anteversion, acetabular position, and component size, while adjusting for surgical approach and spinal pathology. RESULTS: NAS under-restored 4.8 mm of lateral femoral offset (43.9 ± 8.7 mm) after THA when compared to the uninjured side (48.7 ± 7.1 mm, p = 0.044). NAS were at risk for under-restoring lateral femoral offset when compared to EAS (p = 0.040). There was no association between lateral acetabular offset, leg length, acetabular position, or component size and surgeon type. CONCLUSIONS: Lateral femoral offset is at risk for under-restoration after THA for femoral neck fractures, when performed by surgeons that do not regularly perform elective THA. This indicates that lateral femoral offset is an under-appreciated contributor to hip instability when performing THA for a femoral neck fracture. Lateral femoral offset deserves as much attention and awareness as acetabular component position since a secondary analysis of our data reveal that preoperative templating and intraoperative imaging did not prevent under-restoration.

Shifting institutional culture to develop climate solutions with Open Science.

To address our climate emergency, "we must rapidly, radically reshape society"-Johnson & Wilkinson, All We Can Save. In science, reshaping requires formidable technical (cloud, coding, reproducibility) and cultural shifts (mindsets, hybrid collaboration, inclusion). We are a group of cross-government and academic scientists that are exploring better ways of working and not being too entrenched in our bureaucracies to do better science, support colleagues, and change the culture at our organizations. We share much-needed success stories and action for what we can all do to reshape science as part of the Open Science movement and 2023 Year of Open Science.

Efficacy and safety of crofelemer for noninfectious diarrhea in HIV-seropositive individuals (ADVENT trial): a randomized, double-blind, placebo-controlled, two-stage study.

BACKGROUND: HIV-associated diarrhea remains a significant concern with limited treatment options. OBJECTIVE: To determine the optimal dose, efficacy, and safety of crofelemer for noninfectious diarrhea. METHODS: This randomized, double-blind, phase 3 trial used a 2-stage design. Both stages included 2-week screening, 4-week placebo-controlled treatment, and 20-week placebo-free (open-label) extension phases. In stage I, 196 HIV-seropositive patients with chronic diarrhea were randomized to crofelemer 125 mg, 250 mg, or 500 mg or placebo twice daily. Using a prospective analysis, the 125-mg twice-daily dose was selected for stage II. In stage II, 180 new patients were randomized to crofelemer 125 mg twice daily or placebo for 4 weeks. Primary efficacy analysis was the percentage of patients (stages I/II combined) who achieved clinical response (defined as ≤2 watery stools/week during ≥2 of 4 weeks). During the placebo-free extension phase, response (≤2 watery stools) was assessed weekly. RESULTS: Significantly more patients receiving crofelemer 125 mg achieved clinical response versus placebo (17.6% vs 8.0%; one-sided, P = .01). Crofelemer 125 mg resulted in a greater change from baseline in number of daily watery bowel movements (P = .04) and daily stool consistency score (P = .02) versus placebo. During the placebo-free extension phase, percentages of weekly responders ranged from 40% to 56% at weeks 11 to 24. Crofelemer was minimally absorbed, well tolerated, did not negatively impact clinical immune parameters, and had a safety profile comparable to placebo. CONCLUSIONS: In HIV-seropositive patients taking stable antiretroviral therapy, crofelemer provided significant improvement in diarrhea with a favorable safety profile.