Learning skillful medium-range global weather forecasting.

Global medium-range weather forecasting is critical to decision-making across many social and economic domains. Traditional numerical weather prediction uses increased compute resources to improve forecast accuracy but does not directly use historical weather data to improve the underlying model. Here, we introduce GraphCast, a machine learning-based method trained directly from reanalysis data. It predicts hundreds of weather variables for the next 10 days at 0.25° resolution globally in under 1 minute. GraphCast significantly outperforms the most accurate operational deterministic systems on 90% of 1380 verification targets, and its forecasts support better severe event prediction, including tropical cyclone tracking, atmospheric rivers, and extreme temperatures. GraphCast is a key advance in accurate and efficient weather forecasting and helps realize the promise of machine learning for modeling complex dynamical systems.

Comparison of technical success and complications of percutaneous transhepatic cholangiography and biliary drainage between patients with and without transplanted liver.

OBJECTIVE: The purpose of this study is to compare technical success and complications of percutaneous transhepatic cholangiography (PTC) and percutaneous transhepatic biliary drainage (PTBD) between patients with and without transplanted liver. MATERIALS AND METHODS: Between 2007 and 2011, 89 PTCs, including 34 PTBDs, in 87 patients with transplanted liver were attempted, and 131 PTCs, including 118 PTBDs, in 126 patients without transplanted liver were attempted. Technical success, diameters of the bile ducts, fluoroscopy time, and complications were statistically compared between the two groups. RESULTS: The technical success rate of PTC for transplanted liver was significantly lower than that for nontransplanted liver (88.8% vs 98.5%; p = 0.004). Consequently, the technical success rate of PTBD for transplanted liver was also significantly lower than that for nontransplanted liver (75.0% vs 95.8%; p < 0.001). The average diameters of the first branches and second branches of the bile ducts of transplanted liver were significantly smaller than those of nontransplanted liver (5.8 ± 3.4 mm vs 8.7 ± 3.9 mm for the first branches [p < 0.001]; and 3.7 ± 1.7 mm vs 5.8 ± 2.4 mm for the second branches [p < 0.001]). No significant difference of fluoroscopy time of unilateral successful PTBD was observed (21.8 ± 11.7 vs 19.3 ± 12.9 min; p = 0.372), and no significant difference of overall complication rates was observed (8.0% vs 8.7%; p = 1.000) between transplanted and nontransplanted liver. CONCLUSION: The technical success rates of PTC and PTBD for transplanted liver are slightly lower than those for nontransplanted liver because the bile ducts are smaller. There is no significant difference in complication rate.

Results of 'two-in-one' single-stage revision total knee arthroplasty for infection with associated bone loss : prospective five-year follow up.

AIMS: Periprosthetic joint infection (PJI) occurs in approximately 1% to 2% of total knee arthroplasties (TKA) presenting multiple challenges, such as difficulty in diagnosis, technical complexity, and financial costs. Two-stage exchange is the gold standard for treating PJI but emerging evidence suggests 'two-in-one' single-stage revision as an alternative, delivering comparable outcomes, reduced morbidity, and cost-effectiveness. This study investigates five-year results of modified single-stage revision for treatment of PJI following TKA with bone loss. METHODS: Patients were identified from prospective data on all TKA patients with PJI following the primary procedure. Inclusion criteria were: revision for PJI with bone loss requiring reconstruction, and a minimum five years' follow-up. Patients were followed up for recurrent infection and assessment of function. Tools used to assess function were Oxford Knee Score (OKS) and American Knee Society Score (AKSS). RESULTS: A total of 24 patients were included with a mean age of 72.7 years (SD 7.6), mean BMI of 33.3 kg/m2 (SD 5.7), and median ASA grade of 2 (interquartile range 2 to 4). Mean time from primary to revision was 3.0 years (10 months to 8.3 years). At revision, six patients had discharging sinus and three patients had negative cultures from tissue samples or aspirates. Two patients developed recurrence of infection: one was treated successfully with antibiotic suppression and one underwent debridement, antibiotics, and implant retention. Mean AKSS scores at two years showed significant improvement from baseline (27.1 (SD 10.2 ) vs 80.3 (SD 14.8); p < 0.001). There was no significant change in mean AKSS scores between two and five years (80.3 (SD 14.8 ) vs 74.1 (SD 19.8); p = 0.109). Five-year OKS scores were not significantly different compared to two-year scores (36.17 (SD 3.7) vs 33.0 (SD 8.5); p = 0.081). CONCLUSION: 'Two-in-one' single-stage revision is effective for treating PJI following TKA with bone loss, providing patients with sustained improvements in outcomes and infection clearance up to five years post-procedure. Cite this article: Bone Jt Open 2022;3(2):107-113.

Results of Using a "2-in-1" Single-Stage Revision Total Knee Arthroplasty for Infection with Associated Bone Loss: Prospective 2-Year Follow-Up.

Prosthetic joint infections provide a complex challenge for management, owing to their often difficult diagnoses, need for multiple surgeries, and increased technical and financial requirements. The '2 in 1' single-stage approaches have been recently advocated in the field of arthroplasty on account of their reduction in risks, costs, and complications. The aim of our study was to investigate the outcomes of this variant of single-stage revision, which is used in the setting of infection following primary total knee replacement (TKR) and associated bone loss. Prospective data were collected from all patients presenting with an infection following primary TKR over an 8-year period (2009-2017). We examined revision procedures that were undertaken as a single-stage procedure and had bone loss present. Patients were followed-up for evidence of recurrent infection. Functional assessments were conducted using range of motion, Oxford Knee Score (OKS), American Knee Society Score (AKSS), and Short Form-12 (SF-12) survey. Twenty-six patients were included in the analysis, two of whom had previously failed 2 stage revision; another three among them had failed debridement, antibiotics, irrigation, and implant retention procedures. The mean age was 72.5 years, mean body mass index was 33.4, and median American Society of Anesthesiologists (ASA) physical status classification was 2. The mean time to revision was 3.5 years (3 months to 12 years). Six patients had actively been discharging sinuses at the time of surgery. Only 4/26 patients possessed no positive microbiological cultures from deep tissue samples or joint aspirates. One patient was afflicted with a recurrence of infection. This patient did not require further surgery and was successfully treated with the help of long-term antibiotic suppression. There were statistically significant improvements in both the pain component of AKSS scores (preoperative 4.3 to postoperative 32.4) and the functional component of AKSS scores (preoperative 10.7 to postoperative 15.7). There was no significant improvement in flexion; however, mean extension (increased from 18.5 to 6.9 postoperative) and total range of motion (increased from 69.2 preoperative to 90.3 postoperative) both showed statistically significant improvements. The use of "2-in-1" single-stage revision can be considered as an effective option for treating infection following TKR and associated bone loss.

Patellar cartilage loss does not affect early outcomes of total knee arthroplasty performed without patella resurfacing.

BACKGROUND: The aim of this study was to compare the outcomes and cost economics of TKA without patella resurfacing in patients with and without patellar cartilage loss. METHODS: Prospective case control study of 209 consecutive patients undergoing TKA without patella resurfacing. Patella cartilage status was documented intra-operatively: 108 patients had patella cartilage loss (mean age 70 ± 9.7, mean BMI 31 ± 6.2, 72 (67%) female) and 101 control patients did not (age 68 ± 9.2, BMI 31 ± 5.6, 52 (51%) female). The primary outcome measure was Oxford Knee Score (OKS) improvement at one year. Secondary outcomes included OKS, EQ-5D, anterior knee pain (AKP), Kujala scores and reoperation at 2-4 years. The cost to prevent secondary patella resurfacing was calculated. RESULTS: There were more women in the patella cartilage loss group (67% Vs 51%, p = 0.037), but no other preoperative characteristics differed. There was no difference in OKS improvement between those with and without patella cartilage loss at 1 year (mean difference -1.03, -3.68 to 1.62 95%CI, p = 0.446) or 2-4 years (mean difference 1.52, -1.43 to 4.45 95%CI, p = 0.310). At 2-4 years there was no difference in AKP (14/87 with vs 17/80 without, p = 0.430) nor Kujala score (mean difference 2.66, -3.82 to 9.13 95%CI, p = 0.418). Routine patella resurfacing would have cost £58,311 to prevent one secondary resurfacing. CONCLUSION: There was no difference in OKS, anterior knee pain, reoperation or Kujala scores up to 2-4 years between patients with and without patellar cartilage loss following TKA without patella resurfacing. Resurfacing for this indication would not have been a cost effective intervention.

Radiographic severity, extent and pattern of cartilage loss are not associated with patient reported outcomes before or after total knee arthroplasty in end-stage knee osteoarthritis.

BACKGROUND: The aim of this study was to determine if radiographic severity, extent or pattern of knee osteoarthritis was associated with pain and function before total knee arthroplasty (TKA) or improvement therein one year after TKA. METHODS: A prospective study of 259 patients undergoing unilateral TKA for Kellgren-Lawrence (KL) grade ≥ 3 knee osteoarthritis was conducted: mean age 69.8 ± 9.7 (44-91); mean BMI 31.0 ± 5.8 (17-52); 152/259 (58.7%) female. Preoperative radiographs were assessed using the KL and Ahlback systems. Preoperatively and 1 year postoperatively patients completed Oxford Knee Scores, VAS-Pain and EQ-5D scores. Full thickness cartilage loss was recorded intraoperatively. RESULTS: Median radiographic severity was Ahlback 2, KL 4: 51/259 (19.7%) hypertrophic; 23/259 (8.8%) atrophic. Neither Ahlback nor Kellgren-Lawrence OA grade was associated with OKS, VAS Pain or EQ-5D prior to TKA (p > 0.05). The extent and pattern of cartilage loss did not affect preoperative PROMs. Radiographic OA severity, compartment involvement, and pattern of cartilage loss were not significantly associated with PROMs or improvements therein following TKA (p > 0.05). Hypertrophic OA was associated with less pain before TKA (difference 6.8, 0.23-13.9 95%CI, p = 0.044), and worse improvement in OKS following TKA (difference -3.41, -6.8 to -0.05 95%CI, p = 0.047). Better preoperative OKS and hypertrophic OA were independently associated with poorer improvement in OKS 1 year following TKA (R2 = 0.208). CONCLUSION: Provided at least one compartment has KL grade ≥ 3 changes, further radiographic severity, pattern or extent of cartilage loss did not affect PROMs before or after TKA: multicompartmental was no worse than unicompartmental disease.

The ability to kneel before and after total knee arthroplasty : the role of the pattern of osteoarthritis and the position of the femoral component.

AIMS: The aims of this study were to investigate the ability to kneel after total knee arthroplasty (TKA) without patellar resurfacing, and its effect on patient-reported outcome measures (PROMs). Secondary aims included identifying which kneeling positions were most important to patients, and the influence of radiological parameters on the ability to kneel before and after TKA. METHODS: This prospective longitudinal study involved 209 patients who underwent single radius cruciate-retaining TKA without patellar resurfacing. Preoperative EuroQol five-dimension questionnaire (EQ-5D), Oxford Knee Score (OKS), and the ability to achieve four kneeling positions were assessed including a single leg kneel, a double leg kneel, a high-flexion kneel, and a praying position. The severity of radiological osteoarthritis (OA) was graded and the pattern of OA was recorded intraoperatively. The flexion of the femoral component, posterior condylar offset, and anterior femoral offset were measured radiologically. At two to four years postoperatively, 151 patients with a mean age of 70.0 years (SD 9.44) were included. Their mean BMI was 30.4 kg/m2 (SD 5.36) and 60 were male (40%). They completed EQ-5D, OKS, and Kujala scores, assessments of the ability to kneel, and a visual analogue scale for anterior knee pain and satisfaction. RESULTS: The ability to kneel in the four positions improved in between 29 (19%) and 53 patients (35%) after TKA, but declined in between 35 (23%) and 46 patients (30%). Single-leg kneeling was most important to patients. After TKA, 62 patients (41%) were unable to achieve a single-leg kneel, 76 (50%) were unable to achieve a double-leg kneel, 102 (68%) were unable to achieve a high-flexion kneel and 61 (40%) were unable to achieve a praying position. Posterolateral cartilage loss significantly affected preoperative deep flexion kneeling (p = 0.019). A postoperative inability to kneel was significantly associated with worse OKS, Kujala scores, and satisfaction (p < 0.05). Multivariable regression analysis identified significant independent associations with the ability to kneel after TKA (p < 0.05): better preoperative EQ-5D and flexion of the femoral component for single-leg kneeling; the ability to achieve it preoperatively and flexion of the femoral component for double-leg kneeling; male sex for high-flexion kneeling; and the ability to achieve it preoperatively, anterior femoral offset, and patellar cartilage loss for the praying position. CONCLUSION: The ability to kneel was important to patients and significantly influenced knee-specific PROMs, but was poorly restored by TKA with equal chances of improvement or decline. Cite this article: Bone Joint J 2021;103-B(9):1514-1525.

Correlations between radiological classification systems and confirmed cartilage loss in severe knee osteoarthritis.

AIMS: Although knee osteoarthritis (OA) is diagnosed and monitored radiologically, actual full-thickness cartilage loss (FTCL) has rarely been correlated with radiological classification. This study aims to analyze which classification system correlates best with FTCL and to assess their reliability. METHODS: A prospective study of 300 consecutive patients undergoing unilateral total knee arthroplasty (TKA) for OA (mean age 69 years (44 to 91; standard deviation (SD) 9.5), 178 (59%) female). Two blinded examiners independently graded preoperative radiographs using five common systems: Kellgren-Lawrence (KL); International Knee Documentation Committee (IKDC); Fairbank; Brandt; and Ahlbäck. Interobserver agreement was assessed using the intraclass correlation coefficient (ICC). Intraoperatively, anterior cruciate ligament (ACL) status and the presence of FTCL in 16 regions of interest were recorded. Radiological classification and FTCL were correlated using the Spearman correlation coefficient. RESULTS: Knees had a mean of 6.8 regions of FTCL (SD 3.1), most common medially. The commonest patterns of FTCL were medial ± patellofemoral (143/300, 48%) and tricompartmental (89/300, 30%). ACL status was associated with pattern of FTCL (p = 0.023). All radiological classification systems demonstrated moderate ICC, but this was highest for the IKDC: whole knee 0.68 (95% confidence interval (CI) 0.60 to 0.74); medial compartment 0.84 (95% CI 0.80 to 0.87); and lateral compartment 0.79 (95% CI 0.73 to 0.83). Correlation with actual FTCL was strongest for Ahlbäck (Spearman rho 0.27 to 0.39) and KL (0.30 to 0.33) systems, although all systems demonstrated medium correlation. The Ahlbäck score was the most discriminating in severe knee OA. Osteophyte presence in the medial compartment had high positive predictive value (PPV) for FTCL, but not in the lateral compartment. CONCLUSION: The Ahlbäck and KL systems had the highest correlation with confirmed cartilage loss at TKA. However, the IKDC system displayed the best interobserver reliability, with favourable correlation with FTCL in medial and lateral compartments, although it was less discriminating in more severe disease. Cite this article: Bone Joint J 2020;102-B(3):301-309.

Patterns of cartilage loss and anterior cruciate ligament status in end-stage osteoarthritis of the knee.

AIMS: This study aims to determine the proportion of patients with end-stage knee osteoarthritis (OA) possibly suitable for partial (PKA) or combined partial knee arthroplasty (CPKA) according to patterns of full-thickness cartilage loss and anterior cruciate ligament (ACL) status. METHODS: A cross-sectional analysis of 300 consecutive patients (mean age 69 years (SD 9.5, 44 to 91), mean body mass index (BMI) 30.6 (SD 5.5, 20 to 53), 178 female (59.3%)) undergoing total knee arthroplasty (TKA) for Kellgren-Lawrence grade ≥ 3 knee OA was conducted. The point of maximal tibial bone loss on preoperative lateral radiographs was determined as a percentage of the tibial diameter. At surgery, Lachman's test and ACL status were recorded. The presence of full-thickness cartilage loss within 16 articular surface regions (two patella, eight femoral, six tibial) was recorded. RESULTS: According to articular cartilage loss and ACL status, 195/293 (67%) were suitable for PKA or CPKA: medial unicompartmental knee arthroplasty (UKA) 97/293 (33%); lateral UKA 25 (9%); medial bicompartmental arthroplasty 31 (11%); lateral bicompartmental arthroplasty 12 (4%); bicondylar-UKA 23 (8%); and patellofemoral arthroplasty (PFA) seven (2%). The ACL was intact in 166 (55%), frayed in 82 (27%), disrupted in 12 (4%), and absent in 33 (11%). Lachman testing was specific (97%) but poorly sensitive (38%) for disrupted/absent ACLs. The point of maximal tibial bone loss showed good interclass correlation (ICC 0.797, 0.73 to 0.85 95% confidence interval (CI); p < 0.001) and was more posterior when the ACL was absent. Maximum tibial bone loss occurring at > 55% of the anterior to posterior distance predicted ACL absence with 93% sensitivity and 91% specificity (area under the curve 0.97 (0.94 to 0.99 95% CI; p < 0.001). CONCLUSION: ACL status can be reliably determined from a lateral radiograph using the location of maximal tibial bone loss. According to regions of cartilage loss and ACL status, two-thirds of patients with end-stage knee OA could potentially be treated with PKA or CPKA. Cite this article: Bone Joint J 2020;102-B(6):716-726.

Population mobility and adult orthopaedic trauma services during the COVID-19 pandemic: fragility fracture provision remains a priority.

AIMS: This study aims to define the epidemiology of trauma presenting to a single centre providing all orthopaedic trauma care for a population of ∼ 900,000 over the first 40 days of the COVID-19 pandemic compared to that presenting over the same period one year earlier. The secondary aim was to compare this with population mobility data obtained from Google. METHODS: A cross-sectional study of consecutive adult (> 13 years) patients with musculoskeletal trauma referred as either in-patients or out-patients over a 40-day period beginning on 5 March 2020, the date of the first reported UK COVID-19 death, was performed. This time period encompassed social distancing measures. This group was compared to a group of patients referred over the same calendar period in 2019 and to publicly available mobility data from Google. RESULTS: Orthopaedic trauma referrals reduced by 42% (1,056 compared to 1,820) during the study period, and by 58% (405 compared to 967) following national lockdown. Outpatient referrals reduced by 44%, and inpatient referrals by 36%, and the number of surgeries performed by 36%. The regional incidence of traumatic injury fell from 5.07 (95% confidence interval (CI) 4.79 to 5.35) to 2.94 (95% CI 2.52 to 3.32) per 100,000 population per day. Significant reductions were seen in injuries related to sports and alcohol consumption. No admissions occurred relating to major trauma (Injury Severity Score > 16) or violence against the person. Changes in population mobility and trauma volume from baseline correlated significantly (Pearson's correlation 0.749, 95% CI 0.58 to 0.85, p < 0.001). However, admissions related to fragility fractures remained unchanged compared to the 2019 baseline. CONCLUSION: The profound changes in social behaviour and mobility during the early stages of the COVID-19 pandemic have directly correlated with a significant decrease in orthopaedic trauma referrals, but fragility fractures remained unaffected and provision for these patients should be maintained.Cite this article: Bone Joint Open 2020;1-6:182-189.

Discovery, modeling, and human pharmacokinetics of N-(2-acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a second generation, ETA selective, and orally bioavailable endothelin antagonist.

Sitaxsentan (1) (Wu et al. J. Med. Chem. 1997, 40, 1690) is our first endothelin antagonist being evaluated in clinical trials. It has demonstrated biological effects in an acute hemodynamic study in CHF (Givertz et al. Circulation 2000, 101, 2922), an open-label 20-patient pulmonary hypertension trial (Barst et al. Chest 2002, 121, 1860-1868), and a 31-patient trial in essential hypertension (Calhoun et al. AHA Scientific Sessions 2000). In a phase 2b/3 pulmonary arterial hypertension trial, once a day treatment of 100 mg of sitaxsentan statistically significantly improved 6-min walk distance and NYHA class at 12 weeks (Barst et al. Am. J. Respir. Crit. Care Med. 2004, 169, 441). We have since reported on our efforts in generating follow-up compounds (Wu et al. J. Med. Chem. 1999, 42, 4485) and recently communicated that an ortho acyl group on the anilino ring enhanced oral absorption in this category of compounds (Wu et al. J. Med. Chem. 2001, 44, 1211). Here we report an expansion of this work by substituting a variety of electron-withdrawing groups at the ortho position and evaluating their effects on oral bioavailability as well as structure-activity relationships. As a result, TBC3711 (7z) was identified as our second endothelin antagonist to enter the clinic due to its good oral bioavailability (approximately 100%) in rats, high potency (ET(A) IC(50) = 0.08 nM), and optimal ET(A)/ET(B) selectivity (441 000-fold). Compound 7z has completed phase-I clinical development and was well tolerated with desirable pharmacokinetics in humans (t(1/2) = 6-7 h, oral availability > 80%).

Recently discovered sulfonamide-, acyl sulfonamide- and carboxylic acid-based endothelin antagonists.

Endothelins (ET-1, 2 and 3) are 21-residue peptides with two disulfide bridges and a highly conserved carboxy terminal. ET-1, the most significant isoform, is a potent vasoconstrictor and mitogen that exerts its biological effects through binding to its two G protein-coupled receptors: ET(A) and ET(B). ET(A) receptors are expressed on vascular smooth muscle cells and mediate vasoconstrictive and proliferative responses to ET-1. ET(B) receptors are mainly located on endothelial cells where they clear ET-1 from circulation and mediate vasodilation via the release of nitric oxide. ET-1 has been associated with a variety of serious diseases such as pulmonary hypertension, heart failure, prostate cancer and renal dysfunction.

Normal adrenal gland: in vivo observations, and high-resolution in vitro chemical shift MR imaging-histologic correlation.

RATIONALE AND OBJECTIVES: The purpose of this study was to determine whether adrenal cortical lipid affects signal intensity on magnetic resonance (MR) images and to evaluate contrast between cortex and medulla. MATERIALS AND METHODS: From their clinical database, the authors selected 37 MR imaging studies of patients with adrenal adenomas. Two independent readers compared in-phase and fat-suppressed T1-weighted images, looking for visible lipid-induced signal intensity loss in the adrenal gland. Six adrenal gland specimens obtained after radical nephrectomy were also studied with high-resolution MR imaging, including in-phase, opposed-phase, and fat-suppressed T1-weighted images, and T2-weighted images. Adjacent histologic sections were stained with oil red O for neutral fats and with hematoxylin-eosin, and they were also viewed with polarization light microscopy. The relative amount of lipid was graded as mild, moderate, or intense, and the appearance of the cortex and medulla was compared with that on the MR images. RESULTS: On the 37 clinical MR studies, there was no visible signal intensity loss within the limbs of the ipsilateral adrenal glands. T2-weighted images of the adrenal specimens showed a thin high-intensity band, corresponding to the appearance of medulla on histologic slices. This could not be seen on any of the T1-weighted images. Region-of-interest measurements were nearly identical for in-phase and opposed-phase images. Histologic analysis showed abundant cortical lipid. CONCLUSION: Adrenal corticomedullary contrast can be depicted on high-resolution T2-weighted images but not on any T1-weighted images. There is abundant cortical lipid in adrenal specimens, but comparison of in-phase with opposed-phase MR images does not depict it.

Discovery, structure-activity relationships, pharmacokinetics, and efficacy of glucokinase activator (2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide (RO0281675).

Glucokinase (GK) is a glucose sensor that couples glucose metabolism to insulin release. The important role of GK in maintaining glucose homeostasis is illustrated in patients with GK mutations. In this publication, identification of the hit molecule 1 and its SAR development, which led to the discovery of potent allosteric GK activators 9a and 21a, is described. Compound 21a (RO0281675) was used to validate the clinical relevance of targeting GK to treat type 2 diabetes.

Development of reliable aqueous solubility models and their application in druglike analysis.

In this work, two reliable aqueous solubility models, ASMS (aqueous solubility based on molecular surface) and ASMS-LOGP (aqueous solubility based on molecular surface using ClogP as a descriptor), were constructed by using atom type classified solvent accessible surface areas and several molecular descriptors for a diverse data set of 1708 molecules. For ASMS (without using ClogP as a descriptor), the leave-one-out q(2) and root-mean-square error (RMSE) were 0.872 and 0.748 log unit, respectively. ASMS-LOGP was slightly better than ASMS (q(2) = 0.886, RMSE = 0.705). Both models were extensively validated by three cross-validation tests and encouraging predictability was achieved. High throughput aqueous solubility prediction was conducted for a number of data sets extracted from several widely used databases. We found that real drugs are about 20-fold more soluble than the so-called druglike molecules in the ZINC database, which have no violation of Lipinski's "Rule of 5" at all. Specifically, oral drugs are about 16-fold more soluble, while injection drugs are 50-60-fold more soluble. If the criterion of a molecule to be soluble is set to -5 log unit, about 85% of real drugs are predicted as soluble; in contrast only 50% of druglike molecules in ZINC are soluble. We concluded that the two models could be served as a rule in druglike analysis and an efficient filter in prioritizing compound libraries prior to high throughput screenings (HTS).

Uterine leiomyomas: MR imaging-guided focused ultrasound surgery--results of different treatment protocols.

PURPOSE: To prospectively assess patient response (after 12 months) to magnetic resonance (MR) imaging-guided focused ultrasound surgery in treatment of uterine leiomyomas by using two treatment protocols. MATERIALS AND METHODS: This prospective clinical trial was approved by institutional review boards and was HIPAA compliant. After giving informed consent, patients with symptomatic leiomyomas were consecutively enrolled and treated at one of five U.S. centers by using an original or a modified protocol. Outcomes were assessed with the symptom severity score (SSS) obtained at baseline and 3, 6, and 12 months after treatment. Adverse events (AEs) were recorded. Statistical analysis included Student t test, Fisher exact test, analysis of covariance, Spearman correlation, and logistic regression. RESULTS: One hundred sixty patients had a mean SSS of 62.1 +/- 16.3 (standard deviation) at baseline, which decreased to 35.5 +/- 19.5 at 3 months (P<.001) and to 32.3 +/- 19.8 at 6 months (P<.001) and was 32.7 +/- 21.0 at 12 months (P<.001). Ninety-six patients (mean age, 46.0 years +/- 4.6) were treated with an original protocol, and 64 (mean age, 45.9 years +/- 3.9) were treated with a modified protocol. Patients in the modified group had a significantly greater SSS decrease at 3 months (P=.037) than those in the original group, and 73% of those in the original group and 91% of those in the modified group reported a significant decrease in SSS (of 10 points or greater) at 12 months. No serious AEs were recorded. Fewer AEs were reported in the modified group than in the original group (25% vs 13% reporting no event). Of evaluable patients, fewer in the modified group chose alternative treatment (28%) than in the original group (37%). CONCLUSION: MR imaging-guided focused ultrasound surgery results in symptomatic improvement, sustained to 12 months after treatment. Treatment with a modified protocol results in greater clinical effectiveness and fewer AEs.

Genetic algorithm-optimized QSPR models for bioavailability, protein binding, and urinary excretion.

In this work, a genetic algorithm (GA) was applied to build up a set of QSPR (quantitative structure-property relationship) models for human absolute oral bioavailability, plasma protein binding, and urinary excretion using the counts of molecular fragments as descriptors. For a pharmacokinetic property, the consensus score of a set of models (20 or 30) was found to improve the correlation coefficient and reduce the standard error significantly. Key fragments that may boost or reduce pharmacokinetic properties were also identified. Databases searches were performed for a set of key fragments identified by bioavailability models. The percentage of hit rates of bioavailability-boosting fragments were significantly higher than those of bioavailability-reducing fragments for MDDR (MDL Drug Data Report), a database of drugs and drug leads entered or entering development. On the other hand, the opposite trend was observed for ACD (Available Chemicals Directory), a database of all kinds of available compounds.

Atypical polypoid adenomyoma mimicking cervical adenocarcinoma.

Atypical polypoid adenomyoma (APA) of the uterus is a rare, benign lesion. Histologically, it is composed of a glandular and squamous cell proliferation with architectural complexity and cytologic atypia of glands, and a hypercellular smooth muscle stroma. APA is difficult to distinguish from well-differentiated adenocarcinoma of the uterus. In the case presented, the diagnosis of APA was confused pathologically, radiographically, and clinically with a cervical adenocarcinoma. A review of the English literature is presented.

Ovarian veins: magnetic resonance imaging findings in an asymptomatic population.

PURPOSE: To evaluate the magnetic resonance (MR) venographic appearance of the ovarian veins in a healthy population, correlated with surgical findings. Our data can be used as a basis for comparison to patients with suspected pelvic congestion syndrome (PCS). MATERIALS AND METHODS: We retrospectively reviewed exams of 22 women who had MR angiography for potential renal donation evaluation (age range, 19.3-60.5 years; mean, 38 years). We evaluated the diameter of the ovarian veins on dynamic multiphasic postcontrast coronal images, the phase of contrast appearance in these veins, the apparent direction of flow, and the presence of ovarian or pelvic varices. Surgical correlation was obtained in 12 patients. Clinical charts were reviewed and patients were asked about symptoms of chronic pelvic pain and the number of their children. RESULTS: Of the 22 exams, 21 left gonadal veins were identified. Passive reflux from the left renal vein into the left gonadal vein was suggested in eight exams (38%). These veins had a mean diameter of 6.4 +/- 1.6 mm, significantly larger than 4.5 +/- 1.3 mm for the other 13 left gonadal veins without reflux (P < 0.005). The right gonadal vein was identified in 8 of 22 women, with a mean diameter of 4.4 +/- 0.5 mm. No patient reported symptoms of chronic pelvic pain. CONCLUSION: Passive reflux from the left renal vein to the left gonadal vein can occur in asymptomatic women. Diagnosis of PCS depends heavily on appropriate clinical history.