Surgery with locking plate or hemiarthroplasty versus nonoperative treatment of 3-4-part proximal humerus fractures in older patients (NITEP): An open-label randomized trial.

BACKGROUND: Proximal humerus fractures (PHFs) are common fractures, especially in older female patients. These fractures are commonly treated surgically, but the consensus on the best treatment is still lacking. METHODS AND FINDINGS: The primary aim of this multicenter, randomized 3-arm superiority, open-label trial was to assess the results of nonoperative treatment and operative treatment either with locking plate (LP) or hemiarthroplasty (HA) of 3- and 4-part PHF with the primary outcome of Disabilities of the Arm, Shoulder, and Hand (DASH) at 2-year follow-up. Between February 2011 and December 2019, 160 patients 60 years and older with 3- and 4-part PHFs were randomly assigned in 1:1:1 fashion in block size of 10 to undergo nonoperative treatment (control) or operative intervention with LP or HA. In total, 54 patients were assigned to the nonoperative group, 52 to the LP group, and 54 to the HA group. Five patients assigned to the LP group were reassigned to the HA group perioperatively due to high comminution, and all of these patients had 4-part fractures. In the intention-to-treat analysis, there were 42 patients in the nonoperative group, 44 in the LP group, and 37 in the HA group. The outcome assessors were blinded to the study group. The mean DASH score at 2-year follow-up was 30.4 (standard error (SE) 3.25), 31.4 (SE 3.11), and 26.6 (SE 3.23) points for the nonoperative, LP, and HA groups, respectively. At 2 years, the between-group differences were 1.07 points (95% CI [-9.5,11.7]; p = 0.97) between nonoperative and LP, 3.78 points (95% CI [-7.0,14.6]; p = 0.69) between nonoperative and HA, and 4.84 points (95% CI [-5.7,15.4]; p = 0.53) between LP and HA. No significant differences in primary or secondary outcomes were seen in stratified age groups (60 to 70 years and 71 years and over). At 2 years, we found 30 complications (3/52, 5.8% in nonoperative; 22/49, 45% in LP; and 5/49, 10% in HA group, p = 0.0004) and 16 severe pain-related adverse events. There was a revision rate of 22% in the LP group. The limitation of the trial was that the recruitment period was longer than expected due to a high number of exclusions after the assessment of eligibility and a larger exclusion rate than anticipated toward the end of the trial. Therefore, the trial was ended prematurely. CONCLUSIONS: In this study, no benefit was observed between operative treatment with LP or HA and nonoperative treatment in displaced 3- and 4-part PHFs in patients aged 60 years and older. Further, we observed a high rate of complications related to operative treatments. TRIAL REGISTRATION: ClinicalTrials.gov NCT01246167.

Time to entry point and distal locking of intramedullary nails: a methodological phantom study comparing biplanar and uniplanar surgical imaging.

BACKGROUND: Intramedullary nailing is the method of choice for diaphyseal fractures of the femur and tibia and is also commonly used to treat trochanteric hip fractures. Perioperative imaging is essential for visualising adequate reduction, achieving an optimal entry point (EP) and performing distal locking (DL) of intramedullary nails. This methodological study aims to compare biplanar and uniplanar imaging in some steps of intramedullary nailing. METHODS: We used a biplanar preassembled imaging device (Biplanar™ 600s, Swemac Imaging) and a uniplanar imaging device (Ziehm Solo FD, Ziehm Imaging) to measure procedural and radiation times for antegrade and retrograde femoral and antegrade tibial nailing in fully soft flexible tissue encased legs with radiopaque sawbones (SKU:1515-7-11, Sawbones Europe, Malmö, Sweden). Four orthopaedic surgeons with different levels of experience performed all procedures in all three phantoms with both image techniques in random order, producing in total 12 EPs and nailings with DL with each imaging device. Time to EP, radiation times, time to DL for both devices and the number of swings of the uniplanar device for the two procedures were measured. Comparisons between the biplanar and uniplanar systems with a paired-samples t-test were conducted. RESULTS: Using the biplanar device, time to optimal EP was shorter for retrograde femoral (26 s (SD15) vs 35 s (SD13), p = 0.01) and for antegrade tibial nailing (23 s (SD13) vs 49 s (SD24), p = 0.001). No statistically significant differences in time to EP, radiation time or time to DL were found for antegrade femoral nailing. A median of two swings of the uniplanar device was needed to obtain optimal EP for all procedures. CONCLUSIONS: Biplanar imaging slightly but statistically significantly reduced time to EP for retrograde femoral and antegrade tibial nailing in this methodological study comparing biplanar and uniplanar imaging techniques. Biplanar imaging can reduce time and radiation exposure when defining the EP around the knee in intramedullary nailing procedures, but the clinical relevance of these time savings remain to be defined. For antegrade femoral nailing we found no clear benefit with biplanar imaging in the investigated steps of nailing.

Multiple Applications of a Novel Biarsenical Imaging Probe in Fluorescence and PET Imaging of Melanoma.

A new fluorescent biarsenical peptide labeling probe was synthesized and labeled with the radioactive isotopes 11C and 18F. The utility of this probe was demonstrated by installing each of these isotopes into a melanocortin 1 receptor (MC1R) binding peptide, which targets melanoma tumors. Its applicability was further showcased by subsequent in vitro imaging in cells as well as in vivo imaging in melanoma xenograft mice by fluorescence and positron emission tomography.

Artificial intelligence for diagnosis and grading of prostate cancer in biopsies: a population-based, diagnostic study.

BACKGROUND: An increasing volume of prostate biopsies and a worldwide shortage of urological pathologists puts a strain on pathology departments. Additionally, the high intra-observer and inter-observer variability in grading can result in overtreatment and undertreatment of prostate cancer. To alleviate these problems, we aimed to develop an artificial intelligence (AI) system with clinically acceptable accuracy for prostate cancer detection, localisation, and Gleason grading. METHODS: We digitised 6682 slides from needle core biopsies from 976 randomly selected participants aged 50-69 in the Swedish prospective and population-based STHLM3 diagnostic study done between May 28, 2012, and Dec 30, 2014 (ISRCTN84445406), and another 271 from 93 men from outside the study. The resulting images were used to train deep neural networks for assessment of prostate biopsies. The networks were evaluated by predicting the presence, extent, and Gleason grade of malignant tissue for an independent test dataset comprising 1631 biopsies from 246 men from STHLM3 and an external validation dataset of 330 biopsies from 73 men. We also evaluated grading performance on 87 biopsies individually graded by 23 experienced urological pathologists from the International Society of Urological Pathology. We assessed discriminatory performance by receiver operating characteristics and tumour extent predictions by correlating predicted cancer length against measurements by the reporting pathologist. We quantified the concordance between grades assigned by the AI system and the expert urological pathologists using Cohen's kappa. FINDINGS: The AI achieved an area under the receiver operating characteristics curve of 0·997 (95% CI 0·994-0·999) for distinguishing between benign (n=910) and malignant (n=721) biopsy cores on the independent test dataset and 0·986 (0·972-0·996) on the external validation dataset (benign n=108, malignant n=222). The correlation between cancer length predicted by the AI and assigned by the reporting pathologist was 0·96 (95% CI 0·95-0·97) for the independent test dataset and 0·87 (0·84-0·90) for the external validation dataset. For assigning Gleason grades, the AI achieved a mean pairwise kappa of 0·62, which was within the range of the corresponding values for the expert pathologists (0·60-0·73). INTERPRETATION: An AI system can be trained to detect and grade cancer in prostate needle biopsy samples at a ranking comparable to that of international experts in prostate pathology. Clinical application could reduce pathology workload by reducing the assessment of benign biopsies and by automating the task of measuring cancer length in positive biopsy cores. An AI system with expert-level grading performance might contribute a second opinion, aid in standardising grading, and provide pathology expertise in parts of the world where it does not exist. FUNDING: Swedish Research Council, Swedish Cancer Society, Swedish eScience Research Center, EIT Health.

Forecasting leachate generation from pilot woodchip stockpiles using a three-dimensional transient flow model.

Leachate generation from open stockpiles of recycled woodchip materials is potentially harmful to aquatic ecosystems. There is growing interest in using numerical models to simulate leachate generation from outdoor piles, but this requires information about the hydraulic properties of the materials. The objectives of this study were to simulate leachate from woodchip piles with the numerical model HYDRUS-3D and to optimize subsets of parameters for single (SPM) and dual (DPM) pore flow models with the Bayesian Markov Chain Monte Carlo algorithm DREAMZS. Three experimental piles, each approximately 30 m3, were setup with mixtures of either once (coarse) or twice (fine) ground woodchips. Leachate continuously collected over a period of six months was similar across piles. As a result, subsets of optimized flow parameters for the coarse and fine woodchips were not different. Leachate predictions by the two pore flow models were similar and agreed reasonably with the field measurements, as indicated by Nash-Sutcliffe efficiency values greater than 0.6. This result suggests the simpler SPM is adequate for field predictions of leachate. However, leachate was consistently under-predicted by both pore models by 13-27% during rainfall events with more than 1 cm in 6 h. The optimized flow models can be used as a tool for studying pile management strategies.

Operative versus non-operative treatment for 2-part proximal humerus fracture: A multicenter randomized controlled trial.

BACKGROUND: Although increasingly used, the benefit of surgical treatment of displaced 2-part proximal humerus fractures has not been proven. This trial evaluates the clinical effectiveness of surgery with locking plate compared with non-operative treatment for these fractures. METHODS AND FINDINGS: The NITEP group conducted a superiority, assessor-blinded, multicenter randomized trial in 6 hospitals in Finland, Estonia, Sweden, and Denmark. Eighty-eight patients aged 60 years or older with displaced (more than 1 cm or 45 degrees) 2-part surgical or anatomical neck proximal humerus fracture were randomly assigned in a 1:1 ratio to undergo either operative treatment with a locking plate or non-operative treatment. The mean age of patients was 72 years in the non-operative group and 73 years in the operative group, with a female sex distribution of 95% and 87%, respectively. Patients were recruited between February 2011 and April 2016. The primary outcome measure was Disabilities of Arm, Shoulder, and Hand (DASH) score at 2-year follow-up. Secondary outcomes included Constant-Murley score, the visual analogue scale for pain, the quality of life questionnaire 15D, EuroQol Group's 5-dimension self-reported questionnaire EQ-5D, the Oxford Shoulder Score, and complications. The mean DASH score (0 best, 100 worst) at 2 years was 18.5 points for the operative treatment group and 17.4 points for the non-operative group (mean difference 1.1 [95% CI -7.8 to 9.4], p = 0.81). At 2 years, there were no statistically or clinically significant between-group differences in any of the outcome measures. All 3 complications resulting in secondary surgery occurred in the operative group. The lack of blinding in patient-reported outcome assessment is a limitation of the study. Our assessor physiotherapists were, however, blinded. CONCLUSIONS: This trial found no significant difference in clinical outcomes at 2 years between surgery and non-operative treatment in patients 60 years of age or older with displaced 2-part fractures of the proximal humerus. These results suggest that the current practice of performing surgery on the majority of displaced proximal 2-part fractures of the humerus in older adults may not be beneficial. TRIAL REGISTRATION: ClinicalTrials.gov NCT01246167.

Effectiveness of cervical screening after age 60 years according to screening history: Nationwide cohort study in Sweden.

BACKGROUND: The relatively high incidence of cervical cancer in women at older ages is a continuing concern in countries with long-established cervical screening. Controversy remains on when and how to cease screening. Existing population-based studies on the effectiveness of cervical screening at older ages have not considered women's screening history. We performed a nationwide cohort study to investigate the incidence of cervical cancer after age 60 years and its association with cervical screening at age 61-65, stratified by screening history at age 51-60. METHODS AND FINDINGS: Using the Total Population Register, we identified 569,132 women born between 1 January 1919 and 31 December 1945, resident in Sweden since age 51. Women's cytological screening records, cervical cancer occurrence, and FIGO stage (for those diagnosed with cancer) were retrieved from national registers and medical charts. We calculated the cumulative incidence of cervical cancer from age 61 to age 80 using a survival function considering competing risk, and estimated the hazard ratio (HR) of cervical cancer in relation to screening status at age 61-65 from Cox models, adjusted for birth cohort and level of education, conditioning on women's screening history in their 50s. In women unscreened in their 50s, the cumulative incidence up to age 80 was 5.0 per 1,000 women, and screening at age 61-65 was associated with a lower risk for cervical cancer (HR = 0.42, 95% CI 0.24-0.72), corresponding to a decrease of 3.3 cancer cases per 1,000 women. A higher cumulative incidence and similarly statistically significant risk decrease was seen for women with abnormal smears in their 50s. In women adequately or inadequately screened with only normal results between age 51 and age 60, the cumulative incidence of cervical cancer from age 61 to 80 was 1.6 and 2.5 per 1,000 women, respectively, and further screening at age 61-65 was not associated with statistically significant decreases of cervical cancer risk up to age 80, but with fewer cancer cases of advanced stages at age 61-65. Adjustment for potential lifestyle confounders was limited. CONCLUSIONS: In this study, cervical screening with cytology at age 61-65 was associated with a statistically significant reduction of subsequent cervical cancer risk for women who were unscreened, or screened with abnormalities, in their 50s. In women screened with normal results in their 50s, the risk for future cancer was not sizeable, and the risk reduction associated with continued screening appeared limited. These findings should inform the current debate regarding age and criteria to discontinue cervical screening.

Risk for Congenital Malformation With H1N1 Influenza Vaccine: A Cohort Study With Sibling Analysis.

BACKGROUND: Earlier studies reporting varying risk estimates for congenital malformation in offspring of mothers undergoing vaccination against H1N1 influenza during pregnancy did not consider the potential role of confounding by familial (genetic and shared environmental) factors. OBJECTIVE: To evaluate an association between maternal H1N1 vaccination during pregnancy and offspring malformation, with familial factors taken into account. DESIGN: Population-based prospective study. SETTING: Sweden. PARTICIPANTS: Liveborn offspring born between 1 October 2009 and 1 October 2011 to mothers receiving monovalent AS03-adjuvanted H1N1 influenza vaccine (Pandemrix [GlaxoSmithKline]) during pregnancy. A total of 40 983 offspring were prenatally exposed to the vaccine, 14 385 were exposed within the first trimester (14 weeks), and 7502 were exposed during the first 8 weeks of pregnancy. Exposed offspring were compared with 197 588 unexposed offspring. Corresponding risks in exposed versus unexposed siblings were also estimated. MEASUREMENTS: Congenital malformation, with subanalyses for congenital heart disease, oral cleft, and limb deficiency. RESULTS: Congenital malformation was observed in 2037 (4.97%) exposed offspring and 9443 (4.78%) unexposed offspring. Adjusted risk for congenital malformation was 4.98% in exposed offspring versus 4.96% in unexposed offspring (risk difference, 0.02% [95% CI, -0.26% to 0.30%]). The corresponding risk differences were 0.16% (CI, -0.23% to 0.56%) for vaccination during the first trimester and 0.10% (CI, -0.41% to 0.62%) for vaccination in the first 8 weeks. Using siblings as comparators yielded no statistically significant risk differences. LIMITATIONS: The study was based on live births, and the possibility that data on miscarriage or induced abortion could have influenced the findings cannot be ruled out. Study power was limited in analyses of specific malformations. CONCLUSION: When intrafamilial factors were taken into consideration, H1N1 vaccination during pregnancy did not seem to be linked to overall congenital malformation in offspring, although risk increases for specific malformations could not be ruled out completely. PRIMARY FUNDING SOURCE: Swedish Research Council and Swedish Council for Working Life and Social Research.

Characterization of wood mulch and leachate/runoff from three wood recycling facilities.

Large-scale open storage of wood mulch is common practice at wood recycling facilities. During rain and snow melt, leachate with soluble compounds and suspended particles is released from mulch stockpiles. The objective of this study was to determine the quality of leachate/runoff from wood recycling facilities to evaluate its potential to contaminate receiving waterbodies. Wood mulch (n = 30) and leachate/runoff (n = 26) samples were collected over 1.5 years from three wood recycling facilities in New Jersey, USA. Differences by site were found (p < 0.05) for most of the 21 constituents tested in the solid wood mulch samples. Biochemical oxygen demand (range <20-3000 mg/L), chemical oxygen demand (134-6000 mg/L) and total suspended solids (69-401 mg/L) median concentrations of the leachate/runoff samples were comparable to those of untreated domestic wastewater. Total Kjeldahl N, total P and fecal coliform median values were slightly lower than typical wastewater values. Dose-response studies with leachate/runoff samples using zebrafish (Danio rerio) embryos showed that mortality and developmental defects typically did not occur even at the highest concentration tested, indicating low toxicity, although delayed development did occur. Based on this study, leachate/runoff from wood recycling facilities should not be released to surface waters as it is a potential source of organic contamination and low levels of nutrients. A study in which runoff from a controlled drainage area containing wood mulch of known properties is monitored would allow for better assessment of the potential impact of stormwater runoff from wood recycling facilities.

Cigarette- and snus-modified association between unprotected exposure to noise from hunting rifle caliber weapons and high frequency hearing loss. A cross-sectional study among swedish hunters.

AIM: To investigate in this cross-sectional study among Swedish hunters if tobacco use modifies the previously observed association, expressed as prevalence ratio (PR), between unprotected exposure to impulse noise from hunting rifle caliber (HRC) weapons and high-frequency hearing impairment (HFHI). SETTINGS AND DESIGN: A nationwide cross-sectional epidemiologic study was conducted among Swedish sport hunters in 2012. MATERIALS AND METHODS: The study was Internet-based and consisted of a questionnaire and an Internet-based audiometry test. RESULTS: In all, 202 hunters completed a questionnaire regarding the hearing test. Associations were modeled using Poisson regression. Current, daily use of tobacco was reported by 61 hunters (19 used cigarettes, 47 moist snuff, and 5 both). Tobacco users tended to be younger, fire more shots with HRC weapons, and report more hunting days. Their adjusted PR (1-6 unprotected HRC shots versus 0) was 3.2 (1.4-6.7), P < 0.01. Among the nonusers of tobacco, the corresponding PR was 1.3 (0.9-1.8), P = 0.18. P value for the interaction was 0.01. The importance of ear protection could not be quantified among hunters with HRC weapons because our data suggested that the HFHI outcome had led to changes in the use of such protection. Among hunters using weapons with less sound energy, however, no or sporadic use of hearing protection was linked to a 60% higher prevalence of HFHI, relative to habitual use. CONCLUSION: Tobacco use modifies the association between exposure to unprotected impulse noise from HRC weapons and the probability of having HFHI among susceptible hunters. The mechanisms remain to be clarified, but because the effect modification was apparent also among the users of smokeless tobacco, combustion products may not be critical for this effect.

Prospective study of breast cancer in relation to coffee, tea and caffeine in Sweden.

Studies of coffee and tea consumption and caffeine intake as risk factors for breast cancer are inconclusive. We assessed coffee and tea consumption, caffeine intake, and possible confounding factors among 42,099 women from the Swedish Women's Lifestyle and Health study, the participants of which were aged 30-49 years at enrollment in 1991-1992. Complete follow-up for breast cancer incidence was performed through 2012 via linkage to national registries. Poisson regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for breast cancer. During follow-up 1,395 breast cancers were diagnosed. The RR was 0.97 (95% CI 0.94-0.99) for a 1-unit increase in cups of coffee/day, 1.14 (95% CI 1.05-1.24) for a 1-unit increase in cups of tea/day, and 0.97 (95% CI 0.95-1.00) for a 100 mg/day increase in caffeine intake. Although the RR for no consumption (RR = 0.86, 95% CI 0.69-1.08), a group with a relatively small number of women, was not statistically significant, women with higher consumption had a decreased breast cancer risk (3-4 cups/day: RR = 0.87, 95% CI 0.76-1.00; ≥5 cups/day: RR = 0.81, 95% CI 0.70-0.94) compared to women consuming 1-2 cups of coffee/day. Compared to no consumption, women consuming >1 cups tea/day showed an increased breast cancer risk (RR = 1.19, 95% CI 1.00-1.42). Similar patterns of estimates were observed for breast cancer risk overall, during pre- and postmenopausal years, and for ER+ or PR+ breast cancer, but not for ER- and PR- breast cancer. Our findings suggest that coffee consumption and caffeine intake is negatively associated with the risk of overall and ER+/PR- breast cancer, and tea consumption is positively associated with the risk of overall and ER+/PR+ breast cancer.

Adherence to a healthy Nordic food index and breast cancer risk: results from a Swedish cohort study.

BACKGROUND: A healthy Nordic dietary pattern has shown beneficial effects in relation to several chronic diseases. However, no study has evaluated the association between a healthy Nordic food index (HNFI) and risk of breast cancer. METHODS: We conducted a prospective cohort study including 44,296 women, aged 29-49 at baseline in 1991-1992, who completed a food frequency questionnaire at baseline, and have been followed up ever since, through the Swedish Cancer Registry and Cause of Death Registry. Each woman was assigned a HNFI score ranging from 0 to 6. We calculated multivariable relative risks (RRs) and 95% confidence intervals (CIs) using Poisson regression models with attained age as the underlying timescale. The association between the HNFI and risk of breast cancer was assessed both overall, by menopausal status and by hormone receptor status. RESULTS: A total of 1,464 breast cancer cases were diagnosed during a median follow-up time of 20 years. A higher adherence to the HNFI was not associated with a lower risk of breast cancer overall, nor of varied hormone receptor status, or when we examining premenopausal and postmenopausal women separately. The multivariable RRs (95% CI) for breast cancer per 1-point increment in the HNFI were 1.02 (95% CI 0.98-1.06) for all women, 1.01 (95% CI 0.95-1.08) for premenopausal women, and 1.02 (95% CI 0.97-1.07) for postmenopausal women. CONCLUSION: Adherence to a HNFI was not associated with breast cancer incidence in this cohort of relatively young women, regardless of menopausal status or hormone receptor status.

Mediterranean and Nordic diet scores and long-term changes in body weight and waist circumference: results from a large cohort study.

Dietary patterns, which represent a broader picture of food and nutrient consumption, have gained increasing interest over the last decades. In a cohort design, we followed 27 544 women aged 29-49 years from baseline in 1991-1992. We collected data from an FFQ at baseline and body weight (BW) and waist circumference (WC) data both at baseline and at follow-up in 2003. We calculated the Mediterranean diet score (MDS, ranging from 0 to 9) and the Nordic diet score (NDS, ranging from 0 to 6). We used linear regression to examine the association between MDS and NDS (exposures) with subsequent BW change (ΔBW) and WC change (ΔWC) (outcomes) both continuously and categorically. Higher adherence to the MDS or NDS was not associated with ΔBW. The multivariable population average increment in BW was 0·03 kg (95 % CI -0·03, 0·09) per 1-point increase in MDS and 0·04 kg (95 % CI -0·02, 0·10) per 1-point increase in NDS. In addition, higher adherence to the MDS was not associated with ΔWC, with the multivariable population average increment per 1-point increase in MDS being 0·05 cm (95 % CI -0·03, 0·13). Higher adherence to the NDS was not significantly associated with gain in WC when adjusted for concurrent ΔBW. In conclusion, a higher adherence to the MDS or NDS was not associated with changes in average BW or WC in the present cohort followed for 12 years.

Shooting history and presence of high-frequency hearing impairment in swedish hunters: A cross-sectional internet-based observational study.

The aim of this cross-sectional study among Swedish hunters was to examine the association between shooting history and presence of high-frequency hearing impairment (HFHI). All hunters registered with an e-mail address in the membership roster of the Swedish Hunters' Association were invited via e-mail to a secure website with a questionnaire and an Internet-based audiometry test. Associations, expressed as prevalence ratio (PR), were multivariately modelled using Poisson regression. The questionnaire was answered by 1771 hunters (age 11-91 years), and 202 of them also completed the audiometry test. Subjective severe hearing loss was reported by 195/1771 (11%), while 23/202 (11%) exhibited HFHI upon testing with Internet-based audiometry. As many as 328/1771 (19%) had never used hearing protection during hunting. In the preceding 5 years, 785/1771 (45%), had fired >6 unprotected gunshots with hunting rifle calibers. The adjusted PR of HFHI when reporting 1-6 such shots, relative to 0, was 1.5 [95% confidence interval (CI) 1.1-2.1; P = 0.02]. We could not verify any excessive HFHI prevalence among 89 hunters reporting unprotected exposure to such gunshot noise >6 times. Nor did the total number of reported rifle shots seem to matter. These findings support the notion of a wide variation in individual susceptibility to impulse noise; that significant sound energy, corresponding to unprotected noise from hunting rifle calibers, seems to be required; that susceptible individuals may sustain irreversible damage to the inner ear from just one or a few shots; and that use of hearing protection should be encouraged from the first shot with such weapons.

Ligand-based design of [18F]OXD-2314 for PET imaging in non-Alzheimer's disease tauopathies.

Positron emission tomography (PET) imaging of tau aggregation in Alzheimer's disease (AD) is helping to map and quantify the in vivo progression of AD pathology. To date, no high-affinity tau-PET radiopharmaceutical has been optimized for imaging non-AD tauopathies. Here we show the properties of analogues of a first-in-class 4R-tau lead, [18F]OXD-2115, using ligand-based design. Over 150 analogues of OXD-2115 were synthesized and screened in post-mortem brain tissue for tau affinity against [3H]OXD-2115, and in silico models were used to predict brain uptake. [18F]OXD-2314 was identified as a selective, high-affinity non-AD tau PET radiotracer with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primate and is being translated for first-in-human PET studies.

In vitro binding of a radio-labeled positive allosteric modulator for metabotropic glutamate receptor subtype 5.

The positive allosteric modulator (PAM) binding site for metabotropic glutamate receptor subtype 5 (mGlu(5)) lacks a readily available radio-labeled tracer fordetailed structure-activity studies. This communication describes a selective mGlu(5) compound, 7-methyl-2-(4-(pyridin-2-yloxy)benzyl)-5-(pyridin-3-yl)isoindolin-1-one (PBPyl) that binds with high affinity to human mGlu(5) and exhibits functional PAM activity. Analysis of PBPyl by FLIPR revealed an EC(50) of 87 nM with an 89% effect in transfected HEK293 cells and an EC(50) of 81 nM with a 42% effect in rat primary neurons. PBPyl exhibited 5-fold higher functional selectivity for mGlu(5) in a full mGlu receptor panel. Unlabeled PBPyl was tested for specific binding using a liquid chromatography mass spectrometry (LC/MS/MS)-based filtration binding assay and exhibited 40% specific binding in recombinant membranes, a value higher than any candidate compound tested. In competition binding studies with [(3)H]MPEP, the mGlu(5) receptor negative allosteric modulator (NAM), PBPyl exhibited a k(i) value of 34 nM. PBPyl also displaced [(3)H]ABP688, a mGluR(5) receptor NAM, in tissue sections from mouse and rat brain using autoradiography. Areas of specific binding included the frontal cortex, striatum and nucleus accumbens. PBPyl was radiolabeled to a specific activity of 15 Ci/mmol and tested for specific binding in a filter plate format. In recombinant mGlu(5b) membranes, [(3)H] PBPyl exhibited saturable binding with a K(d) value of 18.6 nM. In competition binding experiments, [(3)H] PBPyl was displaced by high affinity mGlu(5) positive and negative modulators. Further tests showed that PBPyl displays less than optimal characteristics as an in vivo tool, including a high volume of distribution and ClogP, making it more suitable as an in vitro compound. However, as a first report of direct binding of an mGlu(5) receptor PAM, this study offers value toward the development of novel PET imaging agents for this important therapeutic target.

Discovery and characterization of AZD9272 and AZD6538-Two novel mGluR5 negative allosteric modulators selected for clinical development.

AZD9272 and AZD6538 are two novel mGluR5 negative allosteric modulators selected for further clinical development. An initial high-throughput screening revealed leads with promising profiles, which were further optimized by minor, yet indispensable, structural modifications to bring forth these drug candidates. Advantageously, both compounds may be synthesized in as little as one step. Both are highly potent and selective for the human as well as the rat mGluR5 where they interact at the same binding site than MPEP. They are orally available, allow for long interval administration due to a high metabolic stability and long half-lives in rats and permeate the blood brain barrier to a high extent. AZD9272 has progressed into phase I clinical studies.

Treatment of Naturally Occurring Periodontitis in Dogs With a New Bio-Absorbable Regenerative Matrix.

Although periodontal disease is one of the most common (oral) diseases in dogs, an effective treatment approach to periodontitis lacks. The aim of this study was to evaluate the safety and efficacy of a regenerative, bio-absorbable implant biomaterial made of medical-grade porcine gelatin, which is cross-linked by transglutaminase into a porous scaffold for the treatment of periodontitis in dogs in a clinical setting. Nine client-owned dogs were included in this multicenter, prospective interventional clinical study. A split-mouth design was used to treat any teeth with periodontitis; teeth on one side of the mouth were treated with open periodontal therapy alone (control teeth) and teeth on the other side were treated with open periodontal therapy and the tested implant (teeth treated with the implant). A recheck under general anesthesia was performed 3 months after the initial treatment and included periodontal probing, dental radiographs, and/or cone-beam computed tomography (CBCT) of the teeth included in the study. This revealed a reduction of the probing depth (PD) at all teeth, but in teeth treated with the implant, a statistically significant improvement (average 2.0 mm) over control teeth (average 1.0 mm) was diagnosed. Similarly, alveolar bone height was increased at most of the teeth, but in teeth treated with the implant, a statistically significant improvement (average 1.26 mm palatally and 1.51 mm buccally) over control teeth (average 0.58 mm palatally and 0.7 mm buccally) was observed for the buccal site. Open periodontal therapy alone improves clinical parameters and alveolar bone height in dogs with periodontitis, which is further significantly improved by the addition of the implant used.

Detection of perineural invasion in prostate needle biopsies with deep neural networks.

The presence of perineural invasion (PNI) by carcinoma in prostate biopsies has been shown to be associated with poor prognosis. The assessment and quantification of PNI are, however, labor intensive. To aid pathologists in this task, we developed an artificial intelligence (AI) algorithm based on deep neural networks. We collected, digitized, and pixel-wise annotated the PNI findings in each of the approximately 80,000 biopsy cores from the 7406 men who underwent biopsy in a screening trial between 2012 and 2014. In total, 485 biopsy cores showed PNI. We also digitized more than 10% (n = 8318) of the PNI negative biopsy cores. Digitized biopsies from a random selection of 80% of the men were used to build the AI algorithm, while 20% were used to evaluate its performance. For detecting PNI in prostate biopsy cores, the AI had an estimated area under the receiver operating characteristics curve of 0.98 (95% CI 0.97-0.99) based on 106 PNI positive cores and 1652 PNI negative cores in the independent test set. For a pre-specified operating point, this translates to sensitivity of 0.87 and specificity of 0.97. The corresponding positive and negative predictive values were 0.67 and 0.99, respectively. The concordance of the AI with pathologists, measured by mean pairwise Cohen's kappa (0.74), was comparable to inter-pathologist concordance (0.68 to 0.75). The proposed algorithm detects PNI in prostate biopsies with acceptable performance. This could aid pathologists by reducing the number of biopsies that need to be assessed for PNI and by highlighting regions of diagnostic interest.