Identification of Dual STRN-NTRK2 Rearrangements in a High Grade Sarcoma, With Good Clinical Response to First-Line Larotrectinib Therapy

BACKGROUND: Among the three NTRK genes, NTRK2 possesses a tremendous structural complexity and involves tumorigenesis of several types of tumors. To date, only STRN and RBPMS are identified in the fusion with NTRK2 in adult soft tissue tumors. More recently, the highly selective Trk tyrosine kinases inhibitors, including larotrectinib and entrectinib, have shown significant efficacy for treating tumors harboring NTRK fusions and were approved by FDA. CASE PRESENTATION: We report a case of sarcoma in a 35-year-old female harboring two STRN-NTRK2 gene fusions, with a good clinical response to first-line larotrectinib treatment. Core biopsy of the 16.5 cm gluteal mass showed a high-grade mesenchymal neoplasm with features reminiscent of a solitary fibrous tumor, but negative for STAT6. In-house next-generation sequencing gene fusion panel showed two in-frame STRN-NTRK2 fusions, which contain the same 5\u27 partner sequence (exon 1-3) of STRN, and the 3\u27 fusion partner starting from either the exon 15 or the exon 16 of NTRK2. Due to the large size and location of the tumor, first-line neoadjuvant therapy with larotrectinib was initiated. The patient has an excellent clinical response with an 83% tumor size reduction by imaging. The tumor was subsequently completely resected. After 130 days, larotrectinib was reinitiated for lung metastasis (up to 7 cm), and a complete resolution was achieved. When compared with NTRK1 and NTRK3, NTRK2 fusions are the least common. Of note, the only other report in the literature on NRTK2 fusion-positive sarcoma also showed solitary fibrous tumor (SFT)-like morphology, and the patient responded well to larotrectinib as the second line adjuvant therapy. CONCLUSIONS: In conclusion, the identification of NTRK2 fusions in patients with soft tissue tumors could significantly improve the clinical outcome through selective NTRK inhibitor therapy, especially in the first-line setting. Prompt RNA-based NGS testing at initial diagnosis may benefit these patients. Our case is among the first few in the literature on NTRK2 fusion sarcoma with first-line larotrectinib therapy in the primary and metastatic setting, with good clinical response and minimal side effects

Mepivacaine versus Bupivacaine Spinal Anesthesia for Early Postoperative Ambulation.

BACKGROUND: Early ambulation after total hip arthroplasty predicts early discharge. Spinal anesthesia is preferred by many practices but can delay ambulation, especially with bupivacaine. Mepivacaine, an intermediate-acting local anesthetic, could enable earlier ambulation than bupivacaine. This study was designed to test the hypothesis that patients who received mepivacaine would ambulate earlier than those who received hyperbaric or isobaric bupivacaine for primary total hip arthroplasty. METHODS: This randomized controlled trial included American Society of Anesthesiologists Physical Status I to III patients undergoing primary total hip arthroplasty. The patients were randomized 1:1:1 to 52.5 mg of mepivacaine, 11.25 mg of hyperbaric bupivacaine, or 12.5 mg of isobaric bupivacaine for spinal anesthesia. The primary outcome was ambulation between 3 and 3.5 h. Secondary outcomes included return of motor and sensory function, postoperative pain, opioid consumption, transient neurologic symptoms, urinary retention, intraoperative hypotension, intraoperative muscle tension, same-day discharge, length of stay, and 30-day readmissions. RESULTS: Of 154 patients, 50 received mepivacaine, 53 received hyperbaric bupivacaine, and 51 received isobaric bupivacaine. Patient characteristics were similar among groups. For ambulation at 3 to 3.5 h, 35 of 50 (70.0%) of patients met this endpoint in the mepivacaine group, followed by 20 of 53 (37.7%) in the hyperbaric bupivacaine group, and 9 of 51 (17.6%) in the isobaric bupivacaine group (P \u3c 0.001). Return of motor function occurred earlier with mepivacaine. Pain and opioid consumption were higher for mepivacaine patients in the early postoperative period only. For ambulatory status, 23 of 50 (46.0%) of mepivacaine, 13 of 53 (24.5%) of hyperbaric bupivacaine, and 11 of 51 (21.5%) of isobaric bupivacaine patients had same-day discharge (P = 0.014). Length of stay was shortest in mepivacaine patients. There were no differences in transient neurologic symptoms, urinary retention, hypotension, muscle tension, or dizziness. CONCLUSIONS: Mepivacaine patients ambulated earlier and were more likely to be discharged the same day than both hyperbaric bupivacaine and isobaric bupivacaine patients. Mepivacaine could be beneficial for outpatient total hip arthroplasty candidates if spinal is the preferred anesthesia type

LSST Science Book, Version 2.0

A survey that can cover the sky in optical bands over wide fields to faint magnitudes with a fast cadence will enable many of the exciting science opportunities of the next decade. The Large Synoptic Survey Telescope (LSST) will have an effective aperture of 6.7 meters and an imaging camera with field of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over 20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a total point-source depth of r~27.5. The LSST Science Book describes the basic parameters of the LSST hardware, software, and observing plans. The book discusses educational and outreach opportunities, then goes on to describe a broad range of science that LSST will revolutionize: mapping the inner and outer Solar System, stellar populations in the Milky Way and nearby galaxies, the structure of the Milky Way disk and halo and other objects in the Local Volume, transient and variable objects both at low and high redshift, and the properties of normal and active galaxies at low and high redshift. It then turns to far-field cosmological topics, exploring properties of supernovae to z~1, strong and weak lensing, the large-scale distribution of galaxies and baryon oscillations, and how these different probes may be combined to constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at http://www.lsst.org/lsst/sciboo

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Diving into the vertical dimension of elasmobranch movement ecology

Knowledge of the three-dimensional movement patterns of elasmobranchs is vital to understand their ecological roles and exposure to anthropogenic pressures. To date, comparative studies among species at global scales have mostly focused on horizontal movements. Our study addresses the knowledge gap of vertical movements by compiling the first global synthesis of vertical habitat use by elasmobranchs from data obtained by deployment of 989 biotelemetry tags on 38 elasmobranch species. Elasmobranchs displayed high intra- and interspecific variability in vertical movement patterns. Substantial vertical overlap was observed for many epipelagic elasmobranchs, indicating an increased likelihood to display spatial overlap, biologically interact, and share similar risk to anthropogenic threats that vary on a vertical gradient. We highlight the critical next steps toward incorporating vertical movement into global management and monitoring strategies for elasmobranchs, emphasizing the need to address geographic and taxonomic biases in deployments and to concurrently consider both horizontal and vertical movements

Diving into the vertical dimension of elasmobranch movement ecology

Knowledge of the three-dimensional movement patterns of elasmobranchs is vital to understand their ecological roles and exposure to anthropogenic pressures. To date, comparative studies among species at global scales have mostly focused on horizontal movements. Our study addresses the knowledge gap of vertical movements by compiling the first global synthesis of vertical habitat use by elasmobranchs from data obtained by deployment of 989 biotelemetry tags on 38 elasmobranch species. Elasmobranchs displayed high intra- and interspecific variability in vertical movement patterns. Substantial vertical overlap was observed for many epipelagic elasmobranchs, indicating an increased likelihood to display spatial overlap, biologically interact, and share similar risk to anthropogenic threats that vary on a vertical gradient. We highlight the critical next steps toward incorporating vertical movement into global management and monitoring strategies for elasmobranchs, emphasizing the need to address geographic and taxonomic biases in deployments and to concurrently consider both horizontal and vertical movements

Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial

Background: The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population. Methods: PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older—or aged 18 years or older with relevant comorbidities—and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (&lt;50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031. Findings: Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81–1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir. Interpretation: Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community

Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial

BackgroundThe safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population.MethodsPANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older—or aged 18 years or older with relevant comorbidities—and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031.FindingsBetween Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81–1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir.InterpretationMolnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community

Identification of dual STRN-NTRK2 rearrangements in a high grade sarcoma, with good clinical response to first-line larotrectinib therapy

Abstract Background Among the three NTRK genes, NTRK2 possesses a tremendous structural complexity and involves tumorigenesis of several types of tumors. To date, only STRN and RBPMS are identified in the fusion with NTRK2 in adult soft tissue tumors. More recently, the highly selective Trk tyrosine kinases inhibitors, including larotrectinib and entrectinib, have shown significant efficacy for treating tumors harboring NTRK fusions and were approved by FDA. Case presentation We report a case of sarcoma in a 35-year-old female harboring two STRN-NTRK2 gene fusions, with a good clinical response to first-line larotrectinib treatment. Core biopsy of the 16.5 cm gluteal mass showed a high-grade mesenchymal neoplasm with features reminiscent of a solitary fibrous tumor, but negative for STAT6. In-house next-generation sequencing gene fusion panel showed two in-frame STRN-NTRK2 fusions, which contain the same 5’ partner sequence (exon 1–3) of STRN, and the 3’ fusion partner starting from either the exon 15 or the exon 16 of NTRK2. Due to the large size and location of the tumor, first-line neoadjuvant therapy with larotrectinib was initiated. The patient has an excellent clinical response with an 83% tumor size reduction by imaging. The tumor was subsequently completely resected. After 130 days, larotrectinib was reinitiated for lung metastasis (up to 7 cm), and a complete resolution was achieved. When compared with NTRK1 and NTRK3, NTRK2 fusions are the least common. Of note, the only other report in the literature on NRTK2 fusion-positive sarcoma also showed solitary fibrous tumor (SFT)-like morphology, and the patient responded well to larotrectinib as the second line adjuvant therapy. Conclusions In conclusion, the identification of NTRK2 fusions in patients with soft tissue tumors could significantly improve the clinical outcome through selective NTRK inhibitor therapy, especially in the first-line setting. Prompt RNA-based NGS testing at initial diagnosis may benefit these patients. Our case is among the first few in the literature on NTRK2 fusion sarcoma with first-line larotrectinib therapy in the primary and metastatic setting, with good clinical response and minimal side effects

2018 international consensus meeting on musculoskeletal infection: Research priorities from the general assembly questions

Musculoskeletal infections (MSKI) remain the bane of orthopedic surgery, and result in grievous illness and inordinate costs that threaten healthcare systems. As prevention, diagnosis, and treatment has remained largely unchanged over the last 50 years, a 2nd International Consensus Meeting on Musculoskeletal Infection (ICM 2018, https://icmphilly.com) was completed. Questions pertaining to all areas of MSKI were extensively researched to prepare recommendations, which were discussed and voted on by the delegates using the Delphi methodology. The questions, including the General Assembly (GA) results, have been published (GA questions). However, as critical outcomes include: (i) incidence and cost data that substantiate the problems, and (ii) establishment of research priorities; an ICM 2018 research workgroup (RW) was assembled to accomplish these tasks. Here, we present the result of the RW consensus on the current and projected incidence of infection, and the costs per patient, for all orthopedic subspecialties, which range from 0.1% to 30%, and $17,000 to$150,000. The RW also identified the most important research questions. The Delphi methodology was utilized to initially derive four objective criteria to define a subset of the 164 GA questions that are high priority for future research. Thirty-eight questions (23% of all GA questions) achieved the requisite &gt; 70% agreement vote, and are highlighted in this Consensus article within six thematic categories: acute versus chronic infection, host immunity, antibiotics, diagnosis, research caveats, and modifiable factors. Finally, the RW emphasizes that without appropriate funding to address these high priority research questions, a 3rd ICM on MSKI to address similar issues at greater cost is inevitable.</p