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Lymphatic filariasis (LF) and onchocerciasis are priority neglected tropical diseases targeted for elimination. The only safe drug treatment with substantial curative activity against the filarial nematodes responsible for LF ( Brugia malayi, Wuchereria bancrofti ) or onchocerciasis ( Onchocerca volvulus ) is doxycycline. The target of doxycycline is the essential endosymbiont, Wolbachia. Four to six weeks doxycycline therapy achieves >90% depletion of Wolbachia in worm tissues leading to blockade of embryogenesis, adult sterility and premature death 18–24 months post-treatment. Long treatment length and contraindications in children and pregnancy are obstacles to implementing doxycycline as a public health strategy. Here we determine, via preclinical infection models of Brugia malayi or Onchocerca ochengi that elevated exposures of orally-administered rifampicin can lead to Wolbachia depletions from filariae more rapidly than those achieved by doxycycline. Dose escalation of rifampicin achieves >90% Wolbachia depletion in time periods of 7 days in B. malayi and 14 days in O. ochengi . Using pharmacokinetic-pharmacodynamic modelling and mouse-human bridging analysis, we conclude that clinically relevant dose elevations of rifampicin, which have recently been determined as safe in humans, could be administered as short courses to filariasis target populations with potential to reduce anti- Wolbachia curative therapy times to between one and two weeks.

Background Data are sparse concerning the sequential use of multiple anaplastic lymphoma kinase (ALK) inhibitors for ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC). Objective This study investigated sequencing and outcomes among patients receiving multiple ALK inhibitors. Patients and Methods This was a retrospective observational cohort study of adult patients with ALK-positive NSCLC treated with available first- and second-generation ALK inhibitors from 1 September 2011 to 31 December 2017. Duration of therapy (DOT) and overall survival (OS) were assessed with the Kaplan–Meier method. A multivariable linear regression analysis was performed to assess if DOT with a preceding ALK inhibitor was predictive of DOT for subsequent ALK inhibitor treatments. Results A total of 410 patients were analyzed: 57% received 1 ALK inhibitor; 35%, 2 ALK inhibitors; and 8%, 3–4 ALK inhibitors. Among those receiving > 1 ALK inhibitor ( n  = 177), 60% received a crizotinib-led sequence and 39% an alectinib-led sequence. Nearly 60% of the overall population received chemotherapy prior to their first ALK inhibitor. Median OS for the study population was 28 months, 15 months in patients who received 1 ALK inhibitor, 42 months in patients who received 2 ALK inhibitors, and 56 months in patients who received 3–4 ALK inhibitors. Longer DOT of the first ALK inhibitor was associated with increased DOT of the second ( p  < 0.0001), and longer DOT of the second ALK inhibitor was associated with increased DOT of the third ( p  < 0.0001). Conclusions This study provides initial information on real-world treatment patterns following the introduction of new ALK inhibitors, and supports the use of sequential ALK therapies.

Each year, millions of African children receive praziquantel (PZQ) by mass drug administration (MDA) to treat schistosomiasis at a standard single dose of 40 mg/kg of body weight, a direct extrapolation from studies of adults. A higher dose of 60 mg/kg is also acceptable for refractory cases. We conducted the first PZQ pharmacokinetic (PK) and pharmacodynamic (PD) study in young children comparing dosing. Sixty Ugandan children aged 3 to 8 years old with egg patent Schistosoma mansoni received PZQ at either 40 mg/kg or 60 mg/kg. PK parameters of PZQ racemate and enantiomers ( R and S ) were quantified. PD outcomes were assessed by standard fecal egg counts and novel schistosome-specific serum (circulating anodic antigen [CAA]) and urine (circulating cathodic antigen [CCA]) antigen assays. Population PK and PD analyses were performed to estimate drug exposure in individual children, and the relationship between drug exposure and parasitological cure was estimated using logistic regression. Monte Carlo simulations were performed to identify better, future dosing regimens. There was marked PK variability between children, but the area under the concentration-time curve (AUC) of PZQ was strongly predictive of the parasitological cure rate (CR). Although no child achieved antigenic cure, which is suggestive of an important residual adult worm burden, higher AUC was associated with greater CAA antigenic decline at 24 days. To optimize the performance of PZQ, analysis of our simulations suggest that higher doses (>60 mg/kg) are needed, particularly in smaller children. IMPORTANCE Schistosomiasis is a neglected tropical disease, typically associated with chronic morbidity, and its control is a global health priority. Praziquantel (PZQ) is the only available antiparasitic drug and is often given out, as a single oral dose (40 mg/kg), to school-aged children by mass drug administration (MDA) schemes operating within preventive chemotherapy campaigns as endorsed by the World Health Organization (WHO). This current strategy has several limitations. (i) It excludes preschool children who can be patently infected. (ii) It delivers PZQ at a dose directly extrapolated from adult pharmacological studies. To address these problems, we conducted the first pharmacokinetic and pharmacodynamic study of young children within an area of Uganda where Schistosoma mansoni is hyperendemic. Our results demonstrate that a higher dose (>60 mg/kg) is required, especially in smaller children, and draw attention to the need for further optimization of PZQ treatment based on schistosome antigenic assays, which are more sensitive to pharmacodynamic markers. Schistosomiasis is a neglected tropical disease, typically associated with chronic morbidity, and its control is a global health priority. Praziquantel (PZQ) is the only available antiparasitic drug and is often given out, as a single oral dose (40 mg/kg), to school-aged children by mass drug administration (MDA) schemes operating within preventive chemotherapy campaigns as endorsed by the World Health Organization (WHO). This current strategy has several limitations. (i) It excludes preschool children who can be patently infected. (ii) It delivers PZQ at a dose directly extrapolated from adult pharmacological studies. To address these problems, we conducted the first pharmacokinetic and pharmacodynamic study of young children within an area of Uganda where Schistosoma mansoni is hyperendemic. Our results demonstrate that a higher dose (>60 mg/kg) is required, especially in smaller children, and draw attention to the need for further optimization of PZQ treatment based on schistosome antigenic assays, which are more sensitive to pharmacodynamic markers.

MET dysregulation promoting tumorigenesis in non-small cell lung cancer (NSCLC) is associated with worse outcomes following chemotherapy as compared to non-driver mutated NSCLC and occurs either through mutations causing MET exon 14 skipping (METex14) or gene amplification and overexpression that result in enhanced receptor signaling. Capmatinib is the first FDA-approved targeted therapy for NSCLC with METex14 skipping mutations, approved in 2020. FoundationOne[R] CDx, a comprehensive genomic profiling test for solid tumors, was concurrently approved as a companion diagnostic for capmatinib use. The GEOMETRY mono-1 phase II trial of capmatinib monotherapy demonstrated an overall response rate (ORR) of 68% in treatment naive (n=28) and 41% in pre-treated (n=69) METex14 skipping advanced NSCLC; in MET amplified advanced NSCLC (gene copy number [greater than or equal to] 10) ORRs of 40% in treatment naive and 29% in pre-treated disease was seen. This review outlines the clinical data supporting capmatinib approval in the treatment of NSCLC and FoundationOne[R] CDx approval as a companion diagnostic. We detail the practical clinical administration of capmatinib, including dosing and toxicity management, compare capmatinib to other approved and investigational MET-targeted therapies, discuss limitations of capmatinib, and highlight ongoing trials of capmatinib in combinatorial approaches. Keywords: capmatinib, MET exon 14 skipping, non-small cell lung cancer, FoundationOne CDx

Within the World Health Organization 2012–2020 roadmap for control and elimination of schistosomiasis, the scale-up of mass drug administration with praziquantel is set to change the epidemiological landscape across Africa and Arabia. Central in measuring progress is renewed emphasis upon diagnostics which operate at individual, community and environmental levels by assessing reductions in disease, infections and parasite transmission. However, a fundamental tension is revealed between levels for present diagnostic tools, and methods applied in control settings are not necessarily adequate for application in elimination scenarios. Indeed navigating the transition from control to elimination needs careful consideration and planning. In the present context of control, we review current options for diagnosis of schistosomiasis at different levels, highlighting several strengths and weaknesses therein. Future challenges in elimination are raised and we propose that more cost-effective diagnostics and clinical staging algorithms are needed. Using the Kingdom of Saudi Arabia as a contemporary example, embedding new diagnostic methods within the primary care health system is discussed with reference to both urogenital and intestinal schistosomiasis.

aim: We identified geographic distribution of Otorhinolaryngologist, Head and Neck surgeons in Aotearoa New Zealand. To identify the future workforce pipeline, we explored trainee intentions for specialist practice. method: A survey was distributed to all New Zealand Society of Otolaryngology, Head and Neck Surgery (NZSOHNS) members and all current New Zealand Otolaryngology, Head and Neck surgery trainees. Data were gathered on work location and patterns of work, including on-call commitments and full-time equivalent hours worked. Trainees were asked about future career plans. results: An 88% response rate was achieved encompassing Senior Medical Officers (SMOs) and trainees. A total of 64.8% (68) of respondents reported primarily working in a metropolitan hospital and 26.7% (28) reported working in a regional centre. Rates of internationally trained surgeons were significantly higher in regional centres compared to metropolitan hospitals (64.3% vs 32.4% p<0.05). Regional respondents had higher after hours on-call burden, a higher full-time equivalent (FTE) worked and higher average hours worked per week. Retirement intentions within the next 10 years were high in both groups (64% regional and 52.9% metropolitan—p<0.05). conclusions: The regional workforce in ORLHNS work longer hours, are older and are reliant on internationally trained surgeons. Current training of ORLHNS surgeons is unlikely to keep pace with expected retirements.

Summary Background This multicenter, open-label, phase Ib study was designed to assess the safety, pharmacokinetics and preliminary efficacy of ME-344, a mitochondrial inhibitor, administered in combination with the topoisomerase I inhibitor, topotecan, in patients with previously treated, locally advanced or metastatic small cell lung (SCLC), ovarian and cervical cancers. Patients and methods In Part 1, patients received ME-344 10 mg/kg intravenously weekly on days 1, 8, 15 and 22 in combination with topotecan 4 mg/m 2 on days 1, 8, and 15 of a 28 day cycle. Cycles were repeated until disease progression or unacceptable toxicity. Patients were evaluated for dose-limiting toxicity (DLT) in cycle 1 and ME-344 pharmacokinetic samples were obtained. In Part 2, patients with locally advanced or metastatic SCLC and ovarian cancer were enrolled in expansion cohorts treated at the recommended phase II dose (RP2D) determined in Part 1. Results Fourteen patients were enrolled in Part 1 and no DLTs were observed. The RP2D of ME-344 in combination with topotecan was established as 10 mg/kg. In Part 2, 32 patients were enrolled. The most common treatment-emergent all-grade and grade 3/4 toxicities included fatigue (65.2%, 6.5%), neutropenia (56.5%, 43.5%) and thrombocytopenia (50%, 23.9%). One patient with recurrent ovarian cancer experienced a partial response by RECIST 1.1 and 21 patients achieved stable disease as best response. Conclusions The combination of ME-344 10 mg/kg weekly and topotecan 4 mg/m 2 was tolerable, however, the degree of anti-cancer activity does not support further investigation of the combination in unselected patients with SCLC, ovarian and cervical cancers.

Breeding biology in grebes (Podicipedidae) is less understood than that of other waterbirds in Australia. This paper reports on a study of breeding Australasian Grebes (Tachybaptus novaehollandiae) on five urban wetlands in Sydney, New South Wales, from 2001 to 2011. During the 10 years of the study, breeding pairs only used the two main study sites (Lime Kiln Bay Wetland and Moore Reserve Wetland) in 20% and 30% of the breeding seasons, respectively. Two nests and two nest building attempts from one site and one pair during the 2010–2011 breeding season are described, while the development and survival of 23 chicks (n = 5 broods) during the 10 years are also described. The proportion of chicks surviving to adult plumage was 39%. Brood rivalry and parental favoritism were observed. Chicks were capable of some independent behavior (e.g., preening and short dives) within 1 week of hatching; chicks not favored by their parents were forced to accelerate their development.

Lapatinib, an oral, reversible inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2) tyrosine kinase, has proven antitumor activity in HER2-positive metastatic breast cancer (MBC). Nanoparticle albumin-bound paclitaxel ( nab -paclitaxel) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. This was an open-label, single-arm, multicenter, Phase II study to evaluate the efficacy and safety of nab -paclitaxel plus lapatinib in women with HER2 over-expressing MBC who had received no more than one prior chemotherapeutic regimen. The primary efficacy endpoint was the overall response rate (ORR). This was defined as the percentage of patients having either a complete response (CR) or partial response (PR). Secondary efficacy endpoints included progression-free survival (PFS), overall survival, duration of response (DoR), time to response (TTR), and time to progression (TTP). Investigator-assessed ORR was 53 % ( n  = 32, 95 % confidence interval (CI): 40.7–66.0) with the majority of patient responses demonstrating a PR (47 %). Four (7 %) patient responses demonstrated a CR, and ten (17 %) a stable disease. The median Kaplan–Meier estimate of investigator-assessed PFS, DoR, TTR, and TTP was 39.7 weeks (95 % CI 34.1–63.9), 48.7 weeks (95 % CI 31.7–57.1), 7.8 weeks (95 % CI 7.4–8.1), and 41 weeks (95 % CI 39.1–64.6), respectively. Lapatinib 1,000 mg with nab -paclitaxel 100 mg/m 2 IV is feasible with manageable and predictable toxicity and an ORR of 53 % comparing favorably with other HER2-based combinations in this setting.

Introduction The aim of this study was to evaluate the suitability of using cone‐beam computed tomography (CBCT) obtained with a mobile C‐arm X‐ray fluoroscopy unit as a single modality for planning of high‐dose‐rate (HDR) prostate brachytherapy treatments. Methods The feasibility of using CBCT images obtained using a Siemens Arcadis Orbic 3D mobile C‐arm was evaluated. A retrospective clinical study was undertaken of six participants undergoing HDR prostate brachytherapy. Plans generated using images from a Toshiba Aquilion One LB CT were compared with those generated using CBCT images. After rigid spatial registration, the plans were compared based on various parameters such as dose‐volume histograms, overlap quantities and metrics, and dose constraints. Results Provided they were within the limited field of view, the brachytherapy catheters and fiducial markers were clearly visible in the CBCT images and thus, localisable and identifiable in the treatment planning process. The Siemens CBCT underestimated CT numbers leading to poorer tissue contrast which exacerbated the difficulties in delineation of the target tumour and the surrounding organs at risk. Between CT‐ and CBCT‐based plans, the mean difference of CTV‐D90 was 1.58 Gy, CTV‐V100 was 12.13%, rectum‐V80 was 0.06% and urethra‐V120 was −0.70%. Conclusion It was not feasible to solely utilise the Siemens Arcadis Orbic 3D for HDR prostate brachytherapy treatment planning due to suboptimal organ delineation. However, the methods in this study could be used to evaluate other mobile CBCT imaging devices for feasibility in HDR brachytherapy treatment planning since the results indicated that it may not be necessary to have standard quality CT images for treatment planning. Cone‐beam computed tomography (CBCT) scanners are becoming more available in surgical theatres and are commonly used for image guidance in radiotherapy, angiography and orthopaedics. This study describes an assessment of a mobile C‐arm CBCT unit (Siemens Arcadis Orbic 3D) for generating CT images for high‐dose‐rate prostate brachytherapy treatment planning. Following generic image quality assessments, an ethics approved retrospective clinical study was conducted to compare qualitative and quantitative differences of treatment plans created based on the Siemens CBCT images and CT images generated from the scanner routinely used (Toshiba Aquilion One LB).