cli Climate Adaptation through Irrigation Modernization Project By www.adb.org Published On :: 2025 The project integrates crop diversification with the adoption of climate-smart irrigated agricultural practices that require modernization of irrigation systems and on-farm water management to improve irrigation efficiency and crop water productivity. It includes the following three outputs: (i) irrigation management services strengthened, (ii) modern irrigation and drainage infrastructure developed, and (iii) efficient on-farm water management practices adopted. Full Article
cli Ha Tinh City Priority Infrastructure for Climate Adaptation Project By www.adb.org Published On :: 2025 Full Article
cli Climate Resilient Urban Services Project – Tham Luong Ben Cat By www.adb.org Published On :: 2025 The project will support Ho Chi Minh City People's Committee and their government to finance sound wastewater and drainage system in the remaining catchments, thereby strengthening its foundation as the socioeconomic growth pole of southern Viet Nam. The impact of the project will be improved surface water quality and drainage capacity in HCMC. The outcome will be increased wastewater and drainage collection and treatment capacity in key catchments in HCMC. Full Article
cli Climate-Resilient Water and Sanitation Services Project By www.adb.org Published On :: 2025 Project objectives. The proposed project will assist the government in addressing climate vulnerabilities and enhancing public health and economic conditions by ensuring inclusive access to safe, reliable, climate-resilient, and sustainable WSS services for the residents of Andijan, Djizzak and Fergana provinces; and the Republic of Karakalpakstan. The project will help upgrade and expand the WSS infrastructure in the project regions and support regional suvtaminots in implementing transformational changes. Full Article
cli Northern China Agriculture and Food Ecosystem Low-Carbon and Climate Resilient Development Project By www.adb.org Published On :: 2025 The proposed Northern China Agriculture and Food Ecosystem Net Zero Transformation Project (project) will support the PRC to achieve its climate commitment through catalyzing financing and strengthening institutional capacity for net zero transformation in agriculture and food ecosystem. Full Article
cli How climate change has pushed our oceans to the brink of catastrophe By www.newscientist.com Published On :: Wed, 14 Aug 2024 17:25:00 +0100 For decades, the oceans have absorbed much of the excess heat caused by greenhouse gases. The latest observations suggest they are reaching their limits, so how worried should we be? Full Article
cli We're finally solving the puzzle of how clouds will affect our climate By www.newscientist.com Published On :: Mon, 02 Sep 2024 17:00:00 +0100 Clouds can trap heat or reflect it away from Earth, making their impact on global warming extraordinarily hard to predict. Now, new ways of studying them are lifting the fog Full Article
cli Is the climate change food crisis even worse than we imagined? By www.newscientist.com Published On :: Mon, 11 Nov 2024 16:00:00 +0000 Extreme weather and a growing population is driving a food security crisis. What can we do to break the vicious cycle of carbon emissions, climate change and soaring food costs – or is it already too late? Full Article
cli These photos show how a warmer climate is damaging Earth's waters By www.newscientist.com Published On :: Wed, 24 Apr 2024 19:00:00 +0100 Photographer Diane Tuft has documented how global warming is affecting bodies of water around the world Full Article
cli The Amazon is teetering on the edge of a climate tipping point By www.newscientist.com Published On :: Tue, 29 Oct 2024 19:00:00 +0000 In some recent years, the Amazon biome released more carbon than it absorbed, and further degradation could make it a permanent shift Full Article
cli COP29: Clashes over cash are set to dominate the climate conference By www.newscientist.com Published On :: Mon, 04 Nov 2024 10:50:55 +0000 The focus is on finance at the UN climate summit in Baku, Azerbaijan, this month, but countries are a long way from any kind of consensus Full Article
cli What preparing for an asteroid strike teaches us about climate change By www.newscientist.com Published On :: Wed, 06 Nov 2024 18:00:00 +0000 Averting an asteroid strike will need many of the same skills we must hone to tackle climate change and future pandemics Full Article
cli Any delay in reaching net zero will influence climate for centuries By www.newscientist.com Published On :: Mon, 11 Nov 2024 10:04:35 +0000 Reaching net-zero emissions is essential for halting climate change - but even after we achieve this goal, parts of the planet will continue to warm. Delaying net zero will worsen these effects Full Article
cli Is the climate change food crisis even worse than we imagined? By www.newscientist.com Published On :: Mon, 11 Nov 2024 16:00:00 +0000 Extreme weather and a growing population is driving a food security crisis. What can we do to break the vicious cycle of carbon emissions, climate change and soaring food costs – or is it already too late? Full Article
cli West Nile Virus Cases Continue to Climb By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: West Nile Virus Cases Continue to ClimbCategory: Health NewsCreated: 8/30/2012 11:00:00 AMLast Editorial Review: 8/30/2012 12:00:00 AM Full Article
cli Mental Skills Decline More Sharply for Women With Alzheimer's: Study By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Mental Skills Decline More Sharply for Women With Alzheimer's: StudyCategory: Health NewsCreated: 8/29/2012 6:05:00 PMLast Editorial Review: 8/30/2012 12:00:00 AM Full Article
cli Urine Test May Show Risk of Mental Decline in People With Type 2 Diabetes By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Urine Test May Show Risk of Mental Decline in People With Type 2 DiabetesCategory: Health NewsCreated: 8/29/2013 5:36:00 PMLast Editorial Review: 8/30/2013 12:00:00 AM Full Article
cli Mental Decline a Risk Factor for Stroke, Study Suggests By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Mental Decline a Risk Factor for Stroke, Study SuggestsCategory: Health NewsCreated: 8/25/2014 12:36:00 PMLast Editorial Review: 8/26/2014 12:00:00 AM Full Article
cli Climate Change May Bring More ER Visits, Deaths, Study Says By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Climate Change May Bring More ER Visits, Deaths, Study SaysCategory: Health NewsCreated: 8/21/2015 12:00:00 AMLast Editorial Review: 8/24/2015 12:00:00 AM Full Article
cli Clinton Edges Trump on Health Care, Survey Finds By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Clinton Edges Trump on Health Care, Survey FindsCategory: Health NewsCreated: 8/22/2016 12:00:00 AMLast Editorial Review: 8/22/2016 12:00:00 AM Full Article
cli Climate Change May Prolong Smog Season in Southeast U.S. By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Climate Change May Prolong Smog Season in Southeast U.S.Category: Health NewsCreated: 8/23/2016 12:00:00 AMLast Editorial Review: 8/23/2016 12:00:00 AM Full Article
cli Use of Cancer-Linked Fibroid Device Declines After FDA Warning By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Use of Cancer-Linked Fibroid Device Declines After FDA WarningCategory: Health NewsCreated: 8/23/2016 12:00:00 AMLast Editorial Review: 8/24/2016 12:00:00 AM Full Article
cli Breast-Feeding Rates Climb, But Many Moms Quit Early: CDC By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Breast-Feeding Rates Climb, But Many Moms Quit Early: CDCCategory: Health NewsCreated: 8/23/2016 12:00:00 AMLast Editorial Review: 8/24/2016 12:00:00 AM Full Article
cli Serious Problems at Florida Stem Cell Clinic By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Serious Problems at Florida Stem Cell ClinicCategory: Health NewsCreated: 8/29/2017 12:00:00 AMLast Editorial Review: 8/29/2017 12:00:00 AM Full Article
cli Will Climate Change Bring More Highway Deaths? By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Will Climate Change Bring More Highway Deaths?Category: Health NewsCreated: 8/31/2017 12:00:00 AMLast Editorial Review: 9/1/2017 12:00:00 AM Full Article
cli Is Climate Change Draining Nutrients From Crops? By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Is Climate Change Draining Nutrients From Crops?Category: Health NewsCreated: 8/27/2018 12:00:00 AMLast Editorial Review: 8/28/2018 12:00:00 AM Full Article
cli STD Rates Continue to Climb in U.S. By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: STD Rates Continue to Climb in U.S.Category: Health NewsCreated: 8/28/2018 12:00:00 AMLast Editorial Review: 8/29/2018 12:00:00 AM Full Article
cli Climate Change Hiking Danger of Flesh-Eating Bacteria Infections By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Climate Change Hiking Danger of Flesh-Eating Bacteria InfectionsCategory: Health NewsCreated: 8/23/2019 12:00:00 AMLast Editorial Review: 8/26/2019 12:00:00 AM Full Article
cli Climate Change Raises Athletes' Risk of Heat Illness By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Climate Change Raises Athletes' Risk of Heat IllnessCategory: Health NewsCreated: 8/27/2019 12:00:00 AMLast Editorial Review: 8/27/2019 12:00:00 AM Full Article
cli Men Should be Included in Breast Cancer Clinical Trials: FDA By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Men Should be Included in Breast Cancer Clinical Trials: FDACategory: Health NewsCreated: 8/26/2019 12:00:00 AMLast Editorial Review: 8/27/2019 12:00:00 AM Full Article
cli For Muslim Pilgrimage, Climate Change Poses Health Risks By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: For Muslim Pilgrimage, Climate Change Poses Health RisksCategory: Health NewsCreated: 8/28/2019 12:00:00 AMLast Editorial Review: 8/29/2019 12:00:00 AM Full Article
cli Monkeypox Cases May Finally Be Ebbing, With Declines Seen in Europe, WHO Says By www.medicinenet.com Published On :: Thu, 25 Aug 2022 00:00:00 PDT Title: Monkeypox Cases May Finally Be Ebbing, With Declines Seen in Europe, WHO SaysCategory: Health NewsCreated: 8/25/2022 12:00:00 AMLast Editorial Review: 8/25/2022 12:00:00 AM Full Article
cli Rapid SARS-CoV-2 surveillance using clinical, pooled, or wastewater sequence as a sensor for population change [METHODS] By genome.cshlp.org Published On :: 2024-10-29T06:46:08-07:00 The COVID-19 pandemic has highlighted the critical role of genomic surveillance for guiding policy and control. Timeliness is key, but sequence alignment and phylogeny slow most surveillance techniques. Millions of SARS-CoV-2 genomes have been assembled. Phylogenetic methods are ill equipped to handle this sheer scale. We introduce a pangenomic measure that examines the information diversity of a k-mer library drawn from a country's complete set of clinical, pooled, or wastewater sequence. Quantifying diversity is central to ecology. Hill numbers, or the effective number of species in a sample, provide a simple metric for comparing species diversity across environments. The more diverse the sample, the higher the Hill number. We adopt this ecological approach and consider each k-mer an individual and each genome a transect in the pangenome of the species. Structured in this way, Hill numbers summarize the temporal trajectory of pandemic variants, collapsing each day's assemblies into genome equivalents. For pooled or wastewater sequence, we instead compare days using survey sequence divorced from individual infections. Across data from the UK, USA, and South Africa, we trace the ascendance of new variants of concern as they emerge in local populations well before these variants are named and added to phylogenetic databases. Using data from San Diego wastewater, we monitor these same population changes from raw, unassembled sequence. This history of emerging variants senses all available data as it is sequenced, intimating variant sweeps to dominance or declines to extinction at the leading edge of the COVID-19 pandemic. Full Article
cli Mutational scanning of CRX classifies clinical variants and reveals biochemical properties of the transcriptional effector domain [RESEARCH] By genome.cshlp.org Published On :: 2024-10-29T06:46:07-07:00 The transcription factor (TF) cone-rod homeobox (CRX) is essential for the differentiation and maintenance of photoreceptor cell identity. Several human CRX variants cause degenerative retinopathies, but most are variants of uncertain significance. We performed a deep mutational scan (DMS) of nearly all possible single amino acid substitutions in CRX using a cell-based transcriptional reporter assay, curating a high-confidence list of nearly 2000 variants with altered transcriptional activity. In the structured homeodomain, activity scores closely aligned to a predicted structure and demonstrated position-specific constraints on amino acid substitution. In contrast, the intrinsically disordered transcriptional effector domain displayed a qualitatively different pattern of substitution effects, following compositional constraints without specific residue position requirements in the peptide chain. These compositional constraints were consistent with the acidic exposure model of transcriptional activation. We evaluated the performance of the DMS assay as a clinical variant classification tool using gold-standard classified human variants from ClinVar, identifying pathogenic variants with high specificity and moderate sensitivity. That this performance could be achieved using a synthetic reporter assay in a foreign cell type, even for a highly cell type-specific TF like CRX, suggests that this approach shows promise for DMS of other TFs that function in cell types that are not easily accessible. Together, the results of the CRX DMS identify molecular features of the CRX effector domain and demonstrate utility for integration into the clinical variant classification pipeline. Full Article
cli A Comprehensive Guide to Long-Acting Injectable Antipsychotics for Primary Care Clinicians By www.jabfm.org Published On :: 2024-10-25T09:26:14-07:00 We propose a paper that provides education on commonly used long-acting injectable antipsychotics (LAIs) to improve primary care based mental health interventions in patients with severe mental illnesses (SMIs) such as schizophrenia, schizoaffective disorder, and bipolar disorders. With the expanding interface of primary care and psychiatry across all healthcare settings, it has become increasingly important for primary care clinicians to have a broader understanding of common psychiatric treatments, including LAIs. Long-acting injectable antipsychotics have been shown to be helpful in significantly improving treatment adherence, preventing disease progression, improving treatment response, decreasing readmission rates, and reducing social impairment. We discuss evidence-based indications and guidelines for use of long-acting injectable antipsychotics. We provide an overview of the treatment of SMI with LAIs, mainly focusing on the most commonly used long-acting injectable antipsychotics, advantages and disadvantages of each, along with outlining important clinical pearls for ease of practical application. Equipped with increased familiarity and understanding of these essential therapies, primary care clinicians can better facilitate early engagement with psychiatric care, promote more widespread use, and thus significantly improve the wellbeing and quality of life of patients with severe mental illness. Full Article
cli Primary Care Clinicians' Interest In, and Barriers To, Medication Abortion By www.jabfm.org Published On :: 2024-10-25T09:26:14-07:00 Purpose: Providing medication abortion in the primary care setting is a promising way to increase access to abortion, a threatened service in many States. This study aimed to characterize primary care clinicians’ interest in prescribing medication abortion, what barriers they face in adding this service, and what support they need. Methods: Data were collected from 162 practicing primary care clinicians in Minnesota using an online survey with closed- and open-ended response options. Data were analyzed using descriptive statistics, group comparison analyses, and content analysis for the open-ended questions. Results: Participants represented a diverse range of ages, years in practice, credentials, genders, and urban/rural practice settings, and held mixed knowledge and attitudes around medication abortion. All demographic groups surveyed expressed interest in prescribing medication abortion, with the strongest interest represented among younger respondents, women, and those practicing in urban settings. Clinicians who provide prenatal care or who already work with these medications in other contexts were more likely to want to add medication abortion to their practices. The most common barrier to providing medication abortion was a lack of knowledge about organizational policies and about the medications themselves. To empower clinicians to provide medication abortion, respondents voiced needing their health systems to build clear processes and wanting supportive networks of other clinicians for collaboration. Conclusions: Given the interest of primary care clinicians in providing medication abortion, health systems have a valuable opportunity to increase access. Full Article
cli Clinician-Reported Barriers and Needs for Implementation of Continuous Glucose Monitoring By www.jabfm.org Published On :: 2024-10-25T09:26:14-07:00 Background: Continuous glucose monitoring (CGM) for patients with type 1 and type 2 diabetes is associated with improved clinical, behavioral, and psychosocial patient health outcomes and is part of the American Diabetes Association’s Standards of Medical Care. CGM prescription often takes place in endocrinology practices, yet 50% of adults with type 1 diabetes and 90% of all people with type 2 diabetes receive their diabetes care in primary care settings. This study examined primary care clinicians’ perceptions of barriers and resources needed to support CGM use in primary care. Methods: This qualitative study used semistructured interviews with primary care clinicians to understand barriers to CGM and resources needed to prescribe. Participants were recruited through practice-based research networks. Rapid qualitative analysis was used to summarize themes from interview findings. Results: We conducted interviews with 55 primary care clinicians across 21 states. Participants described CGM benefits for patients with varying levels of diabetes self-management and engagement. Major barriers to prescribing included lack of insurance coverage for CGM costs to patients, and time constraints. Participants identified resources needed to foster CGM prescribing, for example, clinician education, support staff, and EHR compatibility. Conclusion: Primary care clinicians face several challenges to prescribing CGM, but they are interested in learning more to help them offer it to their patients. This study reinforces the ongoing need for improved clinician education on CGM technology and continued expansion of insurance coverage for people with both type 1 and type 2 diabetes. Full Article
cli Associations Between Patient/Caregiver Trust in Clinicians and Experiences of Healthcare-Based Discrimination By www.jabfm.org Published On :: 2024-10-25T09:26:14-07:00 Background: Higher trust in healthcare providers has been linked to better health outcomes and satisfaction. Lower trust has been associated with healthcare-based discrimination. Objective: Examine associations between experiences of healthcare discrimination and patients’ and caregivers of pediatric patients’ trust in providers, and identify factors associated with high trust, including prior experience of healthcare-based social screening. Methods: Secondary analysis of cross-sectional study using logistic regression modeling. Sample consisted of adult patients and caregivers of pediatric patients from 11 US primary care/emergency department sites. Results: Of 1,012 participants, low/medium trust was reported by 26% identifying as non-Hispanic Black, 23% Hispanic, 18% non-Hispanic multiple/other race, and 13% non-Hispanic White (P = .001). Experience of any healthcare-based discrimination was reported by 32% identifying as non-Hispanic Black, 23% Hispanic, 39% non-Hispanic multiple/other race, and 26% non-Hispanic White (P = .012). Participants reporting low/medium trust had a mean discrimination score of 1.65/7 versus 0.57/7 for participants reporting high trust (P < .001). In our adjusted model, higher discrimination scores were associated with lower trust in providers (aOR 0.74, 95%CI = 0.64, 0.85). A significant interaction indicated that prior healthcare-based social screening was associated with reduced impact of discrimination on trust: as discrimination score increased, odds of high trust were greater among participants who had been screened (aOR = 1.28, 95%CI = 1.03, 1.58). Conclusions: Patients and caregivers reporting more healthcare-based discrimination were less likely to report high provider trust. Interventions to strengthen trust need structural antiracist components. Increased rapport with patients may be a potential by-product of social screening. Further research is needed on screening and trust. Full Article
cli Degradation of Obidoxime Chloride Solution for Injection upon Long-Term Storage under Field Conditions of Mediterranean Climate vs the Controlled Environment By journal.pda.org Published On :: 2024-10-22T08:20:35-07:00 Obidoxime chloride is an antidote for nerve gas intoxication. As an emergency medicine, it is being stored by the Israel Defense Forces (IDF) scattered throughout Israel in depots without a controlled environment (field conditions), thus being exposed to high and fluctuating temperatures. These conditions do not meet the manufacturer’s requirements. In addition, due to possible supply shortages, the utilization of expired batches was suggested. The current work investigated these matters. Long-term (15 years) storage under different conditions was initiated. Chemical stability and toxicity in rats were assessed. No difference was found between field conditions vs the controlled environment. The obidoxime assay remained >95% for 5 years and >90% for 7 years. The pH remained above the lower specification limit for 7–8 years. The major degradation product, 4-pyridinealdoxime, surpassed the allowed limit at 5 years. The content of total unknown impurities reached its maximum allowed by the IDF limit at 4–5 years. Threefold higher than clinically utilized doses of valid-to-date Toxogonin batches administered to rats did not cause any abnormality. However, expired batches produced significant toxic effects. Although no difference was found between storage of obidoxime ampoules when adhering to manufacturer’s recommendations vs field conditions, accumulation of degradants over the limit allowed by the IDF at 4–5 years of storage and the toxicity of the expired batches observed in rats led the IDF to a decision to shorten the shelf-life of this product from 5 to 4 years when stored in an uncontrolled environment of the Mediterranean climate. Full Article
cli Clinical review of non-invasive ventilation By erj.ersjournals.com Published On :: 2024-11-07T00:35:55-08:00 Non-invasive ventilation (NIV) is the mainstay to treat patients who need augmentation of ventilation for acute and chronic forms of respiratory failure. The last several decades have witnessed an extension of the indications for NIV to a variety of acute and chronic lung diseases. Evolving advancements in technology and personalised approaches to patient care make it feasible to prioritise patient-centred care models that deliver home-based management using telemonitoring and telemedicine systems support. These trends may improve patient outcomes, reduce healthcare costs and improve the quality of life for patients who suffer from chronic diseases that precipitate respiratory failure. Full Article
cli Reassessing Halm's clinical stability criteria in community-acquired pneumonia management By erj.ersjournals.com Published On :: 2024-11-07T00:35:55-08:00 Background Halm's clinical stability criteria have long guided antibiotic treatment and hospital discharge decisions for patients hospitalised with community-acquired pneumonia (CAP). Originally introduced in 1998, these criteria were established based on a relatively small and select patient population. Consequently, our study aims to reassess their applicability in the management of CAP in a contemporary real-world setting. Methods This cohort study included 2918 immunocompetent patients hospitalised with CAP from three hospitals in Denmark between 2017 and 2020. The primary outcome was time to achieve clinical stability as defined by Halm's criteria. Additionally, we examined recurrence of clinical instability and severe complications. Cumulative incidence function or Kaplan–Meier survival curves were used to analyse these outcomes, considering competing risks. Results The study population primarily comprised elderly individuals (median age 75 years) with significant comorbidities. The median time to clinical stability according to Halm's criteria was 4 days, with one-fifth experiencing recurrence of instability after early clinical response (stability within 3 days). Severe complications within 30 days mainly comprised mortality, with rates of 5.1% (64/1257) overall in those with early clinical response, 1.7% (18/1045) in the subgroup without do-not-resuscitate orders and 17.3% (276/1595) among the rest. Conclusion Halm's clinical stability criteria effectively classify CAP patients with different disease courses, yet achieving stability required more time in this ageing population with substantial comorbidities and more severe disease. Early clinical response indicates reduced risk of complications, especially in those without do-not-resuscitate orders. Full Article
cli Nonclinical Pharmacokinetics Study of OLX702A-075-16, N-Acetylgalactosamine Conjugated Asymmetric Small Interfering RNA (GalNAc-asiRNA) [Articles] By dmd.aspetjournals.org Published On :: 2024-10-16T09:02:03-07:00 In this study, the nonclinical pharmacokinetics of OLX702A-075-16, an RNA interference therapeutic currently in development, were investigated. OLX702A-075-16 is a novel N-acetylgalactosamine conjugated asymmetric small-interfering RNA (GalNAc-asiRNA) used for the treatment of an undisclosed liver disease. Its unique 16/21-mer asymmetric structure reduces nonspecific off-target effects without compromising efficacy. We investigated the plasma concentration, tissue distribution, metabolism, and renal excretion of OLX702A-075-16 following a subcutaneous administration in mice and rats. For bioanalysis, high-performance liquid chromatography with fluorescence detection was used. The results showed rapid clearance from plasma (0.5 to 1.5 hours of half-life) and predominant distribution to the liver and/or kidney. Less than 1% of the liver concentration of OLX702A-075-16 was detected in the other tissues. Metabolite profiling using liquid chromatography coupled with high-resolution mass spectrometry revealed that the intact duplex OLX702A-075-16 was the major compound in plasma. The GalNAc moiety was predominantly metabolized from the sense strand in the liver, with the unconjugated sense strand of OLX702A-075-16 accounting for more than 95% of the total exposure in the rat liver. Meanwhile, the antisense strand was metabolized by the sequential loss of nucleotides from the 3'-terminus by exonuclease, with the rat liver samples yielding the most diverse truncated forms of metabolites. Urinary excretion over 96 hours was less than 1% of the administered dose in rats. High plasma protein binding of OLX702A-075-16 likely inhibited its clearance through renal filtration. SIGNIFICANCE STATEMENT This study presents the first comprehensive characterization of the in vivo pharmacokinetics of GalNAc-asiRNA. The pharmacokinetic insights gained from this research will aid in understanding toxicology and efficacy, optimizing delivery platforms, and improving the predictive power of preclinical species data for human applications. Full Article
cli Development and Piloting of Implementation Strategies to Support Delivery of a Clinical Intervention for Postpartum Hemorrhage in Four sub-Saharan Africa Countries By ghspjournal.org Published On :: 2024-10-29T12:28:39-07:00 ABSTRACTIntroduction:Postpartum hemorrhage (PPH) remains the leading cause of maternal mortality. A new clinical intervention (E-MOTIVE) holds the potential to improve early PPH detection and management. We aimed to develop and pilot implementation strategies to support uptake of this intervention in Kenya, Nigeria, South Africa, and Tanzania.Methods:Implementation strategy development: We triangulated findings from qualitative interviews, surveys and a qualitative evidence synthesis to identify current PPH care practices and influences on future intervention implementation. We mapped influences using implementation science frameworks to identify candidate implementation strategies before presenting these at stakeholder consultation and design workshops to discuss feasibility, acceptability, and local adaptations. Piloting: The intervention and implementation strategies were piloted in 12 health facilities (3 per country) over 3 months. Interviews (n=58), case report forms (n=1,269), and direct observations (18 vaginal births, 7 PPHs) were used to assess feasibility, acceptability, and fidelity.Results:Implementation strategy development: Key influences included shortages of drugs, supplies, and staff, limited in-service training, and perceived benefits of the intervention (e.g., more accurate PPH detection and reduced PPH mortality). Proposed implementation strategies included a PPH trolley, on-site simulation-based training, champions, and audit and feedback. Country-specific adaptations included merging the E-MOTIVE intervention with national maternal health trainings, adapting local PPH protocols, and PPH trollies depending on staff needs. Piloting: Intervention and implementation strategy fidelity differed within and across countries. Calibrated drapes resulted in earlier and more accurate PPH detection but were not consistently used at the start. Implementation strategies were feasible to deliver; however, some instances of limited use were observed (e.g., PPH trolley and skills practice after training).Conclusion:Systematic intervention development, piloting, and process evaluation helped identify initial challenges related to intervention fidelity, which were addressed ahead of a larger-scale effectiveness evaluation. This has helped maximize the internal validity of the trial. Full Article
cli Nonclinical Profile of PF-06952229 (MDV6058), a Novel TGF{beta}RI/Activin Like Kinase 5 Inhibitor Supports Clinical Evaluation in Cancer [Drug Discovery and Translational Medicine] By jpet.aspetjournals.org Published On :: 2024-10-18T07:04:15-07:00 The development of transforming growth factor βreceptor inhibitors (TGFβRi) as new medicines has been affected by cardiac valvulopathy and arteriopathy toxicity findings in nonclinical toxicology studies. PF-06952229 (MDV6058) selected using rational drug design is a potent and selective TGFβRI inhibitor with a relatively clean off-target selectivity profile and good pharmacokinetic properties across species. PF-06952229 inhibited clinically translatable phospho-SMAD2 biomarker (≥60%) in human and cynomolgus monkey peripheral blood mononuclear cells, as well as in mouse and rat splenocytes. Using an optimized, intermittent dosing schedule (7-day on/7-day off/cycle; 5 cycles), PF-06952229 demonstrated efficacy in a 63-day syngeneic MC38 colon carcinoma mouse model. In the pivotal repeat-dose toxicity studies (rat and cynomolgus monkey), PF-06952229 on an intermittent dosing schedule (5-day on/5-day off cycle; 5 cycles, 28 doses) showed no cardiac-related adverse findings. However, new toxicity findings related to PF-06952229 included reversible hepatocellular (hepatocyte necrosis with corresponding clinically monitorable transaminase increases) and lung (hemorrhage with mixed cell inflammation) findings at ≥ targeted projected clinical efficacious exposures. Furthermore, partially reversible cartilage hypertrophy (trachea and femur in rat; femur in monkey) and partially to fully reversible, clinically monitorable decreases in serum phosphorus and urinary phosphate at ≥ projected clinically efficacious exposures were observed. Given the integral role of TGFβ in endochondral bone formation, cartilage findings in toxicity studies have been observed with other TGFβRi classes of compounds. The favorable cumulative profile of PF-06952229 in biochemical, pharmacodynamic, pharmacokinetic, and nonclinical studies allowed for its evaluation in cancer patients using the intermittent dosing schedule (7-day on/7-day off) and careful protocol-defined monitoring. SIGNIFICANCE STATEMENT Only a few TGFβRi have progressed for clinical evaluation due to adverse cardiac findings in pivotal nonclinical toxicity studies. The potential translations of such findings in patients are of major concern. Using a carefully optimized intermittent dosing schedule, PF-06952229 has demonstrated impressive pharmacological efficacy in the syngeneic MC38 colon carcinoma mouse model. Additionally, a nonclinical toxicology package without cardiovascular liabilities and generally monitorable toxicity profile has been completed. The compound presents an acceptable International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use S9-compliant profile for the intended-to-treat cancer patients. Full Article
cli The Dawning of a New Age of Preclinical Analgesic Drug Screening [Viewpoint] By jpet.aspetjournals.org Published On :: 2024-10-18T07:04:15-07:00 Full Article
cli Preclinical Investigation of [212Pb]Pb-DOTAM-GRPR1 for Peptide Receptor Radionuclide Therapy in a Prostate Tumor Model By jnm.snmjournals.org Published On :: 2024-11-01T04:25:31-07:00 The role of gastrin-releasing peptide receptor (GRPR) in various diseases, including cancer, has been extensively studied and has emerged as a promising therapeutic target. In this study, we successfully achieved the use of [212Pb]Pb-DOTAM-GRPR1, comprising the α-particle generator, 212Pb, combined with a GRPR-targeting peptide, GRPR1, in a prostate cancer model. Methods: Pharmacokinetics, toxicity, radiation dosimetry, and efficacy were assessed in GRPR-positive prostate tumor–bearing mice after intravenous administration of [212Pb]Pb-DOTAM-GRPR1 (where DOTAM is 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane). Results: Preclinical studies have shown tumor targeting of up to 5 percent injected dose per gram over 24 h, and optimization of the drug formulation and quantity has led to minimized oxidation and off-target binding, respectively. Particularly, an increase in peptide amount from 28 to 280 ng was shown to reduce off-target uptake, especially at the level of the pancreas, by about 30%. Furthermore, dosimetry studies confirmed the kidney as the dose-limiting organ, and toxicity studies revealed that a nontoxic dose of up to 1,665 kBq could be injected into mice. Efficacy studies indicated a median survival time of 9 wk in the control group, which received only a buffer solution, compared with 19 wk in the group that received 4 injections of 370 kBq at 3-wk intervals. Conclusion: Taken together, these combined data demonstrate the safety, tolerability, and efficacy of [212Pb]Pb-DOTAM-GRPR1, thus warranting further exploration in clinical trials. Full Article
cli Preclinical Evaluation of 226Ac as a Theranostic Agent: Imaging, Dosimetry, and Therapy By jnm.snmjournals.org Published On :: 2024-11-01T04:25:31-07:00 226Ac (t1/2 = 29.37 h) has been proposed as a theranostic radioisotope leveraging both its diagnostic -emissions and therapeutic α-emissions. 226Ac emits 158 and 230 keV -photons ideal for quantitative SPECT imaging and acts as an in vivo generator of 4 high-energy α-particles. Because of these nuclear decay properties, 226Ac has potential to act as a standalone theranostic isotope. In this proof-of-concept study, we evaluated a preclinical 226Ac-radiopharmaceutical for its theranostic efficacy and present the first 226Ac-targeted α-therapy study. Methods: 226Ac was produced at TRIUMF and labeled with the chelator-peptide bioconjugate crown-TATE. [226Ac]Ac-crown-TATE was selected to target neuroendocrine tumors in male NRG mice bearing AR42J tumor xenografts for SPECT imaging, biodistribution, and therapy studies. A preclinical SPECT/CT scanner acquired quantitative images reconstructed from both the 158 and the 230 keV emissions. Mice in the biodistribution study were euthanized at 1, 3, 5, 24, and 48 h after injection, and internal radiation dosimetry was derived for the tumor and organs of interest to establish appropriate therapeutic activity levels. Mice in the therapy study were administered 125, 250, or 375 kBq treatments and were monitored for tumor size and body condition. Results: We present quantitative SPECT images of the in vivo biodistribution of [226Ac]Ac-crown-TATE, which showed agreement with ex vivo measurements. Biodistribution studies demonstrated high uptake (>30%IA/g at 5 h after injection) and retention in the tumor, with an estimated mean absorbed dose coefficient of 222 mGy/kBq. [226Ac]Ac-crown-TATE treatments significantly extended the median survival from 7 d in the control groups to 16, 24, and 27 d in the 125, 250, and 375 kBq treatment groups, respectively. Survival was prolonged by slowing tumor growth, and no weight loss or toxicities were observed. Conclusion: This study highlights the theranostic potential of 226Ac as a standalone therapeutic isotope in addition to its demonstrated diagnostic capabilities to assess dosimetry in matched 225Ac-radiopharmaceuticals. Future studies will investigate maximum dose and toxicity to further explore the therapeutic potential of 226Ac-radiopharmaceuticals. Full Article
cli [18F]AlF-NOTA-FAPI-04 PET/CT for Predicting Pathologic Response of Resectable Esophageal Squamous Cell Carcinoma to Neoadjuvant Camrelizumab and Chemotherapy: A Phase II Clinical Trial By jnm.snmjournals.org Published On :: 2024-11-01T04:25:31-07:00 This single-center, single-arm, phase II trial (ChiCTR2100050057) investigated the ability of 18F-labeled fibroblast activation protein inhibitor ([18F]AlF-NOTA-FAPI-04, denoted as 18F-FAPI) PET/CT to predict the response to neoadjuvant camrelizumab plus chemotherapy (nCC) in locally advanced esophageal squamous cell carcinoma (LA-ESCC). Methods: This study included 32 newly diagnosed LA-ESCC participants who underwent 18F-FAPI PET/CT at baseline, of whom 23 also underwent scanning after 2 cycles of nCC. The participants underwent surgery after 2 cycles of nCC. Recorded PET parameters included maximum, peak, and mean SUVs and tumor-to-background ratios (TBRs), metabolic tumor volume, and total lesion FAP expression. PET parameters were compared between patient groups with good and poor pathologic responses, and the predictive performance for treatment response was analyzed. Results: The good and poor response groups each included 16 participants (16/32, 50.0%). On 18F-FAPI PET/CT, the posttreatment SUVs were significantly lower in good responders than in poor responders, whereas the changes in SUVs with treatment were significantly higher (all P < 0.05). SUVmax (area under the curve [AUC], 0.87; P = 0.0026), SUVpeak (AUC, 0.89; P = 0.0017), SUVmean (AUC, 0.88; P = 0.0021), TBRmax (AUC, 0.86; P = 0.0031), and TBRmean (AUC, 0.88; P = 0.0021) after nCC were significant predictors of pathologic response to nCC, with sensitivities of 63.64%–81.82% and specificities of 83.33%–100%. Changes in SUVmax (AUC, 0.81; P = 0.0116), SUVpeak (AUC, 0.82; P = 0.0097), SUVmean (AUC, 0.81; P = 0.0116), and TBRmean (AUC, 0.74; P = 0.0489) also were significant predictors of the pathologic response to nCC, with sensitivities and specificities in similar ranges. Conclusion: 18F-FAPI PET/CT parameters after treatment and their changes from baseline can predict the pathologic response to nCC in LA-ESCC participants. Full Article
cli Impact of 18F-FES PET/CT on Clinical Decisions in the Management of Recurrent or Metastatic Breast Cancer By jnm.snmjournals.org Published On :: 2024-11-01T04:25:31-07:00 The clinical impact of 16α-18F-fluoro-17β-estradiol (18F-FES) PET/CT on patient management has not been well investigated. The aim of this study was to assess the clinical impact of 18F-FES PET/CT on the management of patients with recurrent or metastatic breast cancer. Methods: Study subjects were identified retrospectively from a database of a prospective trial for postmarketing surveillance of 18F-FES between 2021 and 2023. Patients who were suspected or known to have recurrent or metastatic estrogen receptor–positive breast cancer based on a routine standard workup were included. Planned management before and actual management after 18F-FES PET/CT were assessed by 2 experienced medical oncologists via medical chart review. A 5-point questionnaire was provided to evaluate the value of 18F-FES PET/CT for management planning. The rate of intention-to-treat and interdisciplinary changes, and the impact of 18F-FES PET/CT according to PET/CT result or clinical indication, were examined. Results: Of the 344 included patients, 120 (35%) experienced a change in management after 18F-FES PET/CT. In 139 (40%) patients,18F-FES PET/CT supported the existing management decision without a change in management. Intention-to-treat and interdisciplinary changes accounted for 64% (77/120) and 68% (82/120) of all changes, respectively. A higher rate of change was observed when lesions were 18F-FES–negative (44% [36/81]) than 18F-FES–positive (30% [51/172]) or mixed 18F-FES–positive/negative (36% [33/91]). Regarding clinical indications, the highest rate of change was shown when evaluating the origins of metastasis of double primary cancers (64% [9/14]). Conclusion: 18F-FES PET/CT modified the management of recurrent or metastatic breast cancer, serving as an impactful imaging modality in clinical practice. Full Article
cli Reimagining Biologically Adapted Somatostatin Receptor-Targeted Radionuclide Therapy: Perspectives Based on Personal Experience and Observations on Recent Trials By jnm.snmjournals.org Published On :: 2024-11-01T04:25:31-07:00 Full Article