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Lecithin:cholesterol acyltransferase (LCAT) deficiencies represent severe disorders characterized by aberrant cholesterol esterification in plasma, leading to life-threatening conditions. This study investigates the efficacy of Compound 2, a piperidinyl pyrazolopyridine allosteric activator that binds the membrane-binding domain of LCAT, in rescuing the activity of LCAT variants associated with disease. The variants K218N, N228K, and G230R, all located in the cap and lid domains of LCAT, demonstrated notable activity restoration in response to Compound 2. Molecular dynamics simulations and structural modeling indicate that these mutations disrupt the lid and membrane binding domain, with Compound 2 potentially dampening these structural alterations. Conversely, variants such as M252K and F382V in the cap and a/b-hydrolase domain, respectively, exhibited limited or no rescue by Compound 2. Future research should prioritize in vivo investigations that would validate the therapeutic potential of Compound 2 and related activators in familial LCAT deficiency patients with mutations in the cap and lid of the enzyme. Significance Statement Lecithin:cholesterol acyltranferase (LCAT) catalyzes the first step of reverse cholesterol transport, namely the esterification of cholesterol in HDL particles. Somatic mutations in LCAT lead to excess cholesterol in blood plasma and, in severe cases, kidney failure. In this study we show that recently discovered small molecule activators can rescue function in LCAT deficient variants when the mutations occur in the lid and cap domains of the enzyme.
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Understanding Li+ ion diffusion pathways in Li-rich layered transition metal (TM) oxides is crucial for understanding the sluggish kinetics in anionic O2- redox. Although Li diffusion within the alkali layers undergoes a low-barrier octahedral-tetrahedral-octahedral pathway, it is less clear how Li diffuses in and out of the TM layers, particularly given the complex structural rearrangements that take place during the oxidation of O2-. Here, we develop simultaneous electron ptychography and annular dark field imaging methods to unlock the Li migration pathways in Li1.2Ni0.13Mn0.54Co0.13O2 associated with structural changes in the charge-discharge cycle. At the end of TM oxidation and before the high-voltage O oxidation plateau, we show that the Li migrating out of the TM layers occupies the alkali-layer tetrahedral sites on opposite sides of the TM layers, forming Li-Li dumbbell configurations, consistent with the density functional theory calculations. Also occurring are the TM migration and phase transition from O3 to O1 stacking, leading to unstable tetrahedral Li and the absence of Li contrast in imaging. Upon further Li deintercalation to 4.8 V, most of the tetrahedral Li are removed. After discharging to 2 V, we did not identify the reformation of tetrahedral Li but observed permanently migrated TMs at the alkali-layer sites, disfavoring the Li occupying the tetrahedral sites for diffusion. Our findings suggest a landscape of Li diffusion pathways in Li-rich layered oxides and strategies for minimizing the disruption of Li diffusion.
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OBJECTIVES: To evaluate the carbon footprint of the perioperative transurethral resection of bladder tumour (TURBT) pathway from decision to treat to postoperative discharge, and model potential greenhouse gas (GHG) emissions reduction strategies. MATERIALS AND METHODS: This process-based attributional cradle-to-grave life-cycle assessment (LCA) of GHG emissions modelled the perioperative TURBT pathway at a hospital in Southwest England. We included travel, energy and water use, all reusable and consumable items, and laundry and equipment sterilisation. Resource use for 30 patients undergoing surgery was recorded to understand average GHG emissions and the inter-case variability. Sensitivity analysis was performed for manufacturing location, pharmaceutical manufacturing carbon-intensity, and theatre list utilisation. RESULTS: The median (interquartile range) perioperative TURBT carbon footprint was 131.8 (119.8-153.6) kg of carbon dioxide equivalent. Major pathway categories contributing to GHG emissions were surgical equipment (22.2%), travel (18.6%), gas and electricity (13.3%), and anaesthesia/drugs and associated adjuncts (27.0%), primarily due to consumable items and processes. Readily modifiable GHG emissions hotspots included patient travel for preoperative assessment, glove use, catheter use, irrigation delivery and extraction, and mitomycin C disposal. GHG emissions were higher for those admitted as inpatients after surgery. CONCLUSIONS: This cradle-to-grave LCA found multiple modifiable GHG emissions hotspots. Key mitigation themes include minimising avoidable patient travel, rationalising equipment use, optimally filling operating theatre lists, and safely avoiding postoperative catheterisation and hospital admission where possible. A crucial next step is to design and deliver an implementation strategy for the environmentally sustainable changes demonstrated herein.
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PURPOSE: Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase I study. We report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase I patients and seven expansion cohorts. METHODS: This is an investigator-initiated, multicenter, phase I trial. CaboNivo doublet expansion cohorts included (1) mUC, (2) mRCC, and (3) adenocarcinoma of the bladder/urachal; CaboNivoIpi triplet expansion cohorts included (1) mUC, (2) mRCC, (3) penile cancer, and (4) squamous cell carcinoma of the bladder and other rare GU tumors (ClinicalTrials.gov identifier: NCT02496208). RESULTS: The study enrolled 120 patients treated with CaboNivo (n = 64) or CaboNivoIpi (n = 56), with a median follow-up of 49.2 months. In 108 evaluable patients (CaboNivo n = 59; CaboNivoIpi n = 49), the ORR was 38% (complete response rate 11%) and the median duration of response was 20 months. The ORR was 42.4% for mUC, 62.5% for mRCC (n = 16), 85.7% for squamous cell carcinoma of the bladder (n = 7), 44.4% for penile cancer (n = 9), and 50.0% for renal medullary carcinoma (n = 2). Grade ≥ 3 treatment-related adverse events occurred in 84% of CaboNivo patients and 80% of CaboNivoIpi patients. CONCLUSION: CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in patients with multiple GU malignancies, especially clear cell RCC, urothelial carcinoma, and rare GU tumors such as squamous cell carcinoma of the bladder, small cell carcinoma of the bladder, adenocarcinoma of the bladder, renal medullary carcinoma, and penile cancer.
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Background and Objective: Public health nurses (PHNs) are vital in the local implementation of the provisions of the Universal Healthcare (UHC) Act of 2019. However, they need adequate competencies in health systems approach to successfully implement the provisions of the law. In response to this, a leadership development course for public health nurses (LDC-PHN), anchored on the building blocks of health systems, was developed and implemented. This paper aims to describe the extent to which training participants have applied the competencies acquired from the LDC-PHN as manifested by the workplace application of their capstone projects. Methods: Following Kirkpatrick's Model of Evaluation, we used a multi-method study design to evaluate the extent of the participants' workplace application of acquired competencies. Sources of data included the Workplace Application Plan (WAP) accomplished by each participant, a questionnaire to determine the perceived implementation status of the participants' capstone project, interviews, and focus group discussions (FGDs) conducted with selected participants and their supervisors, and observation visits. Data were collected from May to December 2022. Data from the semistructured interviews and FGDs were analyzed through content analysis, while the participants' perceived status of their capstone project implementation was summarized as frequencies. Results: Majority of the participants (61.9%) reported partial implementation of their capstone project while 16.77% reported full implementation. Capstone project implementation was facilitated by the support received from their supervisors and local chief executives. Barriers identified included the demands of the COVID-19 pandemic and the challenges imposed by the events before and after the 2022 Philippine National elections. Major themes emerged from the interviews conducted among participants and their supervisors. The workplace application of the training program outcomes, based on participants' perspectives, yielded increased capacity to lead and innovate, improved ability to advocate for capstone project implementation, transferability of acquired skill sets, and improved population outcomes. From supervisors' perspectives, workplace application of training program outcomes include increased ability of PHNs to deliver health services, and visible enhancement of leadership and supervision skills among PHNs. Conclusion: Given ample support and opportunities, and despite the barriers and challenges they faced, LDC-PHN participants, in general, utilized and applied the competencies they gained from the course in their actual work setting. Course graduates participated in health systems strengthening at various capacities by acting upon their capstone projects that addressed UHC challenges within their particular work settings.
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Background and Objective: Midwives play a vital role in the attainment of Sustainable Development Goals related to the health and well-being of mothers and newborns. Strengthening the leadership and management capacities of midwives is pivotal to the fulfillment of their mandate beyond assisting in birth and delivery. The study explores the perspectives of midwives about professional education and practice, which are aimed to serve as bases for developing a leadership course for midwives to enhance their roles in public health. Methods: The study employed a descriptive-qualitative design. Using a semi-structured questionnaire, online focus group discussions (FGDs) with midwives from the academe, professional organization, and clinical practice were conducted. Through directed content analysis, the gathered information was analyzed to include the participants' insights on midwifery competencies, teaching methods and assessment strategies, supplementary courses and training, and factors affecting midwifery practice. Results: A total of eleven (11) participants contributed to the FGDs, which included midwives from the academe (dean, faculty), professional organization (board member of the Professional Regulation Commission), and clinical practice (public and private institutions). Notably, participants shared their perspectives regarding the similarities/differences in the terminal competencies of midwifery programs. The demands of outcomes-based education, coupled by the shift to online learning due to the pandemic, pushed the need for modifications in program delivery for the students. Results highlighted the need for supplementary courses and capacity building on leadership and management, research, and interprofessional collaboration. Midwives shared factors that affect their professional practice, which include insufficient training, inadequate manpower, and differences in expectations/standards in task performance. Conclusion: The findings indicate the need to develop capacity-building courses for midwives to enhance their contribution towards universal health care. The results of this study also highlight the importance of understanding and improving the competencies of midwives across the building blocks of the health system, which include health service delivery, human resources for health, health information systems, health financing, health governance, and health regulation. Notably, key concepts recommended for the Leadership Development Course for Midwives include: leadership and management, research, and interprofessional collaboration.
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Respiratory complex I (R-CI) is an essential enzyme in the mitochondrial electron transport chain but also a major source of reactive oxygen species (ROS), which are implicated in neurodegenerative diseases and ageing. While the mechanism of ROS production by R-CI is well-established, the feedback of ROS on R-CI activity is poorly understood. Here, we perform EPR spectroscopy on R-CI incorporated in artificial membrane vesicles to reveal that ROS (particularly hydroxyl radicals) reduce R-CI activity by making the membrane more polar and by increasing its hydrogen bonding capability. Moreover, the mechanism that we have uncovered reveals that the feedback of ROS on R-CI activity via the membrane is transient and not permanent; lipid peroxidation is negligible for the levels of ROS generated under these conditions. Our successful use of modular proteoliposome systems in conjunction with EPR spectroscopy and other biophysical techniques is a powerful approach for investigating ROS effects on other membrane proteins.
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BACKGROUND: Understanding knowledge and attitudes of health care professionals (HCPs) towards adverse drug reaction (ADR) reporting can inform educational interventions promoting ADR reporting. OBJECTIVE: To explore knowledge, attitudes, practice, and barriers of local HCPs towards ADR reporting. METHODS: Focus groups involving HCPs from different settings were organized to help develop a questionnaire. The questionnaire was validated and disseminated to pharmacists, physicians, dentists and nurses practicing in Malta. A review of ADR reports reported in Malta from 2004 to 2021 was carried out to contextualise questionnaire findings. RESULTS: Overall, HCPs (n = 374) had good knowledge on pharmacovigilance and a positive attitude towards ADR reporting however nurses were found to be less knowledgeable than physicians, dentists, and pharmacists. The main barrier for not reporting ADRs was difficulty to understand whether an adverse event occurred (n = 187). A total of 2581 ADR reports were reported in Malta. Among HCPs, physicians and dentists reported most ADRs (1060 reports), followed by pharmacists (307 reports) and nurses (257 reports). CONCLUSION: Further ADR educational and promotional efforts are needed to increase awareness on the importance of quality ADR reporting and increase the number of ADR reports reported by local HCPs.
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OBJECTIVE: To estimate the occurrence and severity of deformational plagiocephaly among infants. METHODS: A hospital-based, cross-sectional study was done in the pediatric ward of a tertiary care hospital between April 1, 2022 to October 31, 2022. Cranial Vault Asymmetry Index (CVAI) and Argenta Clinical Classification were applied to consecutive infants aged 1 month to 1 year till the calculated sample size was achieved. RESULTS: 67 infants were recruited and the occurrence of deformational plagiocephaly in the sample was estimated to be 46.3%. Level 2 severity of deformational plagiocephaly was the commonest, while as per the Argenta classification, majority belonged to type I (39.2%). Male gender and developmental delay were the significant risk factors for plagiocephaly with an odds ratio (95% CI) of 3.73 (1.23, 11.26) and 19.25 (2.31, 160.3), respectively. CONCLUSION: A high occurrence of deformational plagiocephaly was found in infants studied. There is a need for more studies to further corroborate these findings and study its associated factors.
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Plagiocefalia no Sinostótica , Lactante , Niño , Humanos , Masculino , Plagiocefalia no Sinostótica/diagnóstico , Plagiocefalia no Sinostótica/epidemiología , Estudios Transversales , Estudios Retrospectivos , Oportunidad Relativa , Factores de RiesgoRESUMEN
The Getting It Right First Time (GIRFT) programme is a quality improvement initiative covering the National Health Service in England. The programme aims to standardise clinical practices and improve patient and system level outcomes by utilising data-driven insights and clinically-led recommendations. There are GIRFT workstreams for every medical and surgical specialty, including urology. Defining features of the GIRFT methodology are that it is clinically led by experienced clinicians, data-driven, and specialty specific. Each specialty workstream conducts deep-dive visits to every hospital, analysing performance data and engaging with clinicians and management to identify and share improvement priorities. For urology, GIRFT has completed deep-dive visits and published reports outlining priority areas for development. Reports include recommendations pertaining to streamlining care pathways, reducing the acuity of care environments, enhancing emergency services, optimising utilisation of outpatient services, and workforce training and utilisation. The GIRFT academy provides guides for implementing best practices specific to priority areas of care. These include important disease pathways, and GIRFT-advocated innovations such as urology investigation units and urology area networks. GIRFT offers clinical transformation, cost reduction, equity in access to care, and leaner models of care that are often more environmentally sustainable. Evaluation efforts of the programme have focussed on assessing the adoption of GIRFT recommendations, understanding barriers to change, and modelling the climate impact of advocated practices.
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Mejoramiento de la Calidad , Urología , Humanos , Inglaterra , Medicina EstatalRESUMEN
Nivolumab is used to treat several different types of cancers. Although it is generally considered to be effective and well-tolerated, it has been associated with adverse effects requiring discontinuation of treatment, like many other drugs used for cancer. A 70-year-old male was switched from sunitinib to nivolumab for renal cell carcinoma. The patient developed persistent hypothyroidism, onycholysis, and pneumonitis at nivolumab cycle 6, 10, and 11, respectively. Using the Naranjo causality method, the likelihood of causality was deemed "probable" for pneumonitis and hypothyroidism and "possible" for onycholysis. Nivolumab was eventually discontinued due to disease progression, rather than safety concerns. Eudravigilance, the European pharmacovigilance database, was searched for all nivolumab-related individual case safety reports from Malta, up to September 4, 2023. Six reports were identified in Malta, although the 3 events identified in this case report were not reported, suggesting under-reporting in Malta. This case report identified an uncommon nivolumab adverse drug reaction (ADR), onycholysis and showed how, despite the occurrence of 3 ADRs, it was its lack of efficacy rather than its safety which led to its discontinuation in this particular patient.
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Background Children with nephrotic syndrome (NS) have a higher risk of cardiovascular morbidity. Studies on the evaluation of arterial stiffness and endothelial function and its predictive risk factors in these children are limited. Objective The primary objective of the study was to determine arterial stiffness by measuring carotid intimal medial thickness, flow-mediated dilatation, and physiological parameters in children with nephrotic syndrome to predict the risk of premature atherosclerosis as compared to controls. Participants A total number of 33 children with NS in the age group of 2-14 years in remission and 39 healthy controls were enrolled in the study. Out of 33 children with nephrotic syndrome, five were infrequently relapsing NS, eight were frequently relapsing, 16 were steroid dependent, and four were steroid-resistant NS. Intervention Relevant history, physical examination, anthropometric measurements, and laboratory investigations were done. Carotid intimal medial thickness (cIMT), flow-mediated dilatation (FMD), and other physiological parameters were measured in both children with NS and control groups. Outcome Carotid intimal medial thickness (cIMT), flow-mediated dilatation (FMD), and other physiological parameters were compared between children with NS and healthy controls for detecting arterial stiffness and endothelial dysfunction. Results Dyslipidaemia was seen in more than 50% of children during remission. There was neither significant difference in mean cIMT in the common carotid artery nor FMD between the control and study groups. There was a trend of lower Reactive Hyperemia Index (RHI) in children with NS. Conclusion Dyslipidemia persists even during the remission phase in NS. No statistically significant difference is observed in cIMT and percentage proportionate change in FMD in both the study and control groups. Nevertheless, RHI is notably lower in children with NS. These findings need further validation in future studies.
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OBJECTIVES: To estimate the difference in serum chloride levels between children receiving 5% Dextrose in Ringer's Lactate (RLD5) vs. 5% Dextrose Normal Saline (DNS) and to estimate the incidence of dyselectrolytemia, hyperchloremic metabolic acidosis (HCMA), acute kidney injury (AKI) and all-cause mortality in both groups. METHODS: A randomised controlled trial was conducted in non-critically ill children aged 6 mo to 14 y, admitted between August 2021 and July 2022, requiring intravenous fluids. A sample size of 140 was estimated and randomised, with controls receiving 5% DNS and the intervention group receiving RLD5. Kidney function tests and blood gas analysis were done at admission, 24 h and 48 h after starting the maintenance IV fluid, and outcomes were analysed at 24 h and 48 h. Data was collected using a pre-designed data collection form that included demographic and clinical profile details, and outcomes were analysed using SPSS Version 20 software. RESULTS: Seventy-one children per group were enrolled. The mean chloride difference between the two groups at 24 and 48 h were 1.67 (p-value 0.03) and 2.78 (p-value 0.01), respectively. The incidence of AKI at 24 h and 48 h was 1.4% and 2.8% in the RLD5 group and 0% and 1.4% in the DNS group, respectively. At 24 h and 48 h, 2.8% and 2.8% of children had HCMA in the RLD5 group, and 14% and 4.2% had HCMA in the DNS group, respectively. There was no mortality in either group. CONCLUSIONS: Though clinically insignificant, there was a statistically significant difference in the serum chloride levels between the groups.
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Oxygen redox cathodes, such as Li1.2Ni0.13Co0.13Mn0.54O2, deliver higher energy densities than those based on transition metal redox alone. However, they commonly exhibit voltage fade, a gradually diminishing discharge voltage on extended cycling. Recent research has shown that, on the first charge, oxidation of O2- ions forms O2 molecules trapped in nano-sized voids within the structure, which can be fully reduced to O2- on the subsequent discharge. Here we show that the loss of O-redox capacity on cycling and therefore voltage fade arises from a combination of a reduction in the reversibility of the O2-/O2 redox process and O2 loss. The closed voids that trap O2 grow on cycling, rendering more of the trapped O2 electrochemically inactive. The size and density of voids leads to cracking of the particles and open voids at the surfaces, releasing O2. Our findings implicate the thermodynamic driving force to form O2 as the root cause of transition metal migration, void formation and consequently voltage fade in Li-rich cathodes.
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OBJECTIVES: To assess greenhouse gas (GHG) emissions from a regional hospital laundry unit, and model ways in which these can be reduced. DESIGN: A cradle to grave process-based attributional life-cycle assessment. SETTING: A large hospital laundry unit supplying hospitals in Southwest England. POPULATION: All laundry processed through the unit in 2020-21 and 2021-22 financial years. PRIMARY OUTCOME MEASURE: The mean carbon footprint of processing one laundry item, expressed as in terms of the global warming potential over 100 years, as carbon dioxide equivalents (CO2e). RESULTS: Average annual laundry unit GHG emissions were 2947 t CO2e. Average GHG emissions were 0.225 kg CO2e per item-use and 0.5080 kg CO2e/kg of laundry. Natural gas use contributed 75.7% of on-site GHG emissions. Boiler electrification using national grid electricity for 2020-2022 would have increased GHG emissions by 9.1%, however by 2030 this would reduce annual emissions by 31.9% based on the national grid decarbonisation trend. Per-item transport-related GHG emissions reduce substantially when heavy goods vehicles are filled at ≥50% payload capacity. Single-use laundry item alternatives cause significantly higher per-use GHG emissions, even if reusable laundry were transported long distances and incinerated at the end of its lifetime. CONCLUSIONS: The laundry unit has a large carbon footprint, however the per-item GHG emissions are modest and significantly lower than using single-use alternatives. Future electrification of boilers and optimal delivery vehicle loading can reduce the GHG emissions per laundry item.
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Huella de Carbono , Gases de Efecto Invernadero , Humanos , Efecto Invernadero , Dióxido de Carbono , HospitalesRESUMEN
To date, there is no published overview of the drug pipeline in granulomatosis with polyangiitis (GPA), a rare disease. The aim of this study was to identify clinical trials from two study repositories. A review of clinical trials was conducted using publicly available data. Clinicaltrials.gov and International Clinical Trials Registry Platform were searched from inception until 25 September 2022. Only GPA-specific studies were included; these were described in detail. A total of 137 studies were identified in the trial repositories, of which 108 (79%) studies were found to concern GPA. Of these 108 studies, 67 enrolled GPA patients to investigate pharmacotherapy in this disease (62%). Most studies included all severity types (n = 51; 76%); the scope of almost half of the studies was remission induction (n = 33; 49%). The drug class which was by the most widely investigated in trials was the non-corticosteroid immunosuppressant drug class (46; 68.7%), monoclonal antibodies (32; 47.8%), and corticosteroids (31; 46.3%). There is a need for more GPA trials to generate evidence on effectiveness in terms of severity-specificity and maintenance of remission.
The pharmacological treatment of granulomatosis with polyangiitis: a review of clinical trials To date, there is no published overview of the drug pipeline in granulomatosis with polyangiitis (referred to in this paper as GPA), a rare disease. The aim of this study was to identify such studies from two study archives. Clinicaltrials.gov and International Clinical Trials Registry Platform (ICTRP) were searched from inception until 25th September 2022. Studies recruiting GPA patients were included; these were described in detail. A total of 137 studies were identified in the trial repositories, of which 108 were found to concern GPA. Of these 108 studies, 67 enrolled GPA patients to investigate the treatment of this disease through the administration of drugs. Most studies included all severity types (n = 51); the scope of almost half of the studies was to induce remission (n = 33). The drug classes which were the most widely investigated in trials were non-corticosteroid immunosuppressant drugs (n = 46), monoclonal antibodies (n = 32), and corticosteroids (n = 31). There is a need for more GPA clinical trials to generate evidence on effectiveness of drugs in terms of severity-specificity and maintenance of remission.
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Abstract Objective: This study aimed to review evidence from randomized controlled trials (RCTs) to describe: 1) the active ingredients and desensitizing toothpaste brands; 2) the evaluation of these active ingredients over time, and 3) the fluoride and abrasive content in the formulations designed to treat dentin hypersensitivity (DH). Methodology: In total, 138 RCTs and their tested toothpastes were included. Searches were updated up to August 19, 2021. Formulations, reported brands, active ingredients over time, and type of fluoride (ionizable or ionic fluoride) and abrasive (calcium or silica-based) were analyzed (PROSPERO #CRD42018086815). Results: Our trials assessed 368 toothpaste formulations, including 34 placebo (9%), 98 control toothpastes with fluoride (27%), and 236 (64%) with active ingredients to treat DH. We tested the following active ingredients: potassium compounds (n=68, 19%), calcium sodium phosphosilicate (CSP) (n=37, 10%), strontium compounds (n=28, 8%), arginine (n=29, 8%), stannous fluoride (SnF2) (n=21, 6%), hydroxyapatite (n=9, 2%), potassium combined with another active ingredient (n=19, 5%), inorganic salt compounds (n=11, 3%), citrate (n=5, 1%), formaldehyde (n=3, 1%), herbal (n=4, 1%), copolymer (n=1, 0.5%), and trichlorophosphate (TCP) (n=1, 0.5%). The number of toothpaste formulations increased since 1968, with the greatest increment after 2010. Most toothpastes described their type of fluoride as sodium monofluorphosphate (MFP) (n=105, 29%) and NaF (n=82, 22%), with silica-based (n=84, 23%) and calcium-based (n=64, 17%) abrasives. Conclusion: Patients and dentists enjoy an increasing number of brands and active ingredients to decide what desensitizing toothpaste to use. The most common types of fluoride are MFP and NaF.