The Genetic Discrimination Observatory: confronting novel issues in genetic discrimination.

Genetic discrimination (GD) is the differential or unfair profiling of an individual on the basis of genetic data. This article summarizes the actions of the Genetic Discrimination Observatory (GDO) in addressing GD and recent developments in GD since late 2020. It shows how GD can take many forms in today's rapidly evolving society.

Therapeutic drug monitoring of liposomal amphotericin B in children. Are we there yet? A systematic review.

INTRODUCTION: Therapeutic drug monitoring (TDM) is a tool that supports personalized dosing, but its role for liposomal amphotericin B (L-amb) is unclear. This systematic review assessed the evidence for L-amb TDM in children. OBJECTIVES: To evaluate the concentration-efficacy relationship, concentration-toxicity relationship and pharmacokinetic/pharmacodynamic (PK/PD) variability of L-amb in children. METHODS: We systematically reviewed PubMed and Embase databases following PRISMA guidelines. Eligible studies included L-amb PK/PD studies in children aged 0-18 years. Review articles, case series of 600 mg·h/L for nephrotoxicity. L-amb doses of 2.5-10 mg/kg/day were reported to achieve Cmax/MIC > 25 using an MIC of 1 mg/L. CONCLUSIONS: While significant PK variability was observed in children, evidence to support routine L-amb TDM was limited. Further studies on efficacy and toxicity benefits are required before routine TDM of L-amb can be recommended.

High throughput screening identifies dasatinib as synergistic with trametinib in low grade serous ovarian carcinoma.

BACKGROUND: Low grade serous ovarian carcinoma (LGSOC) is a distinct histotype of ovarian cancer characterised high levels of intrinsic chemoresistance, highlighting the urgent need for new treatments. High throughput screening in clinically-informative cell-based models represents an attractive strategy for identifying candidate treatment options for prioritisation in clinical studies. METHODS: We performed a high throughput drug screen of 1610 agents across a panel of 6 LGSOC cell lines (3 RAS/RAF-mutant, 3 RAS/RAF-wildtype) to identify novel candidate therapeutic approaches. Validation comprised dose-response analysis across 9 LGSOC models and 5 high grade serous comparator lines. RESULTS: 16 hits of 1610 screened compounds were prioritised for validation based on >50% reduction in nuclei counts in over half of screened cell lines at 1000 nM concentration. 11 compounds passed validation, and the four agents of greatest interest (dasatinib, tyrosine kinase inhibitor; disulfiram, aldehyde dehydrogenase inhibitor; carfilzomib, proteasome inhibitor; romidepsin, histone deacetylase inhibitor) underwent synergy profiling with the recently approved MEK inhibitor trametinib. Disulfiram demonstrated excellent selectivity for LGSOC versus high grade serous ovarian carcinoma comparator lines (P = 0.003 for IC50 comparison), while the tyrosine kinase inhibitor dasatinib demonstrated favourable synergy with trametinib across multiple LGSOC models (maximum zero interaction potency synergy score 46.9). The novel, highly selective Src family kinase (SFK) inhibitor NXP900 demonstrated a similar trametinib synergy profile to dasatinib, suggesting that SFK inhibition is the likely driver of synergy. CONCLUSION: Dasatinib and other SFK inhibitors represent novel candidate treatments for LGSOC and demonstrate synergy with trametinib. Disulfiram represents an additional treatment strategy worthy of investigation.

Preclinical 3D model screening reveals digoxin as an effective therapy for a rare and aggressive type of endometrial cancer.

OBJECTIVE: Dedifferentiated endometrial carcinoma (DDEC) characterized by SWItch/Sucrose Non-Fermentable (SWI/SNF) complex inactivation is a highly aggressive type of endometrial cancer without effective systemic therapy options. Its uncommon nature and aggressive disease trajectory pose significant challenges for therapeutic progress. To address this obstacle, we focused on developing preclinical models tailored to this tumor type and established patient tumor-derived three-dimensional (3D) spheroid models of DDEC. METHODS: High-throughput drug repurposing screens were performed on in vitro 3D spheroid models of DDEC cell lines (SMARCA4-inactivated DDEC-1 and ARID1A/ARID1B co-inactivated DDEC-2). The dose-response relationships of the identified candidate drugs were evaluated in vitro, followed by in vivo evaluation using xenograft models of DDEC-1 and DDEC-2. RESULTS: Drug screen in 3D models identified multiple cardiac glycosides including digoxin and digitoxin as candidate drugs in both DDEC-1 and DDEC-2. Subsequent in vitro dose-response analyses confirmed the inhibitory activity of digoxin and digitoxin with both drugs showing lower IC50 in DDEC cells compared to non-DDEC endometrial cancer cells. In in vivo xenograft models, digoxin significantly suppressed the growth of DDEC tumors at clinically relevant serum concentrations. CONCLUSION: Using biologically precise preclinical models of DDEC derived from patient tumor samples, our study identified digoxin as an effective drug in suppressing DDEC tumor growth. These findings provide compelling preclinical evidence for the use of digoxin as systemic therapy for SWI/SNF-inactivated DDEC, which may also be applicable to other SWI/SNF-inactivated tumor types.

Candida parapsilosis: A systematic review to inform the World Health Organization fungal priority pathogens list.

Candida parapsilosis is globally distributed and recognised for causing an increasing proportion of invasive Candida infections. It is associated with high crude mortality in all age groups. It has been particularly associated with nosocomial outbreaks, particularly in association with the use of invasive medical devices such as central venous catheters. Candida parapsilosis is one of the pathogens considered in the WHO priority pathogens list, and this review was conducted to inform the ranking of the pathogen in the list. In this systematic review, we searched PubMed and Web of Science to find studies between 2011 and 2021 reporting on the following criteria for C. parapsilosis infections: mortality, morbidity (hospitalisation and disability), drug resistance, preventability, yearly incidence, and distribution/emergence. We identified 336 potentially relevant papers, of which 51 were included in the analyses. The included studies confirmed high mortality rates, ranging from 17.5% to 46.8%. Data on disability and sequelae were sparse. Many reports highlighted concerns with azole resistance, with resistance rates of >10% described in some regions. Annual incidence rates were relatively poorly described, although there was clear evidence that the proportion of candidaemia cases caused by C. parapsilosis increased over time. While this review summarises current data on C.parapsilosis, there remains an urgent need for ongoing research and surveillance to fully understand and manage this increasingly important pathogen.

Cryptococcosis-a systematic review to inform the World Health Organization Fungal Priority Pathogens List.

Cryptococcosis causes a high burden of disease worldwide. This systematic review summarizes the literature on Cryptococcus neoformans and C. gattii infections to inform the World Health Organization's first Fungal Priority Pathogen List. PubMed and Web of Science were used to identify studies reporting on annual incidence, mortality, morbidity, antifungal resistance, preventability, and distribution/emergence in the past 10 years. Mortality rates due to C. neoformans were 41%-61%. Complications included acute renal impairment, raised intracranial pressure needing shunts, and blindness. There was moderate evidence of reduced susceptibility (MIC range 16-32 mg/l) of C. neoformans to fluconazole, itraconazole, ketoconazole, voriconazole, and amphotericin B. Cryptococcus gattii infections comprised 11%-33% of all cases of invasive cryptococcosis globally. The mortality rates were 10%-23% for central nervous system (CNS) and pulmonary infections, and ∼43% for bloodstream infections. Complications described included neurological sequelae (17%-27% in C. gattii infections) and immune reconstitution inflammatory syndrome. MICs were generally low for amphotericin B (MICs: 0.25-0.5 mg/l), 5-flucytosine (MIC range: 0.5-2 mg/l), itraconazole, posaconazole, and voriconazole (MIC range: 0.06-0.5 mg/l). There is a need for increased surveillance of disease phenotype and outcome, long-term disability, and drug susceptibility to inform robust estimates of disease burden.

Eumycetoma causative agents: A systematic review to inform the World Health Organization priority list of fungal pathogens.

The World Health Organization, in response to the growing burden of fungal disease, established a process to develop a fungal priority pathogens list. This systematic review aimed to evaluate the epidemiology and impact of eumycetoma. PubMed and Web of Science were searched to identify studies published between 1 January 2011 and 19 February 2021. Studies reporting on mortality, inpatient care, complications and sequelae, antifungal susceptibility, risk factors, preventability, annual incidence, global distribution, and emergence during the study time frames were selected. Overall, 14 studies were eligible for inclusion. Morbidity was frequent with moderate to severe impairment of quality of life in 60.3%, amputation in up to 38.5%, and recurrent or long-term disease in 31.8%-73.5% of patients. Potential risk factors included male gender (56.6%-79.6%), younger age (11-30 years; 64%), and farming occupation (62.1%-69.7%). Mycetoma was predominantly reported in Sudan, particularly in central Sudan (37%-76.6% of cases). An annual incidence of 0.1/100 000 persons and 0.32/100 000 persons/decade was reported in the Philippines and Uganda, respectively. In Uganda, a decline in incidence from 3.37 to 0.32/100 000 persons between two consecutive 10-year periods (2000-2009 and 2010-2019) was detected. A community-based, multi-pronged prevention programme was associated with a reduction in amputation rates from 62.8% to 11.9%. With the pre-specified criteria, no studies of antifungal drug susceptibility, mortality, and hospital lengths of stay were identified. Future research should include larger cohort studies, greater drug susceptibility testing, and global surveillance to develop evidence-based treatment guidelines and to determine more accurately the incidence and trends over time.

Candida auris-a systematic review to inform the world health organization fungal priority pathogens list.

The World Health Organization (WHO) in 2022 developed a fungal priority pathogen list. Candida auris was ultimately ranked as a critical priority pathogen. PubMed and Web of Science were used to find studies published from 1 January 2011 to 18 February 2021, reporting on predefined criteria including: mortality, morbidity (i.e., hospitalization and disability), drug resistance, preventability, yearly incidence, and distribution/emergence. Thirty-seven studies were included in the final analysis. The overall and 30-day mortality rates associated with C. auris candidaemia ranged from 29% to 62% and 23% to 67%, respectively. The median length of hospital stay was 46-68 days, ranging up to 140 days. Late-onset complications of C. auris candidaemia included metastatic septic complications. Resistance rates to fluconazole were as high as 87%-100%. Susceptibility to isavuconazole, itraconazole, and posaconazole varied with MIC90 values of 0.06-1.0 mg/l. Resistance rates to voriconazole ranged widely from 28% to 98%. Resistance rates ranged between 8% and 35% for amphotericin B and 0%-8% for echinocandins. Over the last ten years, outbreaks due to C. auris have been reported in in all WHO regions. Given the outbreak potential of C. auris, the emergence and spread of MDR strains, and the challenges associated with its identification, and eradication of its environmental sources in healthcare settings, prevention and control measures based on the identified risk factors should be evaluated for their effectiveness and feasibility. Global surveillance studies could better inform the incidence rates and distribution patterns to evaluate the global burden of C. auris infections.

Candida tropicalis-A systematic review to inform the World Health Organization of a fungal priority pathogens list.

In response to the growing global burden of fungal infections with uncertain impact, the World Health Organization (WHO) established an Expert Group to identify priority fungal pathogens and establish the WHO Fungal Priority Pathogens List for future research. This systematic review aimed to evaluate the features and global impact of invasive candidiasis caused by Candida tropicalis. PubMed and Web of Science were searched for studies reporting on criteria of mortality, morbidity (defined as hospitalization and disability), drug resistance, preventability, yearly incidence, diagnostics, treatability, and distribution/emergence from 2011 to 2021. Thirty studies, encompassing 436 patients from 25 countries were included in the analysis. All-cause mortality due to invasive C. tropicalis infections was 55%-60%. Resistance rates to fluconazole, itraconazole, voriconazole and posaconazole up to 40%-80% were observed but C. tropicalis isolates showed low resistance rates to the echinocandins (0%-1%), amphotericin B (0%), and flucytosine (0%-4%). Leukaemia (odds ratio (OR) = 4.77) and chronic lung disease (OR = 2.62) were identified as risk factors for invasive infections. Incidence rates highlight the geographic variability and provide valuable context for understanding the global burden of C. tropicalis infections. C. tropicalis candidiasis is associated with high mortality rates and high rates of resistance to triazoles. To address this emerging threat, concerted efforts are needed to develop novel antifungal agents and therapeutic approaches tailored to C. tropicalis infections. Global surveillance studies could better inform the annual incidence rates, distribution and trends and allow informed evaluation of the global impact of C. tropicalis infections.

Mucorales: A systematic review to inform the World Health Organization priority list of fungal pathogens.

The World Health Organization, in response to the growing burden of fungal disease, established a process to develop a fungal priority pathogens list (FPPL). This systematic review aimed to evaluate the epidemiology and impact of invasive fungal disease due to Mucorales. PubMed and Web of Science were searched to identify studies published between January 1, 2011 and February 23, 2021. Studies reporting on mortality, inpatient care, complications and sequelae, antifungal susceptibility, risk factors, preventability, annual incidence, global distribution, and emergence during the study time frames were selected. Overall, 24 studies were included. Mortality rates of up to 80% were reported. Antifungal susceptibility varied across agents and species, with the minimum inhibitory concentrations lowest for amphotericin B and posaconazole. Diabetes mellitus was a common risk factor, detected in 65%-85% of patients with mucormycosis, particularly in those with rhino-orbital disease (86.9%). Break-through infection was detected in 13.6%-100% on azole or echinocandin antifungal prophylaxis. The reported prevalence rates were variable, with some studies reporting stable rates in the USA of 0.094-0.117/10 000 discharges between 2011 and 2014, whereas others reported an increase in Iran from 16.8% to 24% between 2011 and 2015. Carefully designed global surveillance studies, linking laboratory and clinical data, are required to develop clinical breakpoints to guide antifungal therapy and determine accurate estimates of complications and sequelae, annual incidence, trends, and global distribution. These data will provide robust estimates of disease burden to refine interventions and better inform future FPPL.

Candida albicans-A systematic review to inform the World Health Organization Fungal Priority Pathogens List.

Candida albicans is a common fungal pathogen and amongst the leading causes of invasive candidiasis globally. This systematic review examines the characteristics and global impact of invasive infections caused by C. albicans. We searched on PubMed and Web of Science for studies reporting on criteria such as mortality, morbidity, drug resistance, preventability, yearly incidence, and distribution/emergence during the period from 2016 to 2021. Our findings indicate that C. albicans is the most common Candida species causing invasive disease and that standard infection control measures are the primary means of prevention. However, we found high rates of mortality associated with infections caused by C. albicans. Furthermore, there is a lack of data on complications and sequelae. Resistance to commonly used antifungals remains rare. Although, whilst generally susceptible to azoles, we found some evidence of increasing resistance, particularly in middle-income settings-notably, data from low-income settings were limited. Candida albicans remains susceptible to echinocandins, amphotericin B, and flucytosine. We observed evidence of a decreasing proportion of infections caused by C. albicans relative to other Candida species, although detailed epidemiological studies are needed to confirm this trend. More robust data on attributable mortality, complications, and sequelae are needed to understand the full extent of the impact of invasive C. albicans infections.

Histoplasmosis: A systematic review to inform the World Health Organization of a fungal priority pathogens list.

Histoplasmosis, a significant mycosis primarily prevalent in Africa, North and South America, with emerging reports globally, poses notable health challenges, particularly in immunocompromised individuals such as people living with HIV/AIDS and organ transplant recipients. This systematic review, aimed at informing the World Health Organization's Fungal Priority Pathogens List, critically examines literature from 2011 to 2021 using PubMed and Web of Science, focusing on the incidence, mortality, morbidity, antifungal resistance, preventability, and distribution of Histoplasma. We also found a high prevalence (22%-44%) in people living with HIV, with mortality rates ranging from 21% to 53%. Despite limited data, the prevalence of histoplasmosis seems stable, with lower estimates in Europe. Complications such as central nervous system disease, pulmonary issues, and lymphoedema due to granuloma or sclerosis are noted, though their burden remains uncertain. Antifungal susceptibility varies, particularly against fluconazole (MIC: ≥32 mg/l) and caspofungin (MICs: 4-32 mg/l), while resistance to amphotericin B (MIC: 0.125-0.16 mg/l), itraconazole (MICs: 0.004-0.125 mg/l), and voriconazole (MICs: 0.004-0.125 mg/l) remains low. This review identifies critical knowledge gaps, underlining the need for robust, globally representative surveillance systems to better understand and combat this fungal threat.

Aspergillus fumigatus-a systematic review to inform the World Health Organization priority list of fungal pathogens.

Recognizing the growing global burden of fungal infections, the World Health Organization established a process to develop a priority list of fungal pathogens (FPPL). In this systematic review, we aimed to evaluate the epidemiology and impact of invasive infections caused by Aspergillus fumigatus to inform the first FPPL. The pre-specified criteria of mortality, inpatient care, complications and sequelae, antifungal susceptibility, risk factors, preventability, annual incidence, global distribution, and emergence were used to search for relevant articles between 1 January 2016 and 10 June 2021. Overall, 49 studies were eligible for inclusion. Azole antifungal susceptibility varied according to geographical regions. Voriconazole susceptibility rates of 22.2% were reported from the Netherlands, whereas in Brazil, Korea, India, China, and the UK, voriconazole susceptibility rates were 76%, 94.7%, 96.9%, 98.6%, and 99.7%, respectively. Cross-resistance was common with 85%, 92.8%, and 100% of voriconazole-resistant A. fumigatus isolates also resistant to itraconazole, posaconazole, and isavuconazole, respectively. The incidence of invasive aspergillosis (IA) in patients with acute leukemia was estimated at 5.84/100 patients. Six-week mortality rates in IA cases ranged from 31% to 36%. Azole resistance and hematological malignancy were poor prognostic factors. Twelve-week mortality rates were significantly higher in voriconazole-resistant than in voriconazole-susceptible IA cases (12/22 [54.5%] vs. 27/88 [30.7%]; P = .035), and hematology patients with IA had significantly higher mortality rates compared with solid-malignancy cases who had IA (65/217 [30%] vs. 14/78 [18%]; P = .04). Carefully designed surveillance studies linking laboratory and clinical data are required to better inform future FPPL.

Candida glabrata (Nakaseomyces glabrata): A systematic review of clinical and microbiological data from 2011 to 2021 to inform the World Health Organization Fungal Priority Pathogens List.

Recognising the growing global burden of fungal infections, the World Health Organization (WHO) established an advisory group consisting of experts in fungal diseases to develop a Fungal Priority Pathogen List. Pathogens were ranked based on their research and development needs and perceived public health importance using a series of global surveys and pathogen characteristics derived from systematic reviews. This systematic review evaluates the features and global impact of invasive disease caused by Candida glabrata (Nakaseomyces glabrata). PubMed and Web of Science were searched for studies reporting on mortality, morbidity (hospitalization and disability), drug resistance (including isolates from sterile and non-sterile sites, since these reflect the same organisms causing invasive infections), preventability, yearly incidence, diagnostics, treatability, and distribution/emergence in the last 10 years. Candida glabrata (N. glabrata) causes difficult-to-treat invasive infections, particularly in patients with underlying conditions such as immunodeficiency, diabetes, or those who have received broad-spectrum antibiotics or chemotherapy. Beyond standard infection prevention and control measures, no specific preventative measures have been described. We found that infection is associated with high mortality rates and that there is a lack of data on complications and sequelae. Resistance to azoles is common and well described in echinocandins-in both cases, the resistance rates are increasing. Candida glabrata remains mostly susceptible to amphotericin and flucytosine. However, the incidence of the disease is increasing, both at the population level and as a proportion of all invasive yeast infections, and the increases appear related to the use of antifungal agents.

Pichia kudriavzevii (Candida krusei): A systematic review to inform the World Health Organisation priority list of fungal pathogens.

In response to the growing global threat of fungal infections, in 2020 the World Health Organisation (WHO) established an Expert Group to identify priority fungi and develop the first WHO fungal priority pathogen list (FPPL). The aim of this systematic review was to evaluate the features and global impact of invasive infections caused by Pichia kudriavzevii (formerly known as Candida krusei). PubMed and Web of Science were used to identify studies published between 1 January 2011 and 18 February 2021 reporting on the criteria of mortality, morbidity (defined as hospitalisation and length of stay), drug resistance, preventability, yearly incidence, and distribution/emergence. Overall, 33 studies were evaluated. Mortality rates of up to 67% in adults were reported. Despite the intrinsic resistance of P. kudriavzevii to fluconazole with decreased susceptibility to amphotericin B, resistance (or non-wild-type rate) to other azoles and echinocandins was low, ranging between 0 and 5%. Risk factors for developing P. kudriavzevii infections included low birth weight, prior use of antibiotics/antifungals, and an underlying diagnosis of gastrointestinal disease or cancer. The incidence of infections caused by P. kudriavzevii is generally low (∼5% of all Candida-like blood isolates) and stable over the 10-year timeframe, although additional surveillance data are needed. Strategies targeting the identified risk factors for developing P. kudriavzevii infections should be developed and tested for effectiveness and feasibility of implementation. Studies presenting data on epidemiology and susceptibility of P. kudriavzevii were scarce, especially in low- and middle-income countries (LMICs). Thus, global surveillance systems are required to monitor the incidence, susceptibility, and morbidity of P. kudriavzevii invasive infections to inform diagnosis and treatment. Timely species-level identification and susceptibility testing should be conducted to reduce the high mortality and limit the spread of P. kudriavzevii in healthcare facilities.

Features and global impact of invasive fungal infections caused by Pneumocystis jirovecii: A systematic review to inform the World Health Organization fungal priority pathogens list.

This systematic review evaluates the current global impact of invasive infections caused by Pneumocystis jirovecii (principally pneumonia: PJP), and was carried out to inform the World Health Organization Fungal Priority Pathogens List. PubMed and Web of Science were used to find studies reporting mortality, inpatient care, complications/sequelae, antifungal susceptibility/resistance, preventability, annual incidence, global distribution, and emergence in the past 10 years, published from January 2011 to February 2021. Reported mortality is highly variable, depending on the patient population: In studies of persons with HIV, mortality was reported at 5%-30%, while in studies of persons without HIV, mortality ranged from 4% to 76%. Risk factors for disease principally include immunosuppression from HIV, but other types of immunosuppression are increasingly recognised, including solid organ and haematopoietic stem cell transplantation, autoimmune and inflammatory disease, and chemotherapy for cancer. Although prophylaxis is available and generally effective, burdensome side effects may lead to discontinuation. After a period of decline associated with improvement in access to HIV treatment, new risk groups of immunosuppressed patients with PJP are increasingly identified, including solid organ transplant patients.

Talaromyces marneffei, Coccidioides species, and Paracoccidioides species-a systematic review to inform the World Health Organization priority list of fungal pathogens.

The World Health Organization, in response to the growing burden of fungal disease, established a process to develop a fungal pathogen priority list. This systematic review aimed to evaluate the epidemiology and impact of infections caused by Talaromyces marneffei, Coccidioides species, and Paracoccidioides species. PubMed and Web of Sciences databases were searched to identify studies published between 1 January 2011 and 23 February 2021 reporting on mortality, complications and sequelae, antifungal susceptibility, preventability, annual incidence, and trends. Overall, 25, 17, and 6 articles were included for T. marneffei, Coccidioides spp. and Paracoccidioides spp., respectively. Mortality rates were high in those with invasive talaromycosis and paracoccidioidomycosis (up to 21% and 22.7%, respectively). Hospitalization was frequent in those with coccidioidomycosis (up to 84%), and while the duration was short (mean/median 3-7 days), readmission was common (38%). Reduced susceptibility to fluconazole and echinocandins was observed for T. marneffei and Coccidioides spp., whereas >88% of T. marneffei isolates had minimum inhibitory concentration values ≤0.015 µg/ml for itraconazole, posaconazole, and voriconazole. Risk factors for mortality in those with talaromycosis included low CD4 counts (odds ratio 2.90 when CD4 count <200 cells/µl compared with 24.26 when CD4 count <50 cells/µl). Outbreaks of coccidioidomycosis and paracoccidioidomycosis were associated with construction work (relative risk 4.4-210.6 and 5.7-times increase, respectively). In the United States of America, cases of coccidioidomycosis increased between 2014 and 2017 (from 8232 to 14 364/year). National and global surveillance as well as more detailed studies to better define sequelae, risk factors, outcomes, global distribution, and trends are required.

Fusarium species,Scedosporium species, and Lomentospora prolificans: A systematic review to inform the World Health Organization priority list of fungal pathogens.

Recognizing the growing global burden of fungal infections, the World Health Organization established a process to develop a priority list of fungal pathogens (FPPL). In this systematic review, we aimed to evaluate the epidemiology and impact of infections caused by Fusarium spp., Scedosporium spp., and Lomentospora prolificans to inform the first FPPL. PubMed and Web of Sciences databases were searched to identify studies published between January 1, 2011 and February 23, 2021, reporting on mortality, complications and sequelae, antifungal susceptibility, preventability, annual incidence, and trends. Overall, 20, 11, and 9 articles were included for Fusarium spp., Scedosporium spp., and L. prolificans, respectively. Mortality rates were high in those with invasive fusariosis, scedosporiosis, and lomentosporiosis (42.9%-66.7%, 42.4%-46.9%, and 50.0%-71.4%, respectively). Antifungal susceptibility data, based on small isolate numbers, showed high minimum inhibitory concentrations (MIC)/minimum effective concentrations for most currently available antifungal agents. The median/mode MIC for itraconazole and isavuconazole were ≥16 mg/l for all three pathogens. Based on limited data, these fungi are emerging. Invasive fusariosis increased from 0.08 cases/100 000 admissions to 0.22 cases/100 000 admissions over the time periods of 2000-2009 and 2010-2015, respectively, and in lung transplant recipients, Scedosporium spp. and L. prolificans were only detected from 2014 onwards. Global surveillance to better delineate antifungal susceptibility, risk factors, sequelae, and outcomes is required.

Dose Monitoring of Lamotrigine Monotherapy in Pregnancy: Are Pregnant Women with Epilepsy Currently Optimally Managed? A Systematic Review.

BACKGROUND: Lamotrigine monotherapy is the first-line treatment for epilepsy in pregnant women. However, altered pharmacokinetics during pregnancy can lead to suboptimal drug levels and increased seizure risk. This systematic review aimed to evaluate current therapeutic drug monitoring (TDM) strategies for lamotrigine monotherapy in pregnant women with epilepsy and provide guidance for monitoring and dose adjustments. METHODS: A systematic search was performed using the Ovid-MEDLINE, Ovid-EMBASE, and Ovid-Cochrane Central Register of Controlled Trials databases. Studies were included if data on lamotrigine dosing, concentration, TDM strategies, efficacy, or safety were available. RESULTS: Eleven studies were analyzed, revealing heterogeneity in outcomes with selective reporting of TDM strategies; however, clear similarities were observed. Blood samples were collected every 1-3 months during pregnancy to maintain prepregnancy baseline drug levels. Lamotrigine's apparent and relative clearance increased across trimesters, particularly in the second and third trimesters, coinciding with a period of increased seizure frequency and required dose adjustments. Details on dose adjustments were limited. Some studies have proposed using the threshold of the ratio to the target concentration to predict increased seizure risk. No distinct association was observed between adverse newborn outcomes and lamotrigine dose or serum concentration. Few maternal adverse effects have been reported after delivery, confirming the necessity of empirical postpartum tapering. CONCLUSIONS: Further studies are required to establish evidence-based standardized protocols encompassing all aspects of TDM. Early interventions, such as empirical dose increases during pregnancy and postpartum tapering, and routine monitoring from preconception to the postpartum period may enhance seizure control, reducing the risk of breakthrough seizures for the mother and unborn child.

Stimulating thyrotropin receptor antibodies in early pregnancy.

OBJECTIVES: Thyrotropin-receptor antibodies (TRAb) are used to diagnose Graves' hyperthyroidism in pregnant women. Bioassays provide a measure of thyrotropin-receptor stimulatory antibodies (TSI) specifically. The objective was to measure TSI in pregnant women for establishment of a pregnancy-specific cut-off and comparison with immunoassay measurements of TRAb. METHODS: The retrospective Danish study was performed within the North Denmark Region Pregnancy Cohort (2011-2015) that includes stored biobank samples from early pregnancy (median week 10) with immunoassay measurements of thyroid function parameters and TRAb. TSI were measured in the same samples using the Turbo TSI bioassay (Quidel/Ortho-Clinical Diagnostics) with a recommended cut-off of 0.0241 IU/L in non-pregnant adults. A pregnancy-specific TSI cut-off (95-percentile) was established using Regression on Order Statistics. RESULTS: The established TSI cut-off was 0.0418 IU/L (95 % CI: 0.0417-0.0419). Among women with early pregnancy hyperthyroidism (n=438), 43 women (9.8 %) were TSI positive using the established cut-off, and these women had lower TSH (median 0.008 mIU/L) compared to women with TSI levels below 0.0241 (median TSH 0.040 mIU/L) or in the range from 0.0241 to 0.0418 (median TSH 0.033 mIU/L). Among the 438 women with early pregnancy hyperthyroidism, 22 women were positive for TSI and TRAb, 388 were negative for both, and 28 women were positive for either TSI or TRAb. CONCLUSIONS: This is the first study on TSI measurements in a large cohort of early pregnant women. A pregnancy-specific cut-off for TSI was established and agreement in the classification with immunoassay measurements of TRAb was seen in 94 % of cases.