A ruler detection method for auto-adjusting scales of shoeprint images.

Digital shoeprint comparison often requires the calibration of the image resolution so that features, such as patterns in shoeprints, can be compared on the same scale. To enable scaling, a shoeprint photograph can be taken with a forensic ruler in the same frame to obtain the pixel distance between two nearby graduations. However, manually measuring the number of pixels is a time-consuming process. Additionally, the measurement process might not be conducted accurately when the image is noisy or there is distortion in the ruler. In this study, we present an automated ruler detection method for adjusting the image scale. We show that this method can accurately estimate the image scale with a mean absolute percentage error of 3%. We also conducted automated shoeprint retrieval experiments on scale-unadjusted shoeprint images to show how the automated image scaling might be used in a common forensic process. Our results from these experiments show an increase in the retrieval performance from 0.735 to 0.929 at S1 by employing this approach to adjust the shoeprint image scales.

The PARP1 selective inhibitor saruparib (AZD5305) elicits potent and durable antitumor activity in patient-derived BRCA1/2-associated cancer models.

BACKGROUND: Poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors (PARPi) are targeted therapies approved for homologous recombination repair (HRR)-deficient breast, ovarian, pancreatic, and prostate cancers. Since inhibition of PARP1 is sufficient to cause synthetic lethality in tumors with homologous recombination deficiency (HRD), PARP1 selective inhibitors such as saruparib (AZD5305) are being developed. It is expected that selective PARP1 inhibition leads to a safer profile that facilitates its combination with other DNA damage repair inhibitors. Here, we aimed to characterize the antitumor activity of AZD5305 in patient-derived preclinical models compared to the first-generation PARP1/2 inhibitor olaparib and to identify mechanisms of resistance. METHODS: Thirteen previously characterized patient-derived tumor xenograft (PDX) models from breast, ovarian, and pancreatic cancer patients harboring germline pathogenic alterations in BRCA1, BRCA2, or PALB2 were used to evaluate the efficacy of AZD5305 alone or in combination with carboplatin or an ataxia telangiectasia and Rad3 related (ATR) inhibitor (ceralasertib) and compared it to the first-generation PARPi olaparib. We performed DNA and RNA sequencing as well as protein-based assays to identify mechanisms of acquired resistance to either PARPi. RESULTS: AZD5305 showed superior antitumor activity than the first-generation PARPi in terms of preclinical complete response rate (75% vs. 37%). The median preclinical progression-free survival was significantly longer in the AZD5305-treated group compared to the olaparib-treated group (> 386 days vs. 90 days). Mechanistically, AZD5305 induced more replication stress and genomic instability than the PARP1/2 inhibitor olaparib in PARPi-sensitive tumors. All tumors at progression with either PARPi (39/39) showed increase of HRR functionality by RAD51 foci formation. The most prevalent resistance mechanisms identified were the acquisition of reversion mutations in BRCA1/BRCA2 and the accumulation of hypomorphic BRCA1. AZD5305 did not sensitize PDXs with acquired resistance to olaparib but elicited profound and durable responses when combined with carboplatin or ceralasertib in 3/6 and 5/5 models, respectively. CONCLUSIONS: Collectively, these results show that the novel PARP1 selective inhibitor AZD5305 yields a potent antitumor response in PDX models with HRD and delays PARPi resistance alone or in combination with carboplatin or ceralasertib, which supports its use in the clinic as a new therapeutic option.

The development of a new oral health patient reported outcome measure: the New South Wales public dental services approach.

BACKGROUND: Addressing Patient Reported Outcomes (PROs) is essential for patient-centred care, shared decision making and improved health outcomes. Value-based health care systems in New South Wales (NSW) have a growing focus on collecting and using PROs that matter most to patients to improve their healthcare outcomes. Developing oral health patient reported outcomes measures (OH-PROM) is a first step towards value-based oral health care. This paper describes the development process of an adult and child OH-PROM tool that can be piloted for NSW public dental patients. METHODS: An expert panel was assembled to undertake a systematic process of developing OH-PROMs for NSW Health. Key methodological considerations included: (1) forming an expert panel to specify the target population and context of implementation, (2) rapid literature review and environmental scan to identify existing validated OH-PROM tools for adults and children. (3) consensus gathering with the expert panel (4) consumer feedback, and (5) finalisation of the tool for electronic oral health record (eOHR) integration to establish a set of questions, that were relevant, context-appropriate, and important to oral healthcare outcomes for patients using public dental services. RESULTS: The panel considered a total of 59 questions from two child (15), and four adult (44) Oral Health Related Quality of Life (OHRQoL) questionnaires used to collect OH-PROMs. These questions were mapped to the four key dimensions of OHRQoL for OH-PROMs: Oral Function, Orofacial Pain, Orofacial Appearance, and Psychosocial Impact. The consensus resulted in seven questions that aligned with these four dimensions to form two new NSW OH-PROM tools: one for adults and one for children. The tools were tested with consumers for understandability and usefulness before being incorporated into the electronic oral health record system, in readiness for future pilot testing. CONCLUSION: The process for developing new OH-PROMs for NSW public dental services took a pragmatic approach that combined literature appraisal, expert consensus, and consumer consultation. Future work will assess the implementation of the OH-PROM tool and test its validity for broader use as an outcome measure for value-based oral healthcare.

Activation of CB2 Receptors by (-)-Cannabichromene but Not (+)-Cannabichromene.

Introduction: Cannabichromene (CBC) is a minor constituent of cannabis that is a selective cannabinoid CB2 receptor agonist and activator of TRPA1. To date, it has not been shown whether (-)-CBC, (+)-CBC, or both can mediate these effects. In this study, we investigate the activity of the CBC enantiomers at CB1, CB2, and Transient receptor potential ankyrin 1 (TRPA1) receptors in vitro. Materials and Methods: CBC enantiomers were purified from synthetic CBC by chiral chromatography, and their optical activity was confirmed by spectroscopy. Human CB1 and CB2 receptor activity was measured using a fluorescent assay of membrane potential in stably transfected AtT20 cells. TRPA1 activation was measured using a fluorescent assay of intracellular calcium in stably transfected HEK293 cells. Results: The (-)-CBC activated CB2 with an EC50 of 1.5 µM, to a maximum of 60% of (-)CP55940. (+)-CBC did not activate CB2 at concentrations up to 30 µM. Only 30 µM (-)-CBC produced detectable activation of CB1, (+)-CBC was inactive. Both (-)-CBC and (+)-CBC activated TRPA1; at 30 µM (-)-CBC produced an activation 50% of that of the reference agonist cinnamaldehyde (300 µM), 30 µM (+)-CBC activated TRPA1 to 38% of the cinnamaldehyde maximum. Discussion: It is unclear whether (-)-CBC is the sole or even the predominant enantiomer of CBC enzymatically synthesized in cannabis. This study shows that (-)-CBC is the active isomer at CB2 receptors, while both isomers activate TRPA1. The results suggest that medicinal preparations of CBC that target cannabinoid receptors would be most effective when (-)-CBC is the dominant isomer.

Genome-scale clustered regularly interspaced short palindromic repeats screen identifies nucleotide metabolism as an actionable therapeutic vulnerability in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common malignancy that develops in patients with ataxia-telangiectasia, a cancer-predisposing inherited syndrome characterized by inactivating germline ATM mutations. ATM is also frequently mutated in sporadic DLBCL. To investigate lymphomagenic mechanisms and lymphoma-specific dependencies underlying defective ATM, we applied ribonucleic acid (RNA)-seq and genome-scale loss-offunction clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screens to systematically interrogate B-cell lymphomas arising in a novel murine model (Atm-/-nu-/-) with constitutional Atm loss, thymic aplasia but residual T-cell populations. Atm-/-nu-/-lymphomas, which phenotypically resemble either activated B-cell-like or germinal center Bcell-like DLBCL, harbor a complex karyotype, and are characterized by MYC pathway activation. In Atm-/-nu-/-lymphomas, we discovered nucleotide biosynthesis as a MYCdependent cellular vulnerability that can be targeted through the synergistic nucleotidedepleting actions of mycophenolate mofetil (MMF) and the WEE1 inhibitor, adavosertib (AZD1775). The latter is mediated through a synthetically lethal interaction between RRM2 suppression and MYC dysregulation that results in replication stress overload in Atm-/-nu-/-lymphoma cells. Validation in cell line models of human DLBCL confirmed the broad applicability of nucleotide depletion as a therapeutic strategy for MYC-driven DLBCL independent of ATM mutation status. Our findings extend current understanding of lymphomagenic mechanisms underpinning ATM loss and highlight nucleotide metabolism as a targetable therapeutic vulnerability in MYC-driven DLBCL.

Single nucleotide polymorphisms in the cannabinoid CB2 receptor: Molecular pharmacology and disease associations.

Preclinical evidence implicating cannabinoid receptor 2 (CB2) in various diseases has led researchers to question whether CB2 genetics influence aetiology or progression. Associations between conditions and genetic loci are often studied via single nucleotide polymorphism (SNP) prevalence in case versus control populations. In the CNR2 coding exon, ~36 SNPs have high overall population prevalence (minor allele frequencies [MAF] ~37%), including non-synonymous SNP (ns-SNP) rs2501432 encoding CB2 63Q/R. Interspersed are ~27 lower frequency SNPs, four being ns-SNPs. CNR2 introns also harbour numerous SNPs. This review summarises CB2 ns-SNP molecular pharmacology and evaluates evidence from ~70 studies investigating CB2 genetic variants with proposed linkage to disease. Although CNR2 genetic variation has been associated with a wide variety of conditions, including osteoporosis, immune-related disorders, and mental illnesses, further work is required to robustly validate CNR2 disease links and clarify specific mechanisms linking CNR2 genetic variation to disease pathophysiology and potential drug responses.

Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations.

Oncology drug combinations can improve therapeutic responses and increase treatment options for patients. The number of possible combinations is vast and responses can be context-specific. Systematic screens can identify clinically relevant, actionable combinations in defined patient subtypes. We present data for 109 anticancer drug combinations from AstraZeneca's oncology small molecule portfolio screened in 755 pan-cancer cell lines. Combinations were screened in a 7 × 7 concentration matrix, with more than 4 million measurements of sensitivity, producing an exceptionally data-rich resource. We implement a new approach using combination Emax (viability effect) and highest single agent (HSA) to assess combination benefit. We designed a clinical translatability workflow to identify combinations with clearly defined patient populations, rationale for tolerability based on tumor type and combination-specific "emergent" biomarkers, and exposures relevant to clinical doses. We describe three actionable combinations in defined cancer types, confirmed in vitro and in vivo, with a focus on hematologic cancers and apoptotic targets. SIGNIFICANCE: We present the largest cancer drug combination screen published to date with 7 × 7 concentration response matrices for 109 combinations in more than 750 cell lines, complemented by multi-omics predictors of response and identification of "emergent" combination biomarkers. We prioritize hits to optimize clinical translatability, and experimentally validate novel combination hypotheses. This article is featured in Selected Articles from This Issue, p. 695.

Preclinical Characterization of AZD9574, a Blood-Brain Barrier Penetrant Inhibitor of PARP1.

PURPOSE: We evaluated the properties and activity of AZD9574, a blood-brain barrier (BBB) penetrant selective inhibitor of PARP1, and assessed its efficacy and safety alone and in combination with temozolomide (TMZ) in preclinical models. EXPERIMENTAL DESIGN: AZD9574 was interrogated in vitro for selectivity, PARylation inhibition, PARP-DNA trapping, the ability to cross the BBB, and the potential to inhibit cancer cell proliferation. In vivo efficacy was determined using subcutaneous as well as intracranial mouse xenograft models. Mouse, rat, and monkey were used to assess AZD9574 BBB penetration and rat models were used to evaluate potential hematotoxicity for AZD9574 monotherapy and the TMZ combination. RESULTS: AZD9574 demonstrated PARP1-selectivity in fluorescence anisotropy, PARylation, and PARP-DNA trapping assays and in vivo experiments demonstrated BBB penetration. AZD9574 showed potent single agent efficacy in preclinical models with homologous recombination repair deficiency in vitro and in vivo. In an O6-methylguanine-DNA methyltransferase (MGMT)-methylated orthotopic glioma model, AZD9574 in combination with TMZ was superior in extending the survival of tumor-bearing mice compared with TMZ alone. CONCLUSIONS: The combination of three key features-PARP1 selectivity, PARP1 trapping profile, and high central nervous system penetration in a single molecule-supports the development of AZD9574 as the best-in-class PARP inhibitor for the treatment of primary and secondary brain tumors. As documented by in vitro and in vivo studies, AZD9574 shows robust anticancer efficacy as a single agent as well as in combination with TMZ. AZD9574 is currently in a phase I trial (NCT05417594). See related commentary by Lynce and Lin, p. 1217.

A Pilot Trial of Continuous Glucose Monitoring Upon Emergency Department Discharge Among People With Diabetes Mellitus.

OBJECTIVE: People with diabetes mellitus, particularly those with limited access to longitudinal care, frequently present to the emergency department (ED). Continuous glucose monitoring (CGM) has been shown to improve outcomes in ambulatory settings, so we hypothesized that it would be beneficial if initiated upon ED discharge. METHODS: We randomized adults with diabetes who were seen in the ED for hypo- or hyperglycemia to either 14 days of flash CGM or care coordination alone. All participants were scheduled to follow up in our diabetes specialty clinic. Outcomes included clinic attendance, the 3-month change in hemoglobin A1c, and repeat ED utilization. RESULTS: We recruited 30 participants, including 13 with newly diagnosed diabetes. All but one (97%) had type 2 diabetes. We found no significant difference between the CGM (n = 16) and control (n = 14) groups in terms of clinic attendance (75 vs 64%, P = .61) or repeat ED utilization (31 vs 50%, P = .35), although our power was low. The absolute reduction in A1c was greater in the CGM group (5.2 vs 2.4%, P = .08). Among newly diagnosed participants for whom we had data, 7 out of 7 in the CGM group had a follow-up A1c under 7% compared to 1 out of 3 in the control group (P = .03). Over 90% of patients and providers found the CGM useful. CONCLUSIONS: Our data demonstrate the feasibility of starting CGM in the ED, a valuable setting for engaging difficult-to-reach patients. Our pilot study was limited by its small sample size, however, as recruitment in the ED can be challenging.

An interdisciplinary synthesis of floodplain ecosystem dynamics in a rapidly deglaciating watershed.

Glacier retreat is rapidly transforming some watersheds, with ramifications for water supply, ecological succession, important species such as Pacific salmon (Oncorhynchus spp.), and cultural uses of landscapes. To advance a more holistic understanding of the evolution of proglacial landscapes, we integrate multiple lines of knowledge starting in the early 1900s with contemporary data from the Taaltsux̱éi (Tulsequah) Watershed in British Columbia, Canada. Our objectives were to: 1) synthesize recent historical geography and Indigenous Knowledge, including glacier dynamics, and hydrology; 2) describe the limnology of a proglacial lake; 3) quantify decadal-scale downstream physical floodplain change; and 4) characterize riverine physical, chemical, and biological differences relative to distance from the proglacial lake. Since 1982, the Tulsequah Glacier has receded 0.07 km/yr, exposing a cold, deep, and growing proglacial lake. The downstream floodplain is rapidly changing; satellite imagery analysis revealed a 14 % increase in vegetation from 2003 to 2017 and Indigenous Knowledge described increases in vegetation and wildlife habitat over the last century. Contemporary measurements of physical-chemical water properties differed across sites representing the upper and lower watershed, and mainstem and off-channel habitats. Catches of juvenile salmonids in the upper watershed (closer to the glacier) were mostly limited to warmer, clearer groundwater-fed channels, whereas in the lower watershed there were salmonids in both groundwater-fed and mainstem habitats. There was limited zooplankton taxa diversity from the proglacial lake and benthic macroinvertebrates in the river. Collectively, our synthesis suggests that the transformation of proglacial landscapes experiencing rapid ice loss can be influenced by interlinked abiotic processes of glacier retreat, lake formation, and altered hydrology, as well as corresponding biological processes such as beaver repopulation, wetland formation, and riparian vegetation growth. These factors, along with expected increases to proglacial lake productivity and salmon habitat suitability, are an important consideration for forward-looking watershed management of glacier-fed rivers.

Mining stakes claim on salmon futures as glaciers retreat.

Future ecological value of emerging habitats must be considered as climate change transforms the planet.

Mechanisms of PARP Inhibitor Resistance.

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) represent the first medicines based on the targeting of the DNA damage response (DDR). PARPi have become standard of care for first-line maintenance treatment in ovarian cancer and have also been approved in other cancer indications including breast, pancreatic and prostate. Despite their efficacy, resistance to PARPi has been reported clinically and represents a growing patient population with unmet clinical need. Here, we describe the various mechanisms of PARPi resistance that have been identified in pre-clinical models and in the clinic.

Dual blockade of BRD4 and ATR/WEE1 pathways exploits ARID1A loss in clear cell ovarian cancer.

ARID1A, an epigenetic tumor suppressor, is the most common gene mutation in clear-cell ovarian cancers (CCOCs). CCOCs are often resistant to standard chemotherapy and lack effective therapies. We hypothesized that ARID1A loss would increase CCOC cell dependency on chromatin remodeling and DNA repair pathways for survival. We demonstrate that combining BRD4 inhibitor (BRD4i) with DNA damage response inhibitors (ATR or WEE1 inhibitors; e.g. BRD4i-ATRi) was synergistic at low doses leading to decreased survival, and colony formation in CCOC in an ARID1A dependent manner. BRD4i-ATRi caused significant tumor regression and increased overall survival in ARID1AMUT but not ARID1AWT patient-derived xenografts. Combination BRD4i-ATRi significantly increased γH2AX, and decreased RAD51 foci and BRCA1 expression, suggesting decreased ability to repair DNA double-strand-breaks (DSBs) by homologous-recombination in ARID1AMUT cells, and these effects were greater than monotherapies. These studies demonstrate BRD4i-ATRi is an effective treatment strategy that capitalizes on synthetic lethality with ARID1A loss in CCOC.

Initial Experience With Intercostal Insertion of an Extravascular ICD Lead Compatible With Existing Pulse Generators.

BACKGROUND: This study assessed safety and feasibility of a novel extravascular implantable cardioverter defibrillator (ICD) lead when inserted anteriorly through a rib space and connected to various commercially available ICD pulse generators (PGs) placed in either a left mid-axillary or left pectoral pocket. Currently available or investigational, extravascular-ICDs include a subcutaneous or subxiphoid lead connected to customized extravascular-ICD PGs. METHODS: This novel extravascular-ICD (AtaCor Medical Inc, San Clemente, CA) employs a unique intercostal implant technique and is designed to function with commercial DF-4 ICD PGs. In this nonrandomized, single-center, acute study, 36 de novo or replacement ICD (transvenous ICD) patients enrolled to receive a concomitant extravascular-ICD lead inserted through an intercostal space along the left parasternal margin. extravascular-ICD leads were connected to DF-4 compatible ICD PGs positioned in either a left mid-axillary or pectoral pocket for acute sensing and defibrillation testing. Defibrillation testing started at 30 Joules (J) and stepped up or down in 5 to 10 joule increments depending on the success and limitations of the generator used. RESULTS: Successful acute defibrillation using ≤35 J was noted in 100% of left mid-axillary PG subjects (n=27, mean 16.3±8.6 J) and 83% of left pectoral PG subjects (n=6, mean 21.0±8.4 J). Furthermore, 24 of 27 (89%) of patients tested with a left, mid-axillary intermuscular PG had successful VF conversion with defibrillation energies at least 10 J below the maximum delivered output of the device. All evaluable episodes (n=93) were automatically sensed, detected, and shocked. No serious device-related intraoperative adverse events were observed. CONCLUSIONS: This first-in-human study documented the safe and reliable placement of a novel extravascular ICD lead with effective sensing and defibrillation of induced ventricular fibrillation using commercial DF-4 ICD PGs.

Combined PARP and WEE1 inhibition triggers anti-tumor immune response in BRCA1/2 wildtype triple-negative breast cancer.

Novel therapeutic strategies that can effectively combine with immunotherapies are needed in the treatment of triple-negative breast cancer (TNBC). We demonstrate that combined PARP and WEE1 inhibition are synergistic in controlling tumour growth in BRCA1/2 wild-type TNBC preclinical models. The PARP inhibitor (PARPi) olaparib combined with the WEE1 inhibitor (WEE1i) adavosertib triggered increases in anti-tumour immune responses, including STING pathway activation. Combinations with a STING agonist resulted in further improved durable tumour regression and significant improvements in survival outcomes in murine tumour models of BRCA1/2 wild-type TNBC. In addition, we have identified baseline tumour-infiltrating lymphocyte (TIL) levels as a potential predictive biomarker of response to PARPi, WEE1i and immunotherapies in BRCA1/2 wild-type TNBC.

Synthesis and Preclinical Evaluation of Fluorinated 5-Azaindoles as CB2 PET Radioligands.

Several classes of cannabinoid receptor type 2 radioligands have been evaluated for imaging of neuroinflammation, with successful clinical translation yet to take place. Here we describe the synthesis of fluorinated 5-azaindoles and pharmacological characterization and in vivo evaluation of 18F-radiolabeled analogues. [18F]2 (hCB2 Ki = 96.5 nM) and [18F]9 (hCB2 Ki = 7.7 nM) were prepared using Cu-mediated 18F-fluorination with non-decay-corrected radiochemical yields of 15 ± 6% and 18 ± 2% over 85 and 80 min, respectively, with high radiochemical purities (>97%) and molar activities (140-416 GBq/µmol). In PET imaging studies in rats, both [18F]2 and [18F]9 demonstrated specific binding in CB2-rich spleen after pretreatment with CB2-specific GW405833. Moreover, [18F]9 exhibited higher brain uptake at later time points in a murine model of neuroinflammation compared with a healthy control group. The results suggest further evaluation of azaindole based CB2 radioligands is warranted in other neuroinflammation models.

A Comparison of Training and Match Play External Load During a Congested In-Season Period in English League 2 Football.

ABSTRACT: Fleming, A, Walker, M, Armitage, M, Connor, M, and Beato, M. A comparison of training and match play external load during a congested in-season period in English League 2 Football. J Strength Cond Res 37(9): e527-e534, 2023-This study aimed to investigate if external training load metrics differ between training days and match day (MD) during a period of fixture congestion and to verify if external load metrics vary based on playing positions. Training and MD data were collected in a part of the competition phase of the 2020-2021 season (6 weeks) in the English Football League 2 ( N = 20 players, mean ± SD s: age = 24.4 ± 4.7 years). Global Navigation Satellite System units (Catapult S7 Vector 10 Hz) were used to monitor external load metrics. The metrics were duration of training, total distance (TD), high-speed running distance (HSR), sprinting distance, relative intensity (m/min), total accelerations (TotAcc) (>3 m·s -2 ), and total decelerations (TotDec) (<-3 m·s -2 ). This study found that duration, TD, relative intensity, HSR distance, sprint distance, TotAcc, and TotDec were different ( p < 0.001, d = small to moderate ) between MD and match day minus two (MD-2) or match day minus one (MD-1); however, during match day minus four (MD-4), only relative intensity was significantly lower ( p < 0.001) compared with MD output. Therefore, MD-4 was the most demanding training session of the week (after the MD), and during MD-2 and MD-1, coaches decreased players' load to favor players' readiness. Moreover, this study found that MD and MD-1 resulted in statistically different values across several metrics between different playing positions (defenders < midfielders and strikers), whereas metrics in MD-4 and MD-2 were not statistically different, which highlights that in these sessions, players have similar external loads independently from their playing positions.

MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells.

The PSMC3IP-MND1 heterodimer promotes meiotic D loop formation before DNA strand exchange. In genome-scale CRISPR-Cas9 mutagenesis and interference screens in mitotic cells, depletion of PSMC3IP or MND1 causes sensitivity to poly (ADP-Ribose) polymerase inhibitors (PARPi) used in cancer treatment. PSMC3IP or MND1 depletion also causes ionizing radiation sensitivity. These effects are independent of PSMC3IP/MND1's role in mitotic alternative lengthening of telomeres. PSMC3IP- or MND1-depleted cells accumulate toxic RAD51 foci in response to DNA damage, show impaired homology-directed DNA repair, and become PARPi sensitive, even in cells lacking both BRCA1 and TP53BP1. Epistasis between PSMC3IP-MND1 and BRCA1/BRCA2 defects suggest that abrogated D loop formation is the cause of PARPi sensitivity. Wild-type PSMC3IP reverses PARPi sensitivity, whereas a PSMC3IP p.Glu201del mutant associated with D loop defects and ovarian dysgenesis does not. These observations suggest that meiotic proteins such as MND1 and PSMC3IP have a greater role in mitotic DNA repair.

A systematic literature review and meta-analysis of the effect of psilocybin and methylenedioxymethamphetamine on mental, behavioural or developmental disorders.

OBJECTIVES: There is an increasing interest in combining psilocybin or methylenedioxymethamphetamine with psychological support in treating psychiatric disorders. Although there have been several recent systematic reviews, study and participant numbers have been limited, and the field is rapidly evolving with the publication of more studies. We therefore conducted a systematic review of PubMed, MEDLINE, PsycINFO, the Cochrane Central Register of Controlled Trials, Embase, and CINAHL for randomised controlled trials of methylenedioxymethamphetamine and psilocybin with either inactive or active controls. METHODS: Outcomes were psychiatric symptoms measured by standardised, validated and internationally recognised instruments at least 2 weeks following drug administration, Quality was independently assessed using the Cochrane risk of bias assessment tool and Grading of Recommendations Assessment, Development and Evaluation framework. RESULTS: There were eight studies on methylenedioxymethamphetamine and six on psilocybin. Diagnoses included post-traumatic stress disorder, long-standing/treatment-resistant depression, obsessive-compulsive disorder, social anxiety in adults with autism, and anxiety or depression in life-threatening disease. The most information and strongest association was for the change in methylenedioxymethamphetamine scores compared to active controls in post-traumatic stress disorder (k = 4; standardised mean difference = -0.86; 95% confidence interval = [-1.23, -0.50]; p < 0.0001). There were also small benefits for social anxiety in adults with autism. Psilocybin was superior to wait-list but not niacin (active control) in life-threatening disease anxiety or depression. It was equally as effective as escitalopram in long-standing depression for the primary study outcome and superior for most of the secondary outcomes in analyses uncorrected for multiple comparisons. Both agents were well tolerated in supervised trials. Trial quality varied with only small proportions of potential participants included in the randomised phase. Overall certainty of evidence was low or very low using the Grading of Recommendations Assessment, Development and Evaluation framework. CONCLUSION: Methylenedioxymethamphetamine and psilocybin may show promise in highly selected populations when administered in closely supervised settings and with intensive support.