Retinal Ciliopathies and Potential Gene Therapies: A Focus on Human iPSC-Derived Organoid Models.

The human photoreceptor function is dependent on a highly specialised cilium. Perturbation of cilial function can often lead to death of the photoreceptor and loss of vision. Retinal ciliopathies are a genetically diverse range of inherited retinal disorders affecting aspects of the photoreceptor cilium. Despite advances in the understanding of retinal ciliopathies utilising animal disease models, they can often lack the ability to accurately mimic the observed patient phenotype, possibly due to structural and functional deviations from the human retina. Human-induced pluripotent stem cells (hiPSCs) can be utilised to generate an alternative disease model, the 3D retinal organoid, which contains all major retinal cell types including photoreceptors complete with cilial structures. These retinal organoids facilitate the study of disease mechanisms and potential therapies in a human-derived system. Three-dimensional retinal organoids are still a developing technology, and despite impressive progress, several limitations remain. This review will discuss the state of hiPSC-derived retinal organoid technology for accurately modelling prominent retinal ciliopathies related to genes, including RPGR, CEP290, MYO7A, and USH2A. Additionally, we will discuss the development of novel gene therapy approaches targeting retinal ciliopathies, including the delivery of large genes and gene-editing techniques.

The fate of rice crop residues and context-dependent greenhouse gas emissions: Model-based insights from Eastern India.

Crop residue burning is a common practice in many parts of the world that causes air pollution and greenhouse gas (GHG) emissions. Regenerative practices that return residues to the soil offer a 'no burn' pathway for addressing air pollution while building soil organic carbon (SOC). Nevertheless, GHG emissions in rice-based agricultural systems are complex and difficult to anticipate, particularly in production contexts with highly variable hydrologic conditions. Here we predict long-term net GHG fluxes for four rice residue management strategies in the context of rice-wheat cropping systems in Eastern India: burning, soil incorporation, livestock fodder, and biochar. Estimations were based on a combination of Tier 1, 2, and 3 modelling approaches, including 100-year DNDC simulations across three representative soil hydrologic categories (i.e., dry, median, and wet). Overall, residue burning resulted in total direct GHG fluxes of 2.5, 6.1, and 8.7 Mg CO2-e in the dry, median, and wet hydrologic categories, respectively. Relative to emissions from burning (positive values indicate an increase) for the same dry to wet hydrologic categories, soil incorporation resulted in a -0.2, 1.8, or 3.1 Mg CO2-e change in emissions whereas use of residues for livestock fodder increased emissions by 2.0, 2.1, or 2.3 Mg CO2-e. Biochar reduced emissions relative to burning by 2.9 Mg CO2-e in all hydrologic categories. This study showed that the production environment has a controlling effect on methane and, therefore, net GHG balance. For example, wetter sites had 2.8-4.0 times greater CH4 emissions, on average, than dry sites when rice residues were returned to the soil. To effectively mitigate burning without undermining climate change mitigation goals, our results suggest that geographically-target approaches should be used in the rice-based systems of Eastern India to incentivize the adoption of regenerative 'no burn' residue management practices.

Assessment of longitudinal changes in body composition of children with lymphoma and rhabdomyosarcoma.

BACKGROUND: Studies examining changes in skeletal muscle and adipose tissue during treatment for cancer in children, adolescents, and young adults and their effect on the risk of chemotherapy toxicity (chemotoxicity) are limited. METHODS: Among 78 patients with lymphoma (79.5%) and rhabdomyosarcoma (20.5%), changes were measured in skeletal muscle (skeletal muscle index [SMI]; skeletal muscle density [SMD]) and adipose tissue (height-adjusted total adipose tissue [hTAT]) between baseline and first subsequent computed tomography scans at the third lumbar vertebral level by using commercially available software. Body mass index (BMI; operationalized as a percentile [BMI%ile]) and body surface area (BSA) were examined at each time point. The association of changes in body composition with chemotoxicities was examined by using linear regression. RESULTS: The median age at cancer diagnosis of this cohort (62.8% male; 55.1% non-Hispanic White) was 12.7 years (2.5-21.1 years). The median time between scans was 48 days (range, 8-207 days). By adjusting for demographics and disease characteristics, this study found that patients undergo a significant decline in SMD (ß ± standard error [SE] = -4.1 ± 1.4; p < .01). No significant changes in SMI (ß ± SE = -0.5 ± 1.0; p = .7), hTAT (ß ± SE = 5.5 ± 3.9; p = .2), BMI% (ß ± SE = 4.1 ± 4.8; p = .3), or BSA (ß ± SE = -0.02 ± 0.01; p = .3) were observed. Decline in SMD (per Hounsfield unit) was associated with a greater proportion of chemotherapy cycles with grade ≥3 nonhematologic toxicity (ß ± SE = 1.09 ± 0.51; p = .04). CONCLUSIONS: This study shows that children, adolescents, and young adults with lymphoma and rhabdomyosarcoma undergo a decline in SMD early during treatment, which is associated with a risk of chemotoxicities. Future studies should focus on interventions designed at preventing the loss of muscle during treatment. PLAIN LANGUAGE SUMMARY: We show that among children, adolescents, and young adults with lymphoma and rhabdomyosarcoma receiving chemotherapy, skeletal muscle density declines early during treatment. Additionally, a decline in skeletal muscle density is associated with a greater risk of nonhematologic chemotoxicities.

Body composition and mortality in men receiving prostate radiotherapy: A pooled analysis of NRG/RTOG 9406 and NRG/RTOG 0126.

PURPOSE: To validate the association between body composition and mortality in men treated with radiation for localized prostate cancer (PCa). Secondarily, to integrate body composition as a factor to classify patients by risk of all-cause mortality. MATERIALS AND METHODS: Participants of NRG/Radiation Therapy Oncology Group (RTOG) 9406 and NRG/RTOG 0126 with archived computed tomography were included. Muscle mass and muscle density were estimated by measuring the area and attenuation of the psoas muscles on a single slice at L4-L5. Bone density was estimated by measuring the attenuation of the vertebral body at mid-L5. Survival analyses, including Cox proportional hazards models, assessed the relationship between body composition and mortality. Recursive partitioning analysis (RPA) was used to create a classification tree to classify participants by risk of death. RESULTS: Data from 2066 men were included in this study. In the final multivariable model, psoas area, comorbidity score, baseline prostate serum antigen, and age were significantly associated with survival. The RPA yielded a classification tree with four prognostic groups determined by age, comorbidity, and psoas area. Notably, the classification among older (≥70 years) men into prognostic groups was determined by psoas area. CONCLUSIONS: This study strongly supports that body composition is related to mortality in men with localized PCa. The inclusion of psoas area in the RPA classification tree suggests that body composition provides additive information to age and comorbidity status for mortality prediction, particularly among older men. More research is needed to determine the clinical impact of body composition on prognostic models in men with PCa.

Meta-Analysis of 49 Roche Oncology Trials Comparing Blinded Independent Central Review (BICR) and Local Evaluation to Assess the Value of BICR.

BACKGROUND: Blinded independent central review (BICR) of radiographic images is frequently conducted in oncology trials to address the potential bias of local evaluation (LE) of endpoints such as progression-free survival (PFS) and objective response rate (ORR). Given that BICR is a complex and costly process, we evaluated the agreement between LE- and BICR-based treatment effect results and the impact of BICR on regulatory decision-making. MATERIALS AND METHODS: Meta-analyses were performed using hazard ratios (HRs) for PFS and odds ratios (ORs) for ORR from all randomized Roche-supported oncology clinical trials during 2006-2020 that had both LE and BICR results (49 studies with a total of over 32 000 patients). RESULTS: Overall, the evaluation bias of LE overestimating the treatment effect compared with BICR based on PFS was numerically small and not clinically meaningful, especially for double-blind studies (HR ratio between BICR and LE: 1.044). A larger bias is more likely to occur in studies with open-label design, smaller sample sizes, or an unequal randomization ratio. The majority (87%) of the PFS comparisons led to the same statistical inference by BICR and LE. For ORR, a high degree of agreement between BICR and LE results was also observed (OR ratio of 1.065), although the agreement was slightly lower than for PFS. CONCLUSION: BICR did not notably impact the study interpretation nor drive the sponsor's regulatory submission decisions. Hence, if bias can be diminished by appropriate means, LE is deemed as reliable as BICR for certain study settings.

Impact of newly diagnosed extramedullary myeloma on outcome after first autograft followed by maintenance: A CMWP-EBMT study.

BACKGROUND: No adequate data exist on the impact of multiple myeloma (MM) with extramedullary disease (EMD) after autograft and maintenance therapy. METHODS: We identified 808 patients with newly diagnosed MM who received first autograft, of whom 107 had EMD (83 paraskeletal and 24 organ involvement), and who had been reported to the EBMT registry December 2018. Distribution according to type of involvement was similar between the treatment groups (p = .69). For EMD, 46 (40%) received thalidomide, 59 (51%) lenalidomide, and 11 (10%) bortezomib. RESULTS: The median follow-up from maintenance start was 44 months. Three-year progression-free survival (PFS) was 52% (48%-57%) for no EMD, 56% (44%-69%) for paraskeletal involvement, and 45% (22%-68%) for organ involvement (p = .146). Early PFS (within first year) appeared to be significantly worse for organ involvement (hazard ratio, 3.40), while no significant influence was found after first year from maintenance start. Three-year overall survival (OS) was 81% (77%-84%), 88% (80%-96%), and 68% (47%-89%; p = .064), respectively. With thalidomide as reference, lenalidomide was significantly associated with better PFS and OS, whereas bortezomib appeared to improve outcome specifically in EMD. CONCLUSION: Lenalidomide maintenance is standard of care for MM without EMD, whereas extramedullary organ involvement remains a significant risk factor for worse outcome, especially for early events after maintenance start.

Stereotactic Body Radiation Therapy Salvage for Lymph Node Recurrent Prostate Cancer in the Era of PSMA PET Imaging.

PURPOSE OF REVIEW: Our understanding of patterns of prostate cancer recurrence after primary treatment of localized disease has significantly evolved since the development of positron emission tomography (PET) agents targeting prostate cancer. Previously, most biochemical recurrences were not associated with imaging correlates when restaging with computed tomography (CT), magnetic resonance imaging (MRI), or bone scintigraphy and, hence, were typically assumed to represent occult metastases. A rising prostate specific antigen (PSA) after previous local therapy prompting a PET scan showing uptake limited to regional lymph nodes is an increasingly common clinical scenario as advanced prostate cancer imaging becomes more widely utilized. The optimal management strategy for patients who have lymph node recurrent prostate cancer is both unclear and evolving, particularly in terms of local and regionally directed therapies. Stereotactic body radiation therapy (SBRT) utilizes ablative radiation doses with steep gradients to achieve local tumor control while sparing nearby normal tissues. SBRT is an attractive therapeutic modality due to its efficacy, favorable toxicity profile, and flexibility to administer elective doses to areas of potential occult involvement. The purpose of this review is to briefly describe how SBRT is being implemented in the era of PSMA PET for the management of solely lymph node recurrent prostate cancer. RECENT FINDINGS: SBRT has been shown to effectively control individual lymph node tumor deposits within the pelvis and retroperitoneum for prostate cancer and is well-tolerated with a favorable toxicity profile. However, a major limitation thus far has been the lack of prospective trials supporting the use of SBRT for oligometastatic nodal recurrent prostate cancer. As further trials are conducted, its exact role in the treatment paradigm of recurrent prostate cancer will be better established. Although PET-guided SBRT appears feasible and potentially beneficial, there is still considerable uncertainty about the use of elective nodal radiotherapy (ENRT) in patients with nodal recurrent oligometastatic prostate cancer. PSMA PET has undoubtedly advanced imaging of recurrent prostate cancer, revealing anatomic correlates for disease recurrence that previously went undetected. At the same time, SBRT continues to be explored in prostate cancer with feasibility, a favorable risk profile, and satisfactory oncologic outcomes. However, much of the existing literature comes from the pre-PSMA PET era and integration of this novel imaging approach has led to greater focus on new and ongoing clinical trials to rigorously evaluate this approach and compare to other established treatment modalities utilized for oligometastatic, nodal recurrence of prostate cancer.

A roadmap for implementation of kV-CBCT online adaptive radiation therapy and initial first year experiences.

PURPOSE: Online Adaptive Radiation Therapy (oART) follows a different treatment paradigm than conventional radiotherapy, and because of this, the resources, implementation, and workflows needed are unique. The purpose of this report is to outline our institution's experience establishing, organizing, and implementing an oART program using the Ethos therapy system. METHODS: We include resources used, operational models utilized, program creation timelines, and our institutional experiences with the implementation and operation of an oART program. Additionally, we provide a detailed summary of our first year's clinical experience where we delivered over 1000 daily adaptive fractions. For all treatments, the different stages of online adaption, primary patient set-up, initial kV-CBCT acquisition, contouring review and edit of influencer structures, target review and edits, plan evaluation and selection, Mobius3D 2nd check and adaptive QA, 2nd kV-CBCT for positional verification, treatment delivery, and patient leaving the room, were analyzed. RESULTS: We retrospectively analyzed data from 97 patients treated from August 2021-August 2022. One thousand six hundred seventy seven individual fractions were treated and analyzed, 632(38%) were non-adaptive and 1045(62%) were adaptive. Seventy four of the 97 patients (76%) were treated with standard fractionation and 23 (24%) received stereotactic treatments. For the adaptive treatments, the generated adaptive plan was selected in 92% of treatments. On average(±std), adaptive sessions took 34.52 ± 11.42 min from start to finish. The entire adaptive process (from start of contour generation to verification CBCT), performed by the physicist (and physician on select days), was 19.84 ± 8.21 min. CONCLUSION: We present our institution's experience commissioning an oART program using the Ethos therapy system. It took us 12 months from project inception to the treatment of our first patient and 12 months to treat 1000 adaptive fractions. Retrospective analysis of delivered fractions showed that the average overall treatment time was approximately 35 min and the average time for the adaptive component of treatment was approximately 20 min.

Crop establishment and diversification strategies for intensification of rice-based cropping systems in rice-fallow areas in Odisha.

Context or problem: In the Indian state of Odisha, rice-based system productivity is poor due to: (i) low rice yield in the monsoon (wet) season (2-4 t ha-1 compared to 6-8 t ha-1 in Punjab or Haryana); and (ii) limited cropping during the post-monsoon (dry) season (59% of the wet season rice area is left fallow in the dry season). Objective: Our study identifies strategies for increasing rice-based system productivity through: (i) alternative crop establishment methods in the wet season (Dry-Direct Seeded Rice or DSR, and mechanical puddled transplanted rice or PTR-M) to traditional methods such as broadcasting followed by post-emergence tillage (locally known as beushening) and manual random puddled transplanted rice (PTR-R); (ii) to identify rice-fallow areas suitable for pulse and oilseed cultivation in the dry season; and (iii) to evaluate the performance of short-duration pulses (green gram, Vigna radiata; black gram, Vigna mungo), and oilseeds (Brassica rapa var. toria, Helianthus annuus) in rice-fallow areas in the dry season. Methods: On-farm experiments were conducted between 2017 and 2019 in three districts of Odisha (Bhadrak, Cuttack and Mayurbhanj) to evaluate DSR compared to beushening and PTR-R; and PTR-M compared to PTR-R and manual line puddled transplanted rice (PTR-L) in the wet season. The data from Landsat-8 Operational Land Imager (OLI) and Sentinel-1satellite sensors was used to identify rice-fallow areas, and the daily SMAP (Soil Moisture Active Passive) L-band soil moisture was used for mapping suitable rice-fallow areas for growing pulses and oilseeds. Short duration crops were evaluated in suitable rice-fallow areas. Results: In the wet season, DSR (range -4 to + 53%) had a significant effect on rice yield over beushening. Similarly, PTR-M consistently increased rice yield by 16-26% over PTR-R, and by 5-23% over PTR-L. In the dry season, pulse crops (green gram and black gram) performed well compared to Indian mustard under rainfed cultivation. However, under irrigated conditions, dry-season rice yield was more productive than the rice equivalent yield of green gram, black gram and sunflower. We found that 1.03 M ha (i.e., ∼50%) of total rice-fallow areas of 2.1 M ha were suitable for growing short duration green gram and black gram in the dry season. Conclusions: We conclude that system productivity and cropping intensity can be increased by adoption of DSR and PTR-M in the wet season, and growing of green gram and black gram in the dry season. Implications: Odisha state can potentially produce an additional 0.67 million tonnes pulses if suitable rice-fallow areas are brought under green gram and black gram cultivation in the dry the season.

Riding the tides: Directions in mental health rehabilitation in NSW.

OBJECTIVE: This paper outlines the evolution of mental health rehabilitation in NSW, where allocation of health resources has repeatedly contradicted the policy intention to reorient services from inpatient to community-based services, leaving community rehabilitation the poor and disconnected cousin of inpatient services. The expanding role of community-managed organisations (CMOs) in psychosocial rehabilitation, the introduction of the National Disability Insurance Scheme (NDIS), and emerging service models have helped foster a maturing housing and social care environment, but present reality and the integration of health and social care services remains at a distance from best evidence practice. CONCLUSION: The challenge of the next decade of mental health reform is to embrace and consolidate greater service diversity and complexity. Understanding what factors influenced present reality is important in providing guardrails for the future, enabling the current wave of renewal and reinvestment in NSW to build on the strengths of past developments and steer a course around their weaknesses.

Effectiveness of Project ECHO Programs in Improving Clinician Knowledge and Confidence in Managing Complex Psychiatric Patients: a Waitlist-Controlled Study.

OBJECTIVE: The authors aimed to determine if Project Extension for Community Healthcare Outcomes (ECHO), a health-education model utilising teleconferencing technology, improves the capacity of clinicians in assessing and managing complex psychiatric patients. METHODS: Three pilot Project ECHO programs were evaluated as a prospective waitlist-controlled trial, focusing on Adult Eating Disorders, Adult Intellectual Disability Mental Health, and General Mental Health. Each program comprised 9-10 weekly teleconferencing group sessions. Participants and waitlist-controls completed pre- and post-program surveys. The primary outcomes were self-reported knowledge and confidence in assessing and managing complex patients relevant to each group. Linear mixed models were used to assess the group-by-time interaction, or change over time, as appropriate. RESULTS: Between July 2020 and June 2021, three series of the Adult Intellectual Disability Mental Health program, two series of the Adult Eating Disorders program, and two series of the General Mental Health program were delivered. Compared to waitlist-controls (n = 21), there were statistically significant improvements in self-reported knowledge and confidence for all topics amongst participants of the Adult Eating Disorders program (n = 44). In the Adult Intellectual Disability Mental Health program, there were significant improvements in self-reported knowledge and confidence amongst participants (n = 67) for most topics compared to controls (n = 21). There were no waitlist-controls for the General Mental Health program, but within-group analysis (n = 28) showed significant improvements in participants' knowledge and confidence following program completion, compared to baseline. CONCLUSION: Project ECHO is a feasible and effective model to develop workforce capacity in managing complex psychiatric conditions.

Implementing conjunctive management of water resources for irrigation development: A framework applied to the Southern Plain of Western Nepal.

Climate variability and insufficient irrigation are primary constraints to stable and higher agricultural productivity and food security in Nepal. Agriculture is the largest global freshwater user, and integration of surface- and ground-water use is frequently presented as an strategy for increasing efficiency as well as climate change adaptation. However, conjunctive management (CM) planning often ignores demand-side requirements and a broader set of sustainable development considerations, including ecosystem health and economics of different development strategies. While there is generic understanding of conjunctive use, detailed technical knowhow to realize the CM is lacking in Nepal. This article presents a holistic framework through literature reviews, stakeholders consultations and expert interviews for assessing CM and implementation prospects from a systems-level perspective. We demonstrate the framework through a case study in Western Nepal, where climatic variability and a lack of irrigation are key impediments to increased agricultural productivity and sustainable development. Results show that knowledge of water resources availability is good and that of water demand low in the Western Terai. Additional and coordinated investments are required to improve knowledge gaps as well as access to irrigation. There is therefore a need to assess water resources availability, water access, use and productivity, to fill the knowledge gaps in order to pave pathways for CM. This paper also discusses some strategies to translate prospects of conjunctive management into implementation.

Farm size limits agriculture's poverty reduction potential in Eastern India even with irrigation-led intensification.

CONTEXT: Millions of people living in the Eastern Gangetic Plains (EGP) of India engage in agriculture to support their livelihoods yet are income poor, and food and climate insecure. To address these challenges, policymakers and development programs invest in irrigation-led agricultural intensification. However, the evidence for agricultural intensification to lift farmers' incomes above the poverty line remains largely anecdotal. OBJECTIVE: The main objective of this study is to use a large household survey (n = 15,572; rice: 8244, wheat: 7328; 2017/18) to assess the link between agricultural intensification and personal daily incomes from farming (FPDI) in the rice-wheat systems of the EGP - the dominant cropping system of the region. METHODS: We use the Intensification Benefit Index (IBI), a measure that relates farm size and household size to FPDI, to assess how daily incomes from rice-wheat production change with irrigation-led intensification across the EGP. RESULTS AND CONCLUSIONS: Relative to the international poverty line of 1.90 Purchasing Power Parity (PPP)$ day-1 and accounting for variations in HH size in the analysis, we found that small farm sizes limit the potential for agricultural intensification from irrigation to transform the poverty status of households in the bottom three quartiles of the IBI. The estimated median FPDI of households with intensified systems in the bottom three quartiles is only 0.51 PPP$ day-1 (a 0.15 PPP$ gain). The median FPDI increases to 2.10 PPP$ day-1 for households in the upper quartile of the IBI distribution (a 0.30 PPP$ gain). Irrigation-led agricultural intensification of rice-wheat systems in the EGP may provide substantial benefits for resilience to climatic change and food security but achieving meaningful poverty reduction will require complementary investments. SIGNIFICANCE: Transforming the poverty status of most smallholder farmers in the EGP requires diversified portfolios of rural on- and off-farm income-generating opportunities. While bolstering food- and climate security, agronomic intervention programs should consider smallholders' limited monetary incentives to invest in intensification. Irrigation-led agricultural intensification programs and policies should explicitly account for the heterogeneity in household resources, irrigation levels, and degree of dependence on agricultural income.

Association between body composition and chemotherapy-related toxicity in children with lymphoma and rhabdomyosarcoma.

BACKGROUND: Body composition is associated with chemotherapy toxicity (chemotoxicity) in adults with cancer; this association remains unexplored in children with cancer. METHODS: Using baseline computed tomography scans of 107 children with Hodgkin lymphoma (n = 45), non-Hodgkin lymphoma (n = 42), or rhabdomyosarcoma (n = 20), this study examined body composition (skeletal muscle index [SMI], skeletal muscle density [SMD], and height-adjusted total adipose tissue [hTAT]) to determine its association with chemotoxicity. Clinical characteristics and chemotoxicities were abstracted from medical records. Primary outcomes included grade 4 or higher hematologic toxicities and grade 3 or higher nonhematologic toxicities within 6 months of the diagnosis. Logistic regression models accounting for repeated measures were constructed to examine the association between body composition indices and chemotoxicities; adjustments were made for age at diagnosis, sex, race/ethnicity, cancer type, risk group, body mass index (measured as a percentile), or body surface area. RESULTS: The median SMI was 41.0 cm2 /m2 (range, 25.8-68.6 cm2 /m2 ), the median SMD was 54.1 HU (range, 35-69.4 HU), and the median hTAT was 19.5 cm2 /m2 (range, 0-226.7 cm2 /m2 ). Grade 4 or higher hematologic toxicities and grade 3 or higher nonhematologic toxicities were observed in 74.7% and 66.3% of the chemotherapy cycles, respectively. A higher SMD at diagnosis was associated with lower odds of grade 4 or higher hematologic toxicity (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.85-0.97; P = .004). SMI (OR, 0.99; 95% CI, 0.95-1.04; P = .7) and hTAT (OR, 1.00; 95% CI, 0.99-1.01; P = .9) were not associated with hematologic toxicities. Nonhematologic toxicities did not show any association with body composition. CONCLUSIONS: The association between low SMD and hematologic toxicities in children with lymphoma or rhabdomyosarcoma could be due to body composition-based biodistribution of chemotherapeutic agents and needs further investigation. LAY SUMMARY: Body composition at cancer diagnosis in children with lymphoma and rhabdomyosarcoma may provide information that could identify those at risk for serious side effects from chemotherapy. Routinely used measures such as body mass index and body surface area show poor correlations with body composition assessed via computed tomography scans.

HNRNPR Variants that Impair Homeobox Gene Expression Drive Developmental Disorders in Humans.

The heterogeneous nuclear ribonucleoprotein (HNRNP) genes code for a set of RNA-binding proteins that function primarily in the spliceosome C complex. Pathogenic variants in these genes can drive neurodegeneration, through a mechanism involving excessive stress-granule formation, or developmental defects, through mechanisms that are not known. Here, we report four unrelated individuals who have truncating or missense variants in the same C-terminal region of hnRNPR and who have multisystem developmental defects including abnormalities of the brain and skeleton, dysmorphic facies, brachydactyly, seizures, and hypoplastic external genitalia. We further identified in the literature a fifth individual with a truncating variant. RNA sequencing of primary fibroblasts reveals that these HNRNPR variants drive significant changes in the expression of several homeobox genes, as well as other transcription factors, such as LHX9, TBX1, and multiple HOX genes, that are considered fundamental regulators of embryonic and gonad development. Higher levels of retained intronic HOX sequences and lost splicing events in the HOX cluster are observed in cells carrying HNRNPR variants, suggesting that impaired splicing is at least partially driving HOX deregulation. At basal levels, stress-granule formation appears normal in primary and transfected cells expressing HNRNPR variants. However, these cells reveal profound recovery defects, where stress granules fail to disassemble properly, after exposure to oxidative stress. This study establishes an essential role for HNRNPR in human development and points to a mechanism that may unify other "spliceosomopathies" linked to variants that drive multi-system congenital defects and are found in hnRNPs.

Use of Single-Item Self-Rated Health Measure to Identify Frailty and Geriatric Assessment-Identified Impairments Among Older Adults with Cancer.

BACKGROUND: Poor self-rated health (SRH) is a known predictor of frailty and mortality in the general population; however, its role among older adults with cancer is unknown. We evaluated the role of SRH as a potential screening tool to identify frailty and geriatric assessment (GA)-identified impairments. MATERIALS AND METHODS: Adults ≥60 years diagnosed with cancer in the UAB Cancer & Aging Resilience Evaluation (CARE) registry underwent a GA at the time of initial consultation. We measured SRH using a single-item from the Patient-Reported Outcomes Measurement Information System global health scale and dichotomized responses as poor (poor, fair) and good (good, very good, and excellent). We evaluated the diagnostic performance of SRH in measuring frailty, and GA impairment (≥2 deficits among a set of seven GA domains). We examined the impact of SRH with survival using a Cox model adjusting for confounders, exploring the mediating role of frailty. RESULTS: Six hundred and three older adults with cancer were included, with a median age of 69 years. Overall, 45% (n = 274) reported poor SRH. Poor SRH demonstrated high sensitivity and specificity for identifying frailty (85% and 78%, respectively) and GA impairment (75% and 78%, respectively). In a Cox regression model, poor SRH was associated with inferior survival (HR = 2.26; 95% CI 1.60-3.18) after adjusting for confounders; frailty mediated 69% of this observed relationship. CONCLUSION: Self-rated health may be used as a screening tool to identify older adults with cancer with frailty and GA impairments. Poor SRH is associated with inferior survival, which is mediated by frailty.

Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial.

Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. Adults age ≥18 years with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in this international phase 3 randomized double-blind placebo-controlled trial. Patients (N = 211) were randomized 2:1 to venetoclax (n = 143) or placebo (n = 68) in 28-day cycles, plus low-dose cytarabine (LDAC) on days 1 to 10. Primary end point was overall survival (OS); secondary end points included response rate, transfusion independence, and event-free survival. Median age was 76 years (range, 36-93 years), 38% had secondary AML, and 20% had received prior hypomethylating agent treatment. Planned primary analysis showed a 25% reduction in risk of death with venetoclax plus LDAC vs LDAC alone (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.52-1.07; P = .11), although not statistically significant; median OS was 7.2 vs 4.1 months, respectively. Unplanned analysis with additional 6-month follow-up demonstrated median OS of 8.4 months for the venetoclax arm (HR, 0.70; 95% CI, 0.50-0.98; P = .04). Complete remission (CR) plus CR with incomplete blood count recovery rates were 48% and 13% for venetoclax plus LDAC and LDAC alone, respectively. Key grade ≥3 adverse events (venetoclax vs LDAC alone) were febrile neutropenia (32% vs 29%), neutropenia (47% vs 16%), and thrombocytopenia (45% vs 37%). Venetoclax plus LDAC demonstrates clinically meaningful improvement in remission rate and OS vs LDAC alone, with a manageable safety profile. Results confirm venetoclax plus LDAC as an important frontline treatment for AML patients unfit for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT03069352.

Tillage and crop establishment effects on weeds and productivity of a rice-wheat-mungbean rotation.

Weeds are one of the key threats in sustaining the productivity of the rice-wheat cropping system in the Indo-Gangetic Plains. The development of sound integrated weed management technologies requires knowledge of mechanisms that influence weed flora composition and weed seedbank dynamics. A long-term study was initiated in 2015 at Patna, Bihar, India to evaluate the effect of seven tillage and crop establishment methods on weed density, weed seedbank composition, and crop productivity in rice-wheat-mungbean rotation. All the treatments included zero-till mungbean after wheat. Tillage and crop establishment methods had differential effects on weed and weed seedbank composition. In rice, zero-till direct-seeded rice recorded 62% lower emergence of Cyperus iria, 82-90% of Echinochloa colona, and 81-83% of total weeds compared to tilled systems, but the system of rice and wheat intensification favoured E. colona. In wheat, the system of wheat intensification favoured the Phalaris minor and Solanum nigrum. Zero-till rice and wheat reduced the seedbank of Trianthema portulacastrum by 95%, and total weed seedbank by 62% compared to the system of rice and wheat intensification. Nearly, 72% of C. iria seeds, 62% of grasses, and 64% of broad-leaved weeds were in 0-15 cm soil layer. Zero-till direct-seeded rice produced a 13% lower rice grain yield than conventional puddled transplanted rice. Compared to the system of wheat intensification, zero-till wheat under triple zero-till systems produced an 11.5% higher grain yield. Managing weed seedbank is a long-term endeavour. The present study revealed that tillage and crop establishment methods influence weed density and diversity. Under zero-till rice-wheat system, rice yield decreases marginally, but the system productivity maintains due to improvement in succeeding wheat yield. This system is also helpful in reducing the weed flora density and soil weed seedbank. Regular monitoring and management of emerging pests such as armyworm (Mythimna separata) are, however, required. The study suggests that the adoption of triple zero-tillage can be a viable option for reducing the weed density and weed seedbank concurrently increasing the system productivity of the rice-wheat-mungbean cropping system in eastern Indo-Gangetic Plains.

Parameter Reliability and Understanding Enzyme Function.

Knowledge of the Michaelis-Menten parameters and their meaning in different circumstances is an essential prerequisite to understanding enzyme function and behaviour. The published literature contains an abundance of values reported for many enzymes. The problem concerns assessing the appropriateness and validity of such material for the purpose to which it is to be applied. This review considers the evaluation of such data with particular emphasis on the assessment of its fitness for purpose.

Pembrolizumab versus brentuximab vedotin in relapsed or refractory classical Hodgkin lymphoma (KEYNOTE-204): an interim analysis of a multicentre, randomised, open-label, phase 3 study.

BACKGROUND: PD-1 blockade via pembrolizumab monotherapy has shown antitumour activity and toxicity in patients with relapsed or refractory classical Hodgkin lymphoma. Here, we present interim analyses from the KEYNOTE-204 study evaluating pembrolizumab versus brentuximab vedotin for relapsed or refractory classical Hodgkin lymphoma. METHODS: In this randomised, open-label, phase 3 study, patients aged 18 years or older with relapsed or refractory classical Hodgkin lymphoma with measurable disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 who were ineligible for or had relapsed after autologous haematopoietic stem-cell transplantation (HSCT) were enrolled at 78 hospitals and cancer centres in 20 countries and territories. Patients were randomly assigned (1:1) with an interactive voice response system to pembrolizumab 200 mg intravenously every 3 weeks or brentuximab vedotin 1·8 mg/kg intravenously every 3 weeks. Randomisation was stratified by previous autologous HSCT and status after front-line therapy. Results from the second interim analysis are presented here, with a database cutoff of Jan 16, 2020. The dual primary endpoints assessed in the intention-to-treat population were progression-free survival as assessed by blinded independent central review, and overall survival (not analysed at this interim analysis). Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT02684292. Recruitment for this trial is closed. FINDINGS: Between July 8, 2016, and July 13, 2018, 151 patients were randomly assigned to pembrolizumab and 153 to brentuximab vedotin. After a median time from randomisation to data cutoff of 25·7 months (IQR 23·4-33·0), median progression-free survival was 13·2 months (95% CI 10·9-19·4) for pembrolizumab versus 8·3 months (5·7-8·8) for brentuximab vedotin (hazard ratio 0·65 [95% CI 0·48-0·88]; p=0·0027). The most common grade 3-5 treatment-related adverse events were pneumonitis (six [4%] of 148 patients in the pembrolizumab group vs one [1%] of 152 patients in the brentuximab vedotin group), neutropenia (three [2%] vs 11 [7%]), decreased neutrophil count (one [1%] vs seven [5%]), and peripheral neuropathy (one [1%] vs five [3%]). Serious treatment-related adverse events occurred in 24 (16%) of 148 patients receiving pembrolizumab and 16 (11%) of 152 patients receiving brentuximab vedotin. One treatment-related death due to pneumonia occurred in the pembrolizumab group. INTERPRETATION: Pembrolizumab showed statistically significant and clinically meaningful improvement in progression-free survival compared with brentuximab vedotin, with safety consistent with previous reports. These data support pembrolizumab as the preferred treatment option for patients with relapsed or refractory classical Hodgkin lymphoma who have relapsed post-autologous HSCT or are ineligible for autologous HSCT. FUNDING: Merck Sharp & Dohme Corp (a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA).