Genome drafts of Pseudogracilibacillus spp. from soil and sediment of Mount Makiling, a dormant volcano in the Philippines.

We present the draft whole-genome sequences of Pseudogracilibacillus spp. isolated from the soils and sediments of Sipit Creek located at Mount Makiling, a dormant volcano in the southern part of Luzon Island, Philippines. This Pseudogracilibacillus spp. genome report extends the body of knowledge on a lesser-known genus of Bacillaceae.

Late Cretaceous ammonoids show that drivers of diversification are regionally heterogeneous.

Palaeontologists have long sought to explain the diversification of individual clades to whole biotas at global scales. Advances in our understanding of the spatial distribution of the fossil record through geological time, however, has demonstrated that global trends in biodiversity were a mosaic of regionally heterogeneous diversification processes. Drivers of diversification must presumably have also displayed regional variation to produce the spatial disparities observed in past taxonomic richness. Here, we analyse the fossil record of ammonoids, pelagic shelled cephalopods, through the Late Cretaceous, characterised by some palaeontologists as an interval of biotic decline prior to their total extinction at the Cretaceous-Paleogene boundary. We regionally subdivide this record to eliminate the impacts of spatial sampling biases and infer regional origination and extinction rates corrected for temporal sampling biases using Bayesian methods. We then model these rates using biotic and abiotic drivers commonly inferred to influence diversification. Ammonoid diversification dynamics and responses to this common set of diversity drivers were regionally heterogeneous, do not support ecological decline, and demonstrate that their global diversification signal is influenced by spatial disparities in sampling effort. These results call into question the feasibility of seeking drivers of diversity at global scales in the fossil record.

Bimodality in Ras signaling originates from processivity of the Ras activator SOS without deterministic bistability.

Ras is a small GTPase that is central to important functional decisions in diverse cell types. An important aspect of Ras signaling is its ability to exhibit bimodal or switch-like activity. We describe the total reconstitution of a receptor-mediated Ras activation-deactivation reaction catalyzed by SOS and p120-RasGAP on supported lipid membrane microarrays. The results reveal a bimodal Ras activation response, which is not a result of deterministic bistability but is rather driven by the distinct processivity of the Ras activator, SOS. Furthermore, the bimodal response is controlled by the condensation state of the scaffold protein, LAT, to which SOS is recruited. Processivity-driven bimodality leads to stochastic bursts of Ras activation even under strongly deactivating conditions. This behavior contrasts deterministic bistability and may be more resistant to pharmacological inhibition.

Endoscopic Normalization and Transition of J-Pouch Phenotypes Over Time in Patients With Inflammatory Bowel Disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) who undergo proctocolectomy with ileal pouch-anal anastomosis may develop pouchitis. We previously proposed a novel endoscopic classification of pouchitis describing 7 phenotypes with differing outcomes. This study assessed phenotype transitions over time. METHODS: We classified pouch findings into 7 main phenotypes: (1) normal, (2) afferent limb (AL) involvement, (3) inlet (IL) involvement, (4) diffuse, (5) focal inflammation of the pouch body, (6) cuffitis, and (7) pouch-related fistulas noted more than 6 months after ileostomy takedown. Among 2 endoscopic phenotypes, the phenotype that was first identified was defined as the primary phenotype, and the phenotype observed later was defined as the subsequent phenotype. RESULTS: We retrospectively reviewed 1359 pouchoscopies from 426 patients (90% preoperative diagnosis of ulcerative colitis). The frequency of primary phenotype was 31% for AL involvement, 42% for IL involvement, 28% for diffuse inflammation, 72% for focal inflammation, 45% for cuffitis, 18% for pouch-related fistulas, and 28% for normal pouch. The most common subsequent phenotype was focal inflammation (64.8%), followed by IL involvement (38.6%), cuffitis (37.8%), AL involvement (25.6%), diffuse inflammation (23.8%), normal pouch (22.8%), and pouch-related fistulas (11.9%). Subsequent diffuse inflammation, pouch-related fistulas, and AL or IL stenoses significantly increased the pouch excision risk. Patients who achieved subsequent normal pouch were less likely to have pouch excision than those who did not (8.1% vs 15.7%; P = .15). CONCLUSIONS: Pouch phenotype and the risk of pouch loss can change over time. In patients with pouch inflammation, subsequent pouch normalization is feasible and associated with favorable outcome.

Endoscopic pouch phenotypes can change over time and subsequent development of diffuse inflammation, pouch-related fistulas, and afferent limb/inlet stenoses significantly worsen pouch outcomes. In patients with pouch inflammation, subsequent pouch normalization is feasible and associated with favorable outcomes.

Neuropsychological Test Performance Differentiates Subgroups of Individuals With Adult Moyamoya Disease: A Cross-Sectional Clinical Study.

BACKGROUND AND OBJECTIVES: Moyamoya disease (MMD) is a rare noninflammatory disorder involving progressive intracranial vasculopathy and impaired cerebral blood flow in the anterior circulation, resulting in stroke and cognitive impairment. We aimed to characterize cognitive impairment and the possible predictive value of sociodemographic and clinical characteristics of adults with MMD. METHODS: This cross-sectional study examined neurocognitive performance in a group of 42 consecutive adult patients (mean age = 40.52 years; 69% female) referred for a presurgical neuropsychological evaluation. Neuropsychological functioning was assessed with a comprehensive battery, and cognitive dysfunction was defined as 1.5 SDs below the mean. Neurocognitive performance correlated with clinical/demographic characteristics and disease markers. RESULTS: Most patients (91%) had a history of stroke, and 45% had cognitive deficits, most notably on measures of attention/speed (48%), executive functioning (47%), visuoconstruction (41%), and memory (31%-54%). Only higher educational attainment and poor collateral blood flow in the right hemisphere differentiated cognitively impaired (n = 19) and intact groups (n = 23), and MMD-related characteristics (eg, disease duration, stroke history) did not differentiate the 2 groups. CONCLUSION: Consistent with previous work, frontal-subcortical cognitive deficits (eg, deficits in mental speed, attention, executive functioning) were found in nearly half of patients with MMD and better cognitive performance was associated with factors related to cognitive reserve. Angiographic metrics of disease burden (eg, Suzuki rating, collateral flow) and hemodynamic reserve were not consistently associated with poorer cognitive outcomes, suggesting that cognition is a crucial independent factor to assess in MMD and has relevance for treatment planning and functional status.

Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial.

Microsatellite stable metastatic colorectal cancer (MSS mCRC; mismatch repair proficient) has previously responded poorly to immune checkpoint blockade. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody designed to expand therapy to cold/poorly immunogenic solid tumors, such as MSS mCRC. BOT with or without balstilimab (BAL; anti-PD-1 antibody) is being evaluated in an ongoing expanded phase 1 study. The primary endpoint is safety and tolerability, which was evaluated separately in the dose-escalation portion of the study and in patients with MSS mCRC (using combined dose-escalation/dose-expansion data). Secondary endpoints include investigator-assessed RECIST version 1.1-confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and progression-free survival (PFS). Here we present outcomes in 148 heavily pre-treated patients with MSS mCRC (six from the dose-escalation cohort; 142 from the dose-expansion cohort) treated with BOT and BAL, 101 of whom were considered response evaluable with at least 6 months of follow-up. Treatment-related adverse events (TRAEs) occurred in 89% of patients with MSS mCRC (131/148), most commonly fatigue (35%, 52/148), diarrhea (32%, 47/148) and pyrexia (24%, 36/148), with no grade 5 TRAEs reported and a 12% discontinuation rate due to a TRAE (18/148; data fully mature). In the response-evaluable population (n = 101), ORR was 17% (17/101; 95% confidence interval (CI), 10-26%), and DCR was 61% (62/101; 95% CI, 51-71%). Median DOR was not reached (NR; 95% CI, 5.7 months-NR), and median PFS was 3.5 months (95% CI, 2.7-4.1 months), at a median follow-up of 10.3 months (range, 0.5-42.6 months; data continuing to mature). The combination of BOT plus BAL demonstrated a manageable safety profile with no new immune-mediated safety signals and encouraging clinical activity with durable responses. ClinicalTrials.gov identifier: NCT03860272 .

The Impact of Behavior Change Counseling Delivered via a Digital Health Tool Versus Routine Care Among Adolescents With Obesity: Pilot Randomized Feasibility Study.

BACKGROUND: Youth overweight and obesity is a public health crisis and increases the risk of poor cardiovascular health (CVH) and chronic disease. Health care providers play a key role in weight management, yet few tools exist to support providers in delivering tailored evidence-based behavior change interventions to patients. OBJECTIVE: The goal of this pilot randomized feasibility study was to determine the feasibility of implementing the Patient-Centered Real-Time Intervention (PREVENT) tool in clinical settings, generate implementation data to inform scale-up, and gather preliminary effectiveness data. METHODS: A pilot randomized clinical trial was conducted to examine the feasibility, implementation, and preliminary impact of PREVENT on patient knowledge, motivation, behaviors, and CVH outcomes. The study took place in a multidisciplinary obesity management clinic at a children's hospital within an academic medical center. A total of 36 patients aged 12 to 18 years were randomized to use PREVENT during their routine visit (n=18, 50%) or usual care control (n=18, 50%). PREVENT is a digital health tool designed for use by providers to engage patients in behavior change education and goal setting and provides resources to support change. Patient electronic health record and self-report behavior data were collected at baseline and 3 months after the intervention. Implementation data were collected via PREVENT, direct observation, surveys, and interviews. We conducted quantitative, qualitative, and mixed methods analyses to evaluate pretest-posttest patient changes and implementation data. RESULTS: PREVENT was feasible, acceptable, easy to understand, and helpful to patients. Although not statistically significant, only PREVENT patients increased their motivation to change their behaviors as well as their knowledge of ways to improve heart health and of resources. Compared to the control group, PREVENT patients significantly improved their overall CVH and blood pressure (P<.05). CONCLUSIONS: Digital tools can support the delivery of behavior change counseling in clinical settings to increase knowledge and motivate patients to change their behaviors. An appropriately powered trial is necessary to determine the impact of PREVENT on CVH behaviors and outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT06121193; https://www.clinicaltrials.gov/study/NCT06121193.

CEA-CD3 bispecific antibody cibisatamab with or without atezolizumab in patients with CEA-positive solid tumours: results of two multi-institutional Phase 1 trials.

Cibisatamab is a bispecific antibody-based construct targeting carcinoembryonic antigen (CEA) on tumour cells and CD3 epsilon chain as a T-cell engager. Here we evaluated cibisatamab for advanced CEA-positive solid tumours in two open-label Phase 1 dose-escalation and -expansion studies: as a single agent with or without obinutuzumab in S1 (NCT02324257) and with atezolizumab in S2 (NCT02650713). Primary endpoints were safety, dose finding, and pharmacokinetics in S1; safety and dose finding in S2. Secondary endpoints were anti-tumour activity (including overall response rate, ORR) and pharmacodynamics in S1; anti-tumour activity, pharmacodynamics and pharmacokinetics in S2. S1 and S2 enrolled a total of 149 and 228 patients, respectively. Grade ≥3 cibisatamab-related adverse events occurred in 36% of S1 and 49% of S2 patients. The ORR was 4% in S1 and 7% in S2. In S2, patients with microsatellite stable colorectal carcinoma (MSS-CRC) given flat doses of cibisatamab and atezolizumab demonstrated an ORR of 14%. In S1 and S2, 40% and 52% of patients, respectively, developed persistent anti-drug antibodies (ADAs). ADA appearance could be mitigated by obinutuzumab-pretreatment, with 8% of patients having persistent ADAs. Overall, cibisatamab warrants further exploration in immunotherapy combination strategies for MSS-CRC.

Evidence for cryptic molting behavior in the trilobite Toxochasmops vormsiensis from the Upper Ordovician Katian Kõrgessaare Formation, Estonia.

Documentation of cryptic trilobite behavior has presented important insights into the paleoecology of this fully extinct arthropod group. One such example is the preservation of trilobites inside the remains of larger animals. To date, evidence for trilobites within cephalopods, gastropods, hyoliths, and other trilobites has been presented. Importantly, most of these interactions show trilobite molts, suggesting that trilobites used larger animals for protection during molting. To expand the record of molted trilobites within cephalopods, we present a unique case of a Toxochasmops vormsiensis trilobite within the body chamber of a Gorbyoceras textumaraneum nautiloid from the Upper Ordovician Kõrgessaare Formation of Estonia. By examining this material, we present new insights into the ecology of pterygometopid trilobites, highlighting how these forms used large cephalopods as areas to successfully molt.

Assisting decision-making on age of neutering for German Short/Wirehaired Pointer, Mastiff, Newfoundland, Rhodesian Ridgeback, Siberian Husky: associated joint disorders, cancers, and urinary incontinence.

Spaying female and castrating male dogs, hereinafter referred to as neutering, is a US convention for the first year in the dog's life. Research on 35 breeds of dogs revealed that early neutering increases risks of joint disorders, such as hip dysplasia (HD), elbow dysplasia (ED), or cranial cruciate ligament (CCL) tear, or cancers, such as lymphosarcoma (LSA), mast cell tumor (MCT), hemangiosarcoma (has), or osteosarcoma (OSA), for some breeds. Joint disorder risks are heightened for some larger breeds and for mixed-breed dogs weighing more than 20 kg. Some breeds had elevated risks for cancers. Several other research teams have reported health complications associated with neutering. The study goal includes using the same methodology for data collection and analyses as in the study on 35 breeds for five additional dog breeds weighing at least 20 kg. The breeds were: German Short/Wirehaired Pointer, Mastiff, Newfoundland, Rhodesian Ridgeback, and Siberian Husky. Major differences among breeds appeared in vulnerability to joint disorders and cancers with early neutering: male and female Pointer breeds had elevated joint disorders and increased cancers; male Mastiff breeds had increased CCL and LSA and females had non-significant elevated CCL risks; female Newfoundland breeds had heightened risks for joint disorders and males had non-significant elevated risks; female Ridgeback breeds had heightened MCT with very early neutering; and Siberian Huskies showed no significant effects on joint disorders or cancers, but female breeds showed a non-significant but elevated CCL. Updated guidelines cover 40 dog breeds. These results further emphasize the importance of personalized decisions regarding the neutering of dogs, considering the dog's breed, sex, and context.

In vitro insecticide resistance patterns in field strains of the sheep blowfly, Lucilia cuprina.

The control of the sheep blowfly relies on the use of insecticides. There have been several reports of in vitro and in vivo resistance to the most widely-used flystrike control chemical, dicyclanil. A recent report also described in vitro resistance to imidacloprid in a strain collected from a single property over three consecutive seasons that also showed resistance to dicyclanil. The present study aimed to use in vitro assays to examine five field-collected blowfly strains to determine if this co-occurrence of resistance to dicyclanil and imidacloprid was present more widely in field strains and to also measure resistance patterns to the other currently-used flystrike control chemicals. Each of the strains showed significant levels of resistance to both dicyclanil and imidacloprid: resistance factors at the IC50 of 9.1-23.8 for dicyclanil, and 8.7-14.1 for imidacloprid. Resistance factors at the IC95 ranged from 16.5 to 53.7, and 14.6-24.3 for dicyclanil and imidacloprid, respectively. Resistance factors were up to 8.5 for cyromazine at the IC95. Resistance to dicyclanil and imidacloprid was suppressed by co-treatment with the cytochrome P450 inhibitor, aminobenzotriazole, implicating this enzyme system in the observed resistances. We discuss the implications of the co-occurrence of resistance to dicyclanil and imidacloprid on insecticide rotation strategies for blowfly control. We also discuss the roles of insecticide resistance, environmental factors (e.g. rainfall), operational factors (e.g. insecticide application technique) and other animal health issues (e.g. scouring / diarrhoea) that together will impact on the likelihood of flystrike occurring at an earlier time point than expected after insecticide application.

The axial skeleton of Tiktaalik roseae.

The axial columns of the earliest limbed vertebrates show distinct patterns of regionalization as compared to early tetrapodomorphs. Included among their novel features are sacral ribs, which provide linkage between the vertebral column and pelvis, contributing to body support and propulsion by the hindlimb. Data on the axial skeletons of the closest relatives of limbed vertebrates are sparce, with key features of specimens potentially covered by matrix. Therefore, it is unclear in what sequence and under what functional context specializations in the axial skeletons of tetrapods arose. Here, we describe the axial skeleton of the elpistostegalian Tiktaalik roseae and show that transformations to the axial column for head mobility, body support, and pelvic fin buttressing evolved in finned vertebrates prior to the origin of limbs. No atlas-axis complex is observed; however, an independent basioccipital-exoccipital complex suggests increased mobility at the occipital vertebral junction. While the construction of vertebrae in Tiktaalik is similar to early tetrapodomorphs, its ribs possess a specialized sacral domain. Sacral ribs are expanded and ventrally curved, indicating likely attachment to the expanded iliac blade of the pelvis by ligamentous connection. Thus, the origin of novel rib types preceded major alterations to trunk vertebrae, and linkage between pelvic fins and axial column preceded the origin of limbs. These data reveal an unexpected combination of post-cranial skeletal characters, informing hypotheses of body posture and movement in the closest relatives of limbed vertebrates.

EVOLUTIONARY CO-OPTION OF AN ANCESTRAL CLOACAL REGULATORY LANDSCAPE DURING THE EMERGENCE OF DIGITS AND GENITALS.

The transition from fins to limbs has been a rich source of discussion for more than a century. One open and important issue is understanding how the mechanisms that pattern digits arose during vertebrate evolution. In this context, the analysis of Hox gene expression and functions to infer evolutionary scenarios has been a productive approach to explain the changes in organ formation, particularly in limbs. In tetrapods, the transcription of Hoxd genes in developing digits depends on a well-characterized set of enhancers forming a large regulatory landscape1,2. This control system has a syntenic counterpart in zebrafish, even though they lack bona fide digits, suggestive of deep homology3 between distal fin and limb developmental mechanisms. We tested the global function of this landscape to assess ancestry and source of limb and fin variation. In contrast to results in mice, we show here that the deletion of the homologous control region in zebrafish has a limited effect on the transcription of hoxd genes during fin development. However, it fully abrogates hoxd expression within the developing cloaca, an ancestral structure related to the mammalian urogenital sinus. We show that similar to the limb, Hoxd gene function in the urogenital sinus of the mouse also depends on enhancers located in this same genomic domain. Thus, we conclude that the current regulation underlying Hoxd gene expression in distal limbs was co-opted in tetrapods from a preexisting cloacal program. The orthologous chromatin domain in fishes may illustrate a rudimentary or partial step in this evolutionary co-option.

Final results of urelumab, an anti-CD137 agonist monoclonal antibody, in combination with cetuximab or nivolumab in patients with advanced solid tumors.

BACKGROUND: Resistance to immune checkpoint inhibitors and targeted treatments for cancer is common; thus, novel immunotherapy agents are needed. Urelumab is a monoclonal antibody agonist that binds to CD137 receptors expressed on T cells. Here, we report two studies that evaluated urelumab in combination with cetuximab or nivolumab in patients with select, advanced solid tumors. METHODS: CA186-018: Patients with metastatic colorectal cancer or metastatic squamous cell carcinoma of the head and neck (SCCHN) were treated in a dose-evaluation phase with urelumab 0.1 mg/kg (urelumab-0.1) every 3 weeks (Q3W)+cetuximab 250 mg/m2 (cetuximab-250) weekly; and in a dose-expansion phase with urelumab 8 mg flat dose (urelumab-8) Q3W+cetuximab-250 weekly. CA186-107: The dose-escalation phase included patients with previously treated advanced solid tumors (or treated or treatment-naive melanoma); patients received urelumab 3 mg flat dose (urelumab-3) or urelumab-8 every 4 weeks+nivolumab 3 mg/kg (nivolumab-3) or 240 mg (nivolumab-240) every 2 weeks. In the expansion phase, patients with melanoma, non-small cell lung cancer, or SCCHN were treated with urelumab-8+nivolumab-240. Primary endpoints were safety and tolerability, and the secondary endpoint included efficacy assessments. RESULTS: CA186-018: 66 patients received study treatment. The most frequent treatment-related adverse events (TRAEs) were fatigue (75%; n=3) with urelumab-0.1+cetuximab-250 and dermatitis (45%; n=28) with urelumab-8+cetuximab-250. Three patients (5%) discontinued due to TRAE(s) (with urelumab-8+cetuximab-250). One patient with SCCHN had a partial response (objective response rate (ORR) 5%, with urelumab-8+cetuximab-250).CA186-107: 134 patients received study treatment. Fatigue was the most common TRAE (32%; n=2 with urelumab-3+nivolumab-3; n=1 with urelumab-8+nivolumab-3; n=40 with urelumab-8+nivolumab-240). Nine patients (7%) discontinued due to TRAE(s) (n=1 with urelumab-3+nivolumab-3; n=8 with urelumab-8+nivolumab-240). Patients with melanoma naive to anti-PD-1 therapy exhibited the highest ORR (49%; n=21 with urelumab-8+nivolumab-240). Intratumoral gene expression in immune-related pathways (CD3, CD8, CXCL9, GZMB) increased on treatment with urelumab+nivolumab. CONCLUSIONS: Although the addition of urelumab at these doses was tolerable, preliminary response rates did not indicate an evident additive benefit. Nevertheless, the positive pharmacodynamics effects observed with urelumab and the high response rate in treatment-naive patients with melanoma warrant further investigation of other anti-CD137 agonist agents for treatment of cancer. TRIAL REGISTRATION NUMBERS: NCT02110082; NCT02253992.

Prevalence of Distal Symmetrical Polyneuropathy by Diabetes Prevention Program Treatment Group, Diabetes Status, Duration of Diabetes, and Cumulative Glycemic Exposure.

OBJECTIVE: To assess associations between distal symmetric polyneuropathy (DSPN) and Diabetes Prevention Program (DPP) treatment groups, diabetes status or duration, and cumulative glycemic exposure approximately 21 years after DPP randomization. RESEARCH DESIGN AND METHODS: In the DPP, 3,234 adults ≥25 years old at high risk for diabetes were randomized to an intensive lifestyle (ILS), metformin, or placebo intervention to prevent diabetes. After the DPP ended, 2,779 joined the Diabetes Prevention Program Outcomes Study (DPPOS). Open-label metformin was continued, placebo was discontinued, ILS was provided in the form of semiannual group-based classes, and all participants were offered quarterly lifestyle classes. Symptoms and signs of DSPN were assessed in 1,792 participants at DPPOS year 17. Multivariable logistic regression models were used to evaluate DSPN associations with treatment group, diabetes status/duration, and cumulative glycemic exposure. RESULTS: At 21 years after DPP randomization, 66% of subjects had diabetes. DSPN prevalence did not differ by initial DPP treatment assignment (ILS 21.5%, metformin 21.5%, and placebo 21.9%). There was a significant interaction between treatment assignment to ILS and age (P < 0.05) on DSPN. At DPPOS year 17, the odds ratio for DSPN in comparison with ILS with placebo was 17.4% (95% CI 3.0, 29.3) lower with increasing 5-year age intervals. DSPN prevalence was slightly lower for those at risk for diabetes (19.6%) versus those with diabetes (22.7%) and was associated with longer diabetes duration and time-weighted HbA1c (P values <0.001). CONCLUSIONS: The likelihood of DSPN was similar across DPP treatment groups but higher for those with diabetes, longer diabetes duration, and higher cumulative glycemic exposure. ILS may have long-term benefits on DSPN for older adults.

Major adverse events in youth-onset type 1 and type 2 diabetes: The SEARCH and TODAY studies.

AIMS: To determine contemporary incidence rates and risk factors for major adverse events in youth-onset T1D and T2D. METHODS: Participant interviews were conducted once during in-person visits from 2018 to 2019 in SEARCH (T1D: N = 564; T2D: N = 149) and semi-annually from 2014 to 2020 in TODAY (T2D: N = 495). Outcomes were adjudicated using harmonized, predetermined, standardized criteria. RESULTS: Incidence rates (events per 10,000 person-years) among T1D participants were: 10.9 ophthalmologic; 0 kidney; 11.1 nerve, 3.1 cardiac; 3.1 peripheral vascular; 1.6 cerebrovascular; and 15.6 gastrointestinal events. Among T2D participants, rates were: 40.0 ophthalmologic; 6.2 kidney; 21.2 nerve; 21.2 cardiac; 10.0 peripheral vascular; 5.0 cerebrovascular and 42.8 gastrointestinal events. Despite similar mean diabetes duration, complications were higher in youth with T2D than T1D: 2.5-fold higher for microvascular, 4.0-fold higher for macrovascular, and 2.7-fold higher for gastrointestinal disease. Univariate logistic regression analyses in T1D associated age at diagnosis, female sex, HbA1c and mean arterial pressure (MAP) with microvascular events. In youth-onset T2D, composite microvascular events associated positively with MAP and negatively with BMI, however composite macrovascular events associated solely with MAP. CONCLUSIONS: In youth-onset diabetes, end-organ events were infrequent but did occur before 15 years diabetes duration. Rates were higher and had different risk factors in T2D versus T1D.

Intensive Glycemic Management Is Associated With Reduced Retinal Structure Abnormalities on Ocular Coherence Tomography in the DCCT/EDIC Study.

OBJECTIVE: To investigate quantitative and qualitative changes in retinal structure using optical coherence tomography (OCT) and their associations with systemic or other risk factors in individuals with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In the Epidemiology of Diabetes Interventions and Complications (EDIC) study, OCT images were obtained during study years 25-28 (2019-2022) in 937 participants; 54% and 46% were from the original intensive (INT) and conventional (CONV) glycemic management treatment groups, respectively. RESULTS: Average age for participants was 61 years old, diabetes duration 39 years, and HbA1c 7.6%. Participants originally in the CONV group were more likely to have disorganization of retinal inner layers (DRIL) (CONV 27.3% vs. INT 18.7%; P = 0.0003), intraretinal fluid (CONV 24.4% vs. INT 19.2%; P = 0.0222), and intraretinal cysts (CONV 20.8% vs. INT 16.6%; P = 0.0471). In multivariable models, sex, age, smoking, mean updated systolic blood pressure, and history of "clinically significant" macular edema (CSME) and of anti-VEGF treatment were independently associated with changes in central subfield thickness, while HbA1c, BMI, and history of CSME and of ocular surgery were associated with DRIL. Visual acuity (VA) decline was associated with significant thinning of all retinal subfields except for the central and inner nasal subfields. CONCLUSIONS: Early intensive glycemic management in T1D is associated with a decreased risk of DRIL. This important morphological abnormality was associated with a history of macular edema, a history of ocular surgery, and worse VA. This study reveals benefits of intensive glycemic management on the retina beyond features detected by fundus photographs and ophthalmoscopy.

Immune checkpoint blockade induced sarcoid-like reaction mimicking progression of disease in a patient with microsatellite instable colorectal cancer: case report and review of the literature.

Background: Oncologists are prescribing checkpoint inhibitors with greater frequency, and an awareness of and ability to recognize immune-related adverse events (irAEs) is a key part of the safe administration of these drugs. Case Description: Herein, we report the case of a 26-year-old male diagnosed with de novo metastatic right-sided colon cancer to the liver, with tumor immunohistochemistry demonstrating loss of MSH2 and MSH6, and a pathogenic mutation in MSH2 identified on germline testing, consistent with Lynch Syndrome. The patient received first-line treatment with pembrolizumab. Following 7 months of immune checkpoint blockade (ICB), new pulmonary findings on routine imaging were felt to be concerning for disease progression, despite ongoing excellent clinical status, disease control in the liver, and stable tumor markers. An endobronchial biopsy of one of the mediastinal lymph nodes demonstrated granulomatous inflammation consistent histologically with sarcoidosis, and a diagnosis of sarcoid-like reaction (SLR) secondary to immunotherapy was established. Pembrolizumab was discontinued, and the patient continued active monitoring off of active therapy, with durable cancer control. After 8 months of watchful waiting, new hepatic lesions and increasing abdomino-pelvic lymphadenopathy were identified on imaging, concerning for progression of disease. Inguinal lymph node biopsy demonstrated findings consistent with ongoing SLR. The patient remains with durable cancer control, now 24 months since receipt of ICB. In addition, he remains asymptomatic of the SLR. Conclusions: This case highlights the propensity of SLRs to imitate progression of disease, and the importance of awareness of this adverse effect, to prompt appropriate investigation and management.

Neuropathic Pain With and Without Diabetic Peripheral Neuropathy in Type 1 Diabetes.

OBJECTIVE: Diabetic peripheral neuropathy (DPN) is common; however, the features and burden of neuropathic pain (NP) in type 1 diabetes (T1D) are poorly understood. We evaluated the incidence of first occurrence, annual prevalence, remission, and risk factors for NP during long-term follow-up of participants with T1D. RESEARCH DESIGN AND METHODS: The Michigan Neuropathy Screening Instrument (MNSI) was administered annually (1994-2020) for 1,324 participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. NP with clinical signs of DPN (NP DPN+) was defined according to self-reported NP plus an examination score >2, while NP without clinical signs of DPN (NP DPN-) was defined according to self-reported NP and an examination score ≤2. RESULTS: At EDIC year 1, median age for participants was 36 years (interquartile range 30, 41), diabetes duration 13 years (10, 18), and HbA1c 7.9% (7.2, 8.9). At year 26 (median diabetes duration 39 years), cumulative incidence of NP was 57%, regardless of concomitant clinical signs of DPN (36% NP DPN+ vs. 46% NP DPN-). NP prevalence was 20% at 26 years (11% NP DPN+ and 9% NP DPN-), suggesting frequent remission. Annualized remission rates were similar regardless of pain medication use. In addition to HbA1c, female sex was associated with NP DPN-. CONCLUSIONS: NP incidence in T1D was high and frequently occurred in the absence of clinical signs of neuropathy, as assessed with the MNSI. Pain remission was not explained by pain medication use. Effective clinical strategies for identification and management are needed.