Global geoepidemiology of gastrointestinal surgery rates in Crohn's disease.

BACKGROUND: Data regarding the worldwide gastrointestinal surgery rates in patients with Crohn's disease (CD) remains limited. AIM: To systematically review the global variation in the rates of surgery in CD. METHODS: A comprehensive search analysis was performed using multiple electronic databases from inception through July 1, 2020, to identify all full text, randomized controlled trials and cohort studies pertaining to gastrointestinal surgery rates in adult patients with CD. Outcomes included continent based demographic data, CD surgery rates over time, as well as the geoepidemiologic variation in CD surgery rates. Statistical analyses were conducted using R. RESULTS: Twenty-three studies spanning four continents were included. The median proportion of persons with CD who underwent gastrointestinal surgery in studies from North America, Europe, Asia, and Oceania were 30% (range: 1.7%-62.0%), 40% (range: 0.6%-74.0%), 17% (range: 16.0%-43.0%), and 38% respectively. No clear association was found regarding the proportion of patients undergoing gastrointestinal surgery over time in North America (R 2 = 0.035) and Europe (R 2 = 0.100). A moderate, negative association was seen regarding the proportion of patients undergoing gastrointestinal surgery over time (R 2 = 0.520) in Asia. CONCLUSION: There appears to be significant inter-continental variation regarding surgery rates in CD. Homogenous evidence-based guidelines accounting for the geographic differences in managing patients with CD is prudent. Moreover, as a paucity of data on surgery rates in CD exists outside the North American and European continents, future studies, particularly in less studied locales, are warranted.

Q fever presenting as splenic infarct without endocarditis.

Q fever is frequently associated with the development of antiphospholipid antibodies though rarely causes thromboses. A 44-year-old man presented with diarrhea and fevers and was found to have a splenic infarct. Infectious work-up revealed acute Q fever as well as high anticardiolipin antibody titers. He was treated with doxycycline and hydroxychloroquine and suffered no further thromboembolic complications. The optimal management of thromboembolic complications is uncertain given the rarity of documented cases. However, the presence of these antibodies has been associated with increased risk of complications. Further investigation into the management of patients with Q fever associated hypercoagulability is needed.

Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer.

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.

Acoustic monitoring of artificial reefs reveals Atlantic cod and weakfish spawning and presence of individual bottlenose dolphins.

The artificial reefs in New York's waters provide structure in areas that are typically flat and sandy, creating habitat for a multitude of species as an area to spawn, forage, and reside. Passive acoustic data collected on the Fire Island and Shinnecock artificial reefs between 2018 and 2022 detected spawning-associated calls of weakfish (Cynoscion regalis) and Atlantic cod (Gadus morhua), as well as the presence of individual bottlenose dolphins (Tursiops truncatus) through their signature whistles. Weakfish and Atlantic cod were more vocally active on the Fire Island reef, where Atlantic cod grunts peaked during a new moon phase in December, and weakfish spawning experienced variable peaks between mid-July and mid-August on both reefs. Fifty-seven individual bottlenose dolphins were identified, with whistle repeats ranging from seconds to years apart. Passive acoustic monitoring allows for simultaneous collection of information on multiple species at different trophic levels as well as behavioral information that helps managers understand how these animals utilize these habitats, which can lead to improved conservation measures.

A Case Report of a Filipino Boy with Childhood Cataract and Clinically Diagnosed Roberts Syndrome.

Childhood cataract is a common cause of visual impairment. Familial types are uncommon among Filipinos. Furthermore, it is not common to have one that follows an autosomal dominant pattern of inheritance but with associated syndromic presentation like Roberts syndrome which is an autosomal recessive disorder. This is a case of a 9-year-old Filipino boy with cataract in the left eye associated with low-set ears, facial asymmetry, underdeveloped nasal ala, cleft lip and palate, macroglossia, micrognathia, short right shin, and absent feet. Patient was clinically diagnosed with Roberts syndrome. We present a clinically diagnosed Roberts syndrome (RS), the first reported RS in a Filipino in local and international literature to our knowledge with an autosomal dominant childhood cataract. Genetic testing can assist in the confirmation of this case.

A Case Report of Inferior Oblique Reattachment after Inferomedial Orbital Wall Reconstruction from Total Maxillectomy.

The detachment and reattachment of inferior oblique (IO) have been done by ophthalmologists in inferomedial orbital wall fracture repair to avoid inducing a new diplopia in patients post-operatively. However, doing them in orbital wall reconstruction in patient who underwent maxillectomy for a malignancy has not been described yet. We describe a case where a disinserted inferior oblique was reattached after titanium mesh implantation to prevent diplopia after the surgery. This is the case of a 40-year-old male diagnosed with recurrent bilateral nasomaxillary ameloblastoma who underwent total maxillectomy of the right with removal of the inferomedial orbital wall, and detachment and reattachment of inferior oblique with no resulting inferior oblique palsy and diplopia from hypotropia or incyclotorsion. This is the first report, to our knowledge, to describe reattachment of IO in its approximate insertion during reconstruction of the inferomedial orbital wall after total maxillectomy from a malignancy with no resulting diplopia.

Differences in stomatal sensitivity to CO2 and light influence variation in water use efficiency and leaf carbon isotope composition in two genotypes of the C4 plant Zea mays.

The ratio of net CO2 uptake (Anet) and stomatal conductance (gs) is an intrinsic measurement of leaf water use efficiency (WUEi) however its measurement can be challenging for large phenotypic screens. Measurements of leaf carbon isotope composition (δ13Cleaf) may be a scalable tool to approximate WUEi for screening because it in part reflects the competing influences of Anet and gs on the CO2 partial pressure (pCO2) inside the leaf over time. However, in C4 photosynthesis the CO2 concentrating mechanism complicates the relationship between δ13Cleaf and WUEi. Despite this complicated relationship, several studies have shown genetic variation in δ13Cleaf across C4 plants. Yet there has not been a clear demonstration of whether Anet or gs are the causal mechanisms controlling WUEi and δ13Cleaf. Our approach was to characterize leaf photosynthetic traits of two Zea mays recombinant inbred lines (Z007E0067 and Z007E0150) which consistently differ for δ13Cleaf even though they have minimal confounding genetic differences. We demonstrate that these two genotypes contrasted in WUEi driven by differences in the speed of stomatal responses to changes in pCO2 and light that lead to unproductive leaf water loss. These findings provide support that differences in δ13Cleaf in closely related genotypes do reflect greater WUEi and further suggests that differences in stomatal kinetic response to changing environmental conditions is a key target to improve WUEi.

Acculturation and Depression Help-Seeking Intentions in a Majority Mexican American College Student Sample.

Work has not examined if acculturation or enculturation may predict endorsed benefits, barriers, and intentions to seek mental health services for depression, specifically among Latino students enrolled in a rural and majority Latino immigrant institution of higher education. An improved understanding of factors informing mental health help-seeking is needed to identify possible intervention points to address gaps in accessing depression treatment. Participants (N = 406) read a vignette depicting a person with depressive symptoms. Participants were asked if they would seek help for depression if in the situation described in the vignette. Participants provided text responses about their preferences for managing depression symptoms and their mental health help-seeking history. Additionally, participants completed a self-report depression symptom screener, demographic surveys, acculturation assessment, and questionnaires on perceived benefits and barriers to seeking mental health services. Path analysis was used to test the link between acculturation status and intent to seek services for depression, with benefits and barriers as mediators. The results revealed that higher perceived benefits and lower barriers were directly associated with greater intentions to seek help. Furthermore, an indirect effect of acculturation on help-seeking intentions via higher perceived benefits of seeking care was observed. These findings persisted after controlling for age, gender, depression, and history of seeking care for depression. Future work should test the replicability of this finding with diverse college students living in predominantly immigrant communities. Universities might consider tailoring outreach initiatives to provide information on the range and accessibility of mental health services, the location of mental health service centers, and the procedures for accessing such services.

Class B1 GPCRs: Insights into Multi-Receptor Pharmacology for the Treatment of Metabolic Disease.

The secretin-like, class B1 sub-family of seven transmembrane-spanning G protein coupled receptors (GPCRs) consists of 15 members that coordinate important physiological processes. These receptors bind peptide ligands and utilize a distinct mechanism of activation that is driven by evolutionarily conserved structural features. For the class B1 receptors, the C-terminus of the cognate ligand is initially recognized by the receptor via a large N-terminal extracellular domain that forms a hydrophobic ligand binding groove. This binding enables the N-terminus of the ligand to engage deep into a large volume, open transmembrane pocket of the receptor. Importantly, the phylogenetic basis of this ligand-receptor activation mechanism has provided opportunities to engineer analogues of several class B1 ligands for therapeutic use. Among the most successful of these are drugs targeting the glucagon-like peptide-1 (GLP-1) receptor for the treatment of type 2 diabetes and obesity. Recently, multi-functional agonists possessing activity at the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor, such as tirzepatide, and others that also contain glucagon receptor activity, have been developed. In this article, we review members of the class B1 GPCR family with focus on receptors for GLP-1, GIP, and glucagon, including their signal transduction and receptor trafficking characteristics. The metabolic importance of these receptors is also highlighted, along with the benefit of poly-pharmacologic ligands. Further, key structural features and comparative analyses of high-resolution cryogenic electron microscopy structures for these receptors in active-state complex with either native ligands or multi-functional agonists are provided, supporting the pharmacological basis of such therapeutic agents.

Pediatric Intraoperative Electromyographic Responses at the Adductor Pollicis and Flexor Hallucis Brevis Muscles: A Prospective, Comparative Analysis.

BACKGROUND: Peripheral nerve stimulation with a train-of-four (TOF) pattern can be used intraoperatively to evaluate the depth of neuromuscular block and confirm recovery from neuromuscular blocking agents (NMBAs). Quantitative monitoring can be challenging in infants and children due to patient size, equipment technology, and limited access to monitoring sites. Although the adductor pollicis muscle is the preferred site of monitoring, the foot is an alternative when the hands are unavailable. However, there is little information on comparative evoked neuromuscular responses at those 2 sites. METHODS: Pediatric patients undergoing inpatient surgery requiring NMBA administration were studied after informed consent. Electromyographic (EMG) monitoring was performed simultaneously in each participant at the hand (ulnar nerve, adductor pollicis muscle) and the foot (posterior tibial nerve, flexor hallucis brevis muscle). RESULTS: Fifty patients with a mean age of 3.0 ± standard deviation (SD) 2.9 years were studied. The baseline first twitch amplitude (T1) of TOF at the foot (12.46 mV) was 4.47 mV higher than at the hand (P <.0001). The baseline TOF ratio (TOFR) before NMBA administration and the maximum TOFR after antagonism with sugammadex were not different at the 2 sites. The onset time until the T1 decreased to 10% or 5% of the baseline value (T1) was delayed by approximately 90 seconds (both P =.014) at the foot compared with the hand. The TOFR at the foot recovered (TOFR ≥0.9) 191 seconds later than when this threshold was achieved at the hand (P =.017). After antagonism, T1 did not return to its baseline value, a typical finding with EMG monitoring, but the fractional recovery (maximum T1 at recovery divided by the baseline T1) at the hand and foot was not different, 0.81 and 0.77, respectively (P =.68). The final TOFR achieved at recovery was approximately 100% and was not different between the 2 sites. CONCLUSIONS: Although this study in young children demonstrated the feasibility of TOF monitoring, interpretation of the depth of neuromuscular block needs to consider the delayed onset and the delayed recovery of TOFR at the foot compared to the hand. The delay in achieving these end points when monitoring the foot may impact the timing of tracheal intubation and assessment of adequate recovery of neuromuscular block to allow tracheal extubation (ie, TOFR ≥0.9).

Automated quantitative assessment of bone contusions and overlying articular cartilage following anterior cruciate ligament injury.

Quantitative methods to characterize bone contusions and associated cartilage injury remain limited. We combined standardized voxelwise normalization and 3D mapping to automate bone contusion segmentation post-anterior cruciate ligament (ACL) injury and evaluate anomalies in articular cartilage overlying bone contusions. Forty-five patients (54% female, 26.4 ± 11.8 days post-injury) with an ACL tear underwent 3T magnetic resonance imaging of their involved and uninvolved knees. A novel method for voxelwise normalization and 3D anatomical mapping was used to automate segmentation, labeling, and localization of bone contusions in the involved knee. The same mapping system was used to identify the associated articular cartilage overlying bone lesions. Mean regional T1ρ was extracted from articular cartilage regions in both the involved and uninvolved knees for quantitative paired analysis against ipsilateral cartilage within the same compartment outside of the localized bone contusion. At least one bone contusion lesion was detected in the involved knee within the femur and/or tibia following ACL injury in 42 participants. Elevated T1ρ (p = 0.033) signal were documented within the articular cartilage overlying the bone contusions resulting from ACL injury. In contrast, the same cartilaginous regions deprojected onto the uninvolved knees showed no ipsilateral differences (p = 0.795). Automated bone contusion segmentation using standardized voxelwise normalization and 3D mapping deprojection identified altered cartilage overlying bone contusions in the setting of knee ACL injury.

Clinical presentation of early syphilis and genomic sequences of Treponema pallidum strains in patient specimens and isolates obtained by rabbit inoculation.

BACKGROUND: The global resurgence of syphilis necessitates vaccine development. METHODS: We collected ulcer exudates and blood from 17 primary syphilis (PS) participants and skin biopsies and blood from 51 secondary syphilis (SS) participants in Guangzhou, China for Treponema pallidum subsp. pallidum (TPA) qPCR, whole genome sequencing (WGS), and isolation of TPA in rabbits. RESULTS: TPA DNA was detected in 15 of 17 ulcer exudates and 3 of 17 blood PS specimens. TPA DNA was detected in 50 of 51 SS skin biopsies and 27 of 51 blood specimens. TPA was isolated from 47 rabbits with success rates of 71% (12/17) and 69% (35/51), respectively, from ulcer exudates and SS bloods. We obtained paired genomic sequences from 24 clinical samples and corresponding rabbit isolates. Six SS14- and two Nichols-clade genome pairs contained rare discordances. Forty-one of the 51 unique TPA genomes clustered within SS14 subgroups largely from East Asia, while 10 fell into Nichols C and E subgroups. CONCLUSIONS: Our TPA detection rate was high from PS ulcer exudates and SS skin biopsies and over 50% from SS blood, with TPA isolation in over two-thirds of samples. Our results support the use of WGS from rabbit isolates to inform vaccine development.

The incidence of new cases of syphilis has skyrocketed globally in the twenty-first century. This global resurgence requires new strategies, including vaccine development. As part of an NIH funded Cooperative Research Center to develop a syphilis vaccine, we established a clinical research site in Guangzhou, China to better define the local syphilis epidemic and obtain samples from patients with primary and secondary syphilis for whole genome sequencing (WGS) of circulating Treponema pallidum strains. Inoculation of rabbits enabled us to obtain T. pallidum genomic sequences from spirochetes disseminating in blood, a compartment of immense importance for syphilis pathogenesis. Collectively, our results further clarify the molecular epidemiology of syphilis in southern China, enrich our understanding of the manifestations of early syphilis, and demonstrate that the genomic sequences of spirochetes obtained by rabbit inoculation accurately represent those of the spirochetes infecting the corresponding patients.

Changes of the serum properties and its effect on the endothelial cells restoration in patients with chronic disease treated with sulodexide.

OBJECTIVE: Inflammation and endothelial dysfunction are important venous changes in patients with chronic venous disease (CVD). The use of the venoactive drugs remains an important treatment modality for CVD patient, reducing severity of the CVD related symptoms and swelling but also reducting inflammation and protecting endothelial cells. In this research, the effects of the serum obtained from CVD patients before and after sulodexide treatment was evaluated for in vivo and in vitro inflammatory markers and endothelial cell function. MATERIAL AND METHODS: Inflammatory markers (IL-6, MMP-9, VCAM-1, vWF) from the incompetent great saphenous (GSV) veins and from the systemic venous circulation were studied in 10 CVD C2s patients before and after 2 months of sulodexide (2 x 500 LSU/day) therapy. Serum from pretreatment and following sulodexide treated patients was evaluated for in vitro cultured human umbilical vein endothelial cells (HUVEC) function. RESULTS: Serum collected from lower leg incompetent GSVs had significantly elevated levels of VCAM-1 (+ 29%, p<0.001) than serum from the systemic circulation. Endothelial cells exposed to the serum from the incompetent lower leg veins of the untreated CVD patients demonstrated higher stimulated synthesis of MMP-9 (+17%, p<0.01), as well as increased markers of senescence (prolongation of PDT, ß-galactosidase activity, expression of p21 and p53 genes). CVD serum induced senescent endothelial cells had a higher expression of genes regulating IL-6, MMP-9, VCAM-1 and vWF synthesis. The overall proinflammatory effect on endothelial cells by serum collected from incompetent GSV was stronger as compared to serum from the systemic circulation. Serum collected from the veins after sulodexide treatment caused lower levels of endothelial cell inflammatory markers as well as respective gene expression than serum obtained at the beginning of the study (before sulodexide treatment). Sulodexide application also reduced the inflammatory secretory activity of the senescent endothelial cells. Sulodexide treatment resulted in the decrease of the majority of the studied inflammatory parameters in both lower limb incompetent vein and systemic blood. CONCLUSIONS: In CVD patients there are significant differences between circulating inflammatory markers analyzed from the lower leg incompetent GSV segments compared to the systemic circulation, indicating a higher inflammatory condition in CVD. Treatment with sulodexide reduces the proinflammatory and endothelial cell activation proprieties of the serum from CVD patients.

Nearly 14-Fold Increased Risk of Manipulation Under Anesthesia After Total Knee Arthroplasty When Previous Contralateral Total Knee Arthroplasty Required Manipulation Under Anesthesia.

BACKGROUND: Stiffness remains a common complication after primary total knee arthroplasty (TKA). Manipulation under anesthesia (MUA) is the gold standard treatment for early postoperative stiffness; however, there remains a paucity of data on the risk of MUA after primary TKA if a prior contralateral TKA required MUA. METHODS: We performed a retrospective review of 3,102 patients who had staged primary TKAs between 2016 and 2021. The mean body mass index was 33 (range, 18 to 59) and the mean age was 67 years (range, 24 to 91). The mean preoperative range of motion for the first TKA was 2 to 104°, and for the contralateral TKA was 1 to 107°. The primary outcomes were MUA following first and second primary TKAs. Multivariable Poisson regressions were used to evaluate associations between risk factors and outcomes. RESULTS: The rate of MUA after the first TKA was 2.6% (n = 83 of 3,102) and 1.3% (n = 40 of 3,102) after the contralateral TKA. After adjustment, there was a nearly 14-fold higher rate of MUA after the second TKA if the patient had an MUA after the first TKA (relative risk, 13.80; 95% CI [confidence interval], 7.14 to 26.66). For the first TKA, increasing age (adjusted risk ratio [ARR], 0.65; 95% CI, 0.50 to 0.83) and increasing body mass index (ARR, 0.65; 95% CI, 0.47 to 0.90) were associated with lower risk for MUA. For the second TKA, increasing age was associated with a lower risk of MUA (ARR, 0.60; 95% CI, 0.45 to 0.80). CONCLUSIONS: For patients undergoing staged bilateral TKA, patients who undergo MUA following the first primary TKA are nearly 14-fold more likely to undergo an MUA following the contralateral primary TKA than those who did not have an MUA after their first TKA.

Genetic studies in clonal haematopoiesis, myelodysplastic neoplasms and acute myeloid leukaemia - a practical guide to WHO-HAEM5.

In recent years, technology developments and increase in knowledge have led to profound changes in the diagnostics of haematologic neoplasms, particularly myeloid neoplasms. Therefore an updated, fifth edition of the World Health Organization (WHO) classification of haematolymphoid neoplasms (WHO-HAEM5) will be issued in 2024. In this context, we present a practical guide for analysing the genetic aspects of clonal haematopoiesis of indeterminate potential (CHIP), clonal cytopenia of undetermined significance (CCUS), myelodysplastic neoplasms (MDS), and acute myeloid leukaemia (AML) based on WHO-HAEM5. This guide navigates through the genetic abnormalities underlying myeloid neoplasms which are required to be detected for classification according to WHO-HAEM5 and provides diagnostic algorithms.

Association of Food Desert Residence and 5-Year Mortality in Lung Cancer Patients Undergoing Resection.

INTRODUCTION: Food desert (FD) residence has emerged as a risk factor for poor outcomes in breast, colon and esophageal cancers. The purpose of this retrospective study was to examine FD residence as an associated risk factor in nonsmall cell lung cancer (NSCLC) patients treated with anatomic lung resection (ALR). METHODS: All consecutive ALRs for stage I-III NSCLC from January 2015 to December 2017 at a single institution were reviewed. The primary exposure of interest was FD residence as defined by the United States Department of Agriculture. The primary outcome was 5-y overall mortality. Secondary outcomes were 30-d complications and 1- and 3-y mortality. Cox proportional hazard analysis was used to model factors associated with each outcome, adjusted for covariates. RESULTS: A total of 348 ALRs were included, with 101 (29%) patients residing in an FD. In the unadjusted Cox model, those residing in FD had an associated lower 5-year mortality risk compared to those not residing in an FD (hazard ratio = 0.56, 95% confidence interval (0.33-0.97); P = 0.04). That association was not statistically significant once adjusted for covariates (hazard ratio = 0.59, 95% confidence interval (0.34-1.04); P = 0.07). CONCLUSIONS: In this study, FD residence was not associated with an increase in the risk of 5-y mortality. Selection bias of patients deemed healthy enough to undergo surgery may have mitigated the negative association of FD residence demonstrated in other cancers. Future work will evaluate all NSCLC patients undergoing treatments at our institution to further evaluate FDs as a risk factor for worse outcomes.

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Trial of AWZ1066S, an Anti-Wolbachia Candidate Macrofilaricide.

AWZ1066S has been developed as a potential treatment for the neglected tropical diseases lymphatic filariasis and onchocerciasis. AWZ1066S targets the Wolbachia bacterial endosymbiont present in the causative nematode parasites. This phase 1, first-in-human study aimed to assess the safety and pharmacokinetics of AWZ1066S in healthy human participants. In a randomized double-blind, placebo-controlled, single ascending dose study, healthy adults received a single oral dose of AWZ1066S (or placebo) and were followed up for 10 days. The planned single doses of AWZ1066S ranged from 100 to 1600 mg, and each dose was administered to a cohort of 8 participants (6 AWZ1066S and 2 placebo). In total 30 people participated, 18 (60%) female, median age 30.0 years (minimum 20, maximum 61). The cohorts administered 100, 200, 300, and 400 mg of AWZ1066S progressed unremarkably. After single 700-mg doses all 4 participants developed symptoms of acute gastritis and transient increases in liver enzymes. The severity of these adverse events ranged from mild to severe, with 1 participant needing hospital admission. Pharmacokinetic analysis indicated that AWZ1066S is rapidly absorbed with predictable pharmacokinetics. In conclusion, safety concerns prevented this study from reaching the human exposures needed for AWZ1066S to be clinically effective against lymphatic filariasis and onchocerciasis.