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Short-term low intensity parent implemented intervention studies for toddlers with autism spectrum disorder (ASD) have found it difficult to demonstrate significantly improved developmental scores or autism severity compared to community treatment. We conducted a randomized comparative intent-to-treat study of a parent implemented intervention to (1) test the effects of an enhanced version on parent and child learning, and (2) evaluate the sensitivity to change of proximal versus distal measures of child behavior. We randomized 45 children with ASD, 12-30 months of age, into one of two versions of parent-implemented Early Start Denver Model (P-ESDM), the basic model, in which we delivered 1.5 h of clinic-based parent coaching weekly, and an enhanced version that contained three additions: motivational interviewing, multimodal learning tools, and a weekly 1.5-h home visit. We delivered the intervention for 12 weeks and measured child and parent change frequently in multiple settings. We found a time-by-group interaction: parents in the enhanced group demonstrated significantly greater gains in interaction skills than did parents in the non-enhanced group. Both interventions were associated with significant developmental acceleration; however, child outcomes did not differ by group. We found a significant relationship between degree of change in parental interaction skill and rate of children's improvement on our proximal measure. Parents in both groups reported satisfaction with the intervention. These findings suggest that parent skills improved more in the enhanced group than the comparison group. Children in the two groups showed similar improvements. Rate of individual parent learning was associated with greater individual child progress on a measure quite proximal to the treatment, though not on standardized assessments.

Objective: To investigate occult enteric infections and morphologic changes in the small intestine in patients with advanced human immunodeficiency virus (HIV) infection and chronic diarrhea of undefined cause.Design: Case-control study.Setting: Referral-based clinic and hospital in tertiary care center.Patients: Twenty-two patients with advanced HIV infection (19 with the acquired immunodeficiency syndrome [AIDS], 3 with AIDS-related complex) with chronic diarrhea, selected because of previously negative stool evaluations for bacterial or parasitic pathogens, were compared with 13 patients with advanced HIV infection (9 with AIDS, 4 with AIDS-related complex) without diarrhea by analysis of endoscopic biopsies using light and electron microscopy, viral culture, and morphometric studies. Both groups were convenience samples and had at least 7 months follow-up.Measurements and Main Results: Eleven of twenty-two patients with HIV infection and chronic diarrhea but only 1 of 13 patients without diarrhea showed occult enteric pathogens (that is, undetected by routine studies) after extensive evaluation of duodenal and colorectal biopsies. Mycobacterium avium-intracellulare and microsporidia were the most common occult agents in study patients with diarrhea (5 each). Patients with diarrhea and occult enteric infections had greater weight loss (mean, 14.3 kg compared with 6.2 kg; P less than 0.05) and shorter survival (1 of 11 compared with 8 of 11 still alive; P less than 0.004) than those with diarrhea but no identified pathogens (defined as "AIDS enteropathy"). Duodenal morphometry showed decreased villus-to-crypt ratios because of villus atrophy and crypt elongation in HIV-infected patients both with and without diarrhea compared with normal controls (P less than 0.001 for each). All three groups showed comparable frequencies of epithelial mitoses.Conclusions: Further endoscopic biopsy evaluation of patients with AIDS who had unexplained chronic diarrhea showed an occult infectious cause in half of the cases. However, altered villus and crypt architecture in advanced HIV infection was independent of the presence of diarrhea or enteric infection and therefore did not correlate with AIDS enteropathy. Subnormal epithelial proliferation in response to injury could be a factor, but the underlying cause of the architectural changes remains obscure. We suggest that T-cell dysfunction may play a role. [ABSTRACT FROM AUTHOR]

TGF-α inhibits gastric acid secretion andmay play an important role in epithelial repair. Wequantitated regional levels of TGF-α in the humanproximal gastrointestinal tract and determined whether they are affected by acid suppression oraspirin-induced injury. Ten healthy volunteers werestudied. After baseline endoscopy with biopsy, fiverandomly received no treatment, aspirin, omeprazole, orcimetidine for one week. Endoscopy was repeated and priorunhealed biopsy sites quantitated. TGF-α levelswere measured by RIA. Five additional subjects thencompleted an extended protocol of three weeks' duration. All subjects were free of H. pylori infection.TGF-α levels in the antrum, 34.76 ± 5.54 pgTGF-α/μg DNA were threefold higher than in thegastric body and duodenum (11.03 ± 2.60 and 10.41± 1.64 respectively, P < 0.01). The number of unhealed sites inthe aspirin group was significantly greater than in thecontrol or acid inhibition groups; however, TGF-αlevels were not different from the surrounding mucosa. TGF-α increased in the controls afterbiopsy; the increase was significant in the body at week2 only. Aspirin significantly increased TGF-αlevels in the gastric body and duodenum after one week. The rise in antral TGF-α appeared delayedand blunted by the aspirin treatment compared tocontrol. There was no relationship between the number ofvisible biopsy sites, degree of aspirin-induced injury, and the TGF-α level. Acid suppression wasassociated with a significant increase in TGF-α inthe gastric body and antrum at one week. Immunochemicalstaining did not demonstrate differences inproliferation in any treatment group compared to controls.TGF-α levels vary by location in the proximalgastrointestinal tract, with significantly greaterlevels in the antrum. After biopsy, TGF-α levelsincrease; short-term aspirin and acid inhibitors modulatethis effect. Aspirin significantly impaired the healingof endoscopic biopsies in the antrum; however, this wasnot associated with changes in TGF-α levels. TGF-α levels did not change in responseto acid secretory state. Further studies of mucosallevels of TGF-α in response to aspirin-inducedinjury in humans appear warranted. [ABSTRACT FROM AUTHOR]

Discusses a case of fulminant hepatic failure in a patient shortly after switching to sustained-release nicotinic acid after having taken ordinary nicotinic acid for over one year without side effects. Features suggesting fulminant hepatic to be resulted from use of sustained-release nicotinic acid; Cause of hepatic necrosis; Awareness regarding side effects of nicotinic acid.

Omeprazole is a new hydrogen-potassium adenosine triphosphatase antagonist with indications for severe reflux esophagitis and Zollinger-Ellison syndrome. Side effects involving the liver have consisted of minimal elevations of hepatocellular enzymes with higher dosages. We present what we believe is the first reported case of fulminant hepatic failure related to omeprazole. [ABSTRACT FROM AUTHOR]

Background: Sulfasalazine is a widely used anti-inflammatory agent in the treatment of inflammatory bowel disease and several rheumatological disorders. Although as many as 20% of treated patients may experience reversible, dose-dependent side effects, less frequent but potentially severe, systemic reactions have also been reported.Case Presentation: A severe systemic reaction to sulfasalazine developed in a 21-year old female with rheumatoid arthritis characterized by eosinophilia, granulomatous enteritis and myelotoxicity, cholestatic hepatitis, and seizures. The clinical course and management of this patient are presented as well as a review of the incidence and outcome of severe systemic reactions to sulfasalazine.Conclusions: Granulomatous myelotoxicity and enteritis developed in a 21 year old female within 3 weeks of initiating sulfasalazine for rheumatoid arthritis. Following a short course of corticosteroids, the patient had resolution of her cholestatic hepatitis, rash, eosinophilia, and gastrointestinal symptoms with no residual manifestations at 7 months follow-up. Although severe reactions to sulfasalazine are rare and unpredictable, practicing physicians should be aware of unusual clinical presentations of toxicity when prescribing sulfasalazine. [ABSTRACT FROM AUTHOR]

Background: The antibody-drug conjugate (ADC) trastuzumab emtansine (T-DM1) combines the antitumor activities of trastuzumab with intracellular delivery of the cytotoxic agent DM1 and represents a new approach to therapy for HER2-positive MBC. Recently, the first phase 3 data have been reported with significant improvements in PFS (9.6 vs 6.4 months; HR=0.650; P<0.0001) and lower incidence of grade ≥ 3 adverse events (AEs) (57% vs 41%) vs capecitabine + lapatinib (Blackwell 2012). This pooled analysis reports the overall safety profile of T-DM1 3.6 mg/kg q3w in 882 patients treated with T-DM1. Methods: Data were included from treated patients in 7 studies of single-agent T-DM1 3.6 mg/kg q3w: 1 phase 1 study in previously treated MBC (TDM3569g, Krop 2010, n=15 treated at 3.6 mg/kg q3w); 3 phase 2 single-arm studies in previously treated MBC (TDM4258g, Burris 2011, N=112; TDM4374g, Krop 2012, N=110; TDM4688g, Gupta 2011, n=51); 1 randomized phase 2 study in previously untreated MBC (Hurvitz 2011, TDM4450g/BO21976, n=69); 1 extension study (TDM4529/BO25430, n=43 from parent studies); and 1 phase 3 study in MBC previously treated with trastuzumab and a taxane (EMILIA, Blackwell 2012, n=490). Data were analyzed in 4 groups: (1) all T-DM1-treated pts (7 studies, N=882), (2) pts originally enrolled in single-arm studies (n = 288), (3) T-DM1 pts from TDM4450g (n = 69), and (4) T-DM1 pts from EMILIA (n = 490). Results: Among all pts (N = 882), median age was 53 years (range 25-85 years); 52.7% had ≥3 metastatic sites; 81.7% had received prior treatment for MBC; and the median number of prior non-endocrine agents for MBC was 3.0 (range 0-19). All-grade AEs occurring in ≥ 25% of patients were fatigue (45.4%), nausea (42.3%), headache (28.7%), thrombocytopenia (28.7%), and constipation (25.5%). Grade ≥3 AEs occurring in 2% were thrombocytopenia, increased AST, increased ALT, fatigue, hypokalemia, and anemia. Table 1 describes the grade ≥ 3 incidence of these AEs, as well as selected AEs with known association to T-DM1 or potential risk based on the components of T-DM1 or on preclinical data. Conclusions: The safety profile of T-DM1 3.6 mg/kg q3w was consistent across the studies and the different patient populations with HER2-positive MBC. Additional analyses on hepatic transaminase increases and those exploring potential associations between thrombocytopenia and hemorrhage will be presented. [ABSTRACT FROM AUTHOR]

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice., (© 2023. Springer Nature Limited.)

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expanded PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS were 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1,681-3,651 cases and 8,696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They were significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values<0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

It is well-documented that autism can be reliably diagnosed by age two and that early signs emerge most often between 18 and 24 months. However, despite the increased awareness and focus on early diagnosis, the average age of diagnosis is over 4 years old; even later for Black children and those who are Medicaid-eligible. In this paper, we will propose a framework for accurate and accelerated autism diagnosis for children before age three. The proposed framework emphasizes a collaborative diagnostic process, which relies heavily on Birth to Three provider knowledge and expertise. Considerations for next steps are presented. This approach could increase access to diagnosis of young children soon after first signs of autism emerge., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Penney, Greenson, Schwartz and Estes.)