We previously identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental outcomes, where severely affected probands carried an excess of rare pathogenic variants compared to mildly affected carrier parents. We hypothesized that the 16p12.1 deletion sensitizes the genome for disease, while “second-hits” in the genetic background modulate the phenotypic trajectory. To test this model, we examined how neurodevelopmental defects conferred by knockdown of individual 16p12.1 homologs are modulated by simultaneous knockdown of homologs of “second-hit” genes in Drosophila melanogaster and Xenopus laevis. We observed that knockdown of 16p12.1 homologs affect multiple phenotypic domains, leading to delayed developmental timing, seizure susceptibility, brain alterations, abnormal dendrite and axonal morphology, and cellular proliferation defects. Compared to genes within the 16p11.2 deletion, which has higher de novo occurrence, 16p12.1 homologs were less likely to interact with each other in Drosophila models or a human brain-specific interaction network, suggesting that interactions with “second-hit” genes may confer higher impact towards neurodevelopmental phenotypes. Assessment of 212 pairwise interactions in Drosophila between 16p12.1 homologs and 76 homologs of patient-specific “second-hit” genes (such as ARID1B and CACNA1A), genes within neurodevelopmental pathways (such as PTEN and UBE3A), and transcriptomic targets (such as DSCAM and TRRAP) identified genetic interactions in 63% of the tested pairs. In 11 out of 15 families, patient-specific “second-hits” enhanced or suppressed the phenotypic effects of one or many 16p12.1 homologs in 32/96 pairwise combinations tested. In fact, homologs of SETD5 synergistically interacted with homologs of MOSMO in both Drosophila and X. laevis, leading to modified cellular and brain phenotypes, as well as axon outgrowth defects that were not observed with knockdown of either individual homolog. Our results suggest that several 16p12.1 genes sensitize the genome towards neurodevelopmental defects, and complex interactions with “second-hit” genes determine the ultimate phenotypic manifestation.

ImportanceBariatric surgery is the mainstay of treatment for medically refractory obesity; however, it is underutilized. Telemedicine affords patient cost and time savings and may increase availability and accessibility of bariatric surgery.ObjectiveTo determine clinical outcomes and postoperative hospital utilization for patients undergoing bariatric surgery who receive fully remote vs in-person preoperative care.Design, Setting, and ParticipantsThis cohort study comparing postoperative clinical outcomes and hospital utilization after telemedicine or in-person preoperative surgical evaluation included patients treated at a US academic hospital. Participants underwent laparoscopic Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy after telemedicine or in-person preoperative surgical evaluation between July 1, 2020, to December 22, 2021, or January 1, 2018, to December 31, 2019, respectively. Follow-up was 60 days from date of surgery.ExposuresTelemedicine-based preoperative care.Main Outcomes and MeasuresClinical outcomes, including operating room delay, procedure duration, length of hospital stay (LOS), and major adverse events (MAE), and postoperative hospital resource utilization, including emergency department (ED) visit or hospital readmission within 30 days of the surgical procedure.ResultsA total of 1182 patients were included; patients in the telemedicine group were younger (mean [SD] age, 40.8 [12.5] years vs 43.0 [12.2] years; P = .01) and more likely to be female (230 of 257 [89.5%] vs 766 of 925 [82.8%]; P = .01) compared with the control group. The control group had a higher frequency of comorbidity (887 of 925 [95.9%] vs 208 of 257 [80.9%]; P < .001). The telemedicine group was found to be noninferior to the control group with respect to operating room delay (mean [SD] minutes, 7.8 [25.1]; 95% CI, 5.1-10.5 vs 4.2 [11.1]; 95% CI, 1.0-7.4; P = .002), procedure duration (mean [SD] minutes, 134.4 [52.8]; 95% CI, 130.9-137.8 vs 105.3 [41.5]; 95% CI, 100.2-110.4; P < .001), LOS (mean [SD] days, 1.9 [1.1]; 95% CI, 1.8-1.9 vs 2.1 [1.0]; 95% CI, 1.9-2.2; P < .001), MAE within 30 days (3.8%; 95% CI, 3.0%-5.7% vs 1.6%; 95% CI, 0.4%-3.9%; P = .001), MAE between 31 and 60 days (2.2%; 95% CI, 1.3%-3.3% vs 1.6%; 95% CI, 0.4%-3.9%; P < .001), frequency of ER visits (18.8%; 95% CI, 16.3%-21.4% vs 17.9%; 95% CI, 13.2%-22.6%; P = .03), and hospital readmission (10.1%; 95% CI, 8.1%-12.0% vs 6.6%; 95% CI, 3.9%-10.4%; P = .02).Conclusions and RelevanceIn this cohort study, clinical outcomes in the telemedicine group were not inferior to the control group. This observation suggests that telemedicine can be used safely and effectively for bariatric surgical preoperative care.

We previously identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental outcomes, where severely affected probands carried an excess of rare pathogenic variants compared to mildly affected carrier parents. We hypothesized that the 16p12.1 deletion sensitizes the genome for disease, while “second hits” in the genetic background modulate the phenotypic trajectory. To test this model, we examined how neurodevelopmental defects conferred by knockdown of individual 16p12.1 homologs are modulated by simultaneous knockdown of homologs of “second hit” genes in Drosophila melanogaster and Xenopus laevis . We observed that knockdown of 16p12.1 homologs affect multiple phenotypic domains, leading to delayed developmental timing, seizure susceptibility, brain alterations, abnormal dendrite and axonal morphology, and cellular proliferation defects. In contrast to genes within the 16p11.2 deletion, which has higher de novo occurrence, 16p12.1 homologs additively interacted and were less connected to each other in a human brain-specific interaction network, suggesting that interactions with second-hit genes confer higher impact towards neurodevelopmental phenotypes. Assessment of 358 pairwise interactions in Drosophila between 16p12.1 homologs and 76 homologs of patient-specific “second-hit” genes (such as ARID1B and CACNA1A ), genes within neurodevelopmental pathways (such as PTEN and UBE3A ), and transcriptomic targets (such as DSCAM and TRRAP ) identified both additive (47%) and epistatic (53%) effects. In 11 out of 15 families, homologs of patient-specific “second-hits” showed distinct patterns of interactions, enhancing or suppressing the phenotypic effects of one or many 16p12.1 homologs. In fact, homologs of SETD5 synergistically interacted with homologs of MOSMO in both Drosophila and X. laevis , leading to modified cellular and brain phenotypes, as well as axon outgrowth defects that were not observed with knockdown of either individual homolog. Our results suggest that several 16p12.1 genes sensitize the genome towards neurodevelopmental defects, and complex interactions with “second-hit” genes determine the ultimate phenotypic manifestation.

S154adeno-associated virus (rAAV) vectors encoding therapeutic genes. Specifically, we generated rAAV vectors (either AAV2 and AAV5 serotypes vectors) encoding canine codon-optimized hyaluronic acid (HA) synthase-2 (HAS2) to provide local and continuous synthesis of HA in the joint. Twenty-two adult healthy dogs that were seronegative for anti-AAV2 and -AAV5 antibodies were injected intra-articularly with rAAV2/HAS2 (1, 5 and 10x10 11 vg/joint), rAAV5/HAS2 (5x10 11 vg/joint) or PBS (control). No adverse clinical signs were observed following the 28-day study period. Histopathological analysis showed minimal synovial inflammation in the joints of dogs treated with rAAV5/HAS2 and no significant changes in the rAAV2/HAS2 treated dogs. Vector genomes (VG) were detected in the synovium of all the rAAV-treated joints and in the majority of cartilage samples tested. The rAAV5/HAS2 vector resulted in findings of higher and more consistent detection of VG and transcripts compared to rAAV2/HAS2 in both the synovial and cartilage samples. Preliminary analysis also showed a trend towards increased HA levels in the synovial fluid of the treated joints. In summary, our study demonstrated that rAAV2 and rAAV5-mediated gene transfer to canine joint tissues is feasible and that both vectors present an acceptable safety profile following a single intra-articular injection.