May 2025

Synopsis:
Penn Surgery chief resident Dr. Rosen and colleagues conducted a retrospective observational cohort study, published in the Journal of the American College of Surgeons, to evaluate the impact of multimorbidity on outcomes in older adults undergoing emergency general surgery. The study found that patients with multimorbidity have significantly worse outcomes than those without, across several measures including all-cause mortality, hospital readmission, post-operative recovery and independence, and health care resource utilization. 

Summary: 
Emergency general surgery patients often experience worse outcomes than those undergoing elective procedures, particularly when multimorbidity is present. Multimorbidity, defined by specific Qualifying Comorbidity Sets, is associated with elevated short-term risk, but its longer-term effects remain understudied. This study evaluated the outcomes of older adults with comorbid medical conditions undergoing emergency general surgery. Using Medicare claims data, the authors identified 174,891 patients aged 65 or older who underwent emergency surgery between 2015 and 2018. Of them, almost half (45.5%) were classified as “multimorbid” based on Qualifying Comorbidity Sets. The primary outcome was mortality from any cause. Secondary outcomes included postoperative complications, readmission rates at multiple time points, hospital length of stay, discharge destination, new use of durable medical equipment, and overall cost of hospitalization. 

The study found that multimorbid patients had significantly higher mortality rates than non-multimorbid counterparts during their index hospitalization (5.9% vs 0.7%, p<0.001) and within six months after discharge (17.1 vs 3.4%, p<0.001). They were also less likely to be discharged home (42.4 vs 74.2%, p<0.001) and more likely to be discharged to acute rehabilitation or skilled nursing facilities (28.3 vs 11.3%, p<0.001). Additionally, multimorbid patients experienced significantly higher readmission rates, greater use of new durable medical equipment, longer hospital stays, and higher healthcare costs. Overall, these patients faced a threefold greater risk of in-hospital mortality and almost double the risk of complications compared to non-multimorbid patients.

The authors acknowledged several limitations to this study. The use of claims data relies on accurate diagnostic coding, which may vary between individuals and institutions. Additionally, the Qualifying Comorbidity Set is a summative measure that does not allow for granular analysis of specific comorbidities or disease states and may mask significant differences. Finally, the study only included patients who had undergone an operation and therefore did not capture the likely significant proportion of older, multimorbid adults with surgical problems who were managed non-operatively.

Bottom Line: 
Multimorbidity is associated with significantly worse outcomes among older patients undergoing emergency surgery and should be recognized as an important prognostic factor to inform preoperative counseling and shared decision-making among this high-risk population.

Synopsis:
Current Penn Surgery chief resident Jacqueline Soegaard and collages recently published a single-institution retrospective study evaluating the impact of preoperative history and physical (H&P) update visits on operative management across eight surgical specialties in the Journal of the American College of Surgeons. The authors found that new physical exam findings and operative plan changes were uncommon, with most visits suitable for telehealth. These findings suggest that in-person H&P updates may impose a significant patient burden with limited clinical benefit. 

Summary: 
Laws require a documented in-person history and physical (H&P) within 30 days of surgery, often leading to additional clinic visits or day-of-surgery evaluations without strong evidence of improved outcomes. These requirements can burden patients and providers, with limited benefit, as prior studies suggest H&P updates rarely alter surgical plans. This retrospective review was conducted at the University of Pennsylvania Health System to assess the clinical utility of in-person preoperative H&P update visits across eight surgical specialties. Electronic health record data from a 12-month period identified 8,683 such visits, from which 691 were randomly selected for manual chart review. Of these, 362 met inclusion criteria and were independently reviewed by two physicians. The study population had a median age of 61 years (range 18–91), was 51.9% male (n=188), and predominantly White (74.6%, n=270), with most patients residing in Pennsylvania. In total, 95.7% (n=337) of patients underwent their planned procedure within 30 days of the H&P update visit, and 61.7% (n=208) were admitted postoperatively, with a median hospital length of stay of 3 days. 

Among the 362 visits reviewed, 60.8% (n=220) were conducted by advanced practice providers and 39.2% (n=142) by surgeons. The median time between the initial and update visits was 40 days (IQR 28–70), with 15 days (IQR 9–22) between the update visit and the procedure. Reviewers identified changes in patient history in 60.8% of visits (κ = 0.75), but changes in physical exam and operative plan were less common—11.9% (κ = 0.76) and 11.6% (κ = 0.44). Specialty-specific variation in exam and plan changes ranged from 4%–20% and 0%–21%, respectively. Of the 42 cases with changes to the operative plan, fewer than 1% were attributed to physical exam findings. Instead, changes were more often driven by updates in patient history (38%), patient preference or social factors (31%), or new diagnostic data (18%). 

Notably, reviewers deemed 99.2% (359 of 362) of in-person H&P update visits suitable for telehealth (κ = 0.66). Additionally, these visits imposed a substantial patient burden: median clinic visit duration was 52 minutes, with a median of 38 minutes spent in the exam room. Patients lived a median of 20.2 miles from the clinic, with an estimated median round-trip driving time of 55.6 minutes. Given their minimal influence on operative decision-making, the authors suggest reconsidering regulatory requirements for in-person preoperative H&P updates. Alternatives include virtual history updates with a physical exam addendum on the day of surgery, or performing the full H&P update in the preoperative area. These strategies may reduce patient burden while maintaining surgical safety and compliance.

The authors note some limitation of their study including, its focus on a single health system and outpatient H&P updates, which may affect the generalizability of the findings. Future research should include a broader population, assess virtual H&P updates post-COVID, and examine updates performed by other providers or on the day of surgery. Additionally, investigating the impact of day-of-surgery H&P updates and identifying the optimal timing for such updates are important next steps.

Bottom line:
In-person preoperative H&P update visits rarely resulted in new physical findings or operative plan changes. Most were suitable for telehealth and imposed significant time and travel burdens. Regulatory reform and workflow redesign may optimize preoperative care without compromising safety.

Synopsis:
This study published by current Penn Surgery chief resident, John Riley, and colleagues in The Journal of Clinical Investigation looks at the effects of preexisting immunity to components of in utero gene editing (IUGE). IUGE is a promising therapy for inherited diseases, however, maternal immunity to the components of gene therapy, like adeno-associated virus (AAV) or Cas9 protein, could potentially interfere with postnatal gene editing. This study demonstrates that preexisting maternal immunity to AAV, but not Cas9, can impair IUGE in mice, and that transplacental transfer of anti-AAV antibodies in humans is limited before the third trimester, highlighting key immunologic considerations for future IUGE clinical protocols.

Summary:
IUGE is a potential treatment option for genetic diseases that manifest early in life. It takes advantage of the tolerogenic fetal immune system as it minimizes fetal immune barrier to IUGE. It has the potential to provide a one-and-done treatment for several diseases that present in early childhood. Riley and colleagues have demonstrated in their earlier work the ability to use in utero base editing to correct the disease phenotype in mouse models of hereditary tyrosinemia type 1 and mucopolysaccharidosis type I. This study is to further investigate and establish a robust framework for IUGE to address the impact of preexisting immunity present in mothers. 

The authors used mouse models, including fluorescent reporter mice and mice with hereditary tyrosinemia type 1 (HT1), to assess the impact of maternal immune sensitization to AAV and Cas9, which are common delivery vehicles and bacteria-base editing enzymes in IUGE. Human maternal and fetal samples were also analyzed to evaluate antibody transfer efficiency. First, they established whether IUGE was affected in healthy, normal mouse models (mTmG+) under different maternal conditions, unsensitized dams (normal), AAV9-sensitive dams, and Cas9-sensitized dams. Their initial experiments showed that mice with preexisting anti-AAV9 IgG transferred these antibodies to their fetuses, impairing fetal liver gene editing in a dose-dependent manner. Editing was completely inhibited at maternal antibody titers >1:25. However, in Cas9-sensitized dams, maternal antibodies and T cells reactive to Cas9 were generated, but T cell immunity was not transferred to fetuses. Vertical transmission of anti-Cas9 IgG did occur, but it did not impair fetal gene editing or cause inflammation or hepatotoxicity. Once the working framework was established in normal mouse models, they tested their theory in a mouse model of hereditary tyrosinemia type 1 (HT1) (Fah-/-). Similar to the findings shown in normal mice, in the HT1 mouse model, AAV9-SpCas9-mediated in utero gene editing rescued mice from liver failure—unless maternal AAV immunity was present, in which case survival was significantly reduced. Cas9 immunity had no detrimental effect.

Lastly, the study investigated how this immune barrier would be applicable to humans, so they collected samples from a cohort of 48 human pregnancies. They found that maternal-fetal transfer of anti-AAV IgG was highly dependent on gestational age. Fetal anti-AAV IgG levels were equal to or higher than maternal levels at term (36-42 weeks) and 6-fold lower than maternal at 24-30 weeks. Only about 12.5% - 16.7% of fetuses at 24 weeks gestation had anti-AAV titers high enough to block IUGE even if the mother was seropositive. This is an important finding as human clinical IUGE is likely to occur at mid-gestation (18-24 weeks), the age at which fetal umbilical vein injection becomes technically feasible.

A limitation of this study noted by the authors is that the mouse gestational period is only 19-20 days which is significantly shorter then human gestation. The mice received IUGE on day 16 which may have not been long enough to mount a full immune response to gene editing compontnets. Further testing in large animal models would help confirm the authors findings prior to translating IUGE to the clinic.

Bottom Line:
Using mouse models and human samples, the authors show that maternal immunity to AAV—but not to Cas9—poses a significant barrier to the success of liver-directed IUGE. Additionally, the study results suggest that maternal AAV serology should be screened before IUGE and support Cas9-based gene editing strategies for fetal interventions.