Leah Z. Rand, Daniel P. Carpenter, Aaron S. Kesselheim, Anushka Bhaskar, Jonathan J. Darrow, and William B. Feldman Reply.

The authors respond to a letter by Mitchell Berger in the March-April 2024 issue of the Hastings Center Report concerning their essay "Securing the Trustworthiness of the FDA to Build Public Trust in Vaccines."

Securing the Trustworthiness of the FDA to Build Public Trust in Vaccines.

The Covid-19 pandemic highlighted the need to examine public trust in the U.S. Food and Drug Administration (FDA) vaccine approval process and the role of political influence in the FDA's decisions. Ensuring that the FDA is itself trustworthy is important for justifying public trust in its actions, like vaccine approvals, thereby promoting public health. We propose five conditions of trustworthiness that the FDA should meet when it reviews vaccines, even during emergencies: consistency with rules, proper expert or political decision-makers, proper decision-making and noninterference, connection to public preference, and transparency of both reasons and procedures. The five conditions provide a road map of procedural and substantive requirements, which the FDA has variably implemented, focused on ensuring appropriate influence of political interests. While being a trustworthy agency cannot guarantee the public's trust, implementing these conditions builds a groundwork for public trust.

Symptomatic aseptic loosening of a short humeral stem following anatomic total shoulder arthroplasty.

INTRODUCTION: The rate of aseptic humeral component loosening with standard-length stems is historically so low (0.3%) that presence of humeral loosening was given substantial weight in defining periprosthetic shoulder infection by the International Consensus Meeting (ICM) in 2018. This study aims to confirm that the historically low rate of humeral stem aseptic loosening is not affected by the adoption of a novel short humeral stem. METHODS: Following institutional review board approval, this retrospective multi-institutional study was undertaken. A review of anatomic total shoulder arthroplasty (TSA) cases at 3 institutions provided 184 shoulders that received TSA with a grit-blasted, rectangular short humeral stem without ingrowth coating (Univers Apex; Arthrex). The average patient age was 62.1 years (range: 30-84), and 57.1% (105/184) were male. One-year radiographic follow-up was achieved in 64.7%. Patient clinical charts were reviewed for onset of newly painful shoulders, radiographic evidence of loosening, and return to the operating room for any reason. All patients with concern for clinically significant humeral loosening underwent workup for periprosthetic shoulder infection. Immediate postoperative films were reviewed to identify any differences in prosthetic canal fit. The definition of periprosthetic shoulder infection used was provided by the recent ICM shoulder guidelines. RESULTS: Twenty-three (12.5%) patients presented with a painful shoulder and radiographic concern for potential humeral loosening at a mean follow-up of 1.5 years (range: 1.5 months-3.4 years). Thirteen (7.1%) of these underwent revision shoulder arthroplasty where a loose stem was confirmed. All revisions underwent tissue culture, and 3 cases were consistent with probable or possible periprosthetic infection at the time of revision arthroplasty. The rate of symptomatic aseptic humeral loosening in this series was 10.9% (20/184), with 5.4% undergoing revision surgery. Patients with symptomatic aseptic humeral loosening were more likely to be male (90.5%) than those patients without symptoms (52.8%, P < .001). There were no differences in canal fit between patients with concern for symptomatic loosening and those with pain-free, stable implants. CONCLUSION: In this multisurgeon, multicenter study, the early humeral loosening rate for this stem design far outpaces previously reported rates, and this study likely under-reports the true incidence of clinically significant loosening as it only contains limited short-term follow-up. The perception that humeral loosening is nearly pathognomonic for periprosthetic shoulder infection should be reconsidered for certain short humeral stem designs.

Trends in open shoulder surgery among early career orthopedic surgeons: who is doing what?

BACKGROUND: The incidence of various open shoulder procedures has changed over time. In addition, various fellowships provide overlapping training in open shoulder surgery. There is a lack of information regarding the relationship between surgeon training and open shoulder procedure type and incidence in early career orthopedic surgeons. METHODS: The American Board of Orthopaedic Surgery Part-II database was queried from 2002 to 2016 for reported open shoulder procedures. The procedures were categorized as follows: arthroplasty, revision arthroplasty, open instability, trauma, and open rotator cuff. We evaluated procedure trends as well as their relationship to surgeon fellowship categorized by Sports, Shoulder/Elbow, Hand, Trauma, and "Other" fellowship as well as no fellowship training. We additionally evaluated complication data as it related to procedure, fellowship category, and volume. RESULTS: Over the 2002-2016 study period, there were increasing cases of arthroplasty, revision arthroplasty, and trauma (P < .001). There were decreasing cases in open instability and open rotator cuff (P < .001). Those with Sports training reported the largest overall share of open shoulder cases. Those with Shoulder/Elbow training reported an increasing overall share of arthroplasty cases and higher per candidate case numbers. The percentage of early career orthopedic surgeons reporting 5 or more arthroplasty cases was highest among Shoulder/Elbow candidates (P < .001). Across all procedures, those without fellowship training were least likely to report a complication (odds ratio [OR], 0.76; 95% confidence interval, 0.67-0.86; P < .001). Shoulder/Elbow candidates were least likely to report an arthroplasty complication (OR, 0.84, P = .03) as was any surgeon reporting 5 or more arthroplasty cases (OR, 0.81; 95% confidence interval, 0.70-0.94; P = .006). CONCLUSION: The type and incidence of open shoulder surgery procedures continues to change. Among early career surgeons, those with more specific shoulder training are now performing the majority of arthroplasty-related procedures, and early career volume inversely correlates with complications.

Spontaneous Healing of a Bucket-Handle Posterior Labral Detachment After Hip Dislocation in a Five-Year-Old Child: A Case Report.

CASE: We report the case of a 5-year-old girl who sustained a traumatic hip dislocation and a spontaneous reduction that was complicated by nonconcentric reduction and a large bucket-handle labral detachment. This injury was managed, via an anterior approach, with capsulotomy and reduction of the large interposed labral tear with an attached osteochondral fragment from the posterior aspect of the acetabulum. No additional surgical treatment was employed for the labral tear. CONCLUSION: The patient ultimately demonstrated radiographic healing and an asymptomatic, clinically stable hip. This case illustrates the spontaneous healing of a large posterior labral detachment in a young pediatric patient with a good outcome at 2.5 years after injury.

Neurogenic Edema from Complex Regional Pain Syndrome Resulting in Fulminant Infection Necessitating Below Elbow Amputation.

We report a case of severe upper extremity complex regional pain syndrome type 1 (CRPS-1) and neurogenic edema that ultimately led to a medically necessary below-elbow amputation. The patient presented with a history of remote bilateral carpal tunnel release complicated by debilitating and recalcitrant bilateral CRPS-1. Following years of severe neurogenic edema of the left upper extremity, the patient had full-thickness skin sloughing on the dorsum of her hand due to massive edema. This subsequently led to maggot infestation of the soft tissues of the left hand ultimately necessitating amputation. We present the case as an illustration of an extreme case of neurogenic edema, a potential physical manifestation of CRPS-1. The case presented discusses upper extremity amputation as an end treatment option for CRPS-1, though in this case amputation was primarily indicated secondary to medical necessity.

Novel Antibiotic-loaded Point-of-care Implant Coating Inhibits Biofilm.

BACKGROUND: Orthopaedic biomaterials are susceptible to biofilm formation. A novel lipid-based material has been developed that may be loaded with antibiotics and applied as an implant coating at point of care. However, this material has not been evaluated for antibiotic elution, biofilm inhibition, or in vivo efficacy. QUESTIONS/PURPOSES: (1) Do antibiotic-loaded coatings inhibit biofilm formation? (2) Is the coating effective in preventing biofilm in vivo? METHODS: Purified phosphatidylcholine was mixed with 25% amikacin or vancomycin or a combination of 12.5% of both. A 7-day elution study for coated titanium and stainless steel coupons was followed by turbidity and zone of inhibition assays against Staphylococcus aureus and Pseudomonas aeruginosa. Coupons were inoculated with bacteria and incubated 24 hours (N = 4 for each test group). Microscopic images of biofilm were obtained. After washing and vortexing, attached bacteria were counted. A mouse biofilm model was modified to include coated and uncoated stainless steel wires inserted into the lumens of catheters inoculated with a mixture of S aureus or P aeruginosa. Colony-forming unit counts (N = 10) and scanning electron microscopy imaging of implants were used to determine antimicrobial activity. RESULTS: Active antibiotics with colony inhibition effects were eluted for up to 6 days. Antibiotic-loaded coatings inhibited biofilm formation on in vitro coupons (log-fold reductions of 4.3 ± 0.4 in S aureus and 3.1 ± 0 for P aeruginosa in phosphatidylcholine-only coatings, 5.6 ± 0 for S aureus and 3.1 ± 0 for P aeruginosa for combination-loaded coatings, 5.5 ± 0.3 for S aureus in vancomycin-loaded coatings, and 3.1 ± 0 for P aeruginosa for amikacin-loaded coatings (p < 0.001 for all comparisons of antibiotic-loaded coatings against uncoated controls for both bacterial strains, p < 0.001 for comparison of antibiotic-loaded coatings against phosphatidylcholine only for S aureus, p = 0.54 for comparison of vancomycin versus combination coating in S aureus, P = 0.99 for comparison of antibiotic- and unloaded phosphatidylcholine coatings in P aeruginosa). Similarly, antibiotic-loaded coatings reduced attachment of bacteria to wires in vivo (log-fold reduction of 2.54 ± 0; p < 0.001 for S aureus and 0.83 ± 0.3; p = 0.112 for P aeruginosa). CONCLUSIONS: Coatings deliver active antibiotics locally to inhibit biofilm formation and bacterial growth in vivo. Future evaluations will include orthopaedic preclinical models to confirm therapeutic efficacy. CLINICAL RELEVANCE: Clinical applications of local drug delivery coating could reduce the rate of implant-associated infections.

Time series analyses of the effect of FDA communications on use of prescription weight loss medications.

OBJECTIVE: To determine the impact of FDA safety communications regarding the weight loss medications sibutramine and orlistat. METHODS: The 2008 to 2011 pharmacy claims data from CVS Caremark were used to determine the effect of the relevant FDA warnings on (1) use of sibutramine and orlistat, (2) their rates of discontinuation, and (3) substitution to an alternate weight loss medication in the 3-month period following discontinuation. RESULTS: The use of sibutramine, orlistat, or phentermine declined from 45 users per 100,000 Caremark enrollees in May 2008 to 24 users per 100,000 enrollees in December 2010. In the time series analyses of overall use of medications, a very small decline in the trend of use of sibutramine after the FDA communication (0.000002% per month decline after the communication; P < 0.001) was found. However, rates of discontinuation of sibutramine and orlistat were similar before and after relevant FDA communications (all P values >0.1 for both level and trend changes post-warning). Patients discontinuing sibutramine post-communication increased use of phentermine at a rate of 0.004% per month after discontinuation (P = 0.01). CONCLUSION: From 2008 to 2010, use of prescription weight loss medications was low and declined over time. FDA communications regarding the safety of these medications had limited effect on use.

Whose deaths matter? Mortality, advocacy, and attention to disease in the mass media.

Diseases capture public attention in varied ways and to varying degrees. In this essay, we use a unique data set that we have collected about print and broadcast media attention to seven diseases across nineteen years in order to address two questions. First, how (if at all) is mortality related to attention? Second, how (if at all) is advocacy, in the form of organized interest group activity, related to media attention? Our analysis of the cross-disease and cross-temporal variation in media attention suggests that who suffers from a disease as well as how many suffer are critical factors in explaining why some diseases get more attention than others. In particular, our data reveal that both the print and the broadcast media tend to be much less attentive to diseases that disproportionately burden blacks relative to whites. We also find a positive link between the size of organizational communities that take an interest in disease and media attention, though this finding depends on the characteristics of those communities. Finally, this study also reveals the limitations of relying on single-disease case studies-and particularly HIV/AIDS-to understand how and why disease captures public attention. Many previous inferences about media attention that have been drawn from the case of AIDS are not reflective of the attention allocated to other diseases.

The political economy of FDA drug review: processing, politics, and lessons for policy.

U.S. Food and Drug Administration (FDA) drug review bears a structural similarity to many decisions made by other regulatory agencies: high uncertainty, low reversibility, avoidance of observable error, and high political stakes that induce lobbying by interested parties. This paper explores the policy lessons to be learned from viewing FDA drug review as a politically shaped exercise in information processing. I argue that the incentives facing regulators induce limits on the degree to which drug review can be accelerated, that the same incentives could render privatization initiatives problematic, and that political pressures could play a useful role in identifying priority drugs.

Defending submission-year analyses of new drug approvals.

In response to the critique of Mary Olsen, Daniel Carpenter, on behalf of his co-authors, addresses the issue of analysis based on the year a new drug is submitted for Food and Drug Administration (FDA) approval, not the year it is approved. Both substantive knowledge of the FDA drug review process and sound social science theory favor submission-year averaging. The history and bureaucratic mechanics of the Center for Drug Evaluation and Review (CDER) conform to the author's assumption. The statistical theory of optimal experimentation also points to the beginning of review as a locus for effects upon decisions.