Pediatric lower limb peripheral nerve blocks: Indications, effectiveness, and the incidence of adverse events.

AIM: While the proportion of pediatric anesthetics with regional anesthesia in pediatric patients has steadily increased, there are only a few series that describe the use of lower limb peripheral nerve blocks in children. Our aim was to describe the indications, anesthetic approach, and complications associated with lower limb blocks in children undergoing orthopedic surgery in a center with a large caseload of complex patients. METHODS: In a retrospective analysis of prospectively collected data, we reviewed children who had a peripheral nerve block for orthopedic surgery placed between January 2016 and January 2021 at the Royal Children's Hospital Melbourne. Block data were sourced from the electronic medical record and departmental regional anesthesia database. Data collected included demographics, the site of catheter placement and technique of nerve block, presence of sensory/motor blockade, the use of perioperative opioids, and any complications related to peripheral nerve block. RESULTS: A total of 1438 blocks were performed in 1058 patients. Four patients had clinical features of perioperative neurological injury giving an incidence of 3 per 1000 blocks (95% CI 1.1-8:1000). Only one patient had a sensory deficit persisting longer than 6 months for an incidence of 0.8 per 1000 blocks (95% CI 0.1-5:1000). All four peripheral nerve injury followed tibial osteotomy for lengthening procedures or correction of tibial torsion. The etiology of the injury could not be determined despite imaging and surgical exploration and the contribution of popliteal sciatic nerve block to the subsequent PNI could not be confirmed. There were no cases of local anesthetic systemic toxicity. CONCLUSION: An increased risk of perioperative peripheral nerve injury is associated with pediatric tibial osteotomy for congenital deformity. While popliteal sciatic nerve block was not directly implicated in the nerve injury the presence of a prolonged sensory block can delay early recognition and treatment of peripheral nerve injury.

Different ODE models of tumor growth can deliver similar results.

BACKGROUND: Simeoni and colleagues introduced a compartmental model for tumor growth that has proved quite successful in modeling experimental therapeutic regimens in oncology. The model is based on a system of ordinary differential equations (ODEs), and accommodates a lag in therapeutic action through delay compartments. There is some ambiguity in the appropriate number of delay compartments, which we examine in this note. METHODS: We devised an explicit delay differential equation model that reflects the main features of the Simeoni ODE model. We evaluated the original Simeoni model and this adaptation with a sample data set of mammary tumor growth in the FVB/N-Tg(MMTVneu)202Mul/J mouse model. RESULTS: The experimental data evinced tumor growth heterogeneity and inter-individual diversity in response, which could be accommodated statistically through mixed models. We found little difference in goodness of fit between the original Simeoni model and the delay differential equation model relative to the sample data set. CONCLUSIONS: One should exercise caution if asserting a particular mathematical model uniquely characterizes tumor growth curve data. The Simeoni ODE model of tumor growth is not unique in that alternative models can provide equivalent representations of tumor growth.

Known Knowns, Known Unknowns, and Unknown Unknowns: Coverage in MS Experiments.

A mathematical model from ecology, namely, the capture-recapture model with a closed population and time-varying and heterogeneous individual probabilities of capture, is implemented to model the number of protein identifications across the various cycles of a mass spectroscopy experiment. Rcapture, a package available in the R computing environment, can easily provide estimates of the cardinality of the proteome from such experiments. Alternatively, model fitting can be undertaken in other software platforms, such as Matlab, that can accommodate general linear models. It has not escaped our notice that capture-recapture models can be more broadly applied to other settings, so as to estimate the number of missing observations in an experiment.

Early detection of hepatocellular carcinoma using autoantibody profiles from a panel of tumor-associated antigens.

BACKGROUND: Multiple antigen miniarrays used for detecting autoantibodies to tumor-associated antigens (TAAs) can be a useful approach for cancer detection and diagnosis. We here address a very specific question: might there be autoimmune responses to TAAs which precede clinical detection of hepatocellular carcinoma (HCC) in HBV and HCV chronic liver disease patients under continuous medical surveillance, and if so, could these anti-TAAs be added to the armamentarium of diagnostic tests? METHODS: We here examine the utility of a panel of 12 TAAs for the diagnosis of hepatocellular carcinoma (HCC). We derived a predictive rule for the presence of HCC based on the panel, from a cohort comprising 160 HCC patients and 90 normals. We then applied this rule to sequential anti-TAA data from a cohort of 17 HCC patients, from whom this information was available prior to diagnosis. RESULTS: The predictors (autoantibodies to HCC1, P16, P53, P90, and survivin) indicated the presence of HCC prior to diagnosis in 16 of the 17 patients, at a median lead time of 0.75 year. CONCLUSIONS: We believe these findings warrant further study of anti-TAA profiles as biomarkers for primary or early diagnosis of HCC.

Heparin and alkalinized lidocaine versus alkalinized lidocaine for treatment of interstitial cystitis symptoms.

INTRODUCTION: Interstitial cystitis (IC), sometimes referred to as IC/bladder pain syndrome, is a substantial health care problem. Once considered a rare, orphan disease, it is now believed to be relatively common. This pilot study was undertaken to determine if the combination of heparin and alkalinized lidocaine (heparin-lidocaine) was more efficacious than alkalinized lidocaine at relieving pain and urgency symptoms associated with IC and also capable of yielding higher lidocaine absorption. MATERIALS AND METHODS: A single blind study was conducted on 14 IC patients with a heparin-lidocaine combination versus alkalinized lidocaine instilled intravesically. In a separate study serum lidocaine levels for heparin-alkalinized lidocaine combination versus USP lidocaine only were determined by high performance liquid chromatography. RESULTS: Alkalinized lidocaine and heparin have been reported to provide relief from pain and urgency symptoms associated with IC. The heparin-lidocaine combination significantly reduced the % of bladder pain (38% versus 13%, p = 0.029) and urgency (42% versus 8% p = 0.003) compared to lidocaine. In addition the GAR was significantly better for the heparin-lidocaine combination at both 1 hr % improved (77% versus 50%, p = 0.04) and 24 hrs (57% versus 23%, p = 0.002) after study drug treatment. Serum lidocaine levels for the heparin-lidocaine combination were significantly higher compared to USP lidocaine (unalkalinized). The mean +/- SEM was 0.45 +/- 0.09 µg/mL and 0.20 +/- 0.05 µg/mL, respectively (p = 0.019). CONCLUSIONS: In this pilot study the heparin-lidocaine combination results in significantly better relief of IC symptoms compared to alkalinized lidocaine and the combination yields higher lidocaine absorption than USP lidocaine.

Glucosamine activates autophagy in vitro and in vivo.

OBJECTIVE: Aging-associated changes in articular cartilage represent a main risk factor for osteoarthritis (OA). Autophagy is an essential cellular homeostasis mechanism. Aging-associated or experimentally induced defects in autophagy contribute to organismal- and tissue-specific aging, while enhancement of autophagy may protect against certain aging-related pathologies such as OA. The objective of this study was to determine whether glucosamine can activate autophagy. METHODS: Chondrocytes from normal human articular cartilage were treated with glucosamine (0.1- 10 mM). Autophagy activation and phosphorylation levels of Akt, FoxO3, and ribosomal protein S6 were determined by Western blotting. Autophagosome formation was analyzed by confocal microscopy. Reporter mice systemically expressing green fluorescent protein (GFP) fused to light chain 3 (LC3) (GFP-LC3-transgenic mice) were used to assess changes in autophagy in response to starvation and glucosamine treatment. RESULTS: Glucosamine treatment of chondrocytes activated autophagy, as indicated by increased LC3-II levels, formation of LC3 puncta, and increased LC3 turnover. This was associated with glucosamine-mediated inhibition of the Akt/FoxO3/mammalian target of rapamycin pathway. Administration of glucosamine to GFP-LC3-transgenic mice markedly activated autophagy in articular cartilage. CONCLUSION: Glucosamine modulates molecular targets of the autophagy pathway in vitro and in vivo, and the enhancement of autophagy is mainly dependent on the Akt/FoxO/mTOR pathway. These findings suggest that glucosamine is an effective autophagy activator and should motivate future studies on the efficacy of glucosamine in modifying aging-related cellular changes and supporting joint health.

Zone-specific gene expression patterns in articular cartilage.

OBJECTIVE: To identify novel genes and pathways specific to the superficial zone (SZ), middle zone (MZ), and deep zone (DZ) of normal articular cartilage. METHODS: Articular cartilage was obtained from the knees of 4 normal human donors. The cartilage zones were dissected on a microtome. RNA was analyzed on human genome arrays. The zone-specific DNA array data obtained from human tissue were compared to array data obtained from bovine cartilage. Genes differentially expressed between zones were evaluated using direct annotation for structural or functional features, and by enrichment analysis for integrated pathways or functions. RESULTS: The greatest differences in genome-wide RNA expression data were between the SZ and DZ in both human and bovine cartilage. The MZ, being a transitional zone between the SZ and DZ, thereby shared some of the same pathways as well as structural/functional features of the adjacent zones. Cellular functions and biologic processes that were enriched in the SZ relative to the DZ included, most prominently, extracellular matrix-receptor interactions, cell adhesion molecule functions, regulation of actin cytoskeleton, ribosome-related functions, and signaling aspects such as the IFN, IL4, Cdc42/Rac, and JAK/STAT signaling pathways. Two pathways were enriched in the DZ relative to the SZ, including PPARG and EGFR/SMRTE. CONCLUSION: These differences in cartilage zonal gene expression identify new markers and pathways that govern the unique differentiation status of chondrocyte subpopulations.

Histopathological changes in the human posterior cruciate ligament during aging and osteoarthritis: correlations with anterior cruciate ligament and cartilage changes.

OBJECTIVES: To determine the histological patterns of posterior cruciate ligament (PCL) degeneration during aging and in relation to changes in articular cartilage and anterior cruciate ligament (ACL) across the entire adult age spectrum. METHODS: Human knee joints (n=120 from 65 donors) were processed within 72 h of postmortem. Articular cartilage surfaces were graded macroscopically. Each PCL was histologically evaluated for inflammation, mucinous changes, chondroid metaplasia, cystic changes and orientation of collagen fibres. The severity of PCL degeneration was classified as normal, mild, moderate or severe. PCL scores were compared to ACL and cartilage scores from the same knees. RESULTS: All knees had intact PCL. Histologically, 6% were normal, 76% showed mild, 12% moderate and 9% severe degeneration. Fibre disorientation was the most prevalent and severe change. Histological grades of PCL and ACL correlated, but significantly fewer PCL than ACL showed severe changes. There was a weaker correlation between aging and total histological PCL scores (R=0.26) compared to aging and ACL scores (R=0.42). ACL scores correlated with cartilage scores (R=0.54) while PCL scores increased with the severity of osteoarthritis from grades 0 to III but not between osteoarthritis grades III-IV (R=0.32). In knees with ruptured ACL, the PCL scores correlated with cartilage scores of the lateral compartment. CONCLUSIONS: PCL histopathological changes were less severe than in the ACL. PCL degeneration was associated with ACL and cartilage damage. The lack of correlation with age indicates independent pathways for PCL versus ACL degeneration.

Anterior cruciate ligament changes in the human knee joint in aging and osteoarthritis.

OBJECTIVE: The development and patterns of spontaneous age-related changes in the anterior cruciate ligament (ACL) and their relationship to articular cartilage degeneration are not well characterized. This study was undertaken to investigate the types and temporal sequence of age-related ACL changes and to determine their correlation with cartilage lesion patterns at all stages of osteoarthritis (OA) development in human knee joints without prior joint trauma. METHODS: Human knee joints (n = 120 from 65 donors ages 23-92) were obtained at autopsy, and ACLs and cartilage were graded macroscopically and histologically. Inflammation surrounding the ACL was assessed separately. RESULTS: Histologic ACL substance scores and ligament sheath inflammation scores increased with age. Collagen fiber disorganization was the earliest and most prevalent change. The severity of mucoid degeneration and chondroid metaplasia in the ACL increased with the development of cartilage lesions. A correlation between ACL degeneration and cartilage degeneration was observed, especially in the medial compartment of the knee joint. CONCLUSION: Our findings indicate that ACL degeneration is highly prevalent in knees with cartilage defects and may even precede cartilage changes. Hence, ACL deficiencies may not only be important in posttraumatic OA, but may also be a feature associated with knee OA pathogenesis in general.

The effect of intraoperative hypotension on the outcomes of initial hybrid palliation for single ventricle congenital heart disease: an historical cohort study.

BACKGROUND: The "hybrid procedure" is an alternative surgical palliation strategy for single ventricle congenital heart disease. The purported benefit is improved cognitive ability secondary to avoidance of cardiopulmonary bypass in the neonatal period when neuronal apoptosis is greater. It is unknown whether survival is improved after this procedure. Intraoperative hypotension is common in these patients, and we hypothesized that this hypotension was associated with mortality or morbidity. METHODS: We reviewed the records of 58/58 patients undergoing a first-stage hybrid procedure from 2004 to 2010 in a tertiary pediatric academic centre. Risk factors for poor outcome and the association between intraoperative hypotension and morbidity or mortality were investigated. RESULTS: Average preoperative arterial blood pressure (ABP) [systolic/diastolic presented as mean (standard deviation)] were 68 (12.7) / 38 (9.4) mmHg. Post-induction ABP was 65 (15.2) / 37 (8.6) mmHg. The average intraoperative nadir of ABP was 45 (7.0) / 26 (4.8) mmHg. On return to the intensive care unit (ICU), the average ABP was 69 (13.7) / 38 (11.6) mmHg. The nadir lasted longer than ten minutes in 32/58 patients. The mortality at 48 hr, 60 days, and 12 months was 3/58 (5%), 10/58 (17%), and 15/58 (26%), respectively. Six patients returned to the ICU on extracorporeal membrane oxygenation (ECMO). There was a weak statistical correlation between the average mean and diastolic BP pre-induction and changes of > 20% in systolic and diastolic BP during the case. CONCLUSION: In this patient cohort, we can show an association between short periods of intraoperative hypotension and mortality or return to the ICU on ECMO, but the importance of this is not certain.

Worldwide Regional Differences in Obesity, Elderly, and COVID-19 Mortality: Do the Exceptions Prove the Rule?

Objectives: Obesity and old age are commonly assumed to be risk factors for COVID-19 mortality. On a worldwide basis, we examine quantitative measures of obesity and elderly in the populations of individual countries and territories, and investigate whether these measures are predictive of COVID-19 mortality in those countries. In particular, we highlight regional differences relative to obesity and elderly metrics, and how these relate to COVID-19 mortality. Methods: In this retrospective, population-based study, we obtained data relating to percentages of obese or elderly individuals in 199 countries, as well as COVID-19 mortality rates in these countries. We used negative binomial regression analyses to assess associations between COVID-19 mortality rates and the putative risk factors, in six regions - Africa, Asia, Europe, North America, Oceania, and South America. Results: We found significant differences between regions relative to COVID-19 mortality, as well as obesity and elderly population proportions. There were also substantial differences between countries within regions relative to proportions of obesity and elderly individuals, and COVID-19 mortality. Conclusions: There are significant differences both between regions and within regions relative to COVID-19 mortality rates, as well as proportions of obese or elderly individuals. A global pronouncement that obesity and elderly constitute definitive risk factors for COVID-19 mortality masks the subtleties engendered by these intra- and inter-regional differences.

State Government Policy Responses to the COVID-19 Pandemic in the United States 2020-2022: Concordant Heterogeneity?

Objectives: We investigate governmental responses to the COVID-19 pandemic on a statewide basis between January 2020 and June 2022, together with mortality rates attributable to COVID-19 over the same period. Our aim is to demarcate the states' responses, and examine whether these differential responses are associated with COVID-19 mortality. Methods: Our study is based on individual state data from the Oxford COVID-19 Government Response Tracker, OxCGRT. We focus on the Government Response Index, the most comprehensive index tracked in the OxCGRT dataset. We use multivariate techniques to group the states into clusters relative to their similarities on the Government Response Index, and determine mortality rates attributable to COVID-19 in the individual groups. Results: We find that the Government Response Index was sustained at relatively constant levels in the states, with two major transition periods: a rapid rise in stringency during April through June of 2020, and a gradual decline in May and June of 2021. Heterogeneity in the Government Response Index dramatically increased in 2022. No consistent patterns emerge when relating government stringency measures with COVID-19 mortality rates. Conclusions: There is inconsistent evidence that increased governmental stringency is associated with lower COVID-19 mortality; judicious selection of time frames can lead to contrasting inferences. Political trends and motivations appear to have an outsized influence on governmental responses to the COVID-19 public health crisis, to the detriment of the populace.

Safety and efficacy of physician-supervised self-managed C1 inhibitor replacement therapy.

BACKGROUND: C1 inhibitor (C1INH) has recently been approved in the USA for the treatment of acute attacks in hereditary angioedema (HAE) patients. The literature suggests that treatment with C1INH is most effective when administered early in an attack. Home infusion of C1INH allows for the earliest possible intervention since patients can initiate therapy at the first sign of symptoms. METHODS: We performed an observational, prospective study on 39 subjects with HAE utilizing two groups of patients: one receiving on-demand C1INH replacement therapy in a medical facility and the other self-managing on-demand C1INH replacement therapy in the home setting under the supervision of a treating physician. All subjects completed online questionnaires weekly for 8 weeks. RESULTS: There were statistically significant decreases in attack duration (p < 0.0001), pain medication use (p < 0.0001) and graded attack severity (p < 0.005) in the subjects who received C1INH in the home setting versus the clinic-based group. Attack frequency was similar between the groups. The home group experienced more frequent injection-related side effects; however, the clinic group noted more severe adverse events from C1INH. CONCLUSION: Physician-supervised self-managed C1INH replacement therapy is a safe and effective treatment for patients with HAE with potential benefits in diminishing attack duration and attack severity.

Alkalinized lidocaine and heparin provide immediate relief of pain and urgency in patients with interstitial cystitis.

INTRODUCTION: It has been reported in an open-label study that the combination of alkalinized lidocaine and heparin can immediately relieve the symptoms of urinary urgency, frequency, and pain associated with interstitial cystitis (IC). This combination has also been reported to relieve pain associated with sex in patients with IC. AIM: The aim of this study was to corroborate these findings in a multicenter setting. METHODS: The study design was a multicenter prospective, double-blind, crossover, placebo-controlled trial. Each participant met all of the clinical National Institute of Diabetes and Digestive and Kidney Diseases criteria (excluding cystoscopy) for IC. Each patient received drug and control, in random order, within 48 hours of enrolling in the study. MAIN OUTCOME MEASURES: The primary outcome measure was percent change in pain score (11-point analog pain scale) 12 hours after receiving the drug or control. Secondary measures were the global assessment response (GAR) of symptoms and 12-hour average urgency reduction determined from 11-point urgency scales. RESULTS: Eighteen (18) patients completed the trial. The average reduction of pain over 12 hours was 21% for control and 42% for active drug (P = 0.0363). GAR was 13% for control and 50% for drug (P = 0.0137). Average urgency reduction was 13% for control and 35% for drug (P = 0.0328). CONCLUSIONS: The combination of alkalinized lidocaine and heparin provides up to 12 hours of relief from urgency and pain associated with IC. This combination provides significant immediate relief of symptoms for patients with IC.

Déjà vu all over again: racial, ethnic and age disparities in mortality from influenza 1918-19 and COVID-19 in the United States.

Background: Examination of the mortality patterns in the United States among racial, ethnic, and age groups attributed to the 1918-19 influenza pandemic revealed stark disparities, causes for which could have been addressed and rectified this past century. However, these disparities have been amplified during the current COVID-19 pandemic.We have ignored the lessons of the past, and were destined to repeat its failings. Objectives: Compare and contrast mortality patterns by age, race, and ethnicity attributable to the 1918-19 influenza pandemic in the United States with corresponding patterns during the COVID-19 pandemic. Methods: This is a retrospective study, establishing mortality rates according to age, race and ethnicity attributable to the 1918-19 influenza pandemic in the United States and to the current COVID-19 pandemic, using mortality data published by the U.S. Public Health Service and the Centers for Disease Control and Prevention. Negative binomial regression models were used to establish rate ratios, that is, ratios of mortality rates across the various racial/ethnic groups, and associated 95% confidence intervals. Results: Mortality patterns by age differ significantly between the 1918-19 influenza pandemic and the COVID-19 pandemic: with infant and young adult (25-40 years old) mortality substantially higher in the former. Disparities in mortality between racial and ethnic groups are amplified in the COVID-19 pandemic compared to the 1918-19 experience. Conclusions: As we evaluate our nation's response to COVID-19 and design public policy to prepare better for coming pandemics, we cannot ignore the stark disparities in mortality rates experienced by different racial and ethnic groups. This will require a sustained resolve by society and government to delineate and remedy the causative factors, through science devoid of political interpretation and exploitation.

Intracerebral hemorrhage and thrombin-induced alterations in cerebral microvessel matrix.

Four phase III clinical trials of oral direct factor Xa or thrombin inhibitors demonstrated significantly lower intracranial hemorrhage compared to warfarin in patients with nonvalvular-atrial fibrillation. This is counter-intuitive to the principle that inhibiting thrombosis should increase hemorrhagic risk. We tested the novel hypothesis that anti-thrombin activity decreases the risk of intracerebral hemorrhage by directly inhibiting thrombin-mediated degradation of cerebral microvessel basal lamina matrix, responsible for preventing hemorrhage. Collagen IV, laminin, and perlecan each contain one or more copies of the unique α-thrombin cleavage site consensus sequence. In blinded controlled experiments, α-thrombin significantly degraded each matrix protein in vitro and in vivo in a concentration-dependent fashion. In vivo stereotaxic injection of α-thrombin significantly increased permeability, local IgG extravasation, and hemoglobin (Hgb) deposition together with microvessel matrix degradation in a mouse model. In all formats the direct anti-thrombin dabigatran completely inhibited matrix degradation by α-thrombin. Fourteen-day oral exposure to dabigatran etexilate-containing chow completely inhibited matrix degradation, the permeability to large molecules, and cerebral hemorrhage associated with α-thrombin. These experiments demonstrate that thrombin can degrade microvessel matrix, leading to hemorrhage, and that inhibition of microvessel matrix degradation by α-thrombin decreases cerebral hemorrhage. Implications for focal ischemia and other conditions are discussed.

Kidney preservation by bone marrow cell transplantation in hereditary nephropathy.

The prospect of cell-based therapy for kidney disease remains controversial despite its immense promise. We had previously shown that transplanting bone marrow and hematopoietic stem cells could generate renal cells and lead to the preservation of kidney function in a mouse model for cystinosis (Ctns(-/-)) that develops chronic kidney injury, 4 months post transplantation. Here, we determined the long-term effects of bone marrow stem cell transplantation on the kidney disease of Ctns(-/-) mice 7 to 15 months post transplantation. Transfer of bone marrow stem cells expressing a functional Ctns gene provided long-term protection to the kidney. Effective therapy, however, depended on achieving a relatively high level of donor-derived blood cell engraftment of Ctns-expressing cells, which was directly linked to the quantity of these cells within the kidney. In contrast, kidney preservation was dependent neither on renal cystine content nor on the age of the mice at the time of transplant. Most of the bone marrow-derived cells within the kidney were interstitial and not epithelial, suggesting that the mechanism involved an indirect protection of the tubules. Thus, our model may help in developing strategies to enhance the potential success of cell-based therapy for kidney injury and in understanding some of the discrepancies currently existing in the field.

Lessons from the Past: Methodological Issues Arising from Comparison of the Disease Burden of the Influenza A (H1N1) Pandemic 2009-10 and Seasonal Influenza 2010-2019 in the United States.

BACKGROUND: Annual influenza outbreaks constitute a major public health concern, both in the United States and worldwide. Comparisons of the health burdens of outbreaks might lead to the identification of specific at-risk populations, for whom public health resources should be marshaled appropriately and equitably. METHODS: We examined the disease burden of the 2009-10 influenza A (H1N1) pandemic relating to illnesses, medical visits, hospitalizations, and mortality, compared to influenza seasons 2010 to 2019, in the United States, as compiled by the Centers for Disease Control. RESULTS: With regard to seasonal influenza, rates of illnesses and medical visits were highest in infants aged 0-4 years, followed by adults aged 50-64 years. Rates of hospitalizations and deaths evinced a starkly different pattern, both dominated by elderly adults aged 65 and over. Youths aged 0 to 17 years were especially adversely affected by the H1N1 pandemic relative to hospitalizations and mortality compared to seasonal influenza; but curiously the opposite pattern was observed in elderly adults (aged 65 and older). CONCLUSIONS: Determination of a baseline influenza mortality profile in the United States over the 2010-19 decade is not straightforward. The disease burden of the 2009-10 influenza A pandemic among the elderly was strikingly unlike that observed in the subsequent influenza seasons 2010 to 2019: the past did not predict the future.

A Note on Excess Mortality Attributable to COVID-19 in the United States.

Background: Annual influenza outbreaks constitute a major public health concern in the United States. But this health burden appears dwarfed by the impact of COVID-19. Our aim is to quantify the excess mortality attributable to COVID-19, compared to previous influenza seasons. Methods: We retrospectively compare weekly mortality figures attributable to influenza and pneumonia in the United States from 2013 to 2019 with corresponding figures attributable to influenza, pneumonia, and COVID-19 from 2019 to 2021. We utilize a difference in differences regression methodology to estimate excess mortality observed in 2019-21 compared to 2013-2019. Results: Mortality patterns attributable to influenza, pneumonia, and COVID-19 differ significantly from the 2013-19 experience. Notably, distinct, aperiodic mortality waves occur in the 2019-2021 window, and mortality is well in excess of what is observed in typical influenza seasons. Conclusions: The COVID-19 pandemic has led to considerable excess mortality in the United States, and has strained public health resources. One might expect that the mortality waves observed during the pandemic will be damped by increasing levels of vaccination, and prior infections.