Pediatric donor heart utilization variability among organ procurement organizations.

BACKGROUND: Organ procurement organizations (OPOs) are responsible for the medical management of organ donors. Given the variability in pediatric donor heart utilization among OPOs, we examined factors that may explain this variability, including differences in donor medical management, organ quality, and candidate factors. METHODS: The Organ Procurement and Transplant Network database was queried for pediatric (<18 years) heart donors and candidates receiving pediatric donor heart offers from 2010 to 2019. OPOs were stratified by pediatric donor heart utilization rate, and the top and bottom quintiles were compared based on donor management strategies and outcomes. A machine learning algorithm, combining 11 OPO, donor, candidate, and offer variables, was used to determine factors most predictive of whether a heart offer is accepted. RESULTS: There was no clinically significant difference between the top and bottom quintile OPOs in baseline donor characteristics, distance between donor and listing center, management strategies, or organ quality. Machine learning modeling suggested neither OPO donor management nor cardiac function is the primary driver of whether an organ is accepted. Instead, number of prior donor offer refusals and individual listing center receiving the offer were two of the most predictive variables of organ acceptance. CONCLUSIONS: OPO clinical practice variation does not seem to account for the discrepancy in pediatric donor heart utilization rates among OPOs. Listing center acceptance practice and prior number of donor refusals seem to be the important drivers of heart utilization and may at least partially account for the variation in OPO heart utilization rates given the regional association between OPOs and listing centers.

The Prostate Cancer Active Lifestyle Study (PALS): A randomized controlled trial of diet and exercise in overweight and obese men on active surveillance.

BACKGROUND: Active surveillance (AS) is increasingly used to monitor patients with lower risk prostate cancer (PCa). The Prostate Cancer Active Lifestyle Study (PALS) was a randomized controlled trial to determine whether weight loss improves obesity biomarkers on the causal pathway to progression in patients with PCa on AS. METHODS: Overweight/obese men (body mass index >25 kg/m2 ) diagnosed with PCa who elected AS were recruited. The intervention was a 6-month, individually delivered, structured diet and exercise program adapted from the Diabetes Prevention Program with a 7% weight loss goal from baseline. Control participants attended one session reviewing the US Dietary and Physical Activity Guidelines. The primary outcome was change in glucose regulation from baseline to the end of the 6-month intervention, which was measured by fasting plasma glucose, C-peptide, insulin, insulin-like growth factor 1, insulin-like growth factor binding protein-3, adiponectin, and homeostatic model assessment for insulin resistance. RESULTS: Among 117 men who were randomized, 100 completed the trial. The mean percentage weight loss was 7.1% and 1.8% in the intervention and control arms, respectively (adjusted between-group mean difference, -6.0 kg; 95% confidence interval, -8.0, -4.0). Mean percentage changes from baseline for insulin, C-peptide, and homeostatic model assessment for insulin resistance in the intervention arm were -23%, -16%, and -25%, respectively, compared with +6.9%, +7.5%, and +6.4%, respectively, in the control arm (all p for intervention effects ≤ .003). No significant between-arm differences were detected for the other biomarkers. CONCLUSIONS: Overweight/obese men with PCa undergoing AS who participated in a lifestyle-based weight loss intervention successfully met weight loss goals with this reproducible lifestyle intervention and experienced improvements in glucose-regulation biomarkers associated with PCa progression.

Reduction of Postoperative Delirium and Opioid Use in Hip Fracture Patients Through Utilization of Emergency Department Physician Administered Regional Nerve Blocks.

Introduction: The complication of delirium for hip fracture patients is a predictor of mortality. Use of opioid medication increases the incidence of delirium in the pre- and postoperative periods. Regional nerve blocks are effective in managing acute pain for acute hip fractures. This study aims to evaluate the utilization of ED physicians to perform fascia iliaca nerve blocks on hip fracture patients to decrease the incidence of delirium by decreasing usage of opioid medication. Methods: A quality improvement project for performing regional nerve blocks on patients with femoral neck fractures was implemented during fiscal year 2019. Data was collected retrospectively for frequency of ED nerve block procedures, amount of opioid medication use, and incidence of delirium in patients diagnosed with hip fracture. This data was compared to baseline data to determine success of the intervention. Results: Utilization of regional nerve blocks in the ED increased from 2% in 2018 to 96% in 2021 and 89% in 2022. Preoperative opioid usage decreased from 38 MMEs to 16.9 and 18 MMEs respectively. Daily average MMEs decreased from 34 to 12.1 and 14 respectively. Postoperative delirium decreased from 6% in 2018 to 0% from 2020 to 2022. Discussion: ED provider administration of fascia iliaca blocks and follow-up is a novel practice in our region to decrease the adverse effects of opiate use and decrease delirium rates. There was a reduction in length of stay and increased discharge home rate despite the Covid-19 pandemic. Conclusion: Administration of regional nerve blocks by ED physicians to hip fracture patients presenting to the ED results in a decrease in opioid medication usage. This also results in a decreased delirium rates in the hip fracture patient population.

The Nitrile Bis-Thiol Bioconjugation Reaction.

Electron-poor aryl nitriles are promising reagents for bioconjugation due to their high electrophilicity and selectivity for reaction with thiols, albeit generally in a reversible manner. A transient species has previously been observed in such reactions, involving the addition of two thiols to the nitrile functional group, forming a tetrahedral amino dithioacetal (ADTA). In this work, the reaction of heteroaryl nitriles with bis-thiols is explored in an attempt to generate stable ADTAs, which could facilitate new bioconjugation protocols. By use of a 1,2-dithiol, or the incorporation of an electrophilic trap into the aryl nitrile design, the formation of stable products is achieved. The resultant "nitrile bis-thiol" (NBT) reaction is then explored in the context of protein modification, specifically to carry out antibody conjugation. By addition of these nitriles to the reduced disulfide bond of an antibody fragment, it is shown that, depending on the reagent design, cysteine-to-lysine transfer or disulfide bridged NBT products can be generated. Both represent site-selective conjugates and are shown to be stable when challenged with glutathione under physiological conditions and upon incubation in serum. Furthermore, the NBT reaction is tested in the more challenging context of a full antibody, and all four disulfide bonds are effectively modified by these new one-carbon bridging reagents. Overall, this reaction of heteroaryl-nitriles with bis-thiols is shown to be highly efficient and versatile, of tunable reversibility, and offers enticing prospects as a new addition to the toolbox of biocompatible "click"-type reactions.

Use of pyridazinediones for tuneable and reversible covalent cysteine modification applied to peptides, proteins and hydrogels.

Reversible cysteine modification has been found to be a useful tool for a plethora of applications such as selective enzymatic inhibition, activity-based protein profiling and/or cargo release from a protein or a material. However, only a limited number of reagents display reliable dynamic/reversible thiol modification and, in most cases, many of these reagents suffer from issues of stability, a lack of modularity and/or poor rate tunability. In this work, we demonstrate the potential of pyridazinediones as novel reversible and tuneable covalent cysteine modifiers. We show that the electrophilicity of pyridazinediones correlates to the rates of the Michael addition and retro-Michael deconjugation reactions, demonstrating that pyridazinediones provide an enticing platform for readily tuneable and reversible thiol addition/release. We explore the regioselectivity of the novel reaction and unveil the reason for the fundamental increased reactivity of aryl bearing pyridazinediones by using DFT calculations and corroborating findings with SCXRD. We also applied this fundamental discovery to making more rapid disulfide rebridging agents in related work. We finally provide the groundwork for potential applications in various areas with exemplification using readily functionalised "clickable" pyridazinediones on clinically relevant cysteine and disulfide conjugated proteins, as well as on a hydrogel material.

The Impact of Dietary Cholesterol on Low-Density Lipoprotein: Lessons in Absorption and Overconsumption.

This case describes a 58-year-old woman with past medical history of ulcerative colitis, hyperlipidemia, and radiological evidence of atherosclerosis without prior cardiovascular disease who presented for management of hyperlipidemia. At baseline, her lipid panel in 2015 noted a calculated low-density lipoprotein (LDL-C) of 125 mg/dL (3.2 mmol/L). Over the course of the next 5 years, she developed severe LDL elevations to >400 mg/dL (>10.3 mmol/L) following the addition of 1600 mg dietary cholesterol daily achieved through 9 eggs. Following cessation of this intake she had dramatic improvements in LDL, which was later further augmented significantly by initiation of ezetimibe. The impact of dietary cholesterol on lipid profiles has long been an area of controversy, and, for the average American, current guidelines do not recommend egg restriction as an effective tool for LDL lowering. However, as highlighted in this case, certain individuals may be more prone to high LDL when consuming high cholesterol diets. Further study on how to better identify these susceptible individuals could help improve nutritional and medication treatment plans for patients with dyslipidemia.

The intersection of video capsule endoscopy and artificial intelligence: addressing unique challenges using machine learning.

Introduction: Technical burdens and time-intensive review processes limit the practical utility of video capsule endoscopy (VCE). Artificial intelligence (AI) is poised to address these limitations, but the intersection of AI and VCE reveals challenges that must first be overcome. We identified five challenges to address. Challenge #1: VCE data are stochastic and contains significant artifact. Challenge #2: VCE interpretation is cost-intensive. Challenge #3: VCE data are inherently imbalanced. Challenge #4: Existing VCE AIMLT are computationally cumbersome. Challenge #5: Clinicians are hesitant to accept AIMLT that cannot explain their process. Methods: An anatomic landmark detection model was used to test the application of convolutional neural networks (CNNs) to the task of classifying VCE data. We also created a tool that assists in expert annotation of VCE data. We then created more elaborate models using different approaches including a multi-frame approach, a CNN based on graph representation, and a few-shot approach based on meta-learning. Results: When used on full-length VCE footage, CNNs accurately identified anatomic landmarks (99.1%), with gradient weighted-class activation mapping showing the parts of each frame that the CNN used to make its decision. The graph CNN with weakly supervised learning (accuracy 89.9%, sensitivity of 91.1%), the few-shot model (accuracy 90.8%, precision 91.4%, sensitivity 90.9%), and the multi-frame model (accuracy 97.5%, precision 91.5%, sensitivity 94.8%) performed well. Discussion: Each of these five challenges is addressed, in part, by one of our AI-based models. Our goal of producing high performance using lightweight models that aim to improve clinician confidence was achieved.

A standardized and automated CBMN assay for biological dosimetry: the CytoRADx™ system.

Major nuclear accidents can result in many casualties, and it is important to assess the absorbed radiation dose to support treatment decisions. Biological dosimetry (BD) allows retrospective determination of dose using biological markers. To achieve consistent cytogenetic assay results across labs, the current practice requires each lab to generate periodic, unique calibration curves using in vitro dose-effect experiments. Here, we present CytoRADx™, a standardized biodosimetry system that integrates automated dose calculation in a high-throughput platform without the need for lab-specific calibration curves. CytoRADx consists of an improved, standardized Cytokinesis Block Micronucleus assay combined with automated analysis utilizing an established slide scanning device. We tested CytoRADx for accuracy and reproducibility across different instruments, sites, days and operators. Our results demonstrate that CytoRADx eliminates the time-consuming, lab-specific calibration curves, allowing multiple laboratories to obtain consistent results and to distribute the testing burden in the event of a large-scale accident.

Room-Temperature One-Pot Synthesis of pH-Responsive Pyridine-Functionalized Carbon Surfaces.

Carbon surfaces (glassy carbon, graphite, and boron-doped diamond) were functionalized with layers composed of linked pyridinium and pyridine moieties using simple electrochemical reduction of trifluoroacetylpyridinium. The pyridinium species was generated in situ in solution by the reaction of trifluoroacetic anhydride and pyridine precursors and underwent electrochemical reduction at -1.97 V vs Fc/Fc+, as determined by cyclic voltammetry. The pyridine/pyridinium films were electrodeposited at room temperature, on a timescale of minutes, and were characterized using X-ray photoelectron spectroscopy. The as-prepared films have a net positive charge in aqueous solution at pH 9 and below due to the pyridinium content, confirmed by the electrochemical response of differently charged redox molecules at the functionalized surfaces. The positive charge can be enhanced further through protonation of the neutral pyridine component by controlling the solution pH. Moreover, the nitrogen-acetyl bond can be cleaved through base treatment to purposefully increase the neutral pyridine proportion of the film. This results in a surface that can be "switched" from functionally near neutral to a positive charge by treatment in basic and acidic solutions, respectively, through manipulation of the protonation state of the pyridine. The functionalization process demonstrated here is readily achievable at a fast timescale at room temperature and hence can allow for rapid screening of surface properties. Such functionalized surfaces present a means to test in isolation the specific catalytic performance of pyridinic groups toward key processes such as oxygen and CO2 reduction.

A Phase 1/2 Study of Rapamycin and Cisplatin/Gemcitabine for Treatment of Patients With Muscle-Invasive Bladder Cancer.

INTRODUCTION: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard for muscle-invasive bladder cancer (MIBC), however, NAC confers only a small survival benefit and new strategies are needed to increase its efficacy. Pre-clinical data suggest that in response to DNA damage the tumor microenvironment (TME) adopts a paracrine secretory phenotype dependent on mTOR signaling which may provide an escape mechanism for tumor resistance, thus offering an opportunity to increase NAC effectiveness with mTOR blockade. PATIENTS & METHODS: We conducted a phase I/II clinical trial to assess the safety and efficacy of gemcitabine-cisplatin-rapamycin combination. Grapefruit juice was administered to enhance rapamycin pharmacokinetics by inhibiting intestinal enzymatic degradation. Phase I was a dose determination/safety study followed by a single arm Phase II study of NAC prior to radical cystectomy evaluating pathologic response with a 26% pCR rate target. RESULTS: In phase I, 6 patients enrolled, and the phase 2 dose of 35 mg rapamycin established. Fifteen patients enrolled in phase II; 13 were evaluable. Rapamycin was tolerated without serious adverse events. At the preplanned analysis, the complete response rate (23%) did not meet the prespecified level for continuing and the study was stopped due to futility. With immunohistochemistry, successful suppression of the mTOR signaling pathway in the tumor was achieved while limited mTOR activity was seen in the TME. CONCLUSION: Adding rapamycin to gemcitabine-cisplatin therapy for patients with MIBC was well tolerated but failed to improve therapeutic efficacy despite evidence of mTOR blockade in tumor cells. Further efforts to understand the role of the tumor microenvironment in chemotherapy resistance is needed.

A novel study of situational awareness among out-of-hospital providers during an online clinical simulation.

BACKGROUND: Out-of-hospital providers must be situationally aware in order to maintain safety for themselves, their patients, the public, and their crew. They must be able to recognize situations, interpret them, and predict how those situations may unfold in the future. METHOD: A mixed-methods explanatory sequential design where out-of-hospital providers in Oklahoma, USA, participated in an 18-minute online simulation and then had their situational awareness (SA) measured. Upon completion, participants provided feedback during scheduled interviews. RESULTS: A total of 156 out-of-hospital providers participated. Participants were not situationally aware. While not statistically significant, those with higher education had higher SA scores. Participants perceived that the simulation processes were beneficial to their ongoing care in the field, and were satisfied with the online simulation environment. CONCLUSIONS: Out-of-hospital providers are not situationally aware during an online clinical simulation. While they are focused intently on the surroundings of the scene, they do not put that same focus on the patient. With the appropriate technology and setup, the use of the Situational Awareness Global Assessment Technique (SAGAT) during online simulation is feasible and could enhance clinical performance. Further studies are needed to determine if overall education or years of clinical experience play a role in out-of-hospital SA.

Does Adding a Fissurectomy to Botox Sphincterotomy Increase Success Rate or Just Cost?

BACKGROUND: While Botox sphincterotomy with or without fissurectomy has been proven effective in healing anal fissures, they have not been directly compared. We evaluated cost-effectiveness and outcomes between Botox sphincterotomies with and without fissurectomy. METHODS: A 5-year retrospective review was conducted comparing all patients undergoing Botox sphincterotomy for anal fissure with or without fissurectomy. Outcomes including recurrence/persistence, additional treatments, complications, and total charges were compared between study groups. RESULTS: Patients treated without fissurectomy (n = 53) had recurrent/persistent fissure more often (56.6 vs 31.0%, P = .001), and required more Botox treatments. Those treated with fissurectomy (n = 154) had more complications (13.5 vs 0%, P = .003). Patients initially treated without fissurectomy had a median total charge of $2 973, while median total charge for those initially treated with fissurectomy was $17 925 (P < .001). CONCLUSIONS: Botox sphincterotomy in an office without fissurectomy is a viable option. It may result in longer healing times but is associated with reduced cost, lower complication rates, and no need for anesthesia or operative intervention in most cases. But the choice of treatment route must be individualized.

Morning SARS-CoV-2 Testing Yields Better Detection of Infection Due to Higher Viral Loads in Saliva and Nasal Swabs upon Waking.

Optimizing specimen collection methods to achieve the most reliable SARS-CoV-2 detection for a given diagnostic sensitivity would improve testing and minimize COVID-19 outbreaks. From September 2020 to April 2021, we performed a household-transmission study in which participants self-collected specimens every morning and evening throughout acute SARS-CoV-2 infection. Seventy mildly symptomatic participants collected saliva, and of those, 29 also collected nasal swab specimens. Viral load was quantified in 1,194 saliva and 661 nasal swab specimens using a high-analytical-sensitivity reverse transcription-quantitative PCR (RT-qPCR) assay. Viral loads in both saliva and nasal swab specimens were significantly higher in morning-collected specimens than in evening-collected specimens after symptom onset. This aspect of the biology of SARS-CoV-2 infection has implications for diagnostic testing. We infer that morning collection would have resulted in significantly improved detection and that this advantage would be most pronounced for tests with low to moderate analytical sensitivity. Collecting specimens for COVID-19 testing in the morning offers a simple and low-cost improvement to clinical diagnostic sensitivity of low- to moderate-analytical-sensitivity tests. IMPORTANCE Our findings suggest that collecting saliva and nasal swab specimens in the morning immediately after waking yields higher SARS-CoV-2 viral loads than collection later in the day. The higher viral loads from morning specimen collection are predicted to significantly improve detection of SARS-CoV-2 in symptomatic individuals, particularly when using moderate- to low-analytical-sensitivity COVID-19 diagnostic tests, such as rapid antigen tests.

Systematic microscopical analysis reveals obligate synergy between extracellular matrix components during Bacillus subtilis colony biofilm development.

Single-species bacterial colony biofilms often present recurring morphologies that are thought to be of benefit to the population of cells within and are known to be dependent on the self-produced extracellular matrix. However, much remains unknown in terms of the developmental process at the single cell level. Here, we design and implement systematic time-lapse imaging and quantitative analyses of the growth of Bacillus subtilis colony biofilms. We follow the development from the initial deposition of founding cells through to the formation of large-scale complex structures. Using the model biofilm strain NCIB 3610, we examine the movement dynamics of the growing biomass and compare them with those displayed by a suite of otherwise isogenic matrix-mutant strains. Correspondingly, we assess the impact of an incomplete matrix on biofilm morphologies and sessile growth rate. Our results indicate that radial expansion of colony biofilms results from the division of bacteria at the biofilm periphery rather than being driven by swelling due to fluid intake. Moreover, we show that lack of exopolysaccharide production has a negative impact on cell division rate, and the extracellular matrix components act synergistically to give the biomass the structural strength to produce aerial protrusions and agar substrate-deforming ability.

Value-Based Health Care in Hand Surgery: Where Are We & Where Do We Go From Here?

Health care delivery is broken. The cost of care continues to skyrocket and the outcomes most important to patients are often a mystery. Further, care is often delivered via a fee-for-service model where surgeons are rewarded for the quantity, not the quality, of services provided. Such a health care delivery system is not sustainable and does not incentivize stakeholders to focus on the most important element of the health care delivery "puzzle": the patient. Fortunately, we are in the midst of transforming our health care delivery system, with a focus on optimizing the value of care delivery (ie, health outcomes achieved per dollar spent across a full care cycle). In hand surgery, progress has been made as part of this health system evolution. However, there remains much to accomplish. In this article, the authors review the 6 components of a strategic agenda for moving to a high-value health care delivery system for hand surgery, focusing on where we are today and where we need to go from here.

Frequency and Characteristics of Social Media Use among General Surgery Trainees.

INTRODUCTION: With increased social isolation due to COVID-19, social media has been increasingly adopted for communication, education, and entertainment. We sought to understand the frequency and characteristics of social media usage among general surgery trainees. MATERIALS AND METHODS: General surgery trainees in 15 American training programs were invited to participate in an anonymous electronic survey. The survey included questions about demographics, frequency of social media usage, and perceptions of risks and benefits of social media. Univariate analysis was performed to identify differences between high users of social media (4-7 h per week on at least one platform) and low users (0-3 h or less on all platforms). RESULTS: One hundred fifty-seven of 591 (26.6%) trainees completed the survey. Most respondents were PGY3 or lower (75%) and high users of social media (74.5%). Among high users, the most popular platforms were Instagram (85.7%), YouTube (85.1%), and Facebook (83.6%). YouTube and Twitter were popular for surgical education (77.3% and 68.2%, respectively). The most reported benefits of social media were improving patient education and professional networking (85.0%), where high users agreed more strongly about these benefits (P = 0.002). The most reported risks were seeing other residents (42%) or attendings (17%) with unprofessional behavior. High users disagreed more strongly about risks, including observing attendings with unprofessional behavior (P = 0.028). CONCLUSIONS: Most respondents were high users of social media, particularly Instagram, YouTube, and Facebook. High users incorporated social media into their surgical education while perceiving more benefits and fewer risks of social media.

Can a targeted educational approach improve situational awareness in paramedicine during 911 emergency calls?

BACKGROUND: Paramedics must be situationally aware in order to avoid human error and protect themselves, their partner, their patient, and the public. Previous research has suggested that paramedics lack situational awareness (SA), possibly due to a lack of an organized approach, distraction, and a poor understanding of SA. There is no educational approach provided to paramedics that is known to improve their levels of SA. If such an approach were provided, it could possibly reduce human error and lead to improved outcomes. OBJECTIVE: The aim of this study is to determine whether providing paramedics with a targeted educational approach, including aspects from crew resource management (CRM) such as sterile cockpit and Endsley's model for SA, can improve overall SA during emergency calls. METHODS: A prospective, quasi-experimental before-and-after study was used, in which out-of hospital paramedics were observed during 911 emergency calls. Baseline SA was measured using the situational awareness global assessment technique (SAGAT). Paramedics were then given a targeted educational lesson focusing on elements of SA and CRM as well as a novel quick reference tool to utilize during 911 calls. Post intervention SA was then measured again, and before-and-after results were compared for difference of mean scores. RESULTS: The overall baseline SA was 62% increasing to 86% following the educational intervention. The Wilcoxon Ranked Sum was used to assess for statistically significant differences between mean SA performance in the same group of paramedics before and after the intervention. The increase in SA was found to be statistically significant where p = 0.011. CONCLUSIONS: A targeted educational approach focusing on CRM and a novel quick reference tool may increase SA levels of paramedics during 911 emergency calls. Further studies are needed with bigger cohorts. Paramedicine educational institutions and out-of-hospital agencies should consider implementing this targeted approach with their students and currently practicing providers.

Building-Level Wastewater Surveillance for SARS-CoV-2 in Occupied University Dormitories as an Outbreak Forecasting Tool: One Year Case Study.

Congregate living poses one of the highest risk situations for the transmission of respiratory viruses including SARS-CoV-2. University dormitories exemplify such high-risk settings. We demonstrate the value of using building-level SARS-CoV-2 wastewater surveillance as an early warning system to inform when prevalence testing of all building occupants is warranted. Coordinated daily testing of composite wastewater samples and clinical testing in dormitories was used to prompt the screening of otherwise unrecognized infected occupants. We overlay the detection patterns in the context of regular scheduled occupant testing to validate a wastewater detection model. The trend of wastewater positivity largely aligned well with the clinical positivity and epidemiology of dormitory occupants. However, the predictive ability of wastewater-surveillance to detect new positive cases is hampered by convalescent shedding in recovered/noncontagious individuals as they return to the building. Building-level pooled wastewater-surveillance and forecasting is most productive for predicting new cases in low-prevalence instances at the community level. For higher-education facilities and other congregate living settings to remain in operation during a pandemic, a thorough surveillance-based decision-making system is vital. Building-level wastewater monitoring on a daily basis paired with regular testing of individual dormitory occupants is an effective and efficient approach for mitigating outbreaks on university campuses.

Quantitative SARS-CoV-2 Viral-Load Curves in Paired Saliva Samples and Nasal Swabs Inform Appropriate Respiratory Sampling Site and Analytical Test Sensitivity Required for Earliest Viral Detection.

Early detection of SARS-CoV-2 infection is critical to reduce asymptomatic and presymptomatic transmission, curb the spread of variants, and maximize treatment efficacy. Low-analytical-sensitivity nasal-swab testing is commonly used for surveillance and symptomatic testing, but the ability of these tests to detect the earliest stages of infection has not been established. In this study, conducted between September 2020 and June 2021 in the greater Los Angeles County, California, area, initially SARS-CoV-2-negative household contacts of individuals diagnosed with COVID-19 prospectively self-collected paired anterior-nares nasal-swab and saliva samples twice daily for viral-load quantification by high-sensitivity reverse-transcription quantitative PCR (RT-qPCR) and digital-RT-PCR assays. We captured viral-load profiles from the incidence of infection for seven individuals and compared diagnostic sensitivities between respiratory sites. Among unvaccinated persons, testing saliva with a high-analytical-sensitivity assay detected infection up to 4.5 days before viral loads in nasal swabs reached concentrations detectable by low-analytical-sensitivity nasal-swab tests. For most participants, nasal swabs reached higher peak viral loads than saliva but were undetectable or at lower loads during the first few days of infection. High-analytical-sensitivity saliva testing was most reliable for earliest detection. Our study illustrates the value of acquiring early (within hours after a negative high-sensitivity test) viral-load profiles to guide the appropriate analytical sensitivity and respiratory site for detecting earliest infections. Such data are challenging to acquire but critical to designing optimal testing strategies with emerging variants in the current pandemic and to respond to future viral pandemics.