Selective Serotonin Reuptake Inhibitors within Cells: Temporal Resolution in Cytoplasm, Endoplasmic Reticulum, and Membrane.

Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed treatment for individuals experiencing major depressive disorder. The therapeutic mechanisms that take place before, during, or after SSRIs bind the serotonin transporter (SERT) are poorly understood, partially because no studies exist on the cellular and subcellular pharmacokinetic properties of SSRIs in living cells. We studied escitalopram and fluoxetine using new intensity-based, drug-sensing fluorescent reporters targeted to the plasma membrane, cytoplasm, or endoplasmic reticulum (ER) of cultured neurons and mammalian cell lines. We also used chemical detection of drug within cells and phospholipid membranes. The drugs attain equilibrium in neuronal cytoplasm and ER at approximately the same concentration as the externally applied solution, with time constants of a few s (escitalopram) or 200-300 s (fluoxetine). Simultaneously, the drugs accumulate within lipid membranes by ≥18-fold (escitalopram) or 180-fold (fluoxetine), and possibly by much larger factors. Both drugs leave cytoplasm, lumen, and membranes just as quickly during washout. We synthesized membrane-impermeant quaternary amine derivatives of the two SSRIs. The quaternary derivatives are substantially excluded from membrane, cytoplasm, and ER for >2.4 h. They inhibit SERT transport-associated currents sixfold or 11-fold less potently than the SSRIs (escitalopram or fluoxetine derivative, respectively), providing useful probes for distinguishing compartmentalized SSRI effects. Although our measurements are orders of magnitude faster than the therapeutic lag of SSRIs, these data suggest that SSRI-SERT interactions within organelles or membranes may play roles during either the therapeutic effects or the antidepressant discontinuation syndrome.SIGNIFICANCE STATEMENT Selective serotonin reuptake inhibitors stabilize mood in several disorders. In general, these drugs bind to SERT, which clears serotonin from CNS and peripheral tissues. SERT ligands are effective and relatively safe; primary care practitioners often prescribe them. However, they have several side effects and require 2-6 weeks of continuous administration until they act effectively. How they work remains perplexing, contrasting with earlier assumptions that the therapeutic mechanism involves SERT inhibition followed by increased extracellular serotonin levels. This study establishes that two SERT ligands, fluoxetine and escitalopram, enter neurons within minutes, while simultaneously accumulating in many membranes. Such knowledge will motivate future research, hopefully revealing where and how SERT ligands engage their therapeutic target(s).

Spectral and RGB analysis of the light climate and its ecological impacts using an all-sky camera system in the Arctic.

The ArcLight observatory provides an hourly continuous time series of all-sky images providing light climate data (intensity, spectral composition, and photoperiod) from the Arctic (Svalbard at 79°N). Until recently, no complete annual time series of light climate relevant for biological processes has been provided from the high Arctic because of insufficient sensitivity of commercial light sensors during the Polar Night. The ArcLight set up is unique, as it provides both all-sky images and the corresponding integrated spectral irradiance in the visible part of the solar electromagnetic spectrum (E P A R ). Here we present a further development providing hourly diel-annual dynamics from 2020 of the irradiance partitioned into the red, green, and blue parts of the solar spectrum and illustrate their relation to weather conditions, and sun and moon trajectories. We show that there is variation between the RGB proportions of irradiance throughout the year, with the blue part of the spectrum showing the greatest variation, which is dependent on weather conditions (i.e., cloud cover). We further provide an example of the biological impact of these spectral variations in the light climate using in vivo Chl a-specific absorption coefficients of diatoms (mean of six low light acclimated northern-Arctic bloom-forming species) to model total algal light absorption (AQ t o t a l ) and the corresponding fraction of quanta used by Photosystem II (AQPSII) (O 2 production) in RGB bands and the potential impacts on the photoreceptor response, suggesting periods where repair and maintenance functions dominate activity in the absence of appreciable levels of red or green light. The method used here can be applied to light climate data and spectral response data worldwide to give localized ecological models of AQ.

Regulation of epithelial sodium channel activity by SARS-CoV-1 and SARS-CoV-2 proteins.

Severe acute respiratory syndrome (SARS) coronavirus (CoV) 2 (SARS-CoV-2), which causes the coronavirus disease 2019, encodes several proteins whose roles are poorly understood. We tested their ability either to directly form plasma membrane ion channels or to change functions of two mammalian plasma membrane ion channels, the epithelial sodium channel (ENaC) and the α3ß4 nicotinic acetylcholine receptor. In mRNA-injected Xenopus oocytes, none of nine SARS-CoV-2 proteins or two SARS-CoV-1 proteins produced conductances, nor did co-injection of several combinations. Immunoblots for ORF8, spike (S), and envelope (E) proteins revealed that the proteins are expressed at appropriate molecular weights. In experiments on coexpression with ENaC, three tested SARS proteins (SARS-CoV-1 E, SARS-CoV-2 E, and SARS-CoV-2 S) markedly decrease ENaC currents. SARS-CoV-1 S protein decreases ENaC currents modestly. Coexpressing the E proteins but not the S proteins with α3ß4 nicotinic acetylcholine receptors significantly reduces acetylcholine-induced currents. ENaC inhibition does not occur if the SARS-CoV protein mRNAs are injected 24 h after the ENaC mRNAs, suggesting that SARS-CoV proteins affect early step(s) in functional expression of channel proteins. Consistent with the hypothesis that the SARS-CoV-2 S protein-induced ENaC inhibition involves competition for available protease, mutating the furin cleavage site in SARS-CoV-2 S protein partially relieves inhibition of ENaC currents. Extending previous suggestions that SARS proteins affect ENaC currents via protein kinase C (PKC) activation, PKC activation via phorbol 12-myristate 13-acetate decreases ENaC and α3ß4 activity. Phorbol 12-myristate 13-acetate application reduced membrane capacitance ∼5%, presumably via increased endocytosis, but this decrease is much smaller than the SARS proteins' effects on conductances. Also, incubating oocytes in Gö-6976, a PKCα and PKCß inhibitor, did not alter E or S protein-induced channel inhibition. We conclude that SARS-CoV-1 and SARS-CoV-2 proteins alter the function of human plasma membrane channels, via incompletely understood mechanisms. These interactions may play a role in the coronavirus 2019 pathophysiology.

National Quality Measure Compliance for Palliative Bone Radiation Among Patients With Metastatic Non-Small Cell Lung Cancer.

BACKGROUND: There exists wide practice variability in palliative treatment schedules for bone metastases. In an effort to reduce variation and promote high-quality, cost-conscious care, the National Quality Forum (NQF) endorsed measure 1822 in 2012. This measure recommends the use of 30 Gy in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions, or 8 Gy in a single fraction for palliative radiation for bone metastases. We report on longitudinal compliance with this measure. METHODS: Using the National Cancer Database, patients with metastatic thoracic non-small cell lung cancer diagnosed between 2004 and 2016 who received radiation therapy for bony sites of metastatic disease were identified. Treatment courses fitting 1 of the 4 recommended schedules under NQF 1822 were coded as compliant. Rates of compliance by patient, tumor, and treatment characteristics were analyzed. RESULTS: A total of 42,685 patients met the criteria for inclusion. Among all patients, 60.2% of treatment courses were compliant according to NQF 1822. Compliance increased over time and was highest for treatments to the extremity (69.8%), lowest for treatments to the skull or head (48.8%), and higher for academic practice (67.1%) compared with community (56.0%) or integrated network facilities (61.2%). On multivariable analysis, predictors of NQF 1822 compliance included year of diagnosis after 2011, treatment to an extremity, or treatment at an academic facility. Of noncompliant treatment courses, extended fractionation (≥11 fractions) occurred in 62.6% and was more common before 2012, in community practice, and for treatments of the skull or head. CONCLUSIONS: Among patients treated for metastatic non-small cell lung cancer, compliance with NQF 1822 increased over time. Although extended fractionation constituted a majority of noncompliant treatment courses, a substantial proportion also involved shorter courses.

All-sky camera system providing high temporal resolution annual time series of irradiance in the Arctic.

The ArcLight observatory provides hourly continuous time series of light regime data (intensity, spectral composition, and photoperiod) from the Arctic, Svalbard at 79° N. Until now, no complete annual time series of biologically relevant light has been provided from the high Arctic due to insufficient sensitivity of commercial light sensors during the Polar Night. We describe a camera system providing all-sky images and the corresponding integrated spectral irradiance (EPAR) in energy or quanta units, throughout a complete annual cycle. We present hourly-diel-annual dynamics from 2017 to 2020 of irradiance and its relation to weather conditions, sun and moon trajectories.

Non-English language validation of patient-reported outcome measures in cancer clinical trials.

Patient-reported outcome measures (PROMs) are increasingly incorporated as endpoints in oncology clinical trials but are often only validated in English. ClinicalTrials.gov was queried for cancer-specific randomized control trials (RCTs) addressing a therapeutic intervention and enrolling primarily in the USA. Peer-reviewed validation of Spanish and Chinese versions of each PROM was assessed. Of 103 eligible trials, a PROM was used as a primary endpoint in 25 RCTs (24.3%) and as a secondary endpoint in 78 RCTs (75.7%). A total of 61 of the 103 eligible trials (59.2%) and 17 of the 25 trials with a PROM primary endpoint (68.0%) used a PROM with either no Spanish or Chinese validation. The absence of validated PROM translations may diminish the voices of non-English language speaking trial participants. With an increasingly diverse US population, validation of non-English PROM translations may decrease disparities in trial participation and improve generalizability of study results.

Single-item discrimination of quality-of-life-altering dysphagia among 714 long-term oropharyngeal cancer survivors: Comparison of patient-reported outcome measures of swallowing.

BACKGROUND: Two patient-reported outcomes (PROs) of swallowing and their correlation to quality of life (QOL) were compared in long-term survivors of oropharyngeal cancer (OPC). METHODS: Scores on the single dysphagia item from the 28-item, multisymptom MD Anderson Symptom Inventory-Head and Neck (MDASI-HN-S) were compared with scores on the dysphagia-specific composite MD Anderson Dysphagia Inventory (MDADI) and the EuroQol visual analog scale (EQ-VAS) in 714 patients who had received definitive radiotherapy ≥12 months before the survey. An MDASI-HN-S score ≥6 and an MDADI composite score <60 were considered representative of moderate/severe swallowing dysfunction. RESULTS: Moderate/severe dysphagia was reported by 17% and 16% of respondents on the MDASI-HN-S and the composite MDADI, respectively. Both swallow PROs were predictive of QOL, and the MDASI-HN-S model was slightly more parsimonious for the discrimination of EQ-VAS scores compared with MDADI scores (Bayesian information criteria, 6062 vs 6076, respectively). An MDASI-HN-S cutoff score of ≥6 correlated best with a declining EQ-VAS score (P < .0001) and was associated with increased radiotherapy dose to several normal swallowing structures. CONCLUSIONS: In this cohort, the single-item MDASI-HN-S performed favorably for the discrimination of QOL compared with the multi-item MDADI. A time-efficient model for PRO measurement of swallowing is proposed in which the MDADI may be reserved for patients who score ≥6 on the MDASI-HN-S.

A brighter future? The impact of insurance and socioeconomic status on cancer outcomes in the USA: a review.

Uninsured and Medicaid-insured cancer patients have been shown to present with more advanced disease, less often receive cancer-directed therapy and suffer higher rates of mortality than those with private insurance. The Patient Protection and Affordable Care Act was signed into law in March of 2010 and seeks to increase rates of public and private health insurance. Although several provisions will in particular benefit those with chronic and high-cost medical conditions such as cancer, the extent to which disparities in cancer care will be eliminated is uncertain. Further legislative changes may be needed to ensure equal and adequate cancer care for all patients regardless of insurance or socioeconomic status.

Variation in insurance status by patient demographics and tumor site among nonelderly adult patients with cancer.

BACKGROUND: In the United States, an estimated 48 million individuals live without health insurance. The purpose of the current study was to explore the Variation in insurance status by patient demographics and tumor site among nonelderly adult patients with cancer. METHODS: A total of 688,794 patients aged 18 to 64 years who were diagnosed with one of the top 25 incident cancers (representing 95% of all cancer diagnoses) between 2007 and 2010 in the Surveillance, Epidemiology, and End Results (SEER) database were analyzed. Patient characteristics included age, race, sex, marital status, and rural or urban residence. County-level demographics included percent poverty level. Insurance status was defined as having non-Medicaid insurance, Medicaid coverage, or no insurance. RESULTS: On multivariate logistic regression analyses, younger age, male sex, nonwhite race, being unmarried, residence in counties with higher levels of poverty, and rural residence were associated with being uninsured versus having non-Medicaid insurance (all P <.001). The highest rates of non-Medicaid insurance were noted among patients with prostate cancer (92.3%), melanoma of the skin (92.5%), and thyroid cancer (89.5%), whereas the lowest rates of non-Medicaid insurance were observed among patients with cervical cancer (64.2%), liver cancer (67.9%), and stomach cancer (70.9%) (P <.001). Among uninsured individuals, the most prevalent cancers were lung cancer (14.9%), colorectal cancer (12.1%), and breast cancer (10.2%) (P <.001). Lung cancer caused the majority of cancer mortality in all insurance groups. CONCLUSIONS: Rates of insurance coverage vary greatly by demographics and by cancer type. The expansion of health insurance coverage would be expected to disproportionally benefit certain demographic populations and cancer types.

Improving cardiovascular clinical trials conduct in the United States: recommendation from clinicians, researchers, sponsors, and regulators.

Advances in medical therapies leading to improved patient outcomes are in large part related to successful conduct of clinical trials that offer critical information regarding the efficacy and safety of novel interventions. The conduct of clinical trials in the United States, however, continues to face increasing challenges with recruitment and retention. These trends are paralleled by an increasing shift toward more multinational trials where most participants are enrolled in countries outside the United States, bringing into question the generalizability of the results to the American population. This manuscript presents the perspectives and recommendations from clinicians, researchers, sponsors, and regulators who attended a meeting facilitated by the Food and Drug Administration to improve upon the current clinical trial trends in the United States.

Drinking cholera: salinity levels and palatability of drinking water in coastal Bangladesh.

OBJECTIVES: To measure the salinity levels of common water sources in coastal Bangladesh and explore perceptions of water palatability among the local population to investigate the plausibility of linking cholera outbreaks in Bangladesh with ingestion of saline-rich cholera-infected river water. METHODS: Hundred participants took part in a taste-testing experiment of water with varying levels of salinity. Salinity measurements were taken of both drinking and non-drinking water sources. Informal group discussions were conducted to gain an in-depth understanding of water sources and water uses. RESULTS: Salinity levels of non-drinking water sources suggest that the conditions for Vibrio cholerae survival exist 7-8 days within the local aquatic environment. However, 96% of participants in the taste-testing experiment reported that they would never drink water with salinity levels that would be conducive to V. cholerae survival. Furthermore, salinity levels of participant's drinking water sources were all well below the levels required for optimal survival of V. cholerae. Respondents explained that they preferred less salty and more aesthetically pleasing drinking water. CONCLUSION: Theoretically, V. cholerae can survive in the river systems in Bangladesh; however, water sources which have been contaminated with river water are avoided as potential drinking water sources. Furthermore, there are no physical connecting points between the river system and drinking water sources among the study population, indicating that the primary driver for cholera cases in Bangladesh is likely not through the contamination of saline-rich river water into drinking water sources.

Evolution of conically diffracted Gaussian beams in free space.

We present results of our observations on the free space evolution of conically diffracted beams from both single and cascade systems using various combinations of four biaxial crystals of the monoclinic double tungstate family [KGd(WO4)2]. Longitudinal shifts and radii of the Hamilton-Lloyd pair of rings were measured. In each case, the symmetric - forward and backward - evolution of the beam in free space from its focal image plane was monitored and quantified. Theoretical ring plane patterns based on a recently presented theoretical model are also compared to experimental patterns and found to be in good agreement.

On the frequency-doubled conically-refracted Gaussian beam.

A Potassium Titanyl Phosphate (KTP) crystal has been used in conjunction with a 10-ps pulsed laser to produce a frequency-doubled conically-refracted Gaussian beam. The 'free' and 'forced' beams that make up the scheme for nonlinear conical refraction were readily observable in non-phase-matched conditions. The dependency of the frequency-doubled beam patterns on the incident beam polarization, which until now has remained unexplored, was examined in detail. We have also revealed the existence of two orthogonally polarized 'free' rays for particular orientations of the incident beam polarization.

Azimuthally and radially polarized light in conical diffraction.

Azimuthal and radial polarization states of light are used to produce conical diffraction (CD) from a KGd(WO4)2 crystal. The patterns produced in the ring plane in each case display marked differences than those seen when linearly polarized incident light is used, with the production of a splitting of the CD ring into two concentric rings of equal intensity. The free space evolution for each type of polarization state is also experimentally recorded and investigated. Comparison with theory shows agreement with the experimentally observed results.

Cancer-Specific Alterations in Nuclear Matrix Proteins Determined by Multi-omics Analyses of Ductal Carcinoma in Situ.

Breast cancer (BC) is the most common cancer affecting women in the United States. Ductal carcinoma in situ (DCIS) is the earliest identifiable pre-invasive BC lesion. Estimates show that 14 to 50% of DCIS cases progress to invasive BC. Our objective was to identify nuclear matrix proteins (NMP) with specifically altered expression in DCIS and later stages of BC compared to non-diseased breast reduction mammoplasty and a contralateral breast explant using mass spectrometry and RNA sequencing to accurately identify aggressive DCIS. Sixty NMPs were significantly differentially expressed between the DCIS and non-diseased breast epithelium in an isogenic contralateral pair of patient-derived extended explants. Ten of the sixty showed significant mRNA expression level differences that matched the protein expression. These 10 proteins were similarly expressed in non-diseased breast reduction cells. Three NMPs (RPL7A, RPL11, RPL31) were significantly upregulated in DCIS and all other BC stages compared to the matching contralateral breast culture and an unrelated non-diseased breast reduction culture. RNA sequencing analyses showed that these three genes were upregulated increasingly with BC progression. Finally, we identified three NMPs (AHNAK, CDC37 and DNAJB1) that were significantly downregulated in DCIS and all other BC stages compared to the isogenically matched contralateral culture and the non-diseased breast reduction culture using both proteomics and RNA sequencing techniques.

Investigation of autosegmentation techniques on T2-weighted MRI for off-line dose reconstruction in MR-linac workflow for head and neck cancers.

BACKGROUND: In order to accurately accumulate delivered dose for head and neck cancer patients treated with the Adapt to Position workflow on the 1.5T magnetic resonance imaging (MRI)-linear accelerator (MR-linac), the low-resolution T2-weighted MRIs used for daily setup must be segmented to enable reconstruction of the delivered dose at each fraction. PURPOSE: In this pilot study, we evaluate various autosegmentation methods for head and neck organs at risk (OARs) on on-board setup MRIs from the MR-linac for off-line reconstruction of delivered dose. METHODS: Seven OARs (parotid glands, submandibular glands, mandible, spinal cord, and brainstem) were contoured on 43 images by seven observers each. Ground truth contours were generated using a simultaneous truth and performance level estimation (STAPLE) algorithm. Twenty total autosegmentation methods were evaluated in ADMIRE: 1-9) atlas-based autosegmentation using a population atlas library (PAL) of 5/10/15 patients with STAPLE, patch fusion (PF), random forest (RF) for label fusion; 10-19) autosegmentation using images from a patient's 1-4 prior fractions (individualized patient prior [IPP]) using STAPLE/PF/RF; 20) deep learning (DL) (3D ResUNet trained on 43 ground truth structure sets plus 45 contoured by one observer). Execution time was measured for each method. Autosegmented structures were compared to ground truth structures using the Dice similarity coefficient, mean surface distance (MSD), Hausdorff distance (HD), and Jaccard index (JI). For each metric and OAR, performance was compared to the inter-observer variability using Dunn's test with control. Methods were compared pairwise using the Steel-Dwass test for each metric pooled across all OARs. Further dosimetric analysis was performed on three high-performing autosegmentation methods (DL, IPP with RF and 4 fractions [IPP_RF_4], IPP with 1 fraction [IPP_1]), and one low-performing (PAL with STAPLE and 5 atlases [PAL_ST_5]). For five patients, delivered doses from clinical plans were recalculated on setup images with ground truth and autosegmented structure sets. Differences in maximum and mean dose to each structure between the ground truth and autosegmented structures were calculated and correlated with geometric metrics. RESULTS: DL and IPP methods performed best overall, all significantly outperforming inter-observer variability and with no significant difference between methods in pairwise comparison. PAL methods performed worst overall; most were not significantly different from the inter-observer variability or from each other. DL was the fastest method (33 s per case) and PAL methods the slowest (3.7-13.8 min per case). Execution time increased with a number of prior fractions/atlases for IPP and PAL. For DL, IPP_1, and IPP_RF_4, the majority (95%) of dose differences were within ± 250 cGy from ground truth, but outlier differences up to 785 cGy occurred. Dose differences were much higher for PAL_ST_5, with outlier differences up to 1920 cGy. Dose differences showed weak but significant correlations with all geometric metrics (R2 between 0.030 and 0.314). CONCLUSIONS: The autosegmentation methods offering the best combination of performance and execution time are DL and IPP_1. Dose reconstruction on on-board T2-weighted MRIs is feasible with autosegmented structures with minimal dosimetric variation from ground truth, but contours should be visually inspected prior to dose reconstruction in an end-to-end dose accumulation workflow.

Nucleotide excision repair deficiency is intrinsic in sporadic stage I breast cancer.

The molecular etiology of breast cancer has proven to be remarkably complex. Most individual oncogenes are disregulated in only approximately 30% of breast tumors, indicating that either very few molecular alterations are common to the majority of breast cancers, or that they have not yet been identified. In striking contrast, we now show that 19 of 19 stage I breast tumors tested with the functional unscheduled DNA synthesis assay exhibited a significant deficiency of DNA nucleotide excision repair (NER) capacity relative to normal epithelial tissue from disease-free controls (n = 23). Loss of DNA repair capacity, including the complex, damage-comprehensive NER pathway, results in genomic instability, a hallmark of carcinogenesis. By microarray analysis, mRNA expression levels for 20 canonical NER genes were reduced in representative tumor samples versus normal. Significant reductions were observed in 19 of these genes analyzed by the more sensitive method of RNase protection. These results were confirmed at the protein level for five NER gene products. Taken together, these data suggest that NER deficiency may play an important role in the etiology of sporadic breast cancer, and that early-stage breast cancer may be intrinsically susceptible to genotoxic chemotherapeutic agents, such as cis-platinum, whose damage is remediated by NER. In addition, reduced NER capacity, or reduced expression of NER genes, could provide a basis for the development of biomarkers for the identification of tumorigenic breast epithelium.

Influence of Seasonal Hazards on Water, Sanitation, and Hygiene-Related Behavior and Implications for Cholera Transmission in Bangladesh.

Most cholera outbreaks in Bangladesh are seasonal, peaking in the dry and post-monsoon periods. Therefore, we investigated whether changes in water, sanitation, and hygiene (WASH) behavior in three populations in Bangladesh during the year could help explain why these two periods are particular to cholera transmission. The study used a mixed-method design, including a repeated cross-sectional study, focus group discussions, and key informant interviews. Through a repeated cross-sectional study, WASH-related variables were assessed during the dry, monsoon, and control seasons in 600 households from coastal Satkhira, inland Sirajganj, and the Dhaka slums. Seasonal behavioral changes were observed in all study areas. Dhaka and Satkhira had an increased mean distance to water sources during the dry and monsoon seasons (Dhaka: control season, 12 m [95% CI, 11-13]; dry season, 36 m [95% CI, 18-55]; and monsoon season, 180 m [95% CI, 118-243]; Satkhira: control season, 334 m [95% CI, 258-411]; dry season, 669 m [95% CI, 515-822]; and monsoon season, 2,437 m [95% CI, 1,665-3,209]). The participants attributed this to pollution of the usual water source. Perceived water quantity was lowest during the dry season in Dhaka and Sirajganj, and during the monsoon season in Satkhira. Handwashing with soap declined in all areas during the dry and monsoon seasons. Open defecation was frequent among children younger than 5 years, increasing during seasonal climate hazards. Results show that WASH-related behavior changed seasonally, increasing the risk of cholera transmission through multiple hygiene-related transmission pathways. Future research would benefit by ensuring that the length of studies covers all seasons throughout the year and also by looking in more detail at people's behavior and hygiene practices.

Oxford hip and knee scores deteriorate in patients awaiting lower limb arthroplasty during the COVID-19 pandemic and predict a health state 'worse than death'.

The COVID-19 pandemic has caused unprecedented disruption to elective orthopaedic services. The primary objective of this study was to examine changes in functional scores in patients awaiting total hip arthroplasty (THA), total knee arthroplasty (TKA), and unicompartmental knee arthroplasty (UKA). Secondary objectives were to investigate differences between these groups and identify those in a health state 'worse than death' (WTD). In this prospective cohort study, preoperative Oxford hip and knee scores (OHS/OKS) were recorded for patients added to a waiting list for THA, TKA, or UKA, during the initial eight months of the COVID-19 pandemic, and repeated at 14 months into the pandemic (mean interval nine months (SD 2.84)). EuroQoL five-dimension five-level health questionnaire (EQ-5D-5L) index scores were also calculated at this point in time, with a negative score representing a state WTD. OHS/OKS were analyzed over time and in relation to the EQ-5D-5L. A total of 174 patients (58 THA, 74 TKA, 42 UKA) were eligible, after 27 were excluded (one died, seven underwent surgery, 19 non-responders). The overall mean OHS/OKS deteriorated from 15.43 (SD 6.92), when patients were added to the waiting list, to 11.77 (SD 6.45) during the pandemic (p < 0.001). There were significantly worse EQ-5D-5L index scores in the THA group (p = 0.005), with 22 of these patients (38%) in a health state WTD, than either the TKA group (20 patients; 27% WTD), or the UKA group (nine patients; 21% WTD). A strong positive correlation between the EQ-5D-5L index score and OHS/OKS was observed (r = 0.818; p < 0.001). Receiver operating characteristic analysis revealed that an OHS/OKS lower than nine predicted a health state WTD (88% sensitivity and 73% specificity). OHS/OKS deteriorated significantly among patients awaiting lower limb arthroplasty during the COVID-19 pandemic. Overall, 51 patients were in a health state WTD, representing 29% of our entire cohort, which is considerably worse than existing pre-pandemic data.