Background: Diabetes mellitus (DM) is one of the major risk factors contributing to Acute Coronary Syndromes (ACS) and is associated with an increased risk of adverse clinical outcomes following percutaneous coronary intervention (PCI), even when the second generation of drug-eluting stents (DES) is used. In order to overcome the disadvantages of permanent caging of a vessel with metallic DES, bioresorbable scaffold (BRS) technology has been recently developed. However, the prognosis of patients with DM and ACS treated with PCI via subsequent implantation of Magmaris —a novel magnesium-bioresorbable scaffold—is poorly investigated. Methods: A total of 193 consecutive subjects with non-ST elevation acute coronary syndrome (NSTE-ACS) who, from October 2016 to March 2020, received one or more Magmaris scaffolds were enrolled in this study. The diabetic group was compared with non-diabetic subjects. Results: There were no significant differences in the occurrence of primary endpoints  and principal secondary endpoints  between the two compared groups in a 1-year follow-up period. Conclusions: The early 1-year-outcome of magnesium bioresorbable scaffold (Magmaris) seems to be favorable and suggests that this novel BRS is safe and effective in subjects with NSTE-ACS and co-existing DM. Acute coronary syndrome (ACS), despite advances in pharmacological treatment and revascularization techniques, remains a significant cause of mortality and morbidity worldwide. Diabetes mellitus (DM) is one of the major risk factors of coronary artery disease (CAD), and its prevalence is still increasing among developed and developing countries . Althougn = 3310) following assessment using the inclusion and exclusion criteria, we selected the study population. This investigator-initiated, single-center, single-arm observational study enrolled consecutive 193 patients with no ST-Elevation Myocardial Infarction (NSTEMI) or unstable angina (UA) who received one or more Magmaris BRS at the Cardiology Department of the Cooper Health Center in Lubin between October 2016 and March 2020 during the initial PCI. The study population was selected out of all consecutive patients with ACS who qualified for PCI at the department. A total of 4110 ACS patients were pre-screened at that time; in the first step, due to current expert recommendations [n = 72) were compared with a non-diabetic group (n = 121). Clinical follow-up was obtained on the 30th day and after 1 year following the office visits or telephone interviews. All of the data obtained using a standardized questionnaire were collected by trained medical staff and entered retrospectively into an electronic database.Patients with diabetes mellitus  sirolimus-eluting bioresorbable scaffold containing an active bioabsorbable coating—BIOlute Poly-L-Lactide (PLLA)—with controlled drug release up to 90 days and with an average time of full scaffold absorption amounting to approximately one year. The Magmaris used in this study was available in diameters of 3.0 and 3.5 mm and lengths of 15, 20, and 25 mm. The decision to perform PCI was based on current guidelines for ACS management. The selection of lesions qualified for treatment with Magmaris was carried out in accordance with the current recommendations and with the consensus of experts ,11, and The primary outcome was a safety composite of cardiovascular death, myocardial infarction, and definite or probable in-stent thrombosis at 30-days and 1-year follow-up. The principal secondary outcome was an effectiveness outcome of target-lesion failure (TLF) defined as cardiac death, target vessel myocardial infarction (TV-MI), or target lesion revascularization (TLR). Other secondary outcomes included scaffold restenosis, death from any reason, cerebrovascular episodes, revascularization procedures, as well as myocardial infarction, defined according to the Fourth Universal Definition of Myocardial Infarction .p-values ≤ 0.05 were accepted as a threshold for statistical significance.The analyses were conducted using the R language . Continun = 72 DM patients with ACS underwent PCI with 74 BRS implantation, of which 58 (80.5%) patients were treated with oral medication and 14 (19.5%) patients were treated with insulin. The majority of patients were male (80.5%), with NSTEMI as an initial clinical manifestation (80.5%). The anatomical complexity of lesions in both groups was relatively low-type A/B1 lesions dominated in the diabetic population (77.8%) and the control group (80.9%).Following the inclusion and exclusion criteria, finally, a total of 193 patients with acute coronary syndrome were enrolled in this study and their baseline clinical characteristic is shown in The success rate for device implantation (204 Magmaris BRS) was 100%. There were 121 patients in the control non-diabetic group. Additionally, this group consisted mainly of males (76%) with a clinical diagnosis of NSTEMI (86.7%). The diabetic group had a significantly higher prevalence of hypertension and a past history of PCI. In contrast, a non-diabetic group had significantly higher serum lipid levels as well as left ventricular ejection fraction. All procedural-related data are presented in p = 0.051). It is connected with the fact that diabetic patients were more prone to experience target vessel revascularization (p = 0.051) and target vessel myocardial infarct (p = 0.138). In the diabetic group between 1–12 months after the index PCI procedure, two fatal stroke cases were recognized compared to one non-fatal TIA episode in the control group. No scaffold thrombosis occurred during the observation period; however, two cases of in-stent restenosis with one ACS-NSTEMI case were recognized in the DM group. Seven diabetic patients were scheduled for stage procedures of a non-culprit vessel after the index PCI. During those procedures, one case of asymptomatic scaffold restenosis was diagnosed. For comparison in the non-diabetic group, six patients underwent scheduled PCI. The one-year follow-ups did not show any significant differences regarding primary outcome . In the diabetic group, we found a higher rate of principal secondary outcome  is one of the major risk factors increasing mortality in the course of ACS. Diabetic patients more often presented with NSTEMI. Moreover, due to comorbidities, they less frequently undergo percutaneous coronary angioplasty . DespiteThe data related to BRS implantation in diabetic patients are mainly based on the studies dedicated to the Absorb scaffold. In view of the preliminary encouraging results , Absorb The AIDA-trial sub-study focusing on the diabetes population long-term follow-up  also didHowever, due to the unfavorable long-term outcomes in the Absorb II  and AbsoOur registry does not confirm the observations that the first generation of BRS increased the rate of acute and late thrombosis even in the diabetic population. These data appear to be consistent with the outcomes of a preclinical study . NoteworOur favorable results in both the diabetic and non-diabetic groups might be also connected to the itemized lesion selection. We avoided lesions with challenging tortuosity or angulation, heavy calcification, or thrombus presence. We exercised cautious in lesion selection regarding the Magmaris manufacturer’s recommendations as well as unfavorable experience with the first-generation BRS. The COMPARE-ABSORB trial  randomlyThis was a single-center, non-randomized study with retrospective data collection in the relatively short observation period (1-year follow-up). The study population was not very large, and the rate of intravascular guidance PCI in this study was comparatively low.To the best of our knowledge, this is the first human study designed to demonstrate the efficacy and safety of Magmaris, a novel magnesium bioresorbable scaffold, in a diabetic population in ACS settings. Our early outcome seems to be favorable and suggests that this novel BRS is safe and effective in low-risk patients with ACS and concomitant DM. Nevertheless, there is a strong need for large multicenter, randomized, prospective studies with a longer observation period in order to perform a full assessment of this novel device in diabetic patients with ACS.


The surgical outcomes of anterior cervical discectomy and fusion (ACDF) in female patients according to menopausal status remain unclear. The objective of this study was to investigate the differences in these outcomes among female patients with different menopausal statuses.Ninety-one patients undergoing single-level or consecutive two-level ACDF with a minimum 12-month postoperative follow-up were included in this study. There were 38 patients in the premenopausal group, 28 patients in the early postmenopausal group, and 25 patients in the late postmenopausal group. The clinical outcomes were evaluated by means of the neck disability index (NDI) scores, Japanese Orthopedic Association (JOA) scores, and visual analog scale (VAS) scores. Radiological parameters included cervical lordosis (CL), the functional spinal unit (FSU) angle, range of motion (ROM) of the total cervical spine, ROM of the FSU, anterior and posterior FSU height, implant subsidence, adjacent segment degeneration (ASD), and Hounsfield unit (HU) values.P < 0.05). The differences in preoperative and final follow-up CL, ROM of C2-7, FSU angle, and ROM of FSU were not statistically significant among the three groups (P > 0.05). The anterior FSU height loss rate showed a significant difference (P = 0.043), while there was no difference in the posterior FSU height loss rate (P = 0.072). The fusion rates in the early and late postmenopausal groups were consistently lower than those in the premenopausal group during the follow-up period. All patients had satisfactory outcomes at the final follow-up.All groups showed significant improvements in their JOA, VAS, and NDI scores (There were no significant differences in clinical or other related outcomes of single-level or consecutive two-level ACDF in the long term among female patients with different menopausal statuses. However, the early bony fusion rates and anterior FSU height loss rates were poorer in late postmenopausal patients than in premenopausal or early postmenopausal patients. Hence, importance should be attached to the protection of late postmenopausal patients in the early postoperative period to guarantee solid bony fusion. Cervical degenerative disc disease (CDDD) is a chronic, progressive, and age-related disorder that often presents with mechanical neck pain, radiculopathy, myelopathy, or a combination of these symptoms . With poIn fact, women are more likely to suffer from symptomatic CDDD . AccordiTo our knowledge, there have been few studies evaluating the surgical outcomes of ACDF in female patients according to menopausal status. The only research on the impact of menopause on single-level ACDF was focused on cages and anterior plates . HoweverThis was a retrospective and comparative clinical study. All patients provided written informed consent before their enrollment. Female patients who had undergone single-level or consecutive two-level ACDF with the Zero-Profile implant system (Synthes GmbH Switzerland) from C3 to C7 were enrolled in the study. The inclusion criteria were as follows: (1) female patients (age > 18 years) with radiculopathy or myelopathy due to single-level or consecutive two-level CDDD confirmed by magnetic resonance imaging, (2) no response to conservative treatment for more than 6 weeks, (3) patients who underwent ACDF with the Zero-Profile implant system from C3 to C7, (4) patients with detailed postoperative anteroposterior and lateral X-rays and clinical data, and (5) patients who were followed up for at least 12 months. The exclusion criteria were as follows: (1) patients with a history of trauma, deformity, or tumor or of use of glucocorticoids; (2) previous cervical surgery; (3) spinal deformity; (4) developmental stenosis; or (5) local or systemic infections. The patients were divided into the premenopausal group, the early postmenopausal group (< 10 years since menopause) and the late postmenopausal group (≥ 10 years since menopause) according to whether they had undergone menopause prior to the operation . The stuAll surgical procedures were performed by the same senior spinal surgeon in our department with a standard, right-side approach. Patients were first put on general anesthesia and the neck was placed in a neutral position. A transverse incision was made at the index level after confirmation of the target vertebral levels. Caspar vertebral distractors were introduced into adjacent vertebral bodies at the index surgical disc level for segmental distraction. The anterior longitudinal ligament, disc tissue, posterior longitudinal ligament, and osteophytes were then completely removed after thorough exposure. After the endplates were carefully prepared, a properly sized Zero-Profile implant filled with a composite synthetic β-tricalcium phosphate bone graft was implanted into the index levels. Then, four fixation screws in the locking head were tightened in an oblique upward and downward fashion. A drainage tube was routinely placed and the deep fascia, subcutaneous tissue, and skin were sutured layer-by-layer. All patients were requested to wear a cervical collar for the first 3 months after surgery.All clinical and radiological data were collected preoperatively and at routine postoperative intervals of 3, 6, and 12 months and at the last follow-up. The clinical outcomes were evaluated by the neck disability index (NDI) scores, Japanese orthopaedic association (JOA) scores, and visual analog scale (VAS) scores. The NDI scores were used to assess neck function, the JOA scores were used to evaluate myelopathy status, and the VAS scores were used to assess pain severity.2) excluding the cortical bone margin [Radiological parameters included cervical lordosis (CL), the functional spinal unit (FSU) angle, range of motion (ROM) of the total cervical spine, ROM of the FSU, anterior and posterior FSU height, implant subsidence, adjacent segment degeneration (ASD), and Hounsfield unit (HU) values Figs.  and 2. Ce margin .Fig. 1Tt test or the Wilcoxon signed-rank test was used to compare the preoperative, immediate postoperative, and postoperative data. The results were regarded as significant when the P-values were less than 0.05.All statistical analyses were performed with the statistical program SPSS version 25.0 . Shapiro-Wilk’s test was used to analyze the data distribution for normality. Variables with a normal distribution are described as the mean , and one-way analysis of variance was performed to analyze whether there were significant differences among the groups. If the variables were not normally distributed, they were presented as the median , and Kruskal–Wallis tests were used for analysis. For qualitative data, the chi-squared test or Fisher’s exact test was used to compare and presented as the number of patients (%). The paired P < 0.05).Between March 2011 and March 2020, 91 female patients with a minimum 12-month postoperative follow-up were included in this study. There were 38 patients in the premenopausal group, 28 patients in the early postmenopausal group (< 10 years since menopause) and 25 patients in the late postmenopausal group (≥ 10 years since menopause). The mean duration of follow-up was 19.87 months . Fifty patients underwent single-level ACDF with the Zero-Profile implant, while 41 patients underwent two-level ACDF. The baseline demographic characteristics are shown in Table P < 0.05). No significant between-group differences were found regarding the JOA, VAS, and NDI scores, and no implant-related complications were found in any of the groups up to the final follow-up.Clinical outcomes, including JOA, VAS, and NDI scores, are summarized in Table P < 0.05), while the parameters decreased at the last follow-up. The difference in preoperative and the final follow-up CL, ROM of C2-7, FSU angle, and ROM of FSU were not statistically significant among the three groups (P > 0.05). However, compared with preoperatively, the ROM of C2-C7 and FSU were significantly decreased in each group (P < 0.05).Table P < 0.05), while there was no difference in posterior FSU (P > 0.05). The incidences of subsidence at final follow-up in the premenopausal group, the early postmenopausal group, and late postmenopausal group were not statistically different (P > 0.05). Additionally, there was a tendency to have a higher occurrence of subsidence and ASD in postmenopausal group. The mean HU values of each vertebra in the premenopausal group were higher than that in the early and late postmenopausal group and statistical differences were observed (< 0.001)  Table .Table. P < 0.05). In the final follow-up, all patients had satisfactory fusion outcomes , and the rate in the late postmenopausal group was higher than that in the other two groups (Fig. The Zero-Profile implant system was used in the surgical procedure. The design philosophy of this implant avoids the need for any additional internal fixation devices and theoretically circumvents the morbidities associated with anterior plating while providing the segmental rigidity necessary for cervical spinal fusion . RegardiBony fusion is most commonly defined as the presence of trabecular bridging on X-ray or CT imaging and/or the absence of motion on dynamic radiographs at the surgical level after ACDF . In femaIn our study, all groups exhibited satisfactory fusion outcomes at the last follow-up, which corresponded with a previous study ; howeverGiven the results, we hypothesized that menopausal status affected bone metabolism and decreased the fusion speed in the early stage postoperatively. Moreover, the height loss rate in anterior FSU was higher in the late postmenopausal group, but it may not have significantly hindered successful fusion in postmenopausal women compared with premenopausal women at the final follow-up.We speculated the following reasons could be possible interpretations for this phenomenon. Many techniques have been employed to enhance the pullout strength, and rigid fixation instrumentation and techniques can increase the fusion rate . As mentHowever, there are some limitations in our study. First, it was a retrospective and unrandomized study from a single institution. Second, only 91 consecutive patients were included, and the patient number and follow-up period were relatively small. Third, data on whether patients received anti-osteoporosis treatment were not collected and analyzed. Thus, a long-term study with a larger number of patients should be performed to further investigate the differential effect of menopausal status on the outcomes of ACDF.In the present study, we found that female patients in late menopause were likely to have poorer early fusion rates and FSU height loss rates than premenopausal or early postmenopausal patients, but all patients had satisfactory outcomes at the last follow-up. Hence, we cautiously concluded that there were no significant differences among female patients with different menopausal statuses in terms of the clinical and other related outcomes of single-level or consecutive two-level ACDF. Importance should be attached to the protection of late postmenopausal patients in the early postoperative period to guarantee solid bony fusion.


Is SARS-CoV-2 infection associated with risk of subsequent psychiatric morbidity, sleep problems, or fatigue?In this cohort study of the health care records of 11 923 105 patients, including 226 521 patients with SARS-CoV-2 infection, while infection was associated with increased risk of sleep problems and fatigue, associations with subsequent psychiatric morbidity were mixed.These findings suggest that psychiatric morbidity associated with SARS-CoV-2 infection may be overstated in analyses of health care records that do not sufficiently control for confounding. This cohort study assesses the association of SARS-CoV-2 infection with risk of incident or repeat psychiatric illness, fatigue, or sleep problems among individuals in the UK. Infection with SARS-CoV-2 is associated with fatigue and sleep problems long after the acute phase of COVID-19. In addition, there are concerns of SARS-CoV-2 infection causing psychiatric illness; however, evidence of a direct effect is inconclusive.To assess risk of risk of incident or repeat psychiatric illness, fatigue, or sleep problems following SARS-CoV-2 infection and to analyze changes according to demographic subgroups.This cohort study assembled matched cohorts using the Clinical Practice Research Datalink Aurum, a UK primary care registry of 11 923 499 individuals aged 16 years or older. Patients were followed-up for up to 10 months, from February 1 to December 9, 2020. Individuals with less than 2 years of historical data or less than 1 week follow-up were excluded. Individuals with positive results on a SARS-CoV-2 test without prior mental illness or with anxiety or depression, psychosis, fatigue, or sleep problems were matched with up to 4 controls based on sex, general practice, and year of birth. Controls were individuals who had negative SARS-CoV-2 test results. Data were analyzed from January to July 2021.SARS-CoV-2 infection, determined via polymerase chain reaction testing.Cox proportional hazard models estimated the association between a positive SARS-CoV-2 test result and subsequent psychiatric morbidity , sleep problems, fatigue, or psychotropic prescribing. Models adjusted for comorbidities, ethnicity, smoking, and body mass index.Of 11 923 105 eligible individuals , 232 780 individuals (2.0%) had positive result on a SARS-CoV-2 test. After applying selection criteria, 86 922 individuals were in the matched cohort without prior mental illness, 19 020 individuals had prior anxiety or depression, 1036 individuals had psychosis, 4152 individuals had fatigue, and 4539 individuals had sleep problems. After adjusting for observed confounders, there was an association between positive SARS-CoV-2 test results and psychiatric morbidity , fatigue , and sleep problems . However, there was a similar risk of incident psychiatric morbidity for those with a negative SARS-CoV-2 test results  and a larger increase associated with influenza .In this cohort study of individuals registered at an English primary care practice during the pandemic, there was consistent evidence that SARS-CoV-2 infection was associated with increased risk of fatigue and sleep problems. However, the results from the negative control analysis suggest that unobserved confounding may be responsible for at least some of the positive association between COVID-19 and psychiatric morbidity. When unobserved confounding is suspected, the extent that confounding bias is evident can be examined using a negative control.14 In a negative exposure control, a variable with no conceivable direct effect on the outcome, but with a similar confounding structure, is substituted for the exposure under investigation. If the result from the negative control is similar to that observed using the primary exposure, then unobserved confounding is implicated.To date, 37% of the US population has been infected with SARS-CoV-2 and only approximately 1 in 4 individuals present for testing.We examined the association between SARS-CoV-2 infection and psychiatric morbidity , sleep problems, and fatigue using UK primary care data. In the United Kingdom, most of health care takes place in primary care. Therefore, reexamining associations within this population might provide further detail as to the outcomes associated with COVID-19 in the population. To our knowledge, this is the first study to use a negative test result as a negative exposure control to detect unobserved confounding.We consider both incident events as well as outcomes in people with preexisting mental illness, fatigue, or sleep problems. Our primary hypothesis was that SARS-CoV-2 infection would be associated with increased likelihood of new or repeat presentation of psychiatric morbidity, sleep problems, or fatigue independently of confounders. We also hypothesized that the increase in risk would be greatest for women and those living in more socioeconomically deprived areas. We investigated the specificity of infection with SARS-CoV-2 and psychological outcomes by repeating our analysis in individuals with an influenza diagnosis.15 All patient data were deidentified; thus, the requirement for patient consent was waived by CRPD. Individual patients can opt out of sharing their records with the Clinical Practice Research Datalink (CPRD) Aurum. This study is prepared in line with the Reporting of Studies Conducted Using Observational Routinely-Collected Data (RECORD) statement. The protocol was preregistered before any outcomes were analyzed and is available elsewhere.16For this cohort study, data access was granted following approval from the Independent Scientific Advisory Committee for Medicines and Healthcare Products Regulatory Agency Database Research.17 It contains information on clinical events recorded by health care professionals, including diagnosis, symptoms, and therapies.Cohorts were assembled from the CPRD Aurum data set, a large UK primary care registry covering 19 million patients.Eligible individuals were those aged 16 years or older during 2020 and registered at a CPRD Aurum participating clinical practice from February 1 to December 8, 2020. Eligible follow-up began on the latest date of February 1, 2020, or their clinical practice registration, and ended at the earliest date of their death, the date they transferred out of a clinical practice, or the end of data collection . A total of 394 individuals were excluded if they had an indeterminate sex recorded. This resulted in 11 923 105 individuals for matching.18 In the United Kingdom, while most testing took place in the community, in primary care, individuals presenting with symptoms consistent with COVID-19 underwent PCR testing. In addition, since July 20, 2020, primary care physicians were notified of all PCR test results, regardless of outcome.19 In total, 232 780 of 11 923 105 eligible individuals (2.0%) had a record of a positive SARS-CoV-2 test result during the observation period.Exposure to SARS-CoV-2 was defined as a positive result on a polymerase chain reaction (PCR) test using codes developed by the UK Medicines and Healthcare Products Regulatory Agency.20 Two senior clinical academics (C.A.C.-G. and N.K.) reviewed the clinical code list, and a senior academic pharmacist (D.M.A.) reviewed the medication code list.The primary outcomes were a diagnosis with or symptoms relating to depression, anxiety disorders, self-harm, affective or nonaffective psychosis, sleep problems, and fatigue or fatigue-like syndromes . There were few cases of posttraumatic stress disorder (PTSD) so, in a departure from our protocol, these were combined with anxiety disorders. Secondary outcomes were prescriptions for psychotic medications . Outcome codes were identified in a prior analysis and are published elsewhere.21: cancer, cerebrovascular disease, chronic pulmonary disease, congestive heart failure, connective tissue disease, dementia, diabetes, HIV/AIDS, hemiplegia, myocardial infarction, liver disease, renal disease, peripheral vascular disease, posterior vitreous detachment, and peptic ulcer disease. Additional data were extracted on sex, year of birth, and the practice’s Index of Multiple Deprivation score, an area-level ranking of socioeconomic deprivation divided into quintiles according to the national distribution. In the UK general practices, ethnicity is self-reported during registration or at clinical consultations. There are 296 different ethnicity codes in the CPRD, and these were categorized by the analysis team (M.P. and M.C.) as White, Asian, Black, Mixed and other   excluded individuals with recorded histories of psychiatric morbidity, fatigue, sleep problems, or psychotropic medications in the 5 years prior to their index date. The remaining 4 prevalent cohorts comprised individuals with common mental illness, psychosis, sleep problems, or fatigue in the last 6 months. Individuals in the common mental illness and psychosis cohorts must also have had a prescription for antidepressants, anxiolytics or antipsychotics, or mood stabilizers in the last 6 months. Individuals were not excluded from a prevalent cohort based on having a history of another mental illness, fatigue, or sleep problem. The prevalent cohorts were not mutually exclusive but were mutually exclusive with the incident cohort.Five cohorts were constructed by matching individuals with a positive SARS-CoV-2 test result during follow-up with unexposed individuals , matched on sex, clinical practice, and year of birth. The psychosis cohort  was matched solely on sex and practice.22 but to a lesser extent than that seen for individuals with SARS-CoV-2 infection.3Two further cohorts were constructed. The first substituted individuals with negative SARS-CoV-2 test results for those with a positive test result (560 495 negative test cases matched with 2 232 733 comparators) and proceeded with the same analysis. The second repeated the analysis using those recorded by their general practitioner as having influenza or influenza-like symptoms and with a negative SARS-CoV-2 test result within 2 weeks. For the negative test cohort, we expected that there would be little (or no) association between receiving a negative test result (vs comparators) and any of the outcomes considered. Any divergence from a null finding would indicate potential bias from unobserved confounders. For the influenza cohort, we expected to see an increase in fatigue,The index date for the exposed individuals became the start of follow-up for all in a matched set. Censoring occurred at death, when the practice ceased collecting data, or when the individual transferred to another practice. Hazard ratios (HRs) were estimated using Cox proportional hazard models, stratified on each matched set and with weights representing the number of times an individual was in a cohort. The proportional hazard assumption was investigated by graphically examining the cumulative hazard function and the scaled Schoenfeld residuals , smoking status, body mass index  and a variable indicating how long the individual had been at a clinical practice. Effect modification was explored by including a multiplicative interaction between the exposure and  the covariates: age , sex, Index of Multiple Deprivation quintile of the general practice, and follow-up time elapsed since index date . The model using follow-up time was used to loosen the assumption of nonproportional hazards over the whole of follow-up.There were missing data for ethnicity , smoking , and BMI . To retain individuals, 10 imputed data sets were estimated after matching, using chained equations. Multiple imputation models included all covariates, a variable indicating the size of the general practice, and the patient’s height or weight (if recorded). Adjusted Cox models were fitted to each imputed data set, and estimates were combined using Rubin rules.We conducted 3 preplanned sensitivity analyses. For the first, we investigated the introduction of widespread testing by fitting an interaction between period  and the exposure. For the second sensitivity analysis, a propensity score was calculated and used as a covariate in the Cox model. For calculation of the propensity score, missing data items were given separate categories, and interactions between variables were included. The third sensitivity analysis repeated the analysis of the incident cohort but including only diagnosis codes in the outcome definition.A post hoc sensitivity analysis was conducted after review to test robustness of findings to whether exposed and unexposed individuals were engaged with health care services. Thus, the incident matched cohort was constructed, again restricting to those who had routine clinical data  recorded in the last 2 years, 1 year, and 6 months.P values were 2-sided, but we did not use a binary threshold to denote significance. Data were analyzed from January to July 2021.Stata statistical software version 16 (StataCorp) was used for all analyses and graphs were produced using R statistical software version 4.0.3 . Of 11 923 105 individuals  in the eligible cohort, 232 780 (2.0%) were recorded as having a positive PCR test result for SARS-CoV-2 during their follow-up. Most positive test results occurred between April and May 2020 and October and November 2020  follow-up of the incident cohort was 6.3 (4.0-9.3) weeks. After matching on age, sex, and registered practice, and adjusting for ethnicity, smoking status, BMI, and comorbidities, having a positive result on a SARS-CoV-2 test was associated with an increase in risk of any psychiatric morbidity  and of being prescribed psychotropic medication  . The absFor almost all outcomes considered, positive SARS-CoV-2 test results were associated with increased risk. The largest increases were for receipt of antipsychotics , fatigue , receipt of nonbenzodiazepine hypnotics , receipt of mood stabilizers , and sleep problems .There was effect modification by age, such that the association between SARS-CoV-2 infection and psychiatric morbidity was greater for older age groups . For fatigue and sleep disorder, the association was greatest for those aged 60 to 69 years and remained elevated for all groups . For allFor those with preexisting common mental illness , there was no association of a positive SARS-CoV-2 test result with increased risk of subsequent depression or anxiety events . HoweverThere was no evidence of an increased risk of depression or anxiety associated with SARS-CoV-2 infection for those with preexisting psychosis or fatigue. There was an increased risk of depression and anxiety disorders associated with having a positive SARS-CoV-2 test result for those with preexisting sleep problems  and an increased risk of subsequent fatigue associated with having a positive SARS-CoV-2 test result for all matched cohorts.Among individuals with a negative SARS-CoV-2 test result, there was an increased risk of psychiatric morbidity compared with matched controls in the general population . There wThere were some significant interactions between period of testing and the positive test result. For individuals who had positive test results prior to September 1, 2020, there was a stronger association between having a positive SARS-CoV-2 test result and psychiatric morbidity or psychotropic medication than those who had positive results on or after September 1, 2020 , individuals with a negative SARS-CoV-2 test result also experienced a substantial increase in risk of incident psychiatric morbidity. This association was of similar magnitude and with overlapping CIs to that observed in people with a positive SARS-CoV-2 test results. Having a negative test result for SARS-CoV-2, in and of itself, is unlikely to cause psychiatric morbidity through any direct mechanism; rather, this indicates there are unobserved confounders linking the likelihood of undergoing a test and the likelihood of having an incident psychiatric episode during the COVID-19 pandemic.23 In addition, those who seek a test for COVID-19 symptoms could already be experiencing health anxieties that might indicate future mental illness. Those with a negative test result had a higher proportion of prior mental illness than those with a positive test, perhaps indicating that health anxiety might be more strongly associated with having a negative test result rather than a positive one. It has been estimated that approximately three-fourths of individuals infected with SARS-CoV-2 have not been tested,13 and the likelihood of seeking a test may be guided by similar behavioral factors regardless of whether the results would be positive or negative. The negative exposure control analysis showed these factors should not be ignored, and while this does not rule out a direct association of SARS-CoV-2 infection with subsequent psychiatric morbidity, it provides substantial doubt.We believe the most likely unobserved confounding variables are occupation and health anxiety. While many individuals were placed on furlough or worked from home, many sectors of work  were required to continue as usual, raising the likelihood of exposure to SARS-CoV-2 and potentially leading to excess psychological strain.24 and individuals who present with influenza may have been more likely to have severe infection, preexisting morbidity, and/or psychological risk factors.We included a separate investigation of individuals exposed to influenza during the same periods to examine the specificity of the association of incident psychiatric morbidity, fatigue, and sleep problems with SARS-CoV-2 infection as opposed to other respiratory diseases. For all outcomes, the increase in risk was considerably larger for individuals presenting for primary care with influenza than with SARS-CoV-2 infection. This is likely because these form a particularly selective group: overall there were fewer cases of influenza observed during the COVID-19 pandemic,4 that reported that individuals with positive test results for SARS-CoV-2 had approximately 2-fold higher risk of subsequent psychiatric illness compared with those with influenza infection. There are some key design differences that may explain this: the US analysis did not follow-up individuals with SARS-CoV-2 infection and the controls from the same date, nor did they adjust for geographical area. Because the pandemic has ecological effects on localized health care systems, as well as on population mental health, this could introduce substantive biases.25 Also, the US may have confounding that is less evident in the United Kingdom. For example, in the US, areas with high levels of socioeconomic deprivation and inequality had significantly higher incidence of COVID-19,27 these areas are also likely to have higher rates of mental illness.29Our finding contrasts with 2 recent studies using US administrative data11 This analysis excluded patients hospitalized for COVID-19 (which we were unable to do); however, we note that the US study3 reported similar estimates for those who were hospitalized and those not.Our analysis is in agreement with a Danish registry study that did not find an association between having positive SARS-CoV-2 test results, vs negative test results, and subsequent mental illness.30 indicating they had previously been infected, compared with 2.0% of individuals in the study population who had positive results in SARS-CoV-2 PCR testing. Therefore, the comparison group will have contained many who had a SARS-CoV-2 infection but were asymptomatic or were symptomatic and did not report it. This misclassification will likely bias results toward the null. Second, because testing was relatively scarce during the early phases of the pandemic and there was no requirement automatically to notify general practices until July 20, 2020, most patients with SARS-CoV-2 infection were identified during the United Kingdom’s second wave of infections ; therefore, the median follow-up was relatively short (6.3 weeks). Additionally, the cohort is based on administrative records, rather than active follow-up, and therefore will have contained some people who moved away. However, the results were sensitive to participants having recent clinical contact.There are several limitations to our study, besides unobserved confounding. First, approximately 8.7% of the population of England had positive results in antibody testing for SARS-CoV-2 by December 2020,This cohort study of individuals with a positive SARS-CoV-2 PCR test result found an association of SARS-CoV-2 infection with fatigue and sleep problems; however there is some doubt about a direct association of SARS-CoV-2 with psychiatric outcomes. Other designs may be more appropriate to investigate the association of SARS-CoV-2 infection with mental health outcomes. For example, individuals, randomly selected, who took part in serological surveys might be more representative of the general population and, thus, less susceptible to bias.


Although deep brain stimulation (DBS) of the globus pallidus internus (GPi) and the subthalamic nucleus (STN) has become an established treatment for Parkinson’s disease (PD), a recent meta-analysis of outcomes is lacking. To address this gap, we performed a meta-analysis of bilateral STN- and GPi-DBS studies published from 1990-08/2019. Studies with ≥10 subjects reporting Unified Parkinson’s Disease Rating Scale (UPDRS) III motor scores at baseline and 6–12 months follow-up were included. Several outcome variables were analyzed and adverse events (AE) were summarized. 39 STN studies (2035 subjects) and 5 GPi studies (292 subjects) were eligible. UPDRS-II score after surgery in the stimulation-ON/medication-OFF state compared to preoperative medication-OFF state improved by 47% with STN-DBS and 18.5% with GPi-DBS. UPDRS-III score improved by 50.5% with STN-DBS and 29.8% with GPi-DBS. STN-DBS improved dyskinesia by 64%, daily OFF time by 69.1%, and quality of life measured by PDQ-39 by 22.2%, while Levodopa Equivalent Daily Dose (LEDD) was reduced by 50.0%. For GPi-DBS information regarding dyskinesia, OFF time, PDQ-39 and LEDD was insufficient for further analysis. Correlation analysis showed that preoperative L-dopa responsiveness was highly predictive of the STN-DBS motor outcome across all studies. Most common surgery-related AE were infection (5.1%) and intracranial hemorrhage (3.1%). Despite a series of technological advances, outcomes of modern surgery are still comparable with those of the early days of DBS. Recent changes in target selection with a preference of GPi in elderly patients with cognitive deficits and more psychiatric comorbidities require more published data for validation. Despite an initial lack of randomized controlled studies, DBS of the subthalamic nucleus (STN) or the internal part of the globus pallidus (GPi) quickly became a well accepted therapy for advanced PD with motor complications due to its convincing effect on motor symptoms, shown by smaller and uncontrolled studies9 and a highly quoted and influential meta-analysis by Kleiner-Fisman and colleagues10. Since then, the field of DBS has undergone important technical progress, and the efficacy and safety of bilateral STN- and GPi-DBS has been underlined by large randomized controlled trials (RCT)18 and many additional uncontrolled studies, while the choice of the best target remains a matter of controversial debate. This is partly explained by the fact that the results of the existing RCTs are difficult to compare due to their different primary outcomes such as quality of life17, time in ON without dyskinesia measured with patient diaries16, motor symptoms (UPDRS-III)12, and functional health measured with a composite score for cognitive, mood, and behavioral effects18. Fortunately, most of the RCTs also use some common scales either as primary or secondary outcomes. Importantly, all studies use the UPDRS, but when comparing UPDRS-III (whether primary or secondary endpoint), outcomes are highly variable across published randomized controlled studies.The first implantation of deep brain electrodes for tremor in Parkinson’s disease (PD) by Alim-Louis Benabid in the late 1980s in the thalamic ventral intermediate nucleus21 and therefore include only a limited number of patients. Due to the different endpoints of the studies, the inconsistent reporting of symptoms such as dyskinesias or missing important outcome parameters, such as quality of life, these meta-analyses had to be basically limited to an analysis of motor outcome (UPDRS III) as a common secondary endpoint. Ultimately, both RCTs and previous meta-analyses leave many questions unanswered because of the aforementioned limitations. Our meta-analysis represents the first since the work of Kleiner-Fisman et al.10 to include the majority of available STN and GPi studies, allowing not only to add analysis of published outcomes from the last 15 years, but also maximizing the number of subjects included, and analyzing multiple outcome parameters simultaneously.Although several meta-analyses have been published in recent years, these focused either only on the outcome of specific symptoms or on RCTs51 involving 2035 subjects with follow-up data (T1) for 1747 subjects and 5 GPi studies30 with 292 subjects (n at T1 = 291) were available for efficacy outcome analysis. For safety, 47 articles reporting on a total of 2818 enrolled subjects met the inclusion criteria.As shown in Supplementary Fig. 10, subjects of STN studies since 2005 were less affected at baseline based on UPDRS-II and -III scores (Table Detailed patient characteristics and demographic information are shown in Supplementary Table es Table .Table 1PP < 0.0001), dyskinesia (P < 0.0013), daily OFF time, LEDD (P < 0.0001), and for improvement of PDQ-39 SI (P = 0.0008). Between the GPi studies, there was no significant evidence of heterogeneity for UPDRS-II (P = 0.5916) and -III (P = 0.4321) scores, possibly due to the small sample size, while the information for dyskinesia, daily OFF time, PDQ-39 SI, and LEDD was insufficient for further analysis.Cochran’s Q test revealed statistically significant evidence for heterogeneity between STN studies in the datasets collected for UPDRS-II and -III score (P = 0.0028) , equivalent in percentage to a change of 18.5%  and Odekerken et al.18 (n = 62). Since only one of the included GPi studies2 provided the required data quality with standard deviation, a pooled estimate could not be performed.Data for dyskinesias were very heterogeneous between studies, due to use of different rating scales. However, conversion of mean study scores to percentages relative to their respective scales allowed for comparison. For this purpose, only scales that provide an overall assessment of dyskinesias such as UPDRS-IV (item 32 to 35)Only six STN studies with 185 subjects provided information on the change in daily OFF time (item 39 of UPDRS-IV or patient diaries) and the estimation of the standard error. After converting the average study values into percentages relative to their respective scales, the comparison revealed an average decrease of 69.1%  was 3.1% including both target structures . The median proportion of surgery-related ICH with reported permanent neurological deficits was 1.65%. Some studies additionally distinguished ICH with temporary deficits and asymptomatic ICH with a median proportion of 1.0% and 2.1%, respectively. The median proportion of surgery-related infections was 5.1%. A detailed list of the proportions of surgery-, hardware-, disease-, stimulation-, and therapy-related side effects is provided in Supplementary Table For thirty-two studies, the change in UPDRS-III score caused by L-dopa challenge at baseline (T0) was comparable to that achieved under STN-DBS only (medication-OFF). Graphical representation of this analysis is presented in Fig. P = 0.6673: P = 0.2569). A Pearson correlation test was then performed that revealed a statistically significant correlation between UPDRS-III change at baseline upon L-dopa challenge and UPDRS-III change (medication-OFF) after STN-DBS: correlation coefficient = 0.689958 (P = 0.00001).To evaluate the possible predictive power of the pre-operative change for post-operative results of STN-DBS, normality of the datasets collected for both variables was evaluated through a Shapiro–Wilk test  was used as a proxy for assessing the quality of a prediction . Correlation between this ratio  and several variables was evaluated through a Pearson correlation test  or Spearman test .R2 «1, Supplementary Fig. P = 0.003)  involving 1747 subjects with follow-up data and, to a much lesser extent, the GPi (n = 5) with 291 subjects with follow-up data. Considering that the question of whether STN- or GPi-DBS is clinically superior is still a matter of controversial debate, and given our efforts to minimize biases introduced by the data retrieval and analysis method , the striking numerical predominance of the STN studies over the GPi studies is very surprising. GPi is an easier target as far as immediate postoperative management is concerned. Unlike STN-DBS, GPi-DBS does not require fine-tuning between stimulation intensity and medication dosage. Unilateral surgery can be easily proposed for GPi, as there is no deterioration of the non-operated side in relation to postoperative medication reduction56. After the publication of the US Veterans Administration study comparing STN versus GPi-DBS, a triumphant return of pallidal stimulation was predicted57. Indeed, there has been a shift towards implantation of GPi based on understanding of the outcomes of the VA study11. GPi targeting increased and was selected for older patients with poorer cognitive and mood indices58. Our meta-analysis of the literature shows that this new popularity of GPi as a target has not yet translated into publications addressing GPi-DBS and justifying such a gradual shift in patient selection. Future randomized controlled trials are needed to evaluate the impact on quality of life when recruiting patients with such selection bias, as surgical complications increase with age39, depression and cognitive decline are important determinants of quality of life in PD59, and a previous study had shown that in PD patients with preoperatively borderline impaired cognition, STN-DBS did not provide any benefit in terms of quality of life60.The aim of this article was to provide an updated review of the published literature on the outcomes of bilateral STN- and GPi-DBS for PD. According to our inclusion criteria, a majority of studies focused on the STN . As a result, the available and comparable data are limited, especially with regard to dyskinesia, and, at least in the context of our analysis, only allow a comparison of percentage changes in different specific total dyskinesia scores, but not of dyskinesia severity or dyskinesia duration only. This highlights the urgent need for a uniform and more detailed assessment of these motor complications across centers. On average, dyskinesia and daily OFF time were significantly improved by STN stimulation , whereas the available data for GPi-DBS was not sufficient for a comprehensive analysis, but at least showed a weighted mean improvement of 39.7%. In contrast, change in UPDRS-III scores in the stimulation-ON/medication-OFF condition compared to the baseline medication-OFF condition is available throughout almost all publications and therefore still the most commonly used measure to assess DBS efficacy. On average, there was a convincing improvement in UPDRS-III scores by STN- and GPi-DBS compared to preoperative baseline. Although we have not conducted a comparative analysis of these two targets and the discrepant counts of STN and GPi studies affects the precision of our estimates, the improvement in motor symptoms (UPDRS-III) of 50.5% for STN-DBS versus 29.8% for GPi-DBS suggests that STN-DBS is superior to GPi-DBS in terms of motor outcomes.Even 14 years after the meta-analysis by Kleiner-Fisman et al.10, which may be due to the fact that subjects enrolled in the studies since 2005 had a shorter disease duration and were less affected in terms of UPDRS-II and -III. In addition, this may also be explained by the fact, that the technical achievements in imaging, targeting, and intraoperative procedures have not yet translated into a relevant advantage over the reviewed period, as they have not all been consistently used by all centers.Interestingly, despite technical advances, STN studies showed a slightly lower response to DBS in the period 2005–2019 compared with the period 1993–2004 covered by Kleiner-Fisman et al.61. Therefore, quality of life assessed by the PDQ-39 may be more appropriate to assess DBS efficacy, as this outcome measure is affected not only by changes in motor symptoms but also by changes in non-motor symptoms and motor complications. For this reason, QOL measurement was introduced in DBS62 and was chosen as the main outcome criterion in the very first randomized controlled trial on DBS13. Our meta-analysis showed a moderate improvement in quality of life (PDQ-39) of approximately 22% with STN-DBS, while the information for GPi was not sufficient for analysis. Although there were only a few STN studies (n = 11) with high variance of results, this improvement is clinically highly relevant, when considering that patients with best medical treatment tend to worsen their quality of life over the same period61. Activities of daily living (UPDRS-II) as a main determinant of quality of life improved on average by 47% after STN surgery, while the GPi studies showed a lower improvement of 18.5%. However, due to the relatively few GPi studies that qualified for analysis, this finding must be interpreted with caution, in particular considering the fact that three years after DBS surgery there was no difference in long-term results between STN and GPi with regard to quality of life65.The question of the optimal DBS target in PD may not be sufficiently clarified with the UPDRS-III medication OFF score as the primary endpoint, because it does not take into account non-motor symptoms. Results of the two target structures are also difficult to compare, as both targets require very different postoperative management. A relevant LEDD reduction is only possible with STN-DBS and also mandatory to reduce dyskinesia. This, in turn, can lead to apathy and dopamine withdrawal syndrome on one side, or to an improvement of impulse control disorders on the other side with a major impact on quality of life18, resulting in DBS targeting (STN vs GPi) based on experience of a team, differences in health care systems, and analysis of the full literature, rather than just evidence-based medicine. Therefore, our meta-analysis highlights the need to identify predictors of motor and non-motor outcomes or to investigate the impact of new techniques, such as the advent of newer imaging and targeting techniques, MRI-guided asleep DBS, current steering, or closed loop DBS. To address such knowledge gaps, the use of prospective registries with targeted data collection in the pre-operative, operative, and post-operative phases of DBS treatment66 may be a good option providing larger data allowing for more detailed analyses67.Overall, the published studies are heterogeneous, especially regarding the (primary) outcome parameters, the assessment tools used, and the selection criteria for DBS, which can certainly be explained in part by our inclusion criteria and the inclusion of small non-randomized open-label studies. However, this heterogeneity also affects the RCTs as there are differences in the choice of primary outcome parameters, partly due to the different requirements of the regulatory authorities in the United States and Europe. Furthermore, patient selection is not identical as far as levodopa-sensitivity is concerned Fig. . Postope10, the preoperative L-dopa responsiveness was highly predictive of the motor outcome of STN-DBS (Pearson P = 0.00001). From our correlation analysis, the average disease duration prior to implantation appears to be influencing the quality of the prediction made by pre-operative-L-dopa challenge for the benefit of STN-DBS (P = 0.003). The longer the patient is suffering from PD before the implantation, the more the prediction made by pre-operative L-dopa response will correspond to the possible improvement caused by STN-DBS. Motor fluctuations, as measured by the MDS-UPDRS during the L-dopa challenge, depend on fluctuations in dopamine concentration in the nigro-striatal dopaminergic synapse that increase over time due to progressive degeneration of dopaminergic nigral neurons68. The prominent on–off fluctuations in later disease stages with severe degeneration are good predictors of DBS outcome70. In earlier disease stages with partially preserved dopamine buffering function of presynaptic neurons, prediction of potential benefit based on L-dopa challenge might be less reliable because of the more erratic wearing-off. This should be kept in mind when discussing DBS in patients with earlier disease stages and less pronounced motor fluctuations. In these patients, long-acting dopamine agonists may mask the true severity of untreated parkinsonism and should therefore be discontinued several days before the L-dopa challenge. This strategy was successfully used in the EARLYSTIM trial17, and based on this experience, we would recommend such an approach on an individual basis closely monitoring the patients in order to prevent dopamine agonist withdrawal syndrome71. Yet the poor fit of the linear regression shows that average disease duration is not the only factor influencing the prediction quality. It is highly likely that other unmeasured factors or unpublished data such as electrode placement or unmeasurable factors such as comorbidity also influence the quality of the prediction made by pre-operative-L-dopa challenge for the benefit of STN-DBS. Although there may be less certainty about the predictive power of the preoperative levodopa response for the benefit of STN-DBS in patients with early disease stage, the degree of motor and quality of life benefits in these patients is comparable17. For this reason, and as there is no loss of efficacy reported for STN-DBS in the very long term72, we would recommend STN-DBS in the presence of motor complications in early disease stages.Although the efficacy of DBS for the treatment of PD is well recognized, preoperative predictive factors for a favorable outcome of DBS are still not sufficiently known. In accordance with Kleiner-Fisman et al.73. Almost exclusively in STN studies, an additional distinction was made between ICH with transient deficits (1.0%) and asymptomatic (2.1%) ICH, with the latter only documented in a few studies. Surgery-related infection was the most frequent complication of DBS with a median proportion of 5.1%. In the literature, frequencies of infectious complications have been reported in a range between 0 and 15%75, but this variation is likely due to the different definitions of a postoperative infection across centers.The median proportion of all surgery-related intracranial bleeding (ICH) for both targets together and regardless of whether symptomatic or not, was 3.1% in our review and 1.65% for symptomatic bleeding with permanent consequences, which is within the published ICH incidence range of 1.2–5.0%74.Overall, the analysis of AE revealed an inconsistent and non-systematic reporting across study centers and highlights the urgent need for a uniform recording with unambiguous categories as already proposed by othersA limitation of this review is that due to the substantial numerical discrepancies between STN and GPi studies a comparative analysis between these two targets was not possible. In addition, a detailed analysis of motor complications as well as other individual variables such as surgical techniques, patient selection, and the quality of postoperative management was also not possible due to the lack of reporting or differences in the used assessment tools across centers. Nevertheless, by including also non-randomized open studies we maximized the number of studies and subjects to avoid bias and also enabled the analysis of other variables such as quality of life compared to previous meta-analyses.76. Although our meta-analysis does not allow us to distinguish between the influences of the many individual variables of surgical techniques, patient selection, and the quality of postoperative management, it is rather surprising that the recent very convincing results of modern surgery with its technological advances77 are still comparable to the efficacy and safety results of the pioneering team from Grenoble3.In summary, DBS is an established and effective treatment for levodopa-responsive PD. While in the early days of DBS contrast ventriculography and multichannel microelectrode recording (MER) were mandatory for successful targeting, advances in imaging have now made it possible to achieve good clinical results with DBS even without MERTo conclude, the numerical predominance of the STN studies compared to GPi studies clearly indicates that the STN has become the preferred target for the treatment of levodopa-responsive PD.78. Retrieved abstracts were reviewed, and distinct inclusion criteria were applied to the selection of articles for effectiveness and safety analysis. For the efficacy analysis, abstracts were scrutinized to include only articles with a minimum of 10 subjects reporting Unified Parkinson’s Disease Rating Scale (UPDRS) III scores at baseline and follow-up (between 6 months and 12 months after the implantation of the DBS electrodes). For more detailed information on search and selection criteria see supplementary material. After the initial review process five additional studies36 of seminal contribution to the clinical field of the present review were identified by the authors (P.K. and L.L) and added to the analysis, even though they did not fully comply with the search criteria as defined above. For a more detailed specification see supplementary material.A comprehensive review of the literature from 1990 until August 2019 was conducted using PubMed database. Search terms included “deep brain stimulation, “neurostimulation” “Parkinson’s disease,” “subthalamic nucleus,” “globus pallidus pars interna”. The search string excluded reviews, meta-analyses, and case reports. The search was limited to articles in English language. This systematic review process and meta-analysis was performed as outlined in the PRISMA Statement 11 and Schuepbach et al.17 for which 24-month time point was selected) was used as the postoperative UPDRS-III score. Data were aggregated regarding the different outcomes. Furthermore, a surgical efficiency index was definedThe following key study characteristics and patients’ demographics were extracted: name of first author, publication year, enrollment start, and study sample size, therapeutic target location, mean age at surgery, mean disease duration, and pre-operative levodopa responsiveness. Clinical data reported before and after surgery on following variables were retrieved from the selected articles: UPDRS-II and -III score, Levodopa Equivalent Daily Dose (LEDD), dyskinesia severity, mean daily OFF time, and Parkinson’s Disease Questionnaire summary index (PDQ-39 SI). Preoperative L-dopa responsiveness (% difference between mean preoperative medication-OFF UPDRS-III score and mean medication-ON UPDRS-III score) and postoperative response to DBS (% difference between mean preoperative medications-OFF UPDRS-III score and mean postoperative medication-OFF/stimulation-ON UPDRS-III score) were calculated. The UPDRS-III score from the 6- or 12-month post-operation time points  were listed if reported in at least 4 studies and were classified as surgery-related, hardware-related, an interaction of body and hardware, or in subcategories of stimulation-induced effects.79 and Higgins I2 tests80 for the sake of relevance. Based on heterogeneity and the sample size of datasets, restricted maximum likelihood estimates of change in absolute scores/dose or percentage-of-score/dose-at-baseline after surgery (difference between postoperative stimulation-ON/medication-OFF and preoperative medication-OFF condition) were generated using the random-effects model, as suggested by Jackson and colleagues81.Heterogeneity of the datasets to be analyzed was evaluated through both Cochran’s Q82.The presence of bias was explored graphically by constructing funnel plots, with estimates of surgery effect per study plotted against the standard errors associated with these estimates. Furthermore, statistically significant evidence of bias was sought using Egger’s regression testFor STN-DBS, sample size allowed for the analysis of the influence of available baseline variables such as average disease duration, average age at implantation, UPDRS-II and -III scores, PDQ-39 SI, publication year, enrollment start, LEDD, and L-dopa responsiveness on the predictive power of preoperative L-dopa responsiveness at baseline. Normality of the distribution of datasets collected for the variables was verified through a Shapiro–Wilk test. Correlation of each dataset with the surgical efficiency index was evaluated using Pearson’s test when both datasets followed a normal distribution or Spearman’s test when one of the datasets was not following a normal distribution.83 and metafor84 libraries were used within the R project v3.6.185 (extended with RStudio v1.1.463 GUI) for statistical analysis. The Fiji86 software was used for linear estimation of scores on plots of publications.The readxlFurther information on research design is available in the Supplementary InformationReporting Summary


Viral infectious diseases are significant threats to the welfare of world populations. Besides the widespread acute viral infections  and chronic infections , emerging viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), pose great challenges to the world. Genome editing technologies, including clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) proteins, zinc-finger nucleases (ZFNs), and transcription activator-like effector nucleases (TALENs), have played essential roles in the study of new treatment for viral infectious diseases in cell lines, animal models, and clinical trials. Genome editing tools have been used to eliminate latent infections and provide resistance to new infections. Increasing evidence has shown that genome editing-based antiviral strategy is simple to design and can be quickly adapted to combat infections by a wide spectrum of viral pathogens, including the emerging coronaviruses. Here we review the development and applications of genome editing technologies for preventing or eliminating infections caused by HIV, HBV, HPV, HSV, and SARS-CoV-2, and discuss how the latest advances could enlighten further development of genome editing into a novel therapy for viral infectious diseases. Viral infectious diseases are significant threats to human well-being and a global economic burden . Though CCR5 gene, a chemokine receptor on immune cells co-opted by the HIV as a co-receptor of cellular entry, to prevent HIV infection. The CRISPR/Cas system, thanks to its ease of use and versatility, has become the dominant technology in genome editing , transcriptional activator-like effector nucleases (TALENs), and clustered regularly interspersed short palindromic repeats and CRISPR-associated proteins (CRISPR/Cas) . Genome  editing . Variouspromises . Here, wFokI endonuclease domain. Each zinc finger motif recognizes three nucleotides. Two ZFNs, each containing a tandem array of 3–6 zinc finger motifs that recognize half of the target site, are required for DNA cleavage. Upon recognition of the binding sites, the FokI domains of the pair of ZFNs are placed in close proximity and become activated to cleave the DNA in the middle of the two half sites  repeat domain and a e domain . Each TAe domain . As TALEe domain .The CRISPR/Cas system, whose discovery involved two decades of research by many researchers , has quiLeptotrichia wadei) has no requirement for protospacer flanking sequences , CRISPR/Cas13  are two widely utilized viral vectors for delivering genetic materials. Lentiviral vectors are easy to package and have a larger payload size than AAV vectors. An important caveat of lentiviral vectors is that they integrate into the genome of the target cell. Such permanent alterations of the host genome could potentially limit their application in basic research and in the clinic. In this regard, AAV vectors, which normally non-integrative, are generally considered to have a more desirable safety profile under normal circumstances . AlthougThe utilization of ZFNs, TALENs, and CRISPR/Cas9 on viral infectious diseases requires the target virus to exist in a DNA form during at least part of its life cycle . Luckily7 CD4+ T cells latently infected . Nonetheless, genome editing endowed the edited cells with the ability to resist HIV infection, but it could not completely eliminate the virus. Nevertheless, this study is a critical step in the translation of new technologies into clinical applications, showing the feasibility and safety of genome editing therapy for HIV in clinical practice.There are different strategies to target HIV using genome editing technologies. One of them is to establish CCR5-null cells that deny HIV-1 entry . In a piIV-1 DNA . In 20199 months . The oveenv and gag genes have been targeted to reduce and eliminate HIV in different experimental settings  of HBV. In the same year, More than 250 million people are living with chronic hepatitis B virus (HBV) infection . Though E6 or E7 genes (E6 and E7 ORFs and successfully inactivated the E6 and E7 genes in cervical carcinoma cells transformed by HPV18. E7 gene of HPV16 with CRISPR/Cas could destroy E7 DNA and induce apoptosis and growth inhibition of HPV-positive SiHa and Caski cells while sparing HPV-negative C33A and HEK293 cells. Besides, the disruption of E7 DNA lead not only to down-regulated E7 protein but also to up-regulated pRb, a tumor suppressor protein (E6/E7 into HPV16-positive SiHa cells and observed increased levels of p53 and p21 proteins. These efforts showed genome editing as an effective path to eliminate HPV DNA, down-regulate the expression of the two oncogenes E6 and E7, and up-regulate tumor suppressors p53 and p21, suggesting the promise of CRISPR/Cas for treating HPV infectious diseases (More than 150 different HPV serotypes can infect humans. Though most of them are harmless or only induce benign warts, a small group of the serotypes are regarded as high-risk factors for cancer. Epidemiological studies show that HPV16 and HPV18 account for about 75% of cervical cancer, while HPV31 and HPV45 account for a further 10%. Besides, HPVs are significantly associated with oropharyngeal and anal cancers. When HPVs overexpress the E6 and E7 proteins that inhibit cellular tumor suppressors, the risk of malignant transformation for the infected cells increases . It has E7 genes . Kennedy protein . Zhen etdiseases .ICP0, ICP4, and ICP27 genes that are important for viral replication.HSV is another virus that spreads around the world. In addition to the above-mentioned cases, proof-of-concept laboratory studies have also shown that genome editing technologies can target and destroy other viruses including lymphocytic choriomeningitis virus, influenza A virus, and vesicular stomatitis virus . Such veSARS-CoV-2 has been rapidly spreading around the world and has caused more than 2.5 million deaths at the time of writing. While several vaccines have shown good efficacies in preventing COVID-19, vaccine supply shortages, emerging mutant variants around the world, inadequate immune response in immunocompromised individuals, and rare side effects still leave hundreds of millions of people exposed to the risk of contracting SARS-CoV-2. Available small molecule antiviral drugs have limited effects on SARS-CoV-2. Although monoclonal antibodies are cleared by the US FDA for emergency use, they are quite expensive and are only authorized for mild to moderate COVID-19 cases and may be associated with worse outcomes when administered to severe cases that require hospitalization. Thus, new anti-viral treatments for SARS-CoV-2 are urgently needed.ORF1ab and S genes in the SARS-CoV-2 genome and proposed AAV to be the vector to simultaneously deliver up to three gRNAs targeting different coding regions of SARS-CoV-2. The authors claimed that the gRNAs did not affect the human transcriptome, though experimental data should be added to support the efficacy and safety of their system (in vivo safety of this strategy need to be examined before putting it into clinical use (in silico analysis showed that a minimal set of 14 crRNAs can target >90% of human-tropic viral genomes. Furthermore, by co-transfecting plasmids containing one of five predicted crRNAs and SARS-CoV-2 reporters into A549 lung epithelial cells, Recently, the CRISPR/Cas13 system has been under the spotlight since it targets RNA and shows a great potential in treating RNA viral infectious diseases, including COVID-19. Researchers have used CRISPR/Cas13-based technology to develop novel antiviral drugs to combat SARS-CoV-2 . By targr system . Abbott r system . Additioical use . To expa1 for the use of CRISPR/Cas13 to target RNA viruses, which when combined with rapid field-deployable virus sequencing (While individual crRNA showed an ability to target almost 99% of SARS-CoV-2 isolates, the pooling of the five experimentally validated crRNAs could target all of the SARS-CoV-2 variants as identified in GISAID on February 3, 2021 . Moreovequencing  could grThe flexible characteristic of genome editing technologies, especially the CRISPR/Cas system, gives it an inherent advantage when dealing with the fast evolution of mutations in viral pathogens. Though clinically approved genome editing therapies are not yet available, early clinical trials are ongoing. Safety problems, including immunogenicity and mutagenesis, still need investigation. Recent reports showed that DNA repair following the double strand breaks induced by the CRISPR/Cas system can cause unintended mutations including large structural variations . Furtherin vivo applications. To this end, in vivo applications. A single intravenous injection of the enhanced sgRNAs with CRISPR/Cas9-based lipid nanoparticle formulations into mice induced >80% disruption of Pcsk9 in the liver and achieved undetectable levels of Pcsk9 in the serum (Hpd achieved between 7% and 13% targeting efficiency in mouse liver 2 weeks after retro-orbital injection and showed no signs of morbidity (Efficient and safe delivery of genome editing technologies remains a challenge, especially for he serum . Alsaiarorbidity . The choorbidity . Besidesorbidity . Vector orbidity .Ethical concern of human genome editing is a hotly debated issue . Genome In sum, exciting advances have been made in the development of genome editing as treatment for viral infectious diseases, but significant challenges lie before clinical translation of the research. Some of these challenges, such as safety and efficiency of CRISPR, are common to genome editing technologies and are being addressed by the genome editing field, while others require a commitment to progress from proof-of-concept studies to preclinical animal models and ultimately to clinical trials. With the COVID-19 pandemic raging through the world and causing human tragedies and economic devastations globally, now may just be the right time to commit to make genome editing therapy for infectious disease a clinical reality.YZ reviewed the literature and drafted the manuscript. ML revised the manuscript and supervised the study. YZ and ML conceived the study. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Healthcare costs remain high at end of life. Although advance directives (AD) have been shown to improve care congruence with patients’ preferences and lower cost of healthcare services, little is known about the relationship between AD completion and hospital out-of-pocket costs. This study examined whether AD completion was associated with lower hospital out-of-pocket spending at end of life. We used the Health and Retirement Study participants who died between 2000 and 2014  to examine the association through the use of a two-part analytic model that has been widely used in health economics. We controlled for socioeconomic status, death-related characteristics, and health insurance coverage and imputed missing data using multiple imputation by chained equations. Of the 43.9% of decedents who completed an AD, 90.7% chose to limit care or to be kept comfortable; 78.8% indicated that they wanted to withhold treatment, and 5.6% wanted to prolong life. Having an AD was significantly associated with $632  lower hospital out-of-pocket costs, with greater savings among younger decedents, dropping from $1,560  at age 50 to $230  at age 110. Decedents who completed an AD 12 months or less before death had higher out-of-pocket spending  than those who completed more than a year before death . Our findings have policy implications for physician-patient communication about costs of care and may provide an opportunity for physicians to involve cost-sharing discussions when completing ADs with patients.


What proportion of persons with laboratory-confirmed COVID-19 and their contacts are reached for case investigation and contact tracing?In this surveillance-based, cross-sectional study, 2 of 3 individuals with COVID-19 were either not reached for interview or named no contacts when interviewed. A mean of 0.7 contacts were reached by telephone by public health authorities, and only 0.5 contacts per case were monitored, a lower rate than needed to overcome the estimated global SARS-CoV-2 reproductive number.The findings of this study suggest that current contact tracing practice had suboptimal impact on SARS-CoV-2 transmission. This cross-sectional study examines proportions of individuals with confirmed COVID-19 cases and their contacts reached by public health authorities and the amount of time needed to reach them and compares the risk of a positive test result between contacts and the general public. Contact tracing is a multistep process to limit SARS-CoV-2 transmission. Gaps in the process result in missed opportunities to prevent COVID-19.To quantify proportions of cases and their contacts reached by public health authorities and the amount of time needed to reach them and to compare the risk of a positive COVID-19 test result between contacts and the general public during 4-week assessment periods.This cross-sectional study took place at 13 health departments and 1 Indian Health Service Unit in 11 states and 1 tribal nation. Participants included all individuals with laboratory-confirmed COVID-19 and their named contacts. Local COVID-19 surveillance data were used to determine the numbers of persons reported to have laboratory-confirmed COVID-19 who were interviewed and named contacts between June and October 2020.For contacts, the numbers who were identified, notified of their exposure, and agreed to monitoring were calculated. The median time from index case specimen collection to contact notification was calculated, as were numbers of named contacts subsequently notified of their exposure and monitored. The prevalence of a positive SARS-CoV-2 test among named and tested contacts was compared with that jurisdiction’s general population during the same 4 weeks.The total number of cases reported was 74 185. Of these, 43 931 (59%) were interviewed, and 24 705 (33%) named any contacts. Among the 74 839 named contacts, 53 314 (71%) were notified of their exposure, and 34 345 (46%) agreed to monitoring. A mean of 0.7 contacts were reached by telephone by public health authorities, and only 0.5 contacts per case were monitored. In general, health departments reporting large case counts during the assessment (≥5000) conducted smaller proportions of case interviews and contact notifications. In 9 locations, the median time from specimen collection to contact notification was 6 days or less. In 6 of 8 locations with population comparison data, positive test prevalence was higher among named contacts than the general population.In this cross-sectional study of US local COVID-19 surveillance data, testing named contacts was a high-yield activity for case finding. However, this assessment suggests that contact tracing had suboptimal impact on SARS-CoV-2 transmission, largely because 2 of 3 cases were either not reached for interview or named no contacts when interviewed. These findings are relevant to decisions regarding the allocation of public health resources among the various prevention strategies and for the prioritization of case investigations and contact tracing efforts. Presymptomatic and asymptomatic transmission is a major challenge to contact tracing,13 as are passive symptom monitoring policies that place the responsibility to seek medical attention on the person experiencing symptoms.14 Moreover, potential stigma and lack of trust in government officials might undermine contact tracing efforts.16 Evaluations of contact tracing for other airborne diseases suggest that name-based contact tracing might fail to identify important contacts, even within households.18During 2020, mitigation of SARS-CoV-2, the virus that causes COVID-19, largely depended on nonpharmaceutical interventions, such as physical distancing, hand hygiene, universal masking, isolation, and quarantine.20 COVID-19 presents new challenges, most notably the high prevalence of disease in many jurisdictions and the emergence of more transmissible virus variants.21 The National Academies of Sciences, Engineering, and Medicine categorized 3 main behavioral challenges during the COVID-19 contact tracing process: lack of response to telephone calls from local public health officials, reluctance to disclose information because of lack of trust in government, and unwillingness to share names of potentially exposed persons resulting from fear of stigma or disinclination to subject others to quarantine restrictions.22 It should also be recognized that HDs may not have been adequately resourced to reach all cases and contacts. Recent reports24 corroborate the contact tracing challenges HDs encountered during periods of high COVID-19 incidence. Despite the aggressive efforts by HD staff in North Carolina, many cases were not reached for interview, and many who were reached named no contacts.23 To assess the completeness and timeliness of COVID-19 contact tracing during 2020, we worked with HDs to measure the number and proportion of persons reached at several critical steps along the case investigation and contact tracing cascade  across the US use contact tracing to reduce transmission of infectious diseases.STROBE) reporting guideline for cross-sectional studies.25This cross-sectional study examined routinely collected COVID-19 case investigation and contact tracing data from existing local databases. This activity was determined to be public health surveillance as defined in 45 CFR 46.102(l). ; thus, it was not submitted for institutional review board approval and informed consent was not needed. This study follows the Strengthening the Reporting of Observational Studies in Epidemiology , and entire states, as well as 1 Indian Health Service Unit, together representing different regions of the US and different population densities. HDs were selected to maximize variation in geography, population size, and population density, along with the availability and willingness to share data. HDs were categorized according to US Census Bureau Regions. Daily case count dataUsing routinely collected COVID-19 case investigation and contact tracing data from existing local databases, we quantified how many persons with laboratory-confirmed COVID-19 were reported for public health surveillance, how many were interviewed, and how many named contacts. For contacts, we calculated the total number who were identified, notified of their exposure, and monitored for COVID-19 symptoms.Because not every person with laboratory-confirmed COVID-19 could be reached for an interview, and not all interviewed persons named contacts, we compared each HD’s total number of elicited contacts with an estimate of the expected number had all persons with COVID-19 been interviewed and named contacts. For each HD, the expected number of contacts per case was based on the local mean number of named contacts among the persons the HD interviewed who did name contacts. This local mean was then multiplied by the total number of reported cases during that HD’s 4-week assessment period.28 and 95% CIs to test the rate of change for each trend. The weekly percentage change was significantly different from 0 at α = .05.Epidemiological trends for each study locations were characterized on the basis of the mean weekly percentage change in incidence over an 8-week period (encompassing the 4-week assessment period and the 4 weeks prior). We used regression analysis with Joinpoint statistical software version 4.8.0.1 Four HDs provided race and ethnicity data for persons with COVID-19. We used prevalence ratios (PRs) and 95% CIs to examine whether contact elicitation differed across racial and ethnic groups. We also calculated the median, interquartile range (IQR), and range for the time from index case specimen collection to when test results were reported to the HD and to when the HD notified contacts of their exposure. Eight HDs provided SARS-CoV-2 test positivity data for named contacts. We compared the prevalence of a positive SARS-CoV-2 test result among named contacts with that in the jurisdiction’s general population using a PR and 95% CI. The prevalence of a positive test in the general population was calculated on the basis of the total number of positive polymerase chain reaction test results among the total reported test results in each location during the assessment period.Seven HDs reported more than 5000 COVID-19 cases during the 4-week assessment; the remaining 7 HDs reported fewer than 1000 cases . The meaAmong the total 74 185 persons across all locations reported to HDs as having laboratory-confirmed COVID-19, 43 931 (59%) received case interviews, and 24 705 (33%) named contacts . HoweverWide variations in key case investigation and contact tracing metrics were observed across the 14 locations. In rural location A, the mean weekly COVID-19 incidence was 30.9 cases per 100 000 persons and decreased by a mean of 20.9% per week during the study period . This HDHDs in locations with higher case counts conducted proportionally fewer case interviews than HDs with lower case counts . Six of Public health informatics capacity varied across HDs. Three HDs relied on paper-based data systems for collecting and managing information, and 11 HDs used digital data systems.HDs notified 53 314 of 74 839 named contacts (71%) of their COVID-19 exposure. The proportion of contacts notified of their exposure ranged from 53% to 95% . A mean Three HDs  did not include active contact monitoring . Eleven HDs offered active monitoring; among the 47 056 contacts notified of their exposure from these locations, 34 345 (73%) agreed to participate. Thus, 46% of all named contacts from all participating locations were actively monitored by public health authorities during their quarantine periods.We estimated that an expected total of 218 389 named contacts would have been generated from the 74 185 persons with COVID-19, rather than the observed 74 839. Thus, we estimated that 143 550 contacts (66%) at risk of recent exposure to SARS-CoV-2 might have been missed.In the locations where timeliness could be assessed  , the medThe prevalence of a positive test result among contacts was available from 8 locations . Compare0 .29In this 14-location assessment, no contacts were reported for two-thirds of persons with laboratory-confirmed COVID-19 because they were either not reached for an interview or were interviewed and named no contacts. This assessment suggests that contact tracing activities were not sufficient for reducing SARS-CoV-2 transmission in most communities during June to October 2020. A mean of 0.7 contacts were reached by telephone by public health authorities, and only 0.5 contacts per case were monitored, a lower rate than needed to overcome the estimated global SARS-CoV-2 reproductive number, ROn the other hand, when the contacts identified through case interviews were notified and tested, in most locations their SARS-CoV-2 test positivity was higher than that in the general population. Because contacts are known to have been recently exposed, we expect to find more undiagnosed COVID-19 cases among them, demonstrating that contact tracing can be beneficial when case interviews reveal names of important contacts. In the 4 locations that submitted data by race and ethnicity, naming 0 contacts appeared similar by racial and ethnic groups.30; this policy likely contributed to the high proportion of contacts who underwent SARS-CoV-2 testing. Because of these differences, it is not appropriate to directly compare performance by locations.Populations, cultures, public health programs, and COVID-19 transmission intensity all varied widely by location and likely were associated with HDs’ ability to reach cases and elicit contacts. Case volumes generally aligned with broader national epidemiological trends, such that locations assessed earlier during the outbreak were generally experiencing lower levels of incidence than those assessed later. For example, location A is a small, geographically dispersed yet interconnected community where case investigators and contact tracers were trusted members of the community, often going door-to-door to elicit contacts and provide care for patients with COVID-19. However, many locations, specifically those with large and more dense populations, relied on telephone calls to reach cases and elicit contacts. Another example of a programmatic difference was that location C adopted a test-out-of-quarantine policy before this assessment31; most of the HDs in this assessment met that threshold. To improve timeliness, locations C, H, and M adopted the practice of notifying household contacts during index case interviews of the need to quarantine.Despite media reports of slow SARS-CoV-2 test turnaround times through the summer of 2020, HDs in this assessment received results quickly after specimen collection. To effectively reduce SARS-CoV-2 transmission, contact notification should occur within 6 days of exposure33 These challenges included missing and incomplete data, paper-based records, disparate digital databases without common identifiers, and insufficient personnel to maintain, improve, or implement new systems. Most data systems were rapidly designed and were primarily intended to prioritize individual patient care and follow-up, rather than produce summary data describing the HD’s case investigation and contact tracing performance. A dedicated team of 3 persons, on average, worked 1 week to gather and summarize findings at each HD. Such an effort is not sustainable for HDs wishing to do ongoing self-assessment, particularly when local COVID-19 incidence is dynamic and increasing. However, for HDs seeking more systematic and ongoing evaluation, this report contributes standardized contact tracing performance metrics that could help HDs assess performance.Timely collection and communication of relevant information are essential for performing contact tracing. We observed that all 14 HDs in this assessment, regardless of the sophistication of their data collection and informatics systems, faced hurdles.20 However, most COVID-19 interviews occur over the telephone, are more time-sensitive, and do not have the benefit of multiple encounters with HD staff to establish trust. This trust is needed for COVID-19 contact tracing to overcome barriers such as concerns about subjecting contacts to quarantine and the perception that there is no tangible benefit to contacts. Educating communities about the importance of contact tracing, such as the Answer the Call campaign,34 is one strategy to help persons with COVID-19 feel more comfortable about having confidential conversations with health care practitioners and HD staff.Contact tracing for other diseases, such as sexually transmitted infections and tuberculosis, typically rely on in-person interviews to develop rapport.35 often within hours of receiving the positive test result, to help increase the number of contacts who are confidentially notified about their exposure. In addition, automated symptom monitoring tools and case management software can help eliminate the need for HD staff to make daily telephone calls to asymptomatic contacts,36 perhaps allowing them to reallocate that time for more productive case interviews. Prospects for 7- to 10-day quarantine periods combined with symptom monitoring and testing as an exit strategy might make quarantine more palatable.37 Finally, it is also important to acknowledge that many persons might require additional social support services  to complete isolation or quarantine.Complementary strategies include wider uptake of digital contact tracing tools. These include opt-in smartphone applications that can automate exposure notifications,38 and COVID-19 modeling studies suggest upward of 30 contacts per case.6 However, perhaps many of the persons with COVID-19 who named no contacts had truly isolated themselves, had fewer contacts as they became aware of the magnitude of the pandemic, or might have notified their contacts on their own, and those contacts chose to self-quarantine without requiring any HD involvement in the process. Fourth, the higher SARS-CoV-2 test positivity rates among named contacts might have been biased because these data were not routinely captured for all contacts. Testing of contacts, particularly asymptomatic contacts,39 might not have been readily available and could have been further confounded by changing recommendations regarding the importance of testing all contacts. Fifth, effective contact tracing is dependent on transmission intensity, as well as resources available. Estimating the number of the staff needed to adequately perform contact tracing was important for program planning and implementation. We sought to measure this, but because each location chose to manage and divide the contact tracing workload differently, standardizing these measurements was challenging and, ultimately, beyond the scope of this study. Future evaluations should seek to measure the associations between staffing levels, training, job experience, and the performance of contact tracing.Our assessment has several limitations. First, case investigation and contact tracing activities are designed to encourage case isolation and contact quarantine. We could not directly assess these actual interventions. Therefore, the assessment should be viewed as an indirect assessment of the effectiveness of COVID-19 case investigation and contact tracing. A second limitation is that these results might not generalize to other locations or time periods. However, we were able to include HDs from all regions of the US, representing different population characteristics and experiencing different epidemic trajectories. Additionally, because only 4 locations submitted data on reporting contacts by race and ethnicity, our observations about similarities across racial subgroups should not be generalized. Future assessments efforts should include data stratified by race and ethnicity. Third, there is no established standard for the expected number of contacts each person should have. Our methods assumed that those who did not participate would have, on average, provided the same number of contacts as those who did participate; therefore, our estimated number of missed contacts may be biased. However, we believe that our estimated expected number of contacts was conservative because the number of contacts reported per case was low. Contact tracing studies of respiratory infectious diseases with longer infectious periods have observed an average of 11 contacts per case,9 When COVID-19 vaccination coverage increases and disease incidence decreases to manageable numbers, HDs will be better positioned to successfully reach and interview every person in the community with a positive SARS-CoV-2 test result. To end the epidemic, multiple strategies, including contact tracing, universal masking, physical distancing, and COVID-19 vaccination, should be harmonized to reduce global incidence of this disease.Scaling up COVID-19 contact tracing capacity during the pandemic has put enormous strain on every HD in the US. If a HD does not have the capacity to interview the majority of its new cases, then suspending or scaling down contact tracing activities could enable these public health resources to be reallocated for mass vaccination and other mitigation strategies.