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Introduction | postoperative pain, bleeding, Postoperative pain, hemorrhoids, hypertonus, hemorrhoid, tamponade, pain, trauma | BLEEDING, RECURRENCE, HEMORRHOIDS, HEMORRHOIDS, HEMORRHOID, COMPLICATION, SECONDARY, BACTERIAL INFECTIONS, DISEASES, COMPLICATIONS | Hemorrhoids are common and frequently occurring diseases in the clinical setting, and higher degree hemorrhoids require surgical treatment [For prolapsing hemorrhoids, excisional hemorrhoidectomy continues to be the treatment of choice with the lowest recurrence rate [Despite several advantages in surgical technique and perioperative management, most patients still consider hemorrhoidectomy to be a painful procedure [Postoperative pain is a common complication following hemorrhoidectomy, and its severity is influenced by the degree of surgical trauma, the type of anesthesia, any sphincter hypertonus that may be present, secondary bacterial infections, perioperative and postoperative pain management, and individual differences in pain sensitivity [Strong postoperative symptoms frequently prevent outpatient hemorrhoid surgery, lengthen inpatient stays in some circumstances, and occasionally result in emergency readmissions to the hospital because of unbearable discomfort [Numerous studies investigated different methods of reducing postoperative pain, such as altering the surgical technique [Higher satisfaction, earlier mobilization, quicker recovery, and fewer healthcare costs can all result from adequate pain treatment [Accordingly, it seems to be crucial not only to develop a pathway for optimal perioperative surgical and anesthesiologic modulation but also to be able to identify those patients at risk for intensified postoperative discomfort.Earlier, we reported the results from a multicenter, randomized clinical trial comparing the effects of placement of a tamponade dressing after hemorrhoidectomy on postoperative pain development and bleeding complications (The NoTamp study, DRKS00011590) [In the present study, we therefore reanalyzed our data to determine risk factors for the development of postoperative pain and confined health-related quality of life. | PMC10622377 |
Materials and methods | PMC10622377 | |||
Study design | postoperative pain, postoperative bleeding, tamponade | POSTOPERATIVE BLEEDING | The NoTamp study was a German multicenter randomized controlled trial (RCT) designed to compare the effects of perioperative placement of a rectal tamponade on postoperative pain development and occurrence of surgically relevant postoperative bleeding in open hemorrhoidectomy [The trial duration for each randomized patient was 7 days. There was no blinding of participants, physicians, nurses, or outcome assessors. The study received full ethics committee approval of the University of Witten/Herdecke, Germany, and was conducted in accordance with Good Clinical Practice guidelines, with regular external monitoring. | PMC10622377 |
Cohort participants | postoperative pain, Pain, hemorrhoids, pain, HT, NRS | HEMORRHOIDS, SECONDARY, PATHOLOGY, COMPLICATIONS | The target population for this study included adult patients (18 years or above) suffering from symptomatic grade III or IV hemorrhoids requiring Milligan-Morgan or Parks hemorrhoidectomy [The study protocol did not interfere with standard perioperative measures, and all drugs and treatments administered were recorded in case report forms (CRF).The study recorded details such as age, sex, classification of hemorrhoidal pathology before surgery, comorbidities with impact on HD, type, and length (in minutes) of surgical procedure, duration of hospitalization (HT), type of complications developed and their time of onset, in respect to the initial procedure (Table Patient and treatment parameters related to maximum pain level within 72 h after surgery. Differences were calculated using the Fisher’s exact test on the binary data, chi-squared test on nominal data, and Mann–Whitney’s Significant differences (In the present spin-off study, we questioned the already existing data set for variables predicting the development of relevant postoperative pain.Pain intensity was determined at various time points using a Numeric Rating Scale (NRS, ranging from 0 to 10), namely, at 6, 12, 24, and 48 h, as well as on postoperative days 3 and 7. Relevant postoperative pain was defined as NRS rating higher than 5 points. At this pain level, most patients require intense pain medication (e.g., opioids) [The primary endpoint was to identify factors associated with early relevant pain, which was defined as maximum NRS measurement from five postoperative time points up to day 3.The secondary endpoint was to identify predictors for relevant pain at 1 week postoperatively (day 7).Finally, the change in the patients’ quality of life from pre- to postoperative was examined by utilization of the EuroQoL Group (Rotterdam, The Netherlands) index (EQ-5D™) on generic health-related quality of life at screening and on day 7 [ | PMC10622377 |
Statistics | Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 28. Armonk, NY: IBM Corp. All categorical variables were presented as counts (with percentages) and were analyzed with chi-squared or Fisher’s exact test. Continuous data were summarized as mean with standard deviation (SD), or median with interquartile range (IQR), as appropriate, and were compared with Mann-Whiney | PMC10622377 | ||
Results | PMC10622377 | |||
Study cohort | The main data set has been published previously (NoTamp) [ | PMC10622377 | ||
Primary endpoint: relevant early pain | NRS, pain | Figure Distribution of the maximum postoperative pain levels measured by the NRS within the study cohort in the first 3 days after surgery | PMC10622377 | |
Predictors for early relevant pain | postoperative pain, tamponade, pain | We checked possible predictors in both subgroups with and without relevant postoperative pain until day 3. Univariate analysis revealed that younger age, preoperative pain level, long duration of surgery, and usage of a tamponade were associated with relevant pain after surgery (Table In the multivariate analysis, pudendal block was the strongest parameter. Without a pudendal block,the risk for relevant postoperative pain doubles (OR 2.64, CI | PMC10622377 | |
Secondary endpoint: relevant pain after 1 week | postoperative pain, NRS, pain | Secondary endpoint was relevant delayed pain as shown by the NRS > 5 on day 7. For this time point, data of 688 of the 717 in patients (96%) were available. The mean and median (IQR) NRS values at that time were 2.7 and 2 (1–4), respectively. Seventy-four patients (10.8%) complained about relevant pain (NRS 6–10) on day 7 (Fig. Distribution of the postoperative pain levels measured by the NRS within the study cohort 7 days after surgery | PMC10622377 | |
Predictors for relevant delayed pain | pain | Relevant early pain was the strongest predictor for relevant pain after 7 days (OR 3.13, CI95 1.81–5.41, Patient and treatment parameters related to maximum pain level 7 days after surgery. Differences were calculated using the Fisher’s exact test on the binary data, chi-squared test on nominal data, and Mann–Whitney’s Significant differences ( | PMC10622377 | |
Third endpoint: quality of life (QoL) | mean NRS, postoperative pain, Pain, bleeding | ADVERSE EVENT, BLEEDING | Quality of life was assessed preoperatively and with the follow-up on day 7. In the preoperative setting, the indices of 713 of 717 patients were assessed, postoperatively of 690 cases. For this evaluation, we only used pre- and postoperative complete data sets of 686 cases.The mean/median preoperative quality of life index overall was 82.3/92.6 (IQR 79.5–92.6). One week after surgery, the mean/median values were rather similar: 83.6/92.6 (IQR 79.5–92.6).Although this seems to show an unaltered quality of life throughout the perioperative setting, the in-detail comparison of the intra-individual changes draws a different picture.The dot plot in Fig. Combined distribution of pre- and postoperative values of the EuroQoL. Every dot represents one or more patients. Patients on the diagonal (31%) show an unchanged quality of lifePatient and treatment parameters subdivided in patients with lower, unchanged, or higher QoL as shown by the EuroQol after surgery. Differences were calculated using the Fisher’s exact test on the binary data, chi-squared test on nominal data, and Mann–Whitney’s Significant differences (As shown in Table Pain level early postoperative or on day 7, surprisingly, did not lead to a decline in QoL. Overall, in our data set, we were not able to point out significant predictive measures for a quality-of-life drop postoperatively. This group of patients had only marginal higher early postoperative pain (mean NRS 2.9 ± SD 2.2), and relevant postoperative pain on day 7 was prevalent in only 14% of cases. Adverse events or bleeding did not occur more often compared to the other groups. | PMC10622377 |
Acknowledgements | DKD, P. | The authors thank the patients and the investigators who participated in this clinical study and every study site that took part: Helios St. Elisabeth Klinik Oberhausen, Helios Klinikum Wuppertal, Helios Klinikum Berlin-Buch, Helios St. Johannes Klinik, Helios Klinik Lengerich, Helios Klinik Hüls, Helios Klinik Jerichower Land (Burg), Helios Klinikum Krefeld, DKD Helios Klinik Wiesbaden, Helios St. Josefs-Hospital Bochum-Linden, Helios Kliniken Niederberg, Helios Klinik München Perlach, Helios Klinik Blankenhain, Helios Klinik Wipperfürth, Helios Klinik Siegburg, Helios St. Elisabeth Klinik Hünfeld, and Helios Klinikum Schwerin. The development of the study design was supported by D. Seidel at the Institute for Research in Operative Medicine, University of Witten/Herdecke, Cologne, Germany. Administrative support was kindly provided by P. Thürmann at the Department for Clinical Pharmacology, University of Witten/Herdecke. | PMC10622377 | |
Author contribution | CM | CM, LB, and MRL had full access to all study data and take responsibility for the integrity of the data and the accuracy of the analysis. CM and LB were also responsible for the concept and design of this study and drafting of the manuscript. All authors (CM, MRL, R-VF, AK, JB, J-PR, FG, RL, and L) were responsible for acquisition, analysis, and interpretation of data and critical revision of the manuscript for important intellectual content. RL was responsible for statistical analysis. CM, MRL, LB, and FG were responsible for administrative, technical, and material support. The work was supervised by LB. | PMC10622377 | |
Funding | Open Access funding enabled and organized by Projekt DEAL. The Helios Center for Research and Innovation (HCRI), a subsidiary company of the Helios Hospital Group, funded this study. Helios also supported acquisition of study sites and data collection, without having any influence on data analysis, interpretation, or reporting. No honoraria or payments were made for authorship. | PMC10622377 | ||
Data availability | Data will be made available at the website of the NoTamp study. Anonymized raw data are available upon request from the corresponding author or the trial statistician. | PMC10622377 | ||
Declarations | PMC10622377 | |||
Competing interests | The authors declare no competing interests. | PMC10622377 | ||
References | PMC10622377 | |||
Background | CRF, fatigue, breast cancer | CRF, BREAST CANCER | Radiotherapy (RT) can lead to cancer-related fatigue (CRF) and decreased health-related quality of life (HRQoL) in breast cancer patients. The purpose of this trial was to examine the feasibility and efficacy of a home-based resistance and aerobic exercise intervention for reducing CRF and improving HRQoL in breast cancer patients during RT. | PMC9813229 |
Methods | breast cancer | BREAST CANCER | Women with breast cancer ( | PMC9813229 |
Results | CRF | CRF | Eighty-nine women completed the study (EX = 43, CON = 46). Over the 12-week intervention, EX completed 1–2 resistance training sessions and accumulated 30–40 min of aerobic exercise weekly. For CRF, EX had a quicker recovery both during and post-RT compared to CON ( | PMC9813229 |
Conclusions | CRF | CRF, BREAST CANCER | Home-based resistance and aerobic exercise during RT is safe, feasible, and effective in accelerating CRF recovery and improving HRQoL. Improvements in CRF and HRQoL for these patients can be achieved with smaller exercise dosages than stated in the generic recommendations for breast cancer.
| PMC9813229 |
Keywords | Open Access funding enabled and organized by CAUL and its Member Institutions | PMC9813229 | ||
Introduction | cancer, Breast cancer, CRF | CANCER, BREAST CANCER, CRF | Breast cancer (BCa) is the most common form of cancer among women. In Australia, 1 in 8 women will be diagnosed with BCa by the age of 85 [Exercise could offer a potent stimulus to counteract CRF as it elicits positive adaptations in most of the factors believed to be associated with CRF, HRQoL, and sleep [It has previously been shown that higher resistance and aerobic exercise intensity can significantly reduce CRF and improve sleep in patients undergoing chemotherapy for BCa [Given the above, the purpose of this study was to (a) examine the effects of a 12-week home-based resistance and aerobic exercise program on CRF, HRQoL, and sleep quality and duration in BCa patients during and up to 12 months after RT, and (b) investigate how CRF, HRQoL, and sleep quality and duration affect the participants’ ability to follow their prescribed exercise program. | PMC9813229 |
Materials and methods | CRF | CRF | This was a two-arm, randomized controlled clinical trial (Fig. Schematic of the research project design. *The serial assessment of CRF and physical activity level at the start of each week | PMC9813229 |
Participants | One hundred and six (Consort diagram of the study | PMC9813229 | ||
Measurements | CRF | SECONDARY, CRF | Assessment of primary and secondary outcome measures took place at: (1) baseline (i.e., week 0, prior to initiating RT and the intervention period); (2) post-RT (i.e., 6 weeks after baseline, after completing RT and mid-way through the intervention period); (3) post-exercise (i.e., 12 weeks after baseline); and (4) follow-up (i.e., 6 and 12 months after the completion of RT). Additionally, serial assessments of CRF (FACIT-F), physical activity, and exercise dosage (through a logbook completed by the participants) were conducted each week throughout RT. All assessments were conducted during scheduled visits to the radiation oncology clinic. | PMC9813229 |
Primary endpoints | cancer, Chronic Illness, fatigue, Fatigue | CANCER, CHRONIC ILLNESS | Cancer-related fatigue was assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire. The FACIT-F is a 13-item scale commonly used to assess fatigue in cancer patients [Fatigue was also assessed using the Brief Fatigue Inventory (BFI) at baseline, post-RT, post-exercise, and at follow-up. The BFI is a reliable instrument that allows for the rapid assessment of fatigue level in cancer patients [ | PMC9813229 |
Secondary outcome measures | PMC9813229 | |||
Quality of life | Cancer | CANCER | HRQoL was assessed using the Functional Assessment of Cancer Therapy for patients with BCa (FACT-B + 4) [ | PMC9813229 |
Sleep duration and quality | cancer, Insomnia | CANCER | Insomnia, poor sleep quality and short sleep durations are the most common problems seen in cancer patients [ | PMC9813229 |
Physical activity | Physical activity was assessed using the Godin Leisure-Time Exercise Questionnaire [ | PMC9813229 | ||
Radiotherapy completion rates and adverse side effects | Cancer | ADVERSE EVENT, CANCER | Adherence to prescribed RT treatments was recorded using standard clinical measures. Completion rate was reported as the percentage of the planned dose and planned fractions completed during the treatment course. The presence and severity of any adverse side effects was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE—Version 5.0) [ | PMC9813229 |
Adherence to and adverse side effects from the exercise program | fractures | ADVERSE EVENTS, MUSCULOSKELETAL COMPLICATIONS | Adherence to the exercise program was recorded using detailed logbooks. The frequency, duration and intensity of exercise was examined for both aerobic and resistance exercise. The occurrence and severity of any adverse events including musculoskeletal complications (muscle strains, fractures, etc.) were recorded during the 12-week intervention period, and assessed using the CTCAE—Version 5.0 [ | PMC9813229 |
Exercise | cancer, CRF | CANCER, CRF | The 12-week home-based exercise intervention was a combination of resistance and aerobic exercise. Each participant completed the pre-exercise questionnaire and medical history, and then had a 1-h consultation with an accredited exercise physiologist. The resulting exercise program was relative to the level of fitness and CRF each patient presented with, and individualized to their personal preferences and any pre-existing conditions [Participants randomized to the usual care group received standard usual care throughout the intervention period. The usual care group did not receive any recommendation or support to exercise but were not advised or requested to change their exercise behavior or avoid exercise. At the completion of the follow-up assessment (12 months), this group was provided with the exercise manual and logbook, behavioral guidebook and provided with information of exercise programs available for cancer survivors. | PMC9813229 |
Statistical analysis | RPE, CRF, diabetes | CARDIOVASCULAR DISEASE, CRF, HYPERTENSION, OSTEOPOROSIS, DIABETES | As this was a pragmatic trial, we aimed to recruit as many patients as possible. To calculate the achieved power, we used the primary endpoint of FACIT-F score at immediately post-RT, as we hypothesized that the effect of exercise on CRF would be the strongest at that time point. Achieved power was calculated using G*Power (Version 3.1.9.7, Universitat Kiel, Germany). At post-RT, the difference between groups had an effect size of A linear mixed-effects model was used with participant ID as the random-effects factor, while fixed-effects factors consisted of demographic and physical characteristics (age, baseline body fat percentage), physical symptoms and conditions (hypertension, high cholesterol, cardiovascular disease, diabetes, osteoporosis), and cancer-specific treatments before and during the intervention (chemotherapy, hormone therapy, surgery), as well as exercise dosage for the exercise group only (number of resistance and aerobic sessions, number of resistance exercises, duration of aerobic exercise, and RPE during resistance and aerobic exercise). The assumption of normality and homoscedasticity of the residuals was verified by visual quantile–quantile plot inspection of the plots and a Shapiro–Wilk test. In the case of a significant interaction effect, pairwise comparisons were performed between conditions and timepoints, with a Holm's | PMC9813229 |
Quality of life | Both groups reported improved HRQoL at 6- and 12-month post-RT (Fig. | PMC9813229 | ||
Sleep duration and quality | There were no changes in sleep duration or total PSQI score for any group at any time point (Fig. | PMC9813229 | ||
Author contributions | GM: formal analysis, investigation, writing—original draft, and final draft approval. PC: conceptualization, methodology, project administration, and final draft approval. CJP-M: conceptualization, methodology, formal analysis, investigation, writing—original draft, project administration, and final draft approval. DAG: investigation, writing—original draft, and final draft approval. DRT: investigation, writing—original draft, and final draft approval. CS: formal analysis, writing—original draft, and final draft approval. SR: conceptualization, methodology, writing—original draft, final draft approval. YZ: conceptualization, methodology, writing—original draft, and final draft approval. RUN: conceptualization, methodology, investigation, writing—original draft, and final draft approval. | PMC9813229 | ||
Funding | Open Access funding enabled and organized by CAUL and its Member Institutions. | PMC9813229 | ||
Declarations | PMC9813229 | |||
Conflict of interest | The authors declare that they have no conflicts of interest. No funding was received for this work. | PMC9813229 | ||
References | PMC9813229 | |||
Purpose | Immunocompromised patients have a potentially increased risk for progression to severe COVID-19 and prolonged replication of SARS-CoV-2. This post hoc analysis examined outcomes among immunocompromised participants in the MOVe-OUT trial. | PMC9844162 | ||
Methods | hospitalization/death, non-immunocompromised | ADVERSE EVENTS | In phase 3 of MOVe-OUT, non-hospitalized at-risk adults with mild-to-moderate COVID-19 were randomized to receive molnupiravir 800 mg or placebo twice daily for 5 days. Immunocompromised participants were identified based on prior/concomitant medications and/or medical history. All-cause hospitalization/death, adverse events, SARS-CoV-2 titers, infectivity, and RNA sequences were compared between immunocompromised participants who received molnupiravir or placebo and with non-immunocompromised participants. | PMC9844162 |
Results | molnupiravir-treated immunocompromised | ADVERSE EVENTS, VIRUS | Fifty-five of 1408 participants were considered immunocompromised. Compared to placebo, fewer molnupiravir-treated immunocompromised participants were hospitalized/died through Day 29 (22.6% [7/31] vs. 8.3% [2/24]), with fewer adverse events (45.2% [14/31] vs. 25.0% [6/24]). A larger mean change from baseline in SARS-CoV-2 RNA was observed with molnupiravir compared to placebo in non-immunocompromised participants (least squares mean [LSM] difference Day 5: – 0.31, 95% confidence interval [CI] – 0.47 to – 0.15), while the mean change was comparable between treatment groups in immunocompromised participants (LSM difference Day 5: 0.23, 95% CI – 0.71 to 1.17). Molnupiravir treatment was associated with increased clearance of infectious virus. Increased errors in viral nucleotide sequences in post-baseline samples compared to placebo support molnupiravir’s mechanism of action and were not associated with observation of novel treatment-emergent amino acid substitutions in immunocompromised participants. | PMC9844162 |
Conclusion | Although the study population was small, these data suggest that molnupiravir treatment for mild-to-moderate COVID-19 in non-hospitalized immunocompromised adults is efficacious and safe and quickly reduces infectious SARS-CoV-2. | PMC9844162 | ||
ClinicalTrials.gov Registration Number | NCT04575597. | PMC9844162 | ||
Supplementary Information | The online version contains supplementary material available at 10.1007/s15010-022-01959-9. | PMC9844162 | ||
Keywords | PMC9844162 | |||
Introduction | death, coronavirus disease 2019 | CORONAVIRUS DISEASE 2019, ADVERSE EVENTS, DISEASE, MAY, CORONAVIRUS, SEVERE ACUTE RESPIRATORY SYNDROME | Immunocompromised individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more likely to progress to severe coronavirus disease 2019 (COVID-19) and have poor outcomes [Molnupiravir is an oral, small-molecule ribonucleoside prodrug of β-D-N4-hydroxycytidine (NHC) which has potent activity against SARS-CoV-2, including all variants of concern to date [MOVe-OUT was a phase 2/3 randomized, double-blind, placebo-controlled trial that evaluated molnupiravir for the treatment of non-hospitalized adults with mild-to-moderate COVID-19 and risk factors for progression to severe disease. In the interim analysis for the phase 3 component of MOVe-OUT (enrollment May 6 through August 5, 2021), molnupiravir was superior to placebo in reducing the risk for all-cause hospitalization or death by Day 29 (7.3% vs. 14.1%; difference, – 6.8%; 95% CI, – 11.3 to – 2.4). In the final analysis including all randomized participants (enrollment May 6 through October 2, 2021), molnupiravir demonstrated a reduction in the risk for all-cause hospitalization or death (6.8% vs. 9.7%; difference, – 3.0%; 95% CI, – 5.9 to – 0.1), with an 89% relative risk reduction in all-cause mortality compared with placebo [This post hoc analysis explored virologic data, as well as clinical efficacy and safety, in the cohort of immunocompromised participants from the phase 3 component of MOVe-OUT. We compared all-cause hospitalization or death and adverse events along with SARS-CoV-2 viral RNA, viral infectivity, viral RNA nucleotide error rate, treatment-emergent amino acid changes, and anti-SARS-CoV-2 antibody status among immunocompromised and non-immunocompromised participants treated with molnupiravir versus placebo. | PMC9844162 |
Methods | PMC9844162 | |||
Design overview, setting, and participants | CANCER, DISEASE | Non-hospitalized adults ≥ 18 years old with laboratory-confirmed mild-to-moderate COVID-19 and at least one risk factor for progression to severe disease were included in the phase 3 component of MOVe-OUT (ClinicalTrials.gov NCT04575597). Participants were randomized within 5 days of onset of COVID-19 signs or symptoms and received molnupiravir 800 mg every 12 h or matching placebo for 5 days. Nasopharyngeal swabs and blood samples were collected at baseline on Day 1 and on Days 3, 5, 10, 15, and 29. MOVe-OUT was conducted in accordance with local and/or national regulations (including all applicable data protection laws and regulations), International Council for Harmonization-Good Clinical Practice, and the ethical principles that have their origin in the Declaration of Helsinki regarding independent ethics committee review, informed consent, and the protection of human participants in biomedical research. The full details of the phase 3 component of MOVe-OUT, along with the study protocol, are reported in Jayk Bernal, A. et al. [Immunocompromised participants were identified based on a post hoc review of medical history and/or prior and concomitant use of systemic corticosteroids or immunosuppressant medications, as classified in H02AB and L04 of the World Health Organization Anatomical Therapeutic Chemical Classification System code. The following criteria were applied to identify immunocompromised participants: prior use of systemic corticosteroids for ≤ 4 weeks prior to receipt of the first dose of study drug; prior and/or concomitant use of immunosuppressants for an underlying condition(s); and/or medical history of immunocompromising conditions, including HIV (PLWH receiving a stable antiretroviral regimen), hematopoietic stem cell or solid organ transplant recipient, and active cancer | PMC9844162 | |
Outcomes | death | ADVERSE EVENT | All-cause hospitalization or death through Day 29 and virologic outcomes with molnupiravir and placebo in immunocompromised and non-immunocompromised participants were assessed in the modified intent-to-treat population (MITT, all randomized participants who received ≥ 1 dose of study drug and were not hospitalized prior to the first dose). Adverse events through Day 29 were summarized in the safety population (all randomized participants who received ≥ 1 dose of study drug). Virologic outcomes included mean change from baseline in quantitative SARS-CoV-2 RNA over time, proportion of participants with detectable infectious SARS-CoV-2 over time, SARS-CoV-2 nucleotide error rates at Day 5, treatment-emergent amino acid changes through Day 29, proportion of participants with SARS-CoV-2 nucleocapsid antibody positivity over time, and mean change from baseline in SARS-CoV-2 neutralizing antibody titers on Days 10 and 29. | PMC9844162 |
SARS-CoV-2 RNA | SARS-CoV-2 RNA titers from nasopharyngeal swabs on Days 1, 3, 5, 10, 15, and 29 were measured using a quantitative RT-PCR assay developed at Q | PMC9844162 | ||
SARS-CoV-2 infectivity | Nasopharyngeal specimens collected on Days 1, 3, 5, 10, 15, and 29 with viral RNA > 100,000 copies/mL were serially diluted in duplicate in serum free Eagle Minimum Essential Media and 100 µL of each dilution placed in a 24-well-plate containing > 90% confluent Vero E6 cells. Samples were incubated with cells for 60 min at 37°C and 5% CO | PMC9844162 | ||
Next-generation sequencing (NGS) | NGS analysis was performed on nasopharyngeal samples with RNA titers ≥ 600 copies/mL on Days 1 and 5 and on post-treatment nasopharyngeal samples with RNA titers ≥ 100,000 copies/mL on Days 10, 15, and 29. All NGS analyses were performed by Q | PMC9844162 | ||
Anti-SARS-CoV-2 nucleocapsid antibody assay | ® | The presence of serum antibodies (IgM, IgG, and IgA) to the SARS-CoV-2 nucleocapsid protein were assessed at Days 1, 5, 10, and 29 using the Roche Elecsys® electrochemiluminescence immunoassay performed at a central laboratory (LabCorp, Inc.; Indianapolis, IN, USA). | PMC9844162 | |
Anti-SARS-CoV-2 spike protein neutralizing antibody assay | infection | INFECTION, VIRUS | Assessment for the presence and amount of anti-SARS-CoV-2 spike protein neutralizing antibody activity in serum on Day 1 and on Days 10 and 29 was performed at Monogram Biosciences (South San Francisco, CA, USA) using the SARS-CoV-2 PhenoSense® nAB Assay. Serially diluted (1:40–1:2124 dilutions) serum samples were added to HEK293/ACE2 target cells before infection with a pseudotyped luciferase reporter virus expressing the spike protein from the original Wu-1 strain. Serum neutralizing titers were calculated based on the serum dilution needed to inhibit 50% luciferase signal compared with negative control serum. | PMC9844162 |
Statistical analysis | death | Descriptive statistics were used to summarize efficacy, safety, and virologic data. For categorical variables, frequency and proportions were calculated using the number of participants with available data as the denominator. Differences in the proportion of participants who experienced hospitalization or death through Day 29 were estimated based on the Miettinen & Nurminen method [ | PMC9844162 | |
Role of the sponsor | The trial sponsor, Merck & Co., Inc., Rahway, NJ, USA, was involved in study design, data collection, data analysis, data interpretation, and writing of the report. All authors had access to the study data and final responsibility for the decision to submit for publication. | PMC9844162 | ||
Discussion | death, cancer, Nucleocapsid, infection, infectious SARS-CoV-2 | ADVERSE EVENTS, INFECTION, VIRUS, CANCER | Immunocompromised participants in phase 3 of the MOVe-OUT trial who received molnupiravir had a lower incidence of all-cause hospitalization or death without any concerning adverse events through Day 29 compared to placebo (8.3% [2/24] versus 22.6% [7/31]). Reductions in viral RNA in both treatment groups were generally consistent in immunocompromised participants, but no infectious virus was detected after baseline in any immunocompromised molnupiravir-treated participants, while infectious virus was detected post-baseline in the placebo group. Consistent with its mechanism of action, an increased viral error rate was observed in molnupiravir-treated participants, regardless of immunocompromised status. Immunocompromised participants receiving molnupiravir were not more likely to develop novel treatment-emergent amino acid substitutions in this study. Nucleocapsid antibody positivity was generally similar in both treatment groups irrespective of immunocompromised status, while a smaller mean increase from baseline in neutralizing antibody titers in molnupiravir-treated immunocompromised participants was observed at Day 29.Delayed clearance of infectious virus in immunocompromised individuals is concerning from an infection control standpoint because of increased potential for transmission and emergence of new SARS-CoV-2 variants. Case reports have noted persistent infectious SARS-CoV-2 shedding in immunocompromised individuals [The proportion of immunocompromised participants positive for spike protein neutralizing antibody at baseline was about 10% lower than the proportion positive in non-immunocompromised participants. In general, antibody responses were comparable in both treatment groups regardless of immunocompromised status. The smaller mean change from baseline in neutralizing antibody titers observed in immunocompromised participants in the molnupiravir group compared with the placebo group at Day 29 may have resulted from less antigenic stimulation due to earlier clearance of the virus with molnupiravir therapy.Real-world evidence on the use of molnupiravir in immunocompromised patients is beginning to emerge in published literature [A strength of this analysis is the scope of virologic data that were evaluated in this cohort of immunocompromised participants, with analyses performed on nasopharyngeal samples that were prospectively collected at multiple timepoints in phase 3 of the MOVe-OUT trial. These data add to the very limited literature on outcomes in immunocompromised individuals treated for COVID-19 since they are usually excluded from clinical trials. Our analysis was limited by the small sample of non-hospitalized immunocompromised participants, most of whom had active cancer or well-controlled HIV; therefore, this cohort is not representative of all immunocompromised individuals, for example, patients with depleted T-cells due to uncontrolled HIV or recipients of T-cell depleting agents (i.e., antithymocyte globulin, alemtuzumab) [ | PMC9844162 |
Conclusions | Based on the results of this post hoc analysis in participants from phase 3 of MOVe-OUT, the use of molnupiravir appears to be effective and safe for the treatment of mild-to-moderate COVID-19 in non-hospitalized immunocompromised adults at risk for progression to severe COVID-19. There were no notable differences in virologic outcomes among molnupiravir-treated participants based on immunocompromised status, further corroborating the clinical findings in immunocompromised participants. NGS analyses taken together with infectivity data suggest that immunocompromised individuals are not more likely to develop amino acid substitutions, thereby minimizing the possibility for the development of novel SARS-CoV-2 variants following treatment with molnupiravir. | PMC9844162 | ||
Supplementary Information | Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 48 KB) | PMC9844162 | ||
Abbreviations | respiratory syndrome | CORONAVIRUS | Confidence intervalCoronavirus disease 2019End-of-therapyHuman immunodeficiency virusLower limit of quantificationLeast squaresLeast squares meanModified intention-to-treatMolnupiravir for oral treatment of COVID-19 in non-hospitalized patientsβ-D-N4-hydroxycytidineNext-generation sequencingPlaque-forming unitsPeople living with HIVRibonucleic acidReverse transcriptase-polymerase chain reactionSevere acute respiratory syndrome coronavirus 2Upper limit of quantification | PMC9844162 |
Acknowledgements | We thank the patients and their families and caregivers for participating in this study, along with all investigators and site personnel. We thank Ying Zhang, PhD for her statistical expertise. Medical writing assistance was provided by Dorothy McCoy, PharmD, BCPS, BCIDP and editorial assistance by Carol Zecca, BS, both of Merck & Co., Inc., Rahway, NJ, USA. | PMC9844162 | ||
Author contributions | PD | CDA | MGJ, JMS, MLB, HW, HHS, MR, DFF, PD, IK, JF, LFF, S-CC, AW-D, JD, JAG, AP, and CDA contributed to drafting the manuscript and critically revised it for important intellectual content. All authors read and approved the final manuscript. | PMC9844162 |
Funding | This work was supported by Merck & Co., Inc., Rahway, NJ, USA. | PMC9844162 | ||
Availability of data and materials | The data sharing policy, including restrictions, of Merck & Co., Inc., Rahway, NJ, USA is available at | PMC9844162 | ||
Declarations | PMC9844162 | |||
Conflict of interest | Pierre, HIV, hepatitis | STIS, BROWN | Matthew G. Johnson, Julie M. Strizki, Michelle L. Brown, Hong Wan (at the time of study), Hala H. Shamsuddin, Angela Williams-Diaz, Jiejun Du (at the time of study), Jay A. Grobler, Amanda Paschke, and Carisa De Anda are employees of Merck & Co., Inc., Rahway, NJ, USA. Moti Ramgopal: Consulting fees: Gilead, Merck, ViiV, Janssen; Honoraria: Gilead, ViiV, Janssen. Diana F. Florescu: Grants: Merck, Regeneron, Astellas, Novavax, Bavarian Nordic, Takeda, SymBio, NobelPharma, AlloVir. Consulting fees: Takeda and Merck; Data Safety Monitoring Board/Advisory Board: Medpace. Pierre Delobel: Travel grants: BMS, Gilead, MSD, and Janssen in the last 5 years; Society: HAS/ANRS-MIE/CNS: French recommendations for treatment and prevention of HIV, hepatitis, and STIs; Scientific Committee: ANRS-MIE (CSS13). Ilsiyar Khaertynova: Nothing to disclose. José F. Flores: Nothing to disclose. Leon F. Fouche: Nothing to disclose. Shan-Chwen Chang: Nothing to disclose. | PMC9844162 |
References | PMC9844162 | |||
1. Introduction | Although studies on sports performance, leadership abilities, group cohesion, and learning motivation have revealed that the sport education model contributes considerably to the development of healthy lifestyles, few studies have explored the development of healthy lifestyles from an educational intervention perspective. This study fills this gap in the literature. In addition, studies have mostly recruited elementary or middle school students; few have explored the effectiveness of sport education for college students. To fill this gap, this study conducted quasi-experimental research on university students by using different teaching strategies, with healthy lifestyles as the dependent variable. The research participants consisted of 95 students from Ming Chuang University distributed to an experimental group or control group. The experimental group was taught using the sport education model; the control group was taught using direct instruction. The results indicate that the sport education model has a stronger ability to promote healthy lifestyles than conventional teaching. Additionally, the results suggest that teachers should apply specific teaching strategies to cultivate and reinforce exercise habits and healthy behaviors among students. On the basis of the results, the researchers suggest that physical education teachers establish effective teaching strategies and promote healthy lifestyles to students.Studies have shown that physical education courses have a positive effect on youths’ health [Schools are widely considered the key institutions for promoting physical activity and exercise in youths [Medical, public hygiene, and education institutions have promoted physical training as a key strategy for reducing the high prevalence of physical inactivity [Since the first promotion of the sport education model at an elementary school in the state of Ohio in the 1980s, the contemporary sport education model has gradually replaced conventional physical education courses, which involves students engaging in multiple activities [ | PMC9915953 | ||
2. Methods | PMC9915953 | |||
2.1. Research Participants | The research participants consisted of 95 students (47 men, 48 women) from Ming Chuang University. The participants were recruited from two classes and distributed to the experimental group ( | PMC9915953 | ||
2.2. Experiment Process | Limited by the teaching environment of the classroom system and a fixed class size, this study was unable to conduct randomized equal-group multifactor experiments. For this reason, an unequal-group pretest–posttest design was employed for the experiment. The experiment comprised pretest, intervention, and posttest stages. First, two classes taking a badminton course were recruited and screened using the inclusion criteria. Next, the classes were randomly assigned to the experimental or control groups and provided an explanation of the course framework. Finally, the participants’ consent was obtained.In the intervention stage, participants were divided into the experimental or control groups. The participants underwent one session of a physical education class per week, with each session lasting 100 min, for 10 weeks. The intervention course was taught by a certified physical education instructor with more than 20 years of teaching experience. Both groups received the same physical education and sports technique guidance. However, the sport education model in the experimental group was incorporated as one of six course features. Participants were not permitted to change their exercise partners throughout the course. | PMC9915953 | ||
2.3. Research Tool: Healthy Lifestyle Scale | Amended from the scale proposed in Chen et al. [ | PMC9915953 | ||
2.4. Course Development and the Effectiveness of the Intervention Program | To ensure the effectiveness of the teaching intervention program, the principal investigator recruited one professional badminton instructor and two sport education scholars to convene a sport education model teaching design evaluation group. The group conducted two focus meetings on the intervention program, performed a concrete evaluation of the teaching design method and a substantive examination, and provided suggestions and feedback on the teaching process. The sport education model of the experimental group was incorporated into the six features proposed in Siedentop [ | PMC9915953 | ||
2.5. Statistical Analysis | Statistical analysis was conducted using the SPSS 19.0. The results were analyzed using five methods; (1) participants’ height, weight, and body mass index (BMI) were analyzed using descriptive statistics; (2) homogeneity in sex was tested using a chi-squared test; (3) homogeneity in the participants’ height, weight, and BMI was tested using independent sample | PMC9915953 | ||
3. Results | PMC9915953 | |||
3.1. Homogeneity Testing | REGRESSION | Analysis of the demographic statistics revealed homogeneity between the groups in terms of sex (χThe homogeneity of the within-class regression coefficients for the health promotion (F = 0.567; | PMC9915953 | |
3.2. Healthy Lifestyle Performance | The pretest and posttest scores of the two groups are listed in | PMC9915953 | ||
3.3. Covariance Analysis | The covariance analysis ( | PMC9915953 | ||
4. Discussion | PMC9915953 | |||
4.1. Effect of the Sport Education Model on Healthy Lifestyle Performance | This study evaluated the effect of the sport education intervention on healthy lifestyles among students in terms of health promotion, life satisfaction, and interpersonal interaction. The preliminary results indicate that the sport education model has a stronger ability to promote healthy lifestyles than conventional teaching, which suggests the importance of further research on this topic. The sport education model is a crucial teaching strategy for promoting healthy lifestyles. The results corroborate those of studies specifying that the sport education model positively affects health promotion [Physical education should encourage physical activity in students, particularly for those who do not exercise regularly [Individuals who are satisfied with life experience more positive emotions than negative [Student interaction is a key feature of physical education courses [Given that the ultimate goal of physical education is to improve health and welfare, physical education must improve the social and emotional skills of students, urge students to lead healthy lifestyles, and emphasize the importance of public hygiene. The sport education model is based on games, which play a crucial role in physical education. Games can ensure that students are satisfied with physical education, help students develop skills, allow students to enjoy relaxed gaming environments, and instill in students the value of interpersonal interaction. This quasi-experimental study revealed the ability of the sport education model to cultivate healthy lifestyles in students. The results indicated that the sport education model is effective. The students who participated in the physical education course based on the sport education model exhibited healthy lifestyles. These results provide concrete evidence for teachers of physical education interested in using teaching methods based on the sport education model to promote healthy lifestyles in students. | PMC9915953 | ||
4.2. Research Limitations | This study had several limitations. First, this study did not use a randomized equal-group multifactor experimental design. As a result, the results may have been affected by sampling bias (e.g., the experience and team participation) and thus cannot be completely generalized to students of other countries, regions, or educational backgrounds. Second, the teaching intervention was highly structured and supportive because of the students’ self-efficacy. Finally, the research participants consisted only of students from one university, and the course framework was solely based on badminton. Researchers should exercise caution when generalizing the results to courses based on other sports. | PMC9915953 | ||
4.3. Research Suggestions | The results provide a solid foundation for research on exercise and physical education courses. Researchers should follow-up their participants for 1 or 2 months to determine whether the sport education model has a lasting effect in terms of encouraging healthy lifestyles. In addition, studies can use other indicators of the effectiveness of the sport education model. To explore the model’s ability to promote healthy lifestyles in university students, this study used indicators of healthy lifestyles. Studies can use students’ ability to maintain regular exercise habits and the effect of teams on individuals as indicators. | PMC9915953 | ||
5. Conclusions | This study provided preliminary evidence indicating that incorporating the sport education model into physical education courses promotes healthy lifestyles in students and fills the gap in the literature regarding the sport education model. Organized teaching strategies for physical education courses are crucial to helping youths learn about health. The results can be of use to medical and healthcare providers. Organized physical education scenarios are crucial to preventing sedentary lifestyles. This study provides strong evidence of the ability of the sport education model to promote healthy lifestyles in university students. The results can be applied to other physical education activities to further promote healthy lifestyles in students. Teachers of physical education courses should integrate the sport education model into their courses. Considering the close relationship between youth and adult health, improving youth health through organized physical education strategies is essential. | PMC9915953 | ||
Author Contributions | Conceptualization, C.-C.L., K.-P.K., C.-H.H., Y.-J.L., and C.-C.K.; data curation, C.-C.L., K.-P.K., C.-H.H., Y.-J.L., and C.-C.K.; formal analysis, C.-C.L., K.-P.K., C.-H.H., Y.-J.L., and C.-C.K.; funding acquisition, Y.-J.L.; investigation, C.-C.L., K.-P.K., C.-H.H., Y.-J.L., and C.-C.K.; methodology, C.-C.L., K.-P.K., and C.-C.K.; project administration, C.-C.L. and C.-C.K.; resources, C.-C.L., K.-P.K., C.-H.H., Y.-J.L., and C.-C.K.; software, C.-C.L., K.-P.K., C.-H.H., Y.-J.L., and C.-C.K.; supervision, C.-C.L., C.-H.H., and C.-C.K.; validation, C.-C.L., K.-P.K., C.-H.H., Y.-J.L., and C.-C.K.; visualization, C.-C.L. and C.-C.K.; writing—original draft, C.-C.L., K.-P.K., and C.-C.K.; writing—review and editing, K.-P.K., C.-H.H., and C.-C.K. All authors have read and agreed to the published version of the manuscript. | PMC9915953 | ||
Institutional Review Board Statement | This study was approved by the Institutional Review Board (IRB) of National Taiwan University (serial number: 201812ES018). | PMC9915953 | ||
Informed Consent Statement | Informed consent was obtained from all participants involved in the study; and all participants provided their assent to participate. | PMC9915953 | ||
Data Availability Statement | Data are available from the corresponding author upon reasonable request. | PMC9915953 | ||
Conflicts of Interest | The authors declare no conflict of interest. | PMC9915953 | ||
References | REGRESSION, EVENT | Designing learning materials for educational objectives.Arranging sports seasons and trainingAdjusting time based on teaching items and contentLearning about sports experiencesGaining sports knowledgeAdjusting strategy and applicationCognitive objectives:Game planning and managementSports appreciationRecord keepingStrategy implementationAffective objectives:Rational decision makingEtiquette, history, and rules of gamesTeam collaborationInterpersonal interaction and team adaptationPsychomotor domain:Sport techniquesPhysical fitnessFlexible rules that adapt to the ability levels of studentsHeterogeneous groupingConducting all practices and games in teamsAssigning roles: team captain, referees, and record keepersPlanning jobs and participating in gamesDisclosing the event scheduleDisclosing rewardsArranging warm-up matchesLearning about teamworkConducting strategy drills and developing team chemistryAppreciating the gameDisclosing event schedules for the finalsAnalyzing the competition in the finalsConducting strategy drills and developing team chemistryAppreciating the gameInstruction on the record-keeping methodTeaching the basis for final evaluationLearning the record-keeping methodLearning the evaluation methodMaintaining a joyful atmosphere in classesHosting the awards ceremony in classExperiencing the meaning of sportsAppreciating the ceremonyOrganized by the author according to Jewett et al. [Demographic statistics of participants.Homogeneity of within-class regression coefficients.Adjusted RPretest and posttest performance for each variable.Covariance analysis results.* | PMC9915953 | |
Background | Cancer | CANCER | COVID-19 has impacted both society and medical care. While Germany entered the first lockdown in spring 2020, the PIKKO study (Patient information, communication and competence empowerment in oncology) was still active. The intervention modules, patient navigator (PN), services of the Saarland Cancer Society (SCS), psycho-social counseling and different courses, and online knowledge database (ODB) continued to be offered, but in an adapted form. It was the aim of this supplementary survey to identify the restrictions and burdens of the pandemic containment strategies on the PIKKO patients and thus on the PIKKO study itself. Furthermore, this work shows how the PIKKO modules were used during the lockdown. | PMC10183678 |
Methods | REGRESSION | All patients in the PIKKO intervention group (IG) were invited to complete a questionnaire, n = 503. Furthermore, utilization of the SCS and log files of the ODB were analyzed. For socio-demographic data and contacts with the PN, data from the regular PIKKO surveys were used. In addition to descriptive statistics, chi²-tests, F-tests and linear regression analyses were performed. | PMC10183678 | |
Results | REGRESSION, DISEASE | 356 patients participated in this supplemental survey. 37.6% reported restrictions. “Restrictions on accompanying persons”, “ban on visits to the wards” and “protective mouth-nose-mask” were reported as the greatest burdens. 39.0% expressed fears that the restrictions would have an impact on the course of their disease. Linear regression analyses showed differences in feelings of burden among age groups (more among < 60-year-olds), gender (more among women), children in the household (more with children), and preexisting financial stress (more with financial worries). In April 2020, there was more patient contact with PNs by phone, more SCS psycho-social counseling by phone, adapted SCS course offering, but with significantly fewer participants, and high activity on the ODB. | PMC10183678 | |
Conclusion | Cancer | CANCER | Cancer patients in the IG reported restrictions from the pandemic containment strategies and feared an impact on their recovery. However, whether a burden is perceived as heavy depends more on gender, age, or pre-existing burdens than on whether the lockdown affects PIKKO or not. The utilization of counseling, courses or the ODB despite lockdown shows the need for such services, especially in times of crisis. | PMC10183678 |
Trial registration | This study was retrospectively registered in the German Clinical Trial Register under DRKS00016703 (21 Feb 2019, retrospectively registered). | PMC10183678 |
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