BACKGROUND: Intrauterine insemination (IUI) is one of the most widespread fertility treatments. However, IUI protocols vary significantly amongst fertility clinics. Various add-on interventions have been proposed to boost success rates. These are mostly chosen arbitrarily or empirically. The aim of this systematic review and meta-analysis is to assess the effectiveness and safety of add-on interventions to the standard IUI protocol and to provide evidence-based recommendations on techniques used to optimize the clinical outcomes of IUI treatment.
METHODS: Systematic review and meta-analyses were performed in accordance with PRISMA guidelines. A computerized literature search was performed from database inception to May 2023. Randomized controlled trials (RCTs) were included reporting on couples/single women undergoing IUI with any protocol for any indication using partner\'s or donor sperm. A meta-analysis based on random effects was performed for each outcome and add-on. Three authors independently assessed the trials for quality and risk of bias and overall certainty of evidence. Uncertainties were resolved through consensus. Primary outcomes were ongoing pregnancy rate (OPR) or live birth rate (LBR) per cycle/per woman randomized. Registration number PROSPERO: CRD42022300857.
RESULTS: Sixty-six RCTs were included in the analysis (16 305 participants across 20 countries). Vaginal progesterone as luteal phase support in stimulated cycles was found to significantly increase LBR/OPR (RR 1.37, 95% CI 1.09-1.72, I2 = 4.9%) (moderate/low certainty of the evidence). Endometrial scratch prior/during stimulated IUI cycles may increase LBR/OPR (RR 1.44, 95% CI 1.03-2.01, I2 = 1.8%), but evidence is very uncertain. Results from two studies suggest that follicular phase ovarian stimulation increases LBR/OPR (RR 1.39, 95% CI 1.00-1.94, I2 = 0%) (low certainty of evidence). No significant difference was seen for the primary outcome for the other studied interventions.
CONCLUSIONS: The findings of this systematic review and meta-analysis suggest that vaginal luteal phase progesterone support probably improves LBR/OPR in stimulated IUI treatments. In view of moderate/low certainty of the evidence more research is needed for solid conclusions. Further research is also recommended for the use of endometrial scratch and ovarian stimulation. Future studies should report on results according to subfertility background as it is possible that different add-ons could benefit specific patient groups.

Bed rest and limb immobilization are models of muscle disuse associated with skeletal muscle atrophy and reduced strength. The purpose of this systematic review was to examine the impact of protein or amino acid provision before and/or during a period of muscle disuse on muscle atrophy (primary outcome), strength and muscle protein synthesis (secondary outcomes) following a disuse period. We performed a systematic review of Embase, MEDLINE, Web of Science, PubMed and Clinical Trials in December 2022. Eligible studies were randomized controlled trials that combined a dietary protein or amino acid intervention versus control during an experimental model of disuse (bed rest or unilateral limb immobilization) in healthy individuals aged ≥18 years. Nine articles from eight independent trials were identified and rated for risk of bias by two authors. A meta-analysis of muscle mass data revealed no effect (standardized mean difference: 0.2; 95% confidence interval: -0.18 to 0.57, P = 0.31) of protein/amino acid intervention in preventing disuse-induced muscle atrophy. Although the meta-analysis was not conducted on strength or muscle protein synthesis data, there was insufficient evidence in the reviewed articles to support the use of protein/amino acid provision in mitigating the disuse-induced decline in either outcome measurement. Additional high-quality studies, including the reporting of randomization procedures and blinding procedures and the provision of statistical analysis plans, might be required to determine whether protein or amino acid provision serves as an effective strategy to attenuate muscle atrophy during periods of disuse.

Pregnant women with absolute contraindications may be advised against physical activity throughout pregnancy. In this context, bed rest elevates the short-term risk of neonatal complications, thereby exacerbating negative long-term effects on childhood development. The aim of the current study was to investigate the impact of various physical activity interventions during bed rest or activity restriction in pregnancy on factors such as birth weight, preterm birth, maternal hypertension, gestational age at delivery, and the incidence of cesarean sections. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review was designed. The protocol was registered in the International Prospective Registry of Systematic Reviews (PROSPERO) (CRD42022370875). Nine studies, with a total sample of 3173 women, from six countries on four continents were included. There were significant differences in the relationship between bed rest status and birth weight (Z = 2.64; p = 0.008) (MD = 142.57, 95% CI = 36.56, 248.58, I2 = 0%, Pheterogeneity = 0.45) favourable to active groups. No significant differences were found in other analyzed outcomes. Pregnant women who experience this problem must maintain a minimum of daily activity to alleviate these physiological complications and the medical field must understand the consequences of physical inactivity during pregnancy.

Incidental durotomies are frequent complications of spine surgery associated with cerebrospinal fluid (CSF) leak-related symptoms. Management typically involves prolonged bed rest to reduce CSF pressure at the durotomy site. However, early ambulation may be a safer, effective alternative. PubMed, Web of Science, Embase, Cochrane, and Scopus were systematically searched for studies comparing early ambulation (bed rest ≤ 24 h) with prolonged bed rest (> 24 h) for patients with incidental durotomies in spine surgeries. The outcomes of interest were CSF leak, hypotensive headache, additional surgical repair, pseudomeningocele, and pulmonary complications. Systematic reviews and meta-analysis were performed following the Cochrane Handbook for Systematic Reviews of Interventions. We included a total of 704 patients from 6 studies. There was a significant reduction in the incidence of pulmonary complications (RR 0.23; 95% CI 0.08-0.67; p = 0.007) in the early mobilization group. The incidence of CSF leak (RR 1.34; 95% CI 0.83-2.14; p = 0.23), hypotensive headache (RR 0.72; 95% CI 0.27-1.90; p = 0.50), additional repair surgery (RR 1.29; 95% CI 0.76-2.2; p = 0.35), and pseudomeningocele (RR 1.29; 95% CI 0.20-8.48; p = 0.79) did not differ significantly. In patients with incidental durotomy following spinal surgery, early mobilization was associated with a lower incidence of pulmonary complications as compared with prolonged bed rest. There was no significant difference between groups in terms of CSF leak, need for additional repair, pseudomeningocele, and hypotensive headache.

Approximately 19% of the population is suffering from \"Long COVID\", also known as post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PASC), which often results in exercise intolerance. As COVID infections continue to be common, studying the long-term consequences of coronavirus disease (COVID) on physical function has become increasingly important. This narrative review will aim to summarize the current literature surrounding exercise intolerance following COVID infection in terms of mechanism, current management approaches, and comparison with similar conditions and will aim to define limitations in the current literature. Multiple organ systems have been implicated in the onset of long-lasting exercise intolerance post-COVID, including cardiac impairment, endothelial dysfunction, decreased VO2 max and oxygen extraction, deconditioning due to bed rest, and fatigue. Treatment modalities for severe COVID have also been shown to cause myopathy and/or worsen deconditioning. Besides COVID-specific pathophysiology, general febrile illness as commonly experienced during infection will cause hypermetabolic muscle catabolism, impaired cooling, and dehydration, which acutely cause exercise intolerance. The mechanisms of exercise intolerance seen with PASC also appear similar to post-infectious fatigue syndrome and infectious mononucleosis. However, the severity and duration of the exercise intolerance seen with PASC is greater than that of any of the isolated mechanisms described above and thus is likely a combination of the proposed mechanisms. Physicians should consider post-infectious fatigue syndrome (PIFS), especially if fatigue persists after six months following COVID recovery. It is important for physicians, patients, and social systems to anticipate exercise intolerance lasting for weeks to months in patients with long COVID. These findings underscore the importance of long-term management of patients with COVID and the need for ongoing research to identify effective treatments for exercise intolerance in this population. By recognizing and addressing exercise intolerance in patients with long COVID, clinicians can provide proper supportive interventions, such as exercise programs, physical therapy, and mental health counseling, to improve patient outcomes.

Evidence suggests that exercise during pregnancy is beneficial to both parent and fetus. However, there are high-risk pregnancy conditions that may warrant hospitalization. In our narrative review, we first describe the clinical implications for activity restriction in pregnancy, the effects of hospitalization, and the impact of bed rest on non-pregnant individuals. We provide examples of a 30 min bed-rest exercise program for hospitalized pregnant patients using the principal of suggested frequency, intensity, time (duration) of activity, and type of activity (FITT) using a resistance tool while in bed. If the individual is able to ambulate, we recommend short walks around the ward. Every minute counts and activity should be incorporated into a program at least 3 times per week, or every day if possible. As in all exercise programs, motivation and accountability are essential. Flexibility in timing of the exercise intervention is important due to the scheduling of medical assessments that may occur throughout the day for these hospitalized patients. Evidence suggests that by improving physical and emotional health through a bed-rest exercise program during a hospitalized pregnancy may help the individual resume demanding daily activity in the postpartum period and improve quality of life once birth has occurred. More research is necessary to improve the health of those individuals who are hospitalized during pregnancy, with follow up and support into the postpartum period.

Embryo transfer (ET) is the final step of in vitro fertilization (IVF). Different strategies have been proposed to increase the likelihood of implantation, such as post-transfer bed rest. The objective of this manuscript was to compare the clinical outcomes of embryo transfers after IVF of patients offered rest vs. early ambulation. The patient, intervention, comparison, and outcome(s) (PICO) model was used to select the study population, which included women/couples submitted to IVF and prescribed bed rest or early ambulation. Only studies including live birth (LB) as an outcome were included (www.crd.york.ac.uk/PROSPERO/CRD42020188716) A systematic search for studies was conducted on MEDLINE, ClinicalTrials.gov, PubMed, and the Cochrane Library. A librarian coordinated the searches in May 2020, which considered articles published since 1995. All original peer-reviewed articles in English were included, regardless of study design. The search retrieved 27 citations, of which 14 were eligible for full-text analysis and four accepted for inclusion. The studies included data on 21,598 patients/cycles (rest: 20,138; early ambulation: 1,460). Patients prescribed bed rest had an LB rate of 43.6% vs. 52.5% in the individuals not offered bed rest. The meta-analysis yielded an odds ratio of 0.77 (95% CI 0.5-1.2), which means patients on bed rest were 23% less likely to have a LB; nevertheless, this difference was not statistically significant. Considering that there is no difference between the two strategies, there is no evidence to recommend bed rest after embryo transfer.

As human spaceflight progresses with extended mission durations, the demand for effective and safe drugs will necessarily increase. To date, the accepted medications used during missions (for space motion sickness, sleep disturbances, allergies, pain, and sinus congestion) are administered under the assumption that they act as safely and efficaciously as on Earth. However, physiological changes have been documented in human subjects in spaceflight involving fluid shifts, muscle and bone loss, immune system dysregulation, and adjustments in the gastrointestinal tract and metabolism. These alterations may change the pharmacokinetics (PK) and pharmacodynamics of commonly used medications. Frustratingly, the information gained from bed rest studies and from in-flight observations is incomplete and also demonstrates a high variability in drug PK. Therefore, the objectives of this review are to report (i) the impact of the space environmental stressors on human physiology in relation to PK; (ii) the state-of-the-art on experimental data in space and/or in ground-based models; (iii) the validation of ground-based models for PK studies; and (iv) the identification of research gaps.

Background: Maintaining skeletal muscle mass and function in aging is crucial for preserving the quality of life and health. An experimental bed rest (BR) protocol is a suitable model to explore muscle decline on aging during inactivity. Objective: The purpose of this systematic review and meta-analysis was, therefore, to carry out an up-to-date evaluation of bed rest, with a specific focus on the magnitude of effects on muscle mass, strength, power, and functional capacity changes as well as the mechanisms, molecules, and pathways involved in muscle decay. Design: This was a systematic review and meta-analysis study. Data sources: We used PubMed, Medline; Web of Science, Google Scholar, and the Cochrane library, all of which were searched prior to April 23, 2020. A manual search was performed to cover bed rest experimental protocols using the following key terms, either singly or in combination: \"Elderly Bed rest,\" \"Older Bed rest,\" \"Old Bed rest,\" \"Aging Bed rest,\" \"Aging Bed rest,\" \"Bed-rest,\" and \"Bedrest\". Eligibility criteria for selecting studies: The inclusion criteria were divided into four sections: type of study, participants, interventions, and outcome measures. The primary outcome measures were: body mass index, fat mass, fat-free mass, leg lean mass, cross-sectional area, knee extension power, cytokine pattern, IGF signaling biomarkers, FOXO signaling biomarkers, mitochondrial modulation biomarkers, and muscle protein kinetics biomarkers. Results: A total of 25 studies were included in the qualitative synthesis, while 17 of them were included in the meta-analysis. In total, 118 healthy elderly volunteers underwent 5-, 7-, 10-, or 14-days of BR and provided a brief sketch on the possible mechanisms involved. In the very early phase of BR, important changes occurred in the skeletal muscle, with significant loss of performance associated with a lesser grade reduction of the total body and muscle mass. Meta-analysis of the effect of bed rest on total body mass was determined to be small but statistically significant (ES = -0.45, 95% CI: -0.72 to -0.19, P < 0.001). Moderate, statistically significant effects were observed for total lean body mass (ES = -0.67, 95% CI: -0.95 to -0.40, P < 0.001) after bed rest intervention. Overall, total lean body mass was decreased by 1.5 kg, while there was no relationship between bed rest duration and outcomes (Z = 0.423, p = 672). The meta-analyzed effect showed that bed rest produced large, statistically significant, effects (ES = -1.06, 95% CI: -1.37 to -0.75, P < 0.001) in terms of the knee extension power. Knee extension power was decreased by 14.65 N/s. In contrast, to other measures, meta-regression showed a significant relationship between bed rest duration and knee extension power (Z = 4.219, p < 0.001). Moderate, statistically significant, effects were observed after bed rest intervention for leg muscle mass in both old (ES = -0.68, 95% CI: -0.96 to -0.40, P < 0.001) and young (ES = -0.51, 95% CI: -0.80 to -0.22, P < 0.001) adults. However, the magnitude of change was higher in older (MD = -0.86 kg) compared to younger (MD = -0.24 kg) adults. Conclusion: Experimental BR is a suitable model to explore the detrimental effects of inactivity in young adults, old adults, and hospitalized people. Changes in muscle mass and function are the two most investigated variables, and they allow for a consistent trend in the BR-induced changes. Mechanisms underlying the greater loss of muscle mass and function in aging, following inactivity, need to be thoroughly investigated.

Muscle atrophy and decline in muscle strength appear very rapidly with prolonged disuse or mechanical unloading after acute hospitalization or experimental bed rest. The current study analyzed data from short-, medium-, and long-term bed rest (5-120 days) in a pooled sample of 318 healthy adults and modeled the mathematical relationship between muscle strength decline and atrophy. The results show a logarithmic disuse-induced loss of strength and muscle atrophy of the weight-bearing knee extensor muscles. The greatest rate of muscle strength decline and atrophy occurred in the earliest stages of bed rest, plateauing later, and likely contributed to the rapid neuromuscular loss of function in the early period. In addition, during the first 2 wk of bed rest, muscle strength decline is much faster than muscle atrophy: on day 5, the ratio of muscle atrophy to strength decline as a function of bed rest duration is 4.2, falls to 2.4 on day 14, and stabilizes to a value of 1.9 after ∼35 days of bed rest. Positive regression revealed that ∼79% of the muscle strength loss may be explained by muscle atrophy, while the remaining is most likely due to alterations in single fiber mechanical properties, excitation-contraction coupling, fiber architecture, tendon stiffness, muscle denervation, neuromuscular junction damage, and supraspinal changes. Future studies should focus on neural factors as well as muscular factors independent of atrophy (single fiber excitability and mechanical properties, architectural factors) and on the role of extracellular matrix changes. Bed rest results in nonuniform loss of isometric muscle strength and atrophy over time, where the magnitude of change was greater for muscle strength than for atrophy. Future research should focus on the loss of muscle function and the underlying mechanisms, which will aid in the development of countermeasures to mitigate or prevent the decline in neuromuscular efficiency.NEW & NOTEWORTHY Our study contributes to the characterization of muscle loss and weakness processes reflected by a logarithmic decline in muscle strength induced by chronic bed rest. Acute short-term hospitalization (≤5 days) associated with periods of disuse/immobilization/prolonged time in the supine position in the hospital bed is sufficient to significantly decrease muscle mass and size and induce functional changes related to weakness in maximal muscle strength. By bringing together integrated evaluation of muscle structure and function, this work identifies that 79% of the loss in muscle strength can be explained by muscle atrophy, leaving 21% of the functional loss unexplained. The outcomes of this study should be considered in the development of daily countermeasures for preserving neuromuscular integrity as well as preconditioning interventions to be implemented before clinical bed rest or chronic gravitational unloading (e.g., spaceflights).