The maintenance of well-being, healthcare, and social connection is crucial for older adults (OA) and has become a topic of debate as much of the world faces lockdown during the coronavirus disease ...2019 (COVID-19) pandemic. OAs have been advised to isolate themselves because they are at higher risk for developing serious complications from severe acute respiratory syndrome coronavirus. Additionally, nursing homes and assisted-living facilities across the country have closed their doors to visitors to protect their residents. Mobile technology such as applications (apps) could provide a valuable tool to help families stay connected, and to help OAs maintain mobility and link them to resources that encourage physical and mental well-being. Apps could address cognitive, visual, and hearing impairments. Our objective was to narratively summarize 15 apps that address physical and cognitive limitations and have the potential to improve OAs' quality of life, especially during social distancing or self-quarantine.
Implantation is a critical step in human reproduction. The success of this step is dependent on a competent blastocyst, receptive endometrium, and successful cross talk between the embryonic and ...maternal interfaces. Recurrent implantation failure is the lack of implantation after the transfer of several embryo transfers. As the success of in vitro fertilization has increased and failures have become more unacceptable for patients and providers, the literature on recurrent implantation failure has increased. While this clinical phenomenon is often encountered, there is not a universally agreed-on definition—something addressed in an earlier portion of this Views and Reviews.
Implantation failure can result from several different factors. In this review, we discuss factors including the maternal immune system, genetics of the embryo and parents, anatomic factors, hematologic factors, reproductive tract microbiome, and endocrine milieu, which factors into embryo and endometrial synchrony. These potential causes are at various stages of research and not all have clear implications or immediately apparent treatment.
Metastatic colorectal cancer is a prevalent disease for which novel targeted therapies and biologically based combinations are under development. Cytotoxic chemotherapy doublets (FOLFOX, FOLFIRI) and ...triplets (FOLFOXIRI) in combination with biologics are standard regimens, and efforts are ongoing to delineate the optimal sequence for each patient based on unique underlying tumor biology. Molecular profiling of metastatic colorectal cancer (including mutational analysis for
KRAS, NRAS, BRAF, PIK3CA
, and others) has become increasingly important for identification of prognostic and predictive biomarkers, as well as for insights into the biology that drives the tumor. Large comprehensive analyses such as that of The Cancer Genome Atlas have provided important clues into carcinogenesis and discerned potentially druggable targets for metastatic colorectal cancer. Novel therapeutic agents currently under investigation for subtypes of this disease include immunotherapies such as anti-programmed cell death receptor antibody, cancer stem cell inhibitors, targeted combinations such as
BRAF
and
PI3K
inhibitors, and the anti-
RAS
reovirus Reolysin®.
Summary Background No treatment options are available for patients with metastatic colorectal cancer that progresses after all approved standard therapies, but many patients maintain a good ...performance status and could be candidates for further therapy. An international phase 3 trial was done to assess the multikinase inhibitor regorafenib in these patients. Methods We did this trial at 114 centres in 16 countries. Patients with documented metastatic colorectal cancer and progression during or within 3 months after the last standard therapy were randomised (in a 2:1 ratio; by computer-generated randomisation list and interactive voice response system; preallocated block design (block size six); stratified by previous treatment with VEGF-targeting drugs, time from diagnosis of metastatic disease, and geographical region) to receive best supportive care plus oral regorafenib 160 mg or placebo once daily, for the first 3 weeks of each 4 week cycle. The primary endpoint was overall survival. The study sponsor, participants, and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat. This trial is registered at ClinicalTrials.gov , number NCT01103323. Findings Between April 30, 2010, and March 22, 2011, 1052 patients were screened, 760 patients were randomised to receive regorafenib (n=505) or placebo (n=255), and 753 patients initiated treatment (regorafenib n=500; placebo n=253; population for safety analyses). The primary endpoint of overall survival was met at a preplanned interim analysis; data cutoff was on July 21, 2011. Median overall survival was 6·4 months in the regorafenib group versus 5·0 months in the placebo group (hazard ratio 0·77; 95% CI 0·64–0·94; one-sided p=0·0052). Treatment-related adverse events occurred in 465 (93%) patients assigned regorafenib and in 154 (61%) of those assigned placebo. The most common adverse events of grade three or higher related to regorafenib were hand-foot skin reaction (83 patients, 17%), fatigue (48, 10%), diarrhoea (36, 7%), hypertension (36, 7%), and rash or desquamation (29, 6%). Interpretation Regorafenib is the first small-molecule multikinase inhibitor with survival benefits in metastatic colorectal cancer which has progressed after all standard therapies. The present study provides evidence for a continuing role of targeted treatment after disease progression, with regorafenib offering a potential new line of therapy in this treatment-refractory population. Funding Bayer HealthCare Pharmaceuticals.
Objective To review the mechanisms by which endometriosis may affect reproductive function. Design Review of the English literature from 1986 to 2007 after searching Medline, EMBASE, Cochrane, and ...BIOSIS, as well as relevant meeting abstracts. Setting Fertility research center and obstetrics and gynecology department in a tertiary care hospital. Result(s) There is compelling evidence in the literature that endometriosis has detrimental effects on ovarian and tubal function and uterine receptivity, resulting in female infertility. The mechanisms of infertility associated with endometriosis remain controversial and include abnormal folliculogenesis, elevated oxidative stress, altered immune function, and hormonal milieu in the follicular and peritoneal environments, and reduced endometrial receptivity. These factors lead to poor oocyte quality, impaired fertilization, and implantation. Conclusion(s) Through unraveling the mechanisms by which endometriosis leads to infertility, researchers are sure to find a nonsurgical means to diagnose endometriosis, most likely through serum and peritoneal markers. Cytokines, interleukins, oxidative stress markers, and soluble cellular adhesion molecules all show potential to be used as a reliable marker for diagnosing endometriosis. After analyzing the pathogenic mechanisms of endometriosis, it seems that the future treatment of this entity may include cyclo-oxygenase-2 inhibitors, immunomodulators, or hormonal suppressive therapy to eliminate the need for surgical treatment of endometriosis.
Dravet Syndrome (DS) is a severe neurodevelopmental disorder caused by pathogenic loss of function variants in the gene
which encodes the voltage gated sodium (Na
) channel subunit Nav1.1. GABAergic ...interneurons expressing parvalbumin (PV-INs) and somatostatin (SST-INs) exhibit impaired excitability in DS (
) mice. However, the function of a third major class of interneurons in DS - those expressing vasoactive intestinal peptide (VIP-IN) -is unknown. We recorded VIP-INs in brain slices from
mice and wild-type littermate controls and found prominent impairment of irregular spiking (IS), but not continuous adapting (CA) VIP-INs, in
mice. Application of the Nav1.1-specific toxin Hm1a rescued the observed deficits. The IS vs. CA firing pattern is determined by expression of KCNQ channels; IS VIP-INs switched to tonic firing with both pharmacologic blockade of M-current and muscarinic acetylcholine receptor activation. These results show that VIP-INs express Nav1.1 and are dysfunctional in DS, which may contribute to DS pathogenesis.
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