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Emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) possess mutations that prevent antibody therapeutics from maintaining antiviral binding and neutralizing efficacy. Monoclonal antibodies (mAbs) shown to neutralize Wuhan-Hu-1 SARS-CoV-2 (ancestral) strain have reduced potency against newer variants. Plasma-derived polyclonal hyperimmune drugs have improved neutralization breadth compared with mAbs, but lower titers against SARS-CoV-2 require higher dosages for treatment. We previously developed a highly diverse, recombinant polyclonal antibody therapeutic anti-SARS-CoV-2 immunoglobulin hyperimmune (rCIG). rCIG was compared with plasma-derived or mAb standards and showed improved neutralization of SARS-CoV-2 across World Health Organization variants; however, its potency was reduced against some variants relative to ancestral, particularly omicron. Omicron-specific antibody sequences were enriched from yeast expressing rCIG-scFv and exhibited increased binding and neutralization to omicron BA.2 while maintaining ancestral strain binding and neutralization. Polyclonal antibody libraries such as rCIG can be utilized to develop antibody therapeutics against present and future SARS-CoV-2 threats.

Antiviral compounds displaying several remarkable features have been identified by a uniquely enabling drug screen and advanced through validation in two animal models, and in human primary bronchial epithelial cells grown to an air-liquid interface (ALI) and infected with SARS-CoV-2 (Brazil). Activity is observed in the nanomolar range in mammalian cells in vitro against the six viral families causing most human respiratory viral disease, irrespective of strain, including SARS-CoV-2 delta variant. A substantial barrier to development of viral resistance is demonstrated for influenza (FLUV). The drug target is an allosteric site on a novel host multi-protein complex (MPC) formed transiently, in an energy-dependent fashion, and composed of proteins implicated in viral lifecycles and innate immunity. The composition of this host MPC is modified in viral family-specific ways by FLUV and CoV, and substantially restored to the uninfected state with drug treatment. SQSTM1/p62, a key regulator of the autophagy pathway of innate immunity is i) found in the target MPC from uninfected cells, ii) lost upon infection, and iii) restored by drug treatment of infected cells, as assessed by drug resin affinity chromatography. A small subset of 14-3-3 is identified as the host protein to which the drug is bound. Advanced compounds with good oral bioavailability, half-life, lung exposure, and safety are approaching criteria for a Target Product Profile. We propose these novel drug targets to comprise a previously unappreciated molecular basis for homeostasis that is modified by viruses to facilitate their propagation and is restored by treatment with the therapeutic compounds presented. This discovery has transformative implications for treating respiratory viral-related disease, applicable to everything from COVID-19, seasonal influenza, common ‘winter viruses’ (respiratory syncytial virus, parainfluenza virus, rhinovirus, etc.), emerging respiratory viruses, and prevention of virus-induced asthma/COPD exacerbations. Treating respiratory viral disease with these host-targeted pan-respiratory viral family active compounds early, upon onset of symptoms of viral upper respiratory infection, irrespective of cause, should protect against progression to lower respiratory tract or systemic infection, the hallmarks of serious illness.

Objective Exploration of the possibility that local injury of the endometrium increases the incidence of implantation. Design Prospective study. Setting Clinical IVF unit. Patient(s) A group of 134 patients, defined as good responders to hormonal stimulation, who failed to conceive during one or more cycles of IVF and embryo transfer (ET). Intervention(s) The IVF treatment and ET were preceded by repeated endometrial biopsies, in a randomly selected 45 of a total of 134 patients. Main outcome measure(s) Outcome of IVF-ET treatments. Result(s) Transfer of a similar number of embryos (3.4 ± 1.0 and 3.1 ± 0.9 in the experimental and control patients, respectively) resulted in rates of implantation (27.7% vs. 14.2%, P = .00011), clinical pregnancy (66.7% vs. 30.3%, P = .00009), and live births per ET (48.9% vs. 22.5%, P = .016) that were more than twofold higher in the experimental group as compared to controls. Conclusion(s) These results suggest that IVF treatment that is preceded by endometrial biopsy doubles the chance for a take-home baby.

Objective: To analyze the pattern of connexin43 gene and protein expression in human endometrium throughout the menstrual cycle. Design: Controlled clinical study. Setting: An academic research center. Patient(s): Women with 28-day menstrual cycles who had mechanical infertility and failed to conceive after IVF treatment. Intervention(s): Endometrial and blood samples were collected on days 8, 12, 14, 21, and 25 of spontaneous menstrual cycles. Main Outcome Measure(s): Endometrial expression of connexin43 protein and messenger RNA, endometrial thickness, and serum concentrations of gonadotropins and steroids. Result(s): The expression of connexin43 gene and protein decreased on day 12 and day 14 of the menstrual cycle and then increased on day 21 and day 25, respectively. A serum LH surge accompanied by a peak in the FSH concentration was observed on days 12–14. The progesterone concentration increased on days 21–25, but there was no significant change in the E2 concentration. The thickness of the endometrium increased between days 8 and 12 and did not change further between days 21 and 25. Conclusion(s): The expression of connexin43 gene and protein in human endometrium changes during the menstrual cycle in a pattern that is associated with the secretion of LH, FSH, and progesterone. This pattern may serve as a marker for implantation competence.

Accumulation of oviductal fluid in the ampullar lumen as a result of occlusion of the infundibulum is referred to as hydrosalpinx. A low pregnancy rate (10%) after in-vitro fertilization (IVF) in hydrosalpinx patients and a relatively high incidence (50%) of abortions during the first trimester suggested that leakage of this fluid into the uterine cavity may exert a cytotoxic effect on the developing embryo. To examine this possibility, we analysed the composition of the hydrosalpinx fluid and tested its effect on human granulosa cells and embryos. Hydrosalpinx fluids and granulosa cells were collected from IVF patients at ovum pick-up. IVF eggs containing three pronuclei (3PN) were employed for this study. Analysis of hydrosalpinx fluids revealed electrolyte concentrations similar to those in serum with lower amounts of total protein and albumin. No blood cells were detected and bacterial cultures were negative. Granulosa cells incubated in hydrosalpinx fluid-containing medium (diluted 1:1) were not morphologically different and showed a steroidogenic capacity that was higher than that of cells incubated in its absence. Fertilized 3PN eggs incubated in IVF culture medium successfully developed into 6- to 8- and 8- to 16-cell embryos within 48 and 72 h, respectively. This rate of embryonal development was not impaired by hydrosalpinx fluid (at either 50 or 100% concentration). In the absence of a demonstrable detrimental effect we suggest that the low implantation rate in hydrosalpinx IVF patients may not be due to an embryotoxic effect. We further suggest that constant passage of fluid into the uterine cavity in these patients could possibly introduce some mechanical interference that may result in implantation failure.

In 12 patients stimulated for in vitro fertilization and embryo transfer (IVF-ET), a single leading follicle developed, whereas the other follicles were 6 mm smaller. In 7 patients chosen at random (group A), the leading follicle was aspirated, whereas in the other 5 the leading follicle was allowed to continue growing (group B). Comparison of the hormonal pattern of both groups showed that a premature luteinizing hormone (LH) surge was avoided only in group A, and only in this group a second follicle aspiration for IVF-ET was done, and two pregnancies were achieved. In group B, aspiration for IVF-ET was canceled because of premature LH surge. It is suggested that aspiration of a single leading follicle during ovulation induction may be an efficient method to avoid premature LH surge enabling other follicles to develop up to the preovulatory stage.