In the perifoveal retina of the monkey, Cercopithecus aethiops, the melanin granules are accumulated in apical cytoplasmatic protrusions of the pigment epithelial cells, facing the end of the cones. The rods are inserted deeper into the pigment epithelium than the cones; they reach the bottom of the infoldings of the apical surface membrane of the pigment epithelial cells. No melanin granules or other inclusions are situated at the end of the rods. The outer extremity of the rods is considerably inclined and in sections often appears as groups of rod discs which are incompletely or completely separated from the main part of the outer segments. This separation is regarded as an artifact caused by the inclination of the rods, and it is therefore not considered to represent phagocytosis of the outer segments by the pigment epithelium. The inclusions of the pigment epithelial cells are classified in five categories which seem to be related to each other owing to their shared structural characteristics. It is suggested that melanin granules are produced, modified and destroyed by the pigment epithelial cells of the adult. Because of the relations between the photoreceptors and the melanin granules it is suggested that light scattered by the melanin granules may pass backwards through the outer segments of the cones, but not of the rods.

SUMMARY Reports have appeared of abnormal copper metabolism in retinitis pigmentosa, and of a family with vitelliform retinal degeneration in which other members suffered from hepatolenticular degeneration. In the present study 15 patients with retinitis pigmentosa, 4 with various other retinal degenerations, and 1 with a family disposition to retinitis pigmentosa were examined. The copper concentration in serum and the coeruloplasmin concentration in plasma were found to be within normal limits. In 9 of the patients with retinitis pigmentosa the urinary excretion of copper per 24 hours was determined and was found to be normal. The results of the present study lend no support to the hypothesis of abnormal copper metabolism in retinitis pigmentosa.

The process of wound healing of the avascular outer layers of the retina is studied on a series of Laser lcsions of the monkey, Ccrc.oliitl/fr.ilt;~~~~.~ uelhio/).s. T h e extent of the retinal lesions is limited to thc pigment epithelium and photoreceptor cells, whereas Bruch's membrane anti the vascular inner layers of the retina remain intact. The retinal lesions arc not seen to be invaded by cells from the chortiid. nor from the retinal vessels. During the first three days after irradiation the pigment epithelial cells in a zone, about 7 5 pin wide. around the lesions appear to be changcd into bi-or multinucleate cells with thc additional nuclei situated in apical cytoplasmic protrusions which extend towards and into the lesions. During the second and third days after irradiation the lesions arc invaded by two kinds of cells which both appear to arise through the off-budding of the nucleus-containing apical protrusions of the pigment epithelial cells around the lesions: (a) phagocytic cells which disintegrate the damaged tissue and, as this process is completed 4-9 days after irradiation show cvitlence of melanogcncsis; and (b) regenerated pigment epithelium which forin a single lnycr of rells along Bruch's membrane, but show no evidc nce of phagocytosis or intracellular disintegration of the damaged tissue. Within the lesions both these kinds of cells show mitotic figures the third clay after irratliation.

Study question Does letrozole co-treatment during ovarian stimulation for in vitro fertilization (IVF) impact oocyte yield, embryo development, and live birth rate (LBR) in expected normal responders? Summary answer Letrozole co-treatment leads to similar oocyte yield, embryo- development and utilisation rate, and live birth rate after transfer in the fresh cycle. What is known already Letrozole reduces oestradiol levels by inhibiting the aromatization of androgens, this diminishes pituitary suppression and increases endogenous gonadotrophin release. These effects are utilized in ovulation induction in PCOS patients and may benefit certain patients during IVF treatment. In addition, we have recently reported in an RCT that co-treatment with letrozole increases luteal phase progesterone levels and, consistent with previous studies, no significant effect on pregnancy rates was observed. However, the impact of the changes in the endocrine milieu caused by letrozole co-treatment on the developing oocytes and embryos remains unclear as most published studies are retrospective and lack appropriate control-groups. Study design, size, duration A multicentre double-blinded randomised placebo-controlled trial was conducted in four fertility clinics at University Hospitals in Denmark from August 2016 to November 2018. 159 women were randomised, 129 women received single embryo (cleavage stage or blastocyst) transfer in the fresh cycle, and the surplus 257 embryos were vitrified. The study was conducted following the Helsinki Declaration and the ICH-Good-Clinical-Practice. Data collection and reporting followed the guidelines of CONSORT to achieve transparent reporting of trials. Participants/materials, setting, methods Women with expected normal ovarian response received an antagonist protocol with fixed-dose FSH. Co-treatment consisted of 5mg letrozole or placebo from the start of stimulation until the day of triggering final oocyte maturation with hCG. Standardized morphological evaluation was performed at all centres (applying the Istanbul consensus and Gardner-score). A sub-cohort of the embryos were cultured in an EmbryoScope incubator and further assessed by morphokinetic annotation and reported with.KIDScoreD3. Ongoing pregnancies were followed until birth. Main results and the role of chance A total of 1268 oocytes were retrieved from 154 women, leading to development of 386 usable embryos that were either transferred or vitrified. Utilisation rate (the proportion of usable embryos to oocytes) was similar in the letrozole group and placebo group with 0.31 vs. 0.36 (mean difference (MD): -0.05, 95% CI[-0.03;0.12], P = 0.25). Morphologically grading the embryos as “good”, “fair”, and “poor” quality showed similar results, the odds of having a higher quality were 0.78 times higher in the letrozole- vs. placebo group (CI[0.5;1.1], P = 0.2). Morphokinetic annotations (n = 302 embryos) showed similar results with the odds of having a high KIDScore3 1.3 times higher in the letrozole – vs. placebo group (CI[0.9;2.1], P = 0.2). The endometrial thickness at transfer was thinner in the letrozole compared to the placebo group with 8.5 vs. 9.5 mm (MD 1.0, 95% CI[0.4;1.6], P = 0.001) but with the same ultrasonic echogenicity and a preovulatory three-layer appearance. After embryo transfer in the fresh cycle (n = 129), no differences were seen in the pregnancy outcomes: positive serum hCG, ongoing pregnancy rate, early miscarriage rate, foetal miscarriage rate, or LBR. LBR per initiated cycle were similar as well (n = 159): 23.8% vs. 29.1% (MD of -5,3%, CI[-20.3%;9.6%], P = 0.48) in letrozole vs. placebo group, respectively. Limitations, reasons for caution Four clinics participating could lead to interobserver variability. However, bias was reduced by block-randomised design. All data are derived from an RCT, the primary endpoint of which, preovulatory progesterone, was the basis of the sample size calculation. The study may have been underpowered to show a significant impact on LBR. Wider implications of the findings Letrozole co-treatment during ovarian stimulation with gonadotrophins did not have an impact on the oocyte yield and embryo development. These data suggest that letrozole co-treatment is unlikely to compromise outcomes in its growing indications: ovulation induction, IVF in poor responders, and fertility preservation in breast cancer patients. Trial registration number NCT02946684

The light scattering properties of pigment granules are demonstrated. It is emphasized, that in the micro‐environment of the single photoreceptors, each pigment granule is to be regarded as a new source of light.