High seroprevalence of SARS-CoV-2 but low infection fatality ratio eight months after introduction in Nairobi, Kenya.

BACKGROUND: The lower than expected COVID-19 morbidity and mortality in Africa has been attributed to multiple factors, including weak surveillance. This study estimated the burden of SARS-CoV-2 infections eight months into the epidemic in Nairobi, Kenya. METHODS: A population-based, cross-sectional survey was conducted using multi-stage random sampling to select households within Nairobi in November 2020. Sera from consenting household members were tested for antibodies to SARS-CoV-2. Seroprevalence was estimated after adjusting for population structure and test performance. Infection fatality ratios (IFRs) were calculated by comparing study estimates with reported cases and deaths. RESULTS: Among 1,164 individuals, the adjusted seroprevalence was 34.7% (95% CI 31.8-37.6). Half of the enrolled households had at least one positive participant. Seropositivity increased in more densely populated areas (spearman's r=0.63; p=0.009). Individuals aged 20-59 years had at least two-fold higher seropositivity than those aged 0-9 years. The IFR was 40 per 100,000 infections, with individuals ≥60 years old having higher IFRs. CONCLUSION: Over one-third of Nairobi residents had been exposed to SARS-CoV-2 by November 2020, indicating extensive transmission. However, the IFR was >10-fold lower than that reported in Europe and the USA, supporting the perceived lower morbidity and mortality in sub-Saharan Africa.

Innate Immune Signaling in Drosophila Blocks Insulin Signaling by Uncoupling PI(3,4,5)P3 Production and Akt Activation.

In obese adipose tissue, Toll-like receptor signaling in macrophages leads to insulin resistance in adipocytes. Similarly, Toll signaling in the Drosophila larval fat body blocks insulin-dependent growth and nutrient storage. We find that Toll acts cell autonomously to block growth but not PI(3,4,5)P3 production in fat body cells expressing constitutively active PI3K. Fat body Toll signaling blocks whole-animal growth in rictor mutants lacking TORC2 activity, but not in larvae lacking Pdk1. Phosphorylation of Akt on the Pdk1 site, Thr342, is significantly reduced by Toll signaling, and expression of mutant AktT342D rescues cell and animal growth, nutrient storage, and viability in animals with active Toll signaling. Altogether, these data show that innate immune signaling blocks insulin signaling at a more distal level than previously appreciated, and they suggest that manipulations affecting the Pdk1 arm of the pathway may have profound effects on insulin sensitivity in inflamed tissues.

Efficacy of inactivation of viral contaminants in hyperimmune horse plasma against botulinum toxin by low pH alone and combined with pepsin digestion.

Assuring viral safety of horse plasma-derived products is fundamental for ethical and regulatory reasons. We previously demonstrated the ability of pepsin digestion at low pH to inactivate West Nile and Sindbis viruses in horse plasma. The present study further examined the efficiency of pepsin digestion to inactivate four additional viruses: HSV-1 and BVDV (lipid-enveloped), BPV and Reo-3 (nonenveloped). These viruses were spiked into hyperimmunized horse plasma against botulinum toxin and subjected to low pH (3.2) alone or combined with pepsin digestion (1200 units/ml). Peptic digestion inactivated the lipid-enveloped viruses, whereas the nonenveloped viruses were unaffected. Interestingly, HSV-1 was rapidly inactivated by acidic pH alone (≥4.9 ± 0.6 log10), whereas a non-robust but meaningful BVDV inactivation (2.9 ± 0.7 log10) was achieved by combined low pH and pepsin. The current study demonstrated the ability of low pH alone and in combination with pepsin digestion to inactivate enveloped viral contaminants in anti-toxin horse plasma.

Mitochondrial Replacement Therapy: Halachic Considerations for Enrolling in an Experimental Clinical Trial.

The transition of new biotechnologies into clinical trials is a critical step in approving a new drug or therapy in health care. Ethically recruiting appropriate volunteers for these clinical trials can be a challenging task for both the pharmaceutical companies and the US Food and Drug Administration. In this paper we analyze the Jewish halachic perspectives of volunteering for clinical trials by focusing on an innovative technology in reproductive medicine, mitochondrial replacement therapy. The halachic perspective encourages individuals to volunteer for such clinical trials under the ethical principles of beneficence and social responsibility, when animal studies have shown that health risks are minimal.

Adhesions at repeat cesarean delivery: is there a personal impact?

PURPOSE: The rise in the rate of cesarean deliveries highlights complications related to adhesion formation. This study evaluated whether the incidence and severity of adhesions secondary to repeat cesarean deliveries are a consequence of repeated surgeries or due to an individual's propensity to develop adhesions. METHODS: A retrospective chart review was conducted for 160 patients who had more than two repeat cesarean deliveries in a single teaching hospital. Data regarding intra-abdominal adhesions were collected. The severity, location, density and amount of adhesions were evaluated based on standard operative reports. Adhesion progression in subsequent cesarean deliveries was evaluated for each individual patient. RESULTS: 69/160 (43 %) patients developed significant adhesions following the primary cesarean delivery. Of these, 46 (67 %) had significant adhesions at the second surgery. Of the 91 (57 %) patients, who did not develop significant adhesions after the primary cesarean delivery, 34 (37 %) had significant adhesions at the third surgery. A patient presenting with significant adhesions at her second cesarean had a 1.88-fold risk for significant adhesions at her third cesarean (95 % CI 1.3-2.7). CONCLUSIONS: Our results suggest that adhesion development might be influenced by individual factors more than by the number of cesarean deliveries.

Obstetric and neonatal outcomes after preterm premature rupture of membranes among women carrying group B streptococcus.

OBJECTIVE: To evaluate whether carriers of group B streptococcus (GBS) have adverse obstetric and neonatal outcomes when preterm premature rupture of membranes (PPROM) occurs. METHODS: In a retrospective study, data were reviewed for women with a singleton pregnancy and PPROM before 34 weeks who attended the Meir Medical Center, Kfar Saba, Israel, between 2005 and 2012. All women received roxithromycin for 1 week, and ampicillin until GBS culture results were available. Ampicillin was continued to 1 week if the GBS culture was positive. The primary study outcome measure was the latency period (time from rupture of membranes to active/induced labor). RESULTS: Among 116 eligible patients, 21 (18.1%) were GBS carriers and 95 (81.9%) noncarriers. The latency period was 11.2 ± 18.1 days for GBS carriers versus 7.5 ± 9.6 days for noncarriers (P=0.93). However, there was a correlation between the length of ampicillin treatment and the latency period (Spearman correlation coefficient 0.7; P<0.001). There were no differences in early neonatal outcomes. CONCLUSION: GBS carriers with PPROM did not have adverse outcomes. Longer treatment with ampicillin among GBS carriers prolonged the latency period.

Retained placental tissue as an emerging cause for malpractice claims.

BACKGROUND: Removal of retained placental tissue postpartum and retained products of conception (RPOC) abortion is done by uterine curettage or hysteroscopy. Trauma to the endometrium from surgical procedures, primarily curettage, can cause intrauterine adhesions (Asherman's syndrome) and subsequent infertility. The incidence of malpractice claims relating to intrauterine adhesions is rising, justifying reevaluation of the optimal way of handling these complications. OBJECTIVES: To review malpractice claims regarding intrauterine adhesions, and to explore the clinical approach that might reduce those claims or improve their medical and legal outcomes. METHODS: We examined 42 Asherman's syndrome claims handled by MCI, the largest professional liability insurer in Israel. The clinical chart of each case was reviewed and analyzed by the event preceding the adhesion formations, timing and mode of diagnosis, and outcome. We also assessed whether the adverse outcome was caused by substandard care and it it could have been avoided by different clinical practice. The legal outcome was also evaluated. RESULTS: Forty-seven percent of the cases occurred following vaginal delivery, 19% followed cesarean section, 28% were RPOC following a first-trimester pregnancy termination, and 2% followed a second-trimester pregnancy termination. CONCLUSIONS: It is apparent that due to the lack of an accepted management protocol for cases of RPOC, it is difficult to legally defend those cases when the complication of Asherman syndrome develops.

Telomere shortening in intra uterine growth restriction placentas.

INTRODUCTION: Placentas from pregnancies complicated with IUGR (intrauterine growth restriction) express altered telomere homeostasis. In the current study, we examined mechanisms of telomere shortening in these placentas. METHODS: Placental biopsies from 15 IUGR and 15 healthy control pregnancies were examined. The percentage of trophoblasts with fragmented nuclei: senescence-associated heterochromatin foci (SAHF), was calculated using DAPI staining. The amount of human telomerase reverse transcriptase (hTERT) mRNA was evaluated using RtPCR levels of telomere capture using FISH in those samples were estimated. RESULTS: The percentage of trophoblasts with SAHF was higher in IUGR compared to control samples, (25±13.4% vs. 1.6±1.6%, P<0.0001), hTERT mRNA was decreased (0.5±0.2 vs. 0.9±0.1, P<0.0001) and telomere capture was increased (13.2±9.7% vs.1.3±2.5%, P<0.001). CONCLUSIONS: We suggest that IUGR placentas express increased signs of senescence as part of the impaired telomere homeostasis. One factor that mediates telomere shortening in these placentas is decreased hTERT mRNA, leading to decreased protein expression and therefore, reduced telomere elongation. Telomere capture, which is a healing process, is increased in IUGR trophoblasts as a compensatory mechanism.

Clinical measures associated with dynamic balance and functional movement.

Decreased balance and impaired functional movement have been linked with increased injury risk. The purpose of our study was to determine the association between specific measures of power, strength, flexibility, balance, and endurance compared with more global measures of dynamic balance, using the Y-Balance Test (YBT), and functional movement, using the functional movement screen (FMS), in healthy soldiers. Our participants (n = 64; 53 men, 11 women) were healthy active duty service members (25.2 ± 3.8 years, 25.1 ± 3.1 kg·m(-2)). Seventeen tests with 38 associated measures of strength, power, flexibility, endurance, balance, and functional measures were assessed. A significant Pearson product moment correlation (r > 0.2 and p < 0.01) was used to narrow the number of variables of interest. Two hierarchical stepwise regression analyses were performed to determine the most parsimonious set of variables associated with the YBT and FMS performance scores. Our results included a 4 variable model (F = 13.4, p < 0.001) that was associated with YBT scores (R = 0.72, R2 = 0.51). Superior performance on the YBT was associated with better performance on the FMS lunge and upper trunk mobility tests, decreased number of hops during a 6-m hop test, and greater gastrocnemius flexibility. A second 4 variable model (F = 11.813, p < 0.001) was associated with FMS scores (R = 0.70, R2 = 0.50). Superior performance on the FMS was associated with greater anterior reach on the YBT, greater distance on the crossover hop test, increased hamstring flexibility, and higher levels of self-reported function through the lower-extremity functional scale. Physical fitness leaders and clinicians could use these models to inform decision making when developing and assessing the outcomes of a personalized intervention program for those with low FMS and YBT scores.

Congenital self-healing reticulohistiocytosis.

Congenital self-healing reticulohistiocytosis, also known as congenital self-healing Langerhans cell histiocytosis or Hashimoto-Pritzker disease, is a Langerhans cell histiocytosis. It is characterized by skin lesions in the newborn period in an otherwise healthy infant that show a Langerhans cell infiltrate in the skin on histological analysis. These findings subsequently spontaneously involute. This report describes two newborns who presented at birth with differing presentations of congenital self-healing reticulohistiocytosis. A review of the disorder, including diagnosis and evaluation, is presented.

Senescence in amniocytes and placentas from trisomy 21 pregnancies.

OBJECTIVE: Senescence has been described as a stable cell proliferation arrest resulting from the progression of primary human fibroblasts through a finite number of population doublings in vitro. Accelerated telomere shortening was observed in pregnancies complicated by intrauterine growth restriction, in placentas of diabetic mothers and trisomy 21 amniocytes. We hypothesized that under conditions of stress, telomeres in placentas will be shorter and there will be more cells with the senescence phenotype. METHODS: The two study groups included placental biopsies from 7 cases of trisomy 21 and amniocytes from 10 cases of trisomy 21. The control groups consisted of placental biopsies from 6 cases and amniocytes from 10 pregnancies with a normal karyotype. The samples were analyzed for the presence of senescent cells based on the number of fragments in each cell. RESULTS: A significantly higher percentage of cells in the senescent state, based on a higher percentage of cells with more fragmentations, were found in the amniocytes (20.8%) and in trophoblasts (94.3%) from placentas with trisomy 21 compared to the control groups. CONCLUSION: Among other genetic instability parameters, trisomy 21 amniocytes and trophoblasts express a higher prevalence of senescent cells than were previously reported.

Inhaled lipid cisplatin (ILC) in the treatment of patients with relapsed/progressive osteosarcoma metastatic to the lung.

BACKGROUND: Osteosarcoma treatment failure is most often from the inability to control metastatic disease in the lungs. Encapsulating cisplatin within lipid complexes and delivering the agent via inhalation targets lung metastases with minimal systemic exposure. An open-label, phase Ib/IIa study was performed to characterize the safety and efficacy of inhaled lipid cisplatin (ILC) in recurrent osteosarcoma patients who only had pulmonary metastases. PROCEDURE: ILC was administered via nebulizer every 2 weeks (=1 cycle). Response was evaluated radiographically every 2 cycles. Cisplatin levels were measured in patients. When possible, metastasectomy was undertaken in patients after 2 cycles. RESULTS: Nineteen patients were treated. No patients experienced hematologic toxicity, nephrotoxicity or ototoxicity. Nausea/vomiting (≥grade 3) was attributed to study drug in one patient. Respiratory symptoms were observed in 13/19 patients with only one patient experiencing a ≥grade 3 respiratory symptom (not related to study drug). Systemic cisplatin exposure was minimal. Eleven patients had bulky disease, and all progressed prior to cycle 7. Eight patients had all lesions ≤2 cm. One patient had a sustained partial response. An additional two patients had stable disease after 2 cycles, underwent metastasectomy, and remained free from pulmonary recurrence 1 year after initiation of therapy. CONCLUSIONS: ILC is well tolerated in heavily treated osteosarcoma patients and did not appear to have the typical toxicities associated with intravenous cisplatin. Three of eight patients with less bulky disease had sustained benefit. Further study of ILC is warranted.

Follow-up study comparing necropsy rates and discrepancies between clinical and pathologic diagnoses at a veterinary teaching hospital: 2009 versus 1989 and 1999.

OBJECTIVES: A follow-up, retrospective study to determine whether the proportion of discrepancies between clinical and pathological diagnoses made during 2009, 1999 and 1989 and the proportion of dogs necropsied have changed. METHODS: Medical records of 148 hospitalised dogs that died or were euthanased in a veterinary medical teaching hospital during 2009 were reviewed. Clinical and pathological diagnoses were recorded, categorised and compared to historical controls using a data set of 623 dogs from a previous study. RESULTS: The proportion of discrepancies was significantly (P<0·001) lower in 2009 (14·9%), compared to both 1999 (37%) and 1989 (39·8%). There was also a significant (P<0·001) decrease in the number of necropsies performed during 2009 (21·4%) compared to both 1999 (48·4%) and 1989 (58·9%). CLINICAL SIGNIFICANCE: There was a marked improvement in the ante-mortem diagnosis of patients in 2009 compared with both 1989 and 1999 as evidenced by the decrease in the proportion of discrepancies between the clinical and pathological diagnoses. Necropsies should still be regarded as a vital tool for teaching, determining the pathological basis of disease, identification of new and emerging diseases, and for an individual animal determining the cause of death.

Is it necessary to induce labor in cases of intrauterine growth restriction at term?

OBJECTIVES: Infants with intrauterine growth restriction (IUGR) have increased morbidity and mortality. The decision whether to induce labor at term or to expectantly manage these pregnancies is controversial. The aim of this study was to assess the outcomes of these two management strategies in term pregnancies. STUDY DESIGN: This retrospective cohort study compared neonatal and maternal morbidity and mortality of IUGR fetuses (estimated fetal weight below the 10th percentile) between induced and spontaneous labors. RESULTS: Records of 669 IUGR newborns were reviewed; 499 were delivered through spontaneous labor and 170 were delivered through induced labor. Epidemiology and early perinatal outcomes between the two groups were similar. The cesarean section rate was significantly higher (P<0.005) in the induced group. CONCLUSIONS: Expectant management for term IUGR pregnancies seems to be safe, with lower rates of cesarean deliveries. A large, prospective, randomized controlled trial with long-term neonatal follow-up is indicated.

Endoreduplication in cervical trophoblast cells from normal pregnancies.

OBJECTIVE: Fetal cells represented by extravillous trophoblasts (EVT) obtained from the cervix by a minimally invasive procedure are important for prenatal diagnosis in early pregnancies. Endoreduplication is a duplication of chromosomes without mitosis, leading to polyploidy that might represent increased cellular metabolic activity. In this study, we estimated the normal prevalence of polyploid trophoblasts exfoliated to the cervix between 5 and 13 weeks of gestation. METHODS: Cervical samples were obtained by cytobrush, between 5 and 13 weeks of gestation from 36 randomly selected, singleton pregnancies. FISH was done with X, Y and two 21 probes. RESULTS: We diagnosed 21 pregnancies with female and 15 pregnancies with male fetal karyotypes. A mean of 15.2 (0.02%) tetraploid cells were found in pregnancies with a female fetus and a mean of 2.0 (0.003%) tetraploid cells were found in pregnancies with a male fetus. The tetraploid cells (endoreduplicated trophoblasts) were two to three times larger than the normal cells usually seen in the cervix. CONCLUSIONS: Extravillus trophoblasts tend to form endoreduplication to the ploidy level of 4c-8c of DNA. Those cells may represent a typical phenomenon in the growing placenta. Extravillus trophoblasts from female fetuses tend to form higher rates of endoreduplication.

A comparison of surface acquired uterine electromyography and intrauterine pressure catheter to assess uterine activity.

OBJECTIVE: Intrauterine pressure catheter (IUPC) is the primary device used to evaluate uterine activity. In contrast to the IUPC, electrical uterine myography (EUM) enables noninvasive measurement of frequency, intensity, and tone of contractions. The aim of this study was to determine the accuracy of EUM compared to IUPC. STUDY DESIGN: EUM measured myometrial electrical activity using a multichannel amplifier and a noninvasive position sensor. In all, 47 women in labor were monitored simultaneously with an IUPC and EUM. We compared the frequency, intensity, and tone of uterine contractions between the methods. RESULTS: The correlation of the frequency, intensity, and tone of contractions between uterine electromyography and IUPC was strong with significant r values of 0.808-1 (P < .0001). CONCLUSION: Electrical uterine electromyography yields information about uterine contractility comparable to that obtained with IUPC.

TERC telomerase subunit gene copy number in placentas from pregnancies complicated with intrauterine growth restriction.

INTRODUCTION: intrauterine growth restriction (IUGR) is a significant cause of both short- and long-term morbidity and mortality. IUGR secondary to placental dysfunction is correlated with telomere shortening. Telomerase is an enzyme complex that elongates telomeres. One of its components is encoded by the telomerase RNA component gene (TERC), which serves as the RNA template for the addition of telomeric repeats. We hypothesized decreased TERC gene copy number in IUGR placentas as part of the mechanism of telomere shortening in placental dysfunction. METHODS: we estimated the gene copy number of the TERC gene at 3q26 by applying FISH to trophoblasts of placental biopsies from five pregnancies with IUGR caused by placental insufficiency and compared them to placentas from five gestational-age matched, uncomplicated pregnancies. RESULTS: significantly lower TERC gene copy number was observed in IUGR trophoblasts on the same chromosome and on other chromosomes, compared to the control samples (p<0.05). CONCLUSIONS: the TERC gene copy number is decreased in IUGR trophoblasts. These results support the observations of telomere shortening and decreased telomerase activity in IUGR placentas. We suggest that these findings might play a role in the pathophysiology of IUGR, perhaps by promoting senescence in trophoblasts of IUGR placentas.

The critical role of religion: caring for the dying patient from an Orthodox Jewish perspective.

BACKGROUND AND OBJECTIVE: Culturally competent medical care for the dying patient by families and health care professionals is a challenging task especially when religious values, practices, and beliefs influence treatment decisions for patients at the end of life. This article describes end-of-life guidelines for hospital health care professionals caring for Orthodox Jewish patients and their families. Religious perspectives on advance directives, comfort care and pain control, nutrition and hydration, do not resuscitate/do not intubate (DNR/DNI), and extubation are often unfamiliar to the American medical community. DESIGN: The guidelines for the care of the dying Orthodox Jewish patient were mutually agreed upon by the authors, recognized authorities in medicine, ethics, and Jewish law, who presented their perspectives during a 1-day symposium and who participated in an active working-group session. CONCLUSIONS: Care of the religious patient close to death is enormously complex especially when balancing religious obligations, the role of the rabbi, medical procedures, and personal preferences. These guidelines address from a religious perspective profound issues such as the definition of death, organ donation, and caring for the patient at life's end. The guidelines can be useful for any hospital that serves an Orthodox Jewish population.

Telomeres are shorter in placental trophoblasts of pregnancies complicated with intrauterine growth restriction (IUGR).

OBJECTIVE: Telomeres are nucleoprotein structures located at the termini of chromosomes, and protect them from fusion and degradation. Telomeres are progressively shortened with each mitotic cycle and by environmental factors. We hypothesized that antepartum stress can lead to accelerated telomere shortening in placental trophoblasts, and plays a role in intrauterine growth restriction (IUGR). METHODS: Placental biopsies were derived from 16 pregnancies complicated with IUGR and from 13 uncomplicated pregnancies. Fluorescence-in-situ protocol was used to determine telomere length. Immunohistochemistry for hTERT was performed to assess telomerase activity. Clinical and histopathological characteristics were collected to ensure that IUGR was secondary to placental insufficiency. Fluorescence-in-situ-hybridization was used to rule out aneuploidy as a reason for shortened telomeres. RESULTS: The number and intensity of telomeres staining and telomerase activity were significantly lower in the IUGR placentas. No aneuploidy was detected for the chromosomes checked in the placental biopsies. CONCLUSIONS: Telomeres are shorter in trophoblasts of IUGR placentas.

Telomere aggregates in amniocytes with karyotype of balanced chromosomal rearrangements.

Telomeres are TTAGGG repetitions at the ends of chromosomes. Functioning telomeres are essential for normal segregation and maintenance of chromosomes during mitotic and meiotic divisions. Dysfunctional telomeres support the survival of aneuploid cells, a characteristic of many human malignancies. In contrast to the non-overlapping nature of telomeres in normal nuclei, telomeres of tumor nuclei tend to form aggregates. In this study, our objective was to evaluate the number of telomere aggregates (TAs) in karyotype-balanced structural rearrangements. This is an additional parameter of genetic instability, which might suggest a possible increased risk for diseases related to genomic instability, such as cancer. Twenty-six amniotic fluid cell cultures were established following genetic amniocentesis. Telomere FISH protocol was applied to the samples. Telomere aggregates were counted using a 2D microscope. The results were statistically tested by analysis of variance (ANOVA) and Kruskal-Wallis tests. More telomere aggregates in the structural balanced rearrangements were found in both study groups (balanced translocations and inversions) compared to the control group (P < 0.05). The persistence of TAs in cells is probably related to Breakage-Bridge-Fusion (BBF) cycles, a mechanism of TAs described by Muller and McClintock, resulting in end-to-end fusion that contributes to the onset of genomic instability. BBF cycles contribute to deletions, gene amplification, non-reciprocal translocations, and overall genetic changes associated with tumor genesis. According to our studies, the individuals who are carriers of balanced structural chromosomal rearrangements show some of the genetic instability parameters that appear in other circumstances, such as premalignant and malignant conditions.