Summary Remodeling DNA methylation in mammalian genomes can be global as seen in pre-implantation embryos and primordial germ cells (PGCs), or locus-specific, which can regulate neighboring gene expression. In PGCs global and locus-specific DNA demethylation occur in sequential stages, with an initial global decrease in methylated cytosines (stage I) followed by a Tet methylcytosine dioxygenase (Tet)-dependent decrease in methylated cytosines that act at imprinting control regions (ICRs) and meiotic genes (stage II). The purpose of the two-stage mechanism is unclear. Here we show that Dnmt1 preserves DNA methylation through stage I at ICRs and meiotic gene promoters, and is required for the pericentromeric enrichment of 5hmC. We discovered that the functional consequence of abrogating two-stage DNA demethylation in PGCs was precocious germline differentiation leading to hypogonadism and infertility. Therefore, bypassing stage-specific DNA demethylation has significant consequences for progenitor germ cell differentiation and the ability to transmit DNA from parent to offspring.

osture is the relative art rangement of the various parts of the body. Physical therapists typically perform postural assessment5 as a part of a patient's musculoskeletal evaluation. Individuals experiencing low back pain are often told by physical therapists not to wear high heels because of the lordotic effects that heels have on the lumbar spine area. Recognizing that millions of women wear high heels to be fashionable, several studies have analyzed the changes high heels have on gait and static posture. Gollnick et al (8) found that in a electrogoniometric study of lowheeled (range = -3-7 cm) and highheeled (range = 7-11 cm) gait, an average increase of 20" occurred in ankle plantar flexion, while the knee flexion angle range of motion (ROM) increased during stance phase and decreased during swing phase. In addition to confirming Gollnick et al's results, demonstrated that women in high heels (X = 6.1 cm) have reduced gait velocity, stride lengths, swing phase hip ROM of flexion/ extension and abduction/adduction, heel strike external rotation, pelvic tilt, and upper trunk ROM when compared with low-heeled (X = 1.6 cm) gait. Further, found increased stance phase time and tibia1 internal rotation in highheeled gait when compared with lowheeled gait. In contrast, de Lateur et al (5) ' Staff Physical Therapist, Craven Regional Medical Center, New Bern, NC Staff Physical Therapist, Department of Physical Therapy, Baptist Hospital Medical Center, Winston Salem, NC Staff Physical Therapist, Nash General Hospital, Rocky Mount, NC between the gait kinematics of women in high heels (X = 8.9 cm) compared with low heels (R = 2.2 an).Joseph (1 1) demonstrated that during high-heeled (range = 5.5-8 cm) gait, the electromyographic (EMG) muscle activity was altered, and there was continuous firing of the tibialis anterior, increased activity of the soleus and prolonged continuous firing of the quadriceps in stance phase, and an additional phase of gluteus medius activity in swing phase when compared with low-heeled (range = 1-2.5 cm) gait. In support of Joseph's (1 1) increased muscle activity results, Mathews and Wooten (14) found that oxygen consumption was significantly increased when subjects walked in 7.6-cm high heels compared with saddle shoes and loafers.Static posture analysis has demonstrated that high-heel (X = 6.4 cm) stance moved the knee and ankle joint axis closer and displaced the head and thoracic spine more posterior to the line of gravity when compared with barefoot stance (10,18). A decreased lumbar lordosis and a decreased angle of pelvic inclination have also been shown to occur in women standing and wearing high heels (X = 6.4 cm) (18) and standing on a 4.5-cm wooden heel block (3) when compared with women standing and wearing no heels. However, de Lateur et a1 (5) found that

Serotype-specific surveillance for invasive pneumococcal disease (IPD) is essential for assessing the impact of 10- and 13-valent pneumococcal conjugate vaccines (PCV10/13). The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) project aimed to evaluate the global evidence to estimate the impact of PCV10/13 by age, product, schedule, and syndrome. Here we systematically characterize and summarize the global landscape of routine serotype-specific IPD surveillance in PCV10/13-using countries and describe the subset that are included in PSERENADE. Of 138 countries using PCV10/13 as of 2018, we identified 109 with IPD surveillance systems, 76 of which met PSERENADE data collection eligibility criteria. PSERENADE received data from most (n = 63, 82.9%), yielding 240,639 post-PCV10/13 introduction IPD cases. Pediatric and adult surveillance was represented from all geographic regions but was limited from lower income and high-burden countries. In PSERENADE, 18 sites evaluated PCV10, 42 PCV13, and 17 both; 17 sites used a 3 + 0 schedule, 38 used 2 + 1, 13 used 3 + 1, and 9 used mixed schedules. With such a sizeable and generally representative dataset, PSERENADE will be able to conduct robust analyses to estimate PCV impact and inform policy at national and global levels regarding adult immunization, schedule, and product choice, including for higher valency PCVs on the horizon.

Objective To determine whether assessing the extent of terminal hair growth in a subset of the traditional 9 areas included in the modified Ferriman-Gallwey (mFG) score can serve as a simpler predictor of total body hirsutism when compared to the full scoring system, and to determine if this new model can accurately distinguish hirsute from non-hirsute women. Design Cross-sectional analysis Setting Two tertiary care academic referral centers. Patients 1951 patients presenting for symptoms of androgen excess. Interventions History and physical examination, including mFG score. Main Outcome Measures Total body hirsutism. Results A regression model using all nine body areas indicated that the combination of upper abdomen, lower abdomen and chin was the best predictor of the total full mFG score. Using this subset of three body areas is accurate in distinguishing true hirsute from non-hirsute women when defining true hirsutism as mFG>7. Conclusion Scoring terminal hair growth only on the chin and abdomen can serve as a simple, yet reliable predictor of total body hirsutism when compared to full body scoring using the traditional mFG system.

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