Rapid implementation of triaging system for assessment of breast referrals from primary care centres during the COVID-19 pandemic.

OBJECTIVE: The aim of this study was to establish a triaging system for assessment of breast referrals from primary care to ensure safe and effective breast services without compromising breast cancer management. BACKGROUND: COVID-19 was officially declared a global pandemic on 11 March 2020, and with no effective treatment available, preventing spread has been paramount. Previously, all referrals from primary care were seen in the rapid-access breast clinic (RABC). Clinic appointments exposed patients and healthcare professionals to risk. METHOD: Initial triage during the lockdown was in line with national governing body guidance, rejected low risk referrals and streamed remaining patients through a telephone consultation to RABC or discharge. A modified triage pathway streamed all patients through virtual triage to RABC, telephone clinic or discharge with advice and guidance categories. Demographics, reasons for referral and outcomes data were collected and presented as median with range and frequency with percentages. RESULTS: Initial triage (23 March-23 April 2020) found fewer referrals with a higher percentage of breast cancer diagnoses. Modified triage (22 June-17 July 2020) resulted in a 35.1% (99/282) reduction in RABC attendance. Overall cancer detection rate remained similar at 4.2% of all referrals pre-COVID (18/429) and 4.3% (12/282) during modified triage. After six months follow-up of patients not seen in RABC during the modified triage pathway, 18 patients were re-referred to RABC and none were diagnosed with cancer. CONCLUSION: A modified triage pathway has the potential to improve triage efficiency and prevent unnecessary visits during the COVID-19 pandemic. Further refinement of pathway is feasible in collaboration with primary care.

Spermatogonial asynchrony in Tex14 mutant mice lacking intercellular bridges.

The existence of cytoplasmic passages between germ cells and their potential function in the control of the spermatogenic process has long been an intriguing question. Evidence of the important role of such structures, known as intercellular bridges (ICB), in spermatogenesis has been implicated by the failure of spermatogenesis in testis-expressed gene 14 (Tex14) mutant mice, which lack the ICBs, to progress past the pachytene spermatocyte stage. Using these Tex14 mutants, the present study evaluated, for the first time, the behavior and synchrony of the spermatogonial lineage in the absence of ICBs. Our data suggest that the absence of these cytoplasmic connections between cells affects the expansion of the undifferentiated type A (Aundiff) spermatogonia compartment and their transition to A1, resulting in a significant numerical reduction of differentiating A1 spermatogonia, but did not interfere with cell amplification during subsequent mitotic steps of differentiating spermatogonia from A1 through intermediate (In). However, beginning at the type B spermatogonia, the synchrony of differentiation was impaired as some cells showed delayed differentiation compared to their behavior in a normal seminiferous epithelium cycle. Thus although spermatogonial development is able to proceed, in the absence of ICBs in Tex14-/- mutants, the yield of cells, specific steps of differentiation, the synchrony of the cell kinetics, and the subsequent progression in meiosis are quantitatively lower than normal.

Cost and cost-effectiveness of health behavior change interventions implemented with self-help groups in Bihar, India.

INTRODUCTION: Health interventions implemented with self-help groups (SHGs) enhance the relevance and acceptability of the health services. The Parivartan program was implemented in eight districts of Bihar with women's self-help groups to increase adoption of maternal and newborn health behaviors through layering health behavior change communication. This study estimates the cost and cost-effectiveness of a health behavior change program with SHGs in Bihar. METHODS: Cost analysis was conducted from a provider's perspective. All costs have been presented in US dollars for the purpose of international comparisons and converted to constant values. The effectiveness estimate was based on the reported changes in select newborn care practices. A decision model approach was used to estimate the potential number of neonatal deaths averted based on adoption of key newborn care practices. Using India's life expectancy of 65 years, cost per life year saved was calculated. A one-way sensitivity analysis was conducted using the upper and lower estimates for various variables in the model, and functionality of SHGs. RESULTS: The cost of forming an SHG group was US$254 and that of reaching a woman within the group was US$19. The unit cost for delivering health interventions through the Parivartan program was US$148 per group and US$11 per woman reached. During an 18 months period, Parivartan program reached around 17,120 SHGs and an estimated 20,544 pregnant women resulting in an estimated prevention of 23 neonatal deaths at a cost of US$3,825 per life year saved. CONCLUSION: SHGs can be an effective platform to increase uptake of women's health interventions and follow-up care, and also to broaden their utility beyond microfinance, particularly when they operate at a larger scale.

Effect of hormone modulations on donor-derived spermatogenesis or colonization after syngeneic and xenotransplantation in mice.

BACKGROUND: Cytotoxic cancer treatments, such as irradiation, can cause permanent sterility in male mammals owing to the loss of spermatogonial stem cells. In animal models, spermatogenesis could be restored from transplanted spermatogonial stem cells. Previously, we showed that transient suppression of FSH, LH, and testosterone in the recipient with a gonadotropin-releasing hormone antagonist (GnRH-ant), given immediately after irradiation, enhanced spermatogenesis from transplanted spermatogonial stem cells in mice and monkeys. OBJECTIVES: To explore improvements in the preparation of the recipient for efficient and reliable spermatogenic recovery from spermatogonial stem cell transplantation, so that it can be used effectively in clinical practice. MATERIALS AND METHODS: In mouse recipients, we evaluated the effects of hormone suppression given after germ cell depletion was complete, which is a more clinically relevant model, and also the importance of total androgen ablation and maintenance of FSH levels. Three regimens, GnRH-ant, GnRH-ant plus flutamide (androgen receptor antagonist), and GnRH-ant plus FSH, were administered prior to and around the time of transplantation of testis cells from immature mice or from prepubertal monkeys. RESULTS: Treatment with GnRH-ant resulted in a fourfold increase in spermatogenic recovery from GFP-marked transplanted mouse cells. Total androgen ablation with the addition of flutamide, started two weeks before transplantation, did not further enhance recovery. Surprisingly, FSH supplementation, started around the time of transplantation, actually reduced spermatogenic recovery from transplanted spermatogonial stem cells in GnRH-ant-treated mice. When prepubertal monkey testicular cells were transplanted into nude mice that were given the same hormone treatments, the numbers of donor-derived colonies were independent of hormone treatment. DISCUSSION AND CONCLUSION: The enhancements in spermatogenic recovery may only occur when syngeneic or closely related donor-recipient pairs are used. These results are useful in further investigations in choosing a hormone suppression regimen in combination with spermatogonial transplantation as a treatment to restore fertility in primates after cytotoxic therapy.

Distal pancreatectomy with autologous islet transplantation in chronic pancreatitis patients: First case series from India.

Pancreatectomy and autologous islet transplantation (AIT) are performed in highly specialized centers to alleviate abdominal pain and preserve endocrine function in patients with chronic pancreatitis. We aimed at initiating AIT studies in India for the first time in patients undergoing distal pancreatectomy (DP) to prevent development of diabetes. Four out of 14 chronic pancreatitis patients screened underwent DP with AIT. Pancreatectomy specimen preserved in Wisconsin solution was subjected to islet isolation employing standard protocol using collagenase V. Isolated islets were infused into the liver through portal vein after quality assessment and the four patients were followed for 1 year. During the study period, blood glucose, fasting insulin, and C-peptide were analyzed and glucose tolerance was assessed. Three patients could be infused with islets (4363 Islet equivalents, IEQ/kg, 3860 IEQ/kg, 3600 IEQ/kg) into liver without any infusion-related complications. Two of these patients maintained glucose tolerance and glycemic control (HbA1c: 6.0%) and one became diabetic at the end of 1 year (HbA1c: 7.5%). Circulating fasting insulin increased (2.7-24.4 µU/mL and 4.0-21.2 µU/mL) and C-peptide levels increased (2.2 to 3.6, 3.4-5.6 ng/mL) in these two patients. Circulating insulin was 2.7 µU/mL and C-peptide was 2.4 ng/mL in the patient who became diabetic at the end of 1 year, while insulin was 2.3 µU/mL and C-peptide was 1.2 ng/mL in the patient who could not be infused with islets after DP. Safety and feasibility of autologous islet transplantation is established in India for the first time.

Curcumin treatment leads to better cognitive and mood function in a model of Gulf War Illness with enhanced neurogenesis, and alleviation of inflammation and mitochondrial dysfunction in the hippocampus.

Diminished cognitive and mood function are among the most conspicuous symptoms of Gulf War Illness (GWI). Our previous studies in a rat model of GWI have demonstrated that persistent cognitive and mood impairments are associated with substantially declined neurogenesis, chronic low-grade inflammation, increased oxidative stress and mitochondrial dysfunction in the hippocampus. We tested the efficacy of curcumin (CUR) to maintain better cognitive and mood function in a rat model of GWI because of its neurogenic, antiinflammatory, antioxidant, and memory and mood enhancing properties. Male rats were exposed daily to low doses of GWI-related chemicals, pyridostigmine bromide, N,N-diethyl-m-toluamide (DEET) and permethrin, and 5-minutes of restraint stress for 28 days. Animals were next randomly assigned to two groups, which received daily CUR or vehicle treatment for 30 days. Animals also received 5'-bromodeoxyuridine during the last seven days of treatment for analysis of neurogenesis. Behavioral studies through object location, novel object recognition and novelty suppressed feeding tests performed sixty days after treatment revealed better cognitive and mood function in CUR treated GWI rats. These rats also displayed enhanced neurogenesis and diminished inflammation typified by reduced astrocyte hypertrophy and activated microglia in the hippocampus. Additional studies showed that CUR treatment to GWI rats enhanced the expression of antioxidant genes and normalized the expression of multiple genes related to mitochondrial respiration. Thus, CUR therapy is efficacious for maintaining better memory and mood function in a model of GWI. Enhanced neurogenesis, restrained inflammation and oxidative stress with normalized mitochondrial respiration may underlie better memory and mood function mediated by CUR treatment.

Distinct downstream targets manifest p53-dependent pathologies in mice.

Mdm2, the principal negative regulator of p53, is critical for survival, a fact clearly demonstrated by the p53-dependent death of germline or conditional mice following deletion of Mdm2. On the other hand, Mdm2 hypomorphic (Mdm2Puro/Δ7-12) or heterozygous (Mdm2+/-) mice that express either 30 or 50% of normal Mdm2 levels, respectively, are viable but present distinct phenotypes because of increased p53 activity. Mdm2 levels are also transcriptionally regulated by p53. We evaluated the significance of this reciprocal relationship in a new hypomorphic mouse model inheriting an aberrant Mdm2 allele with insertion of the neomycin cassette and deletion of 184-bp sequence in intron 3. These mice also carry mutations in the Mdm2 P2-promoter and thus express suboptimal levels of Mdm2 entirely encoded from the P1-promoter. Resulting mice exhibit abnormalities in skin pigmentation and reproductive tissue architecture, and are subfertile. Notably, all these phenotypes are rescued on a p53-null background. Furthermore, these phenotypes depend on distinct p53 downstream activities as genetic ablation of the pro-apoptotic gene Puma reverts the reproductive abnormalities but not skin hyperpigmentation, whereas deletion of cell cycle arrest gene p21 does not rescue either phenotype. Moreover, p53-mediated upregulation of Kitl influences skin pigmentation. Altogether, these data emphasize tissue-specific p53 activities that regulate cell fate.

Leydig cells contribute to the inhibition of spermatogonial differentiation after irradiation of the rat.

Irradiation with 6 Gy produces a complete block of spermatogonial differentiation in LBNF1 rats that would be permanent without treatment. Subsequent suppression of gonadotropins and testosterone (T) restores differentiation to the spermatocyte stage; however, this process requires 6 weeks. We evaluated the role of Leydig cells (LCs) in maintenance of the block in spermatogonial differentiation after exposure to radiation by specifically eliminating functional LCs with ethane dimethane sulfonate (EDS). EDS (but not another alkylating agent), given at 10 weeks after irradiation, induced spermatogonial differentiation in 24% of seminiferous tubules 2 weeks later. However, differentiation became blocked again at 4 weeks as LCs recovered. When EDS was followed by treatment with GnRH antagonist and flutamide, sustained spermatogonial differentiation was induced in >70% of tubules within 2 weeks. When EDS was followed by GnRH antagonist plus exogenous T, which also inhibits LC recovery but restores follicle stimulating hormone (FSH) levels, the spermatogonial differentiation was again rapid but transient. These results confirm that the factors that block spermatogonial differentiation are indirectly regulated by T, and probably FSH, and that adult and possibly immature LCs contribute to the production of such inhibitory factors. We tested whether insulin-like 3 (INSL3), a LC-produced protein whose expression correlated with the block in spermatogonial differentiation, was indeed responsible for the block by injecting synthetic INSL3 into the testes and knocking down its expression in vivo with siRNA. Neither treatment had any effect on spermatogonial differentiation. The Leydig cell products that contribute to the inhibition of spermatogonial differentiation in irradiated rats remain to be elucidated.

Correcting deformity in total knee arthroplasty: Techniques to avoid the release of collateral ligaments in severely deformed knees.

Collateral ligament release is advocated in total knee arthroplasty (TKA) to deal with significant coronal plane deformities, but is also associated with significant disadvantages. We describe steps to avoid release of the collateral (superficial medial and lateral collateral) ligaments during TKA in severely deformed knees, while correcting deformity and balancing the knee.

Increasing testicular temperature by exposure to elevated ambient temperatures restores spermatogenesis in adult Utp14b (jsd) mutant (jsd) mice.

Because mutations in the human UTP14C gene are associated with male infertility, we sought to develop a method for fertility restoration in azoospermic mice with a mutation in the orthologous Utp14b(jsd) (jsd) gene that have spermatogonial arrest. The method is based on our observation that elevation of testicular temperatures restores spermatogonial differentiation in jsd mutant mice. To non-surgically raise intrascrotal temperatures we placed these mice in incubators at different elevated ambient temperatures. Exposure of jsd/jsd mice to ambient temperatures of 34.5 °C or 35.5 °C for 24 days increased the proportion of tubules with spermatocytes from 0% in untreated controls to over 80%. As those higher temperatures interfere with spermatid differentiation, the mice were then transferred to incubators at 32-32.5 °C for the next 24 days. These environments allowed differentiation to progress, resulting in up to 42% of tubules having late spermatids and about half of the mutant mice having spermatozoa in testicular suspensions. When these spermatozoa were used in intracytoplasmic sperm injection, all gave rise to viable healthy offspring with normal weight gain and fertility. The successful restoration of fertility in Utp14b mutant mice suggests that transient testicular warming might also be useful for spermatogenesis recovery in infertile men with UTP14C gene mutations.

Cemented stems: a requisite in revision total knee replacement.

Stems may improve fixation and stability of components during revision total knee replacement. However, the choice between cemented and cementless stems is not a clear one. Cemented stems offer several advantages in terms of versatility, mechanical stability, surgical technique and clinical outcome over their cementless counterpart.

India's first successful intestinal transplant: the road traveled and the lessons learnt.

Intestinal transplant is a therapeutic challenge not just surgically but also logistically because of the multidisciplinary expertise and resources required. A large proportion of patients who undergo massive bowel resection and develop intestinal failure have poor outcome, because of inability to sustain long-term parenteral nutrition and limited availability of intestinal and multi-visceral transplantation facilities. We report the first successful isolated intestinal transplant from India.

Acetabular protrusio: surgical technique of dealing with a problem in depth.

There are few reports describing the technique of managing acetabular protrusio in primary total hip replacement. Most are small series with different methods of addressing the challenges of significant medial and proximal migration of the joint centre, deficient medial bone and reduced peripheral bony support to the acetabular component. We describe our technique and the clinical and radiological outcome of using impacted morsellised autograft with a porous-coated cementless cup in 30 primary THRs with mild (n = 8), moderate (n = 10) and severe (n = 12) grades of acetabular protrusio. The mean Harris hip score had improved from 52 pre-operatively to 85 at a mean follow-up of 4.2 years (2 to 10). At final follow-up, 27 hips (90%) had a good or excellent result, two (7%) had a fair result and one (3%) had a poor result. All bone grafts had united by the sixth post-operative month and none of the hips showed any radiological evidence of recurrence of protrusio, osteolysis or loosening. By using impacted morsellised autograft and cementless acetabular components it was possible to achieve restoration of hip mechanics, provide a biological solution to bone deficiency and ensure long-term fixation without recurrence in arthritic hips with protrusio undergoing THR.

Hormone suppression with GnRH antagonist promotes spermatogenic recovery from transplanted spermatogonial stem cells in irradiated cynomolgus monkeys.

Hormone suppression given before or after cytotoxic treatment stimulates the recovery of spermatogenesis from endogenous and transplanted spermatogonial stem cells (SSC) and restores fertility in rodents. To test whether the combination of hormone suppression and transplantation could enhance the recovery of spermatogenesis in primates, we irradiated (7 Gy) the testes of 12 adult cynomolgus monkeys and treated six of them with gonadotropin-releasing hormone antagonist (GnRH-ant) for 8 weeks. At the end of this treatment, we transfected cryopreserved testicular cells with green fluorescent protein-lentivirus and autologously transplanted them back into one of the testes. The only significant effect of GnRH-ant treatment on endogenous spermatogenesis was an increase in the percentage of tubules containing differentiated germ cells (tubule differentiation index; TDI) in the sham-transplanted testes of GnRH-ant-treated monkeys compared with radiation-only monkeys at 24 weeks after irradiation. Although transplantation alone after irradiation did not significantly increase the TDI, detection of lentiviral DNA in the spermatozoa of one radiation-only monkey indicated that some transplanted cells colonized the testis. However, the combination of transplantation and GnRH-ant clearly stimulated spermatogenic recovery as evidenced by several observations in the GnRH-ant-treated monkeys receiving transplantation: (i) significant increases (~20%) in the volume and weight of the testes compared with the contralateral sham-transplanted testes and/or to the transplanted testes of the radiation-only monkeys; (ii) increases in TDI compared to the transplanted testes of radiation-only monkeys at 24 weeks (9.6% vs. 2.9%; p = 0.05) and 44 weeks (16.5% vs. 6.1%, p = 0.055); (iii) detection of lentiviral sequences in the spermatozoa or testes of five of the GnRH-ant-treated monkeys and (iv) significantly higher sperm counts than in the radiation-only monkeys. Thus hormone suppression enhances spermatogenic recovery from transplanted SSC in primates and may be a useful tool in conjunction with spermatogonial transplantation to restore fertility in men after cancer treatment.

Rat models of post-irradiation recovery of spermatogenesis: interstrain differences.

Recently, we reported large differences between rat strains in spermatogenesis recovery at 10 weeks after 5-Gy irradiation suggesting that there are interstrain as well as interspecies differences in testicular radiation response. To determine whether these interstrain differences in sensitivity might be a result of the particular dose and time-point chosen, we performed dose-response and time-course studies on sensitive Brown-Norway (BN) and more resistant spontaneously hypertensive rats (SHR) and Sprague-Dawley (SD) rats. Type A spermatogonia were observed in atrophic tubules at 10 weeks after irradiation in all strains indicating that tubular atrophy was caused by a block in their differentiation, but the doses to produce the block ranged from 4.0 Gy in BN to 10 Gy in SD rats. Although the numbers of type A spermatogonial were unaffected at doses below 6 Gy, higher doses reduced their number, indicating that stem cell killing also contributed to the failure of recovery. After 10 weeks, there was no further recovery and even a decline in spermatogonial differentiation in BN rats, but in SHR rats, sperm production returned to control levels by 20 weeks after 5.0 Gy and, after 7.5 Gy, differentiation resumed in 60% of tubules by 30 weeks. Suppression of testosterone and gonadotropins after irradiation restored production of differentiated cells in nearly all tubules in BN rats and in all tubules in SHR rats. Thus, the differences in recovery of spermatogenesis between strains were a result of both quantitative differences in their sensitivities to a radiation-induced, hormone-dependent block of spermatogonial differentiation and qualitative interstrain differences in the progression of post-irradiation recovery. The progression of recovery in SHR rats was similar to the prolonged delays in recovery of human spermatogenesis after cytotoxic agent exposure and thus may be a system for investigating a phenomenon also observed in men.

Computer-assisted total knee replacement in patients with arthritis and a recurvatum deformity.

We retrospectively reviewed the records of 1150 computer-assisted total knee replacements and analysed the clinical and radiological outcomes of 45 knees that had arthritis with a pre-operative recurvatum deformity. The mean pre-operative hyperextension deformity of 11° (6° to 15°), as measured by navigation at the start of the operation, improved to a mean flexion deformity of 3.1° (0° to 7°) post-operatively. A total of 41 knees (91%) were managed using inserts ≤ 12.5 mm thick, and none had mediolateral laxity > 2 mm from a mechanical axis of 0° at the end of the surgery. At a mean follow-up of 26.4 months (13 to 48) there was significant improvement in the mean Knee Society, Oxford knee and Western Ontario and McMaster Universities Osteoarthritis Index scores compared with the pre-operative values. The mean knee flexion improved from 105° (80° to 125°) pre-operatively to 131° (120° to 145°), and none of the limbs had recurrent recurvatum. These early results show that total knee replacement using computer navigation and an algorithmic approach for arthritic knees with a recurvatum deformity can give excellent radiological and functional outcomes without recurrent deformity.

Single-port laparoscopy-assisted donor right hepatectomy in living donor liver transplantation: sensible approach or unnecessary hindrance?

BACKGROUND: Single-port laparoscopic (SPL) surgery has rapidly gained attention worldwide. Since May 2008, we have propagated the use of SPL surgery, mainly for cholecystectomy and appendectomy. Recently, we have used this modality of minimally invasive surgery for various liver surgeries. We hereby discuss our outcomes of SPL-assisted donor right hepatectomies. METHODS: The preoperative workup is the same as for a standard donor hepatectomy. We retrospectively reviewed the data of 150 patients who underwent donor right hepatectomy from October 2008 to May 2011. We divided them into 3 groups depending on the type of surgical procedure. RESULTS: Among 150 patients, 20 underwent laparoscopy-assisted donor right hepatectomy (LADRH); 40 underwent single-port laparoscopy-assisted donor right hepatectomy (SPLADRH); and 90 underwent open donor right hepatectomy (ODRH). The donor demographics were comparable among the groups. Postoperative complication and reoperation rates revealed no significant differences. The SPLADRH group showed the lowest level of postoperative pain, thereby leading to a better quality of life postoperatively. CONCLUSIONS: SPLADRH seems to be a simple, feasible approach.

Isolation of Serratia marcescens SR1 as a Source of Chitinase Having Potentiality of Using as a Biocontrol Agent.

Serratia marcescens, strain SR(1) was isolated from the local soil of a cultivated farm and it was screened as potent strain for chitinase production. Maximum chitinase production (77.3 u Mh(-1) 100(-1)) was observed after 96 h of incubation period with pH 5.5 at 30°C under shake conditions (120 rpm). Compare to still flasks, shake culture with prawn fish colloidal chitin of 0.5% (w/v) concentration, showed a better enzyme yield. Crude enzyme showed antifungal activity against plant pathogens.